1-Causes of Cell Injury

The causes of cell injury range from the external gross physical violence of an automobile accident to internal endogenous causes, such as a subtle genetic mutation causing Oxygen Deprivation. Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidative respiration. Hypoxia is an extremely important and common cause of cell injury and cell death. Physical Agents. Physical agents capable of causing cell injury include mechanical trauma, extremes of temperature (burns and deep cold), sudden changes in atmospheric pressure, radiation, and electric shock.Chemical Agents and Drugs. The list of chemicals that may produce cell injury defies compilation. Simple chemicals such as glucose or salt in hypertonic concentrations may cause cell injury directly or by deranging electrolyte homeostasis of cells. Infectious Agents. These agents range from the submicroscopic viruses to the large tapeworms. In between are the rickettsiae, bacteria, fungi, and higher forms of parasites Immunologic Reactions. Although the immune system serves an essential function in defense against infectious pathogens, immune reactions may, in fact, cause cell injury Genetic DerangementsThe genetic injury may result in a defect as severe as the congenital malformations associated with Down syndrome, caused by a chromosomal abnormality, or as subtle as the decreased life of red blood cells caused by a single amino acid substitution in hemoglobin S in sickle cell anemia Nutritional Imbalances. Nutritional imbalances continue to be major causes of cell injury. Protein-calorie deficiencies cause an appalling number of deaths, chiefly among underprivileged populations.

Physical Agents e.g.. trauma, thermal injury Chemical Agents e.g. poisons, environmental pollutants and drugs Nutritional Infectious Diseases caused by protozoa, bacteria, viruses Immunological mechanisms Inherited diseases- inborn errors of metabolism

Mechanisms of Cell Injury

Two mechanisms serve as useful models: fatty change hypoxia fatty change is generally a reversible form of sublethal injury whereas the effects of hypoxia depend on the severity, duration and on the vulnerability of the cell Fatty Change Accumulation of fat in hepatocytes depends on rate of fat synthesis, catabolism and on the synthesis and export of lipoproteins. Alcohol increases triglycyeride synthesis and reduces fatty acid catabolism Malnutrition impairs protein synthesis and therefore reduces lipoprotein synthesis Hypoxia Interruption of oxidative phosphorylation within mitochondria- depletion of ATP Progressive loss of membrane functional integrity Increased cytosolic calcium 1

Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components

2-Pathophysiology of cell injury.Effects and responses.

The normal cell is confined to a fairly narrow range of function and structure by its genetic programs of metabolism, differentiation, and specialization; by constraints of neighboring cells; and by the availability of metabolic substrates. It is nevertheless able to handle normal physiologic demands, maintaining a steady state called homeostasis. More severe physiologic stresses and some pathologic stimuli may bring about a number of physiologic and morphologic cellular adaptations, during which new but altered steady states are achieved, preserving the viability of the cell and modulating its function as it responds to such stimuli . The adaptive response may consist of an increase in the number of cells, called hyperplasia, or an increase in the sizes of individual cells, called hypertrophy. Conversely, atrophy is an adaptive response in which there is a decrease in the size and function of cells. If the limits of adaptive response to a stimulus are exceeded, or in certain instances when the cell is exposed to an injurious agent or stress, a sequence of events follows that is loosely termed cell injury. Cell injury is reversible up to a certain point, but if the stimulus persists or is severe enough from the beginning, the cell reaches a "point of no return" and suffers irreversible cell injury and ultimately cell death. Adaptation, reversible injury, and cell death can be considered stages of progressive impairment of the cell's normal function and structure. Cell death, the ultimate result of cell injury, is one of the most crucial events in the evolution of disease of any tissue or organ. It results from diverse causes, including ischemia(lack of blood flow), infection, toxins, and immune reactions. There are two principal patterns of cell death, necrosis and apoptosis. Necrosis is the type of cell death that occurs after such abnormal stresses as ischemia and chemical injury, and it is always pathologic. Apoptosis occurs when a cell dies through activation of an internally controlled suicide program. Cellular Adaptations of Growth and Differentiation Cells respond to increased demand and external stimulation by hyperplasia or hypertrophy, and they respond to reduced supply of nutrients and growth factors by atrophy. In some situations, cells change from one type to another, a process called metaplasia. There are numerous molecular mechanisms for cellular adaptations. Some adaptations are induced by direct stimulation of cells by factors produced by the responding cells themselves or by other cells in the environment. Others are due to activation of various cell surface receptors and downstream signaling pathways. Adaptations may be associated with the induction of new protein synthesis by the target cells, as in the response of muscle cells to increased physical demand, and the induction of cellular proliferation, as in responses of the endometrium to estrogens. Adaptations can also involve a switch by cells from producing one type of proteins to another or markedly overproducing one protein; such is the case in cells producing various types of collagens and extracellular matrix proteins in chronic inflammation and fibrosis. HYPERPLASIA Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting in increased volume of the organ or tissue. HYPERTROPHY 2

Hypertrophy refers to an increase in the size of cells, resulting in an increase in the size of the organ. Thus, the hypertrophied organ has no new cells, just larger cells.

3) Apoptosis
Death of cells occurs in two ways: 1. Necrosis--(irreversible injury) changes produced by enzymatic digestion of dead cellular elements 2. Apoptosis--vital process that helps eliminate unwanted cells--an internally programmed series of events effected by dedicated gene products Mechanisms of Cell Death Mechanisms of cell death caused by different agents may vary. However, certain biochemical events are seen in the process of cell necrosis:

ATP depletion Loss of calcium homeostasis and free cytosolic calcium Free radicals: superoxide anions, Hydroxyl radicals, hydrogen peroxide Defective membrane permeability Mitochondrial damage Cytoskeletal damage

Apoptosis This process helps to eliminate unwanted cells by an internally programmed series of events effected by dedicated gene products. It serves several vital functions and is seen under various settings.

During development for removal of excess cells during embryogenesis To maintain cell population in tissues with high turnover of cells, such as skin, bowels. To eliminate immune cells after cytokine depletion, and autoreactive T-cells in developing thymus. To remove damaged cells by virus To eliminate cells with DNA damage by radiation, cytotoxic agents etc. Hormone-dependent involution - Endometrium, ovary, breasts etc. Cell death in tumors.

Morphology of Apoptosis

Shrinkage of cells Condensation of nuclear chormatin peripherally under nuclear membrane Formation of apoptotic bodies by fragmentation of the cells and nuclei. The fragments remain membrane-bound and contain cell organelles with or without nuclear fragments. Phagocytosis of apoptotic bodies by adjacent healthy cells or phagocytes. Unlike necrosis, apoptosis is not accompanied by inflammatory reaction

Mechanisms of Apoptosis Apoptosis can be induced by various factors under both physiological and pathological conditions: It is an energy-dependent cascade of molecular events which include protein cleavage by a group of enzymes (caspases), protein cross-linking, DNA breakdown. Apoptosis is regulated by a large family of genes some of which are inhibitory (bcl-2) and some are stimulatory (bax).

Apoptosis goes through several complex phases. To put it simply, abnormal mitochondrial membrane permeability is a crucial event which allows escape of cytochrome-c into the cystosol which, in turn, activates proteolytic enzymes (caspases) leading to the execution of the process. The final phase is the removal of dead cell fragments by phagocytosis without inflammatory reactions.

4- Free Radicals ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS)

Cells generate energy by reducing molecular oxygen to water. During this process, small amounts of partially reduced reactive oxygen forms are produced as an unavoidable by product of mitochondrial respiration by phagocytes. Free radicals are chemical species that have a single unpaired electron in an outer orbit. Energy created by this unstable configuration is released through reactions with adjacent molecules, such as inorganic or organic chemicals proteins, lipids, carbohydrates particularly with key molecules in membranes and nucleic acids. Absorption of radiant energy Enzymatic metabolism of exogenous chemicals or drugs The reduction-oxidation reactions that occur during normal metabolic processes. Transition metals Nitric oxide Lipid peroxidation of membranes Oxidative modification of proteins Lesions in DNA. Reactions with thymine in nuclear and mitochondrial DNA produce single-stranded breaks in DNA. This DNA damage has been implicated in cell aging and in malignant transformation of cells Antioxidants either block the initiation of free radical formation or inactivate free radicals and terminate radical damage As we have seen, iron and copper can catalyze the formation of reactive oxygen species A series of enzymes acts as free radical-scavenging systems and break down hydrogen peroxide and superoxide anion

5- Mechanisms of cell death

As stated at the beginning of the chapter, cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents. Injury may progress through a reversible stage and culminate in cell death (Fig. 1-7). An overview of the morphologic changes in cell injury is shown in .The biochemical alterations "Mechanisms of Cell Injury." These alterations may be divided into the following stages: -Reversible cell injury. Initially, injury is manifested as functional and morphologic changes that are reversible if the damaging stimulus is removed. The hallmarks of reversible injury are reduced oxidative phosphorylation, adenosine triphosphate (ATP) depletion, and cellular swelling caused by changes in ion concentrations and water influx. -Irreversible injury and cell death. With continuing damage, the injury becomes irreversible, at which time the cell cannot recover

Cell injury occurs when an adverse stimulus reversibly disrupts the normal complex homeostatic balance of cellular metabolism. If the stimulus is persistent or of sufficient magnitude then irreversible injury may develop. The severity of the injury may also depend on the specific properties of the cell- selective vulnerability Cell death occurs when there is an irreversible loss of integrated cellular function.

Types of Cell Death: Necrosis

Cell death is very often a passive process, an inevitable consequence of severe perturbations of the external environment beyond the limits of homeostatic mechanisms. This type of cell death is known as necrosis. Necrosis is invariably pathological. Caused by infarction, infectious diseases, poisoning etc. Affects contiguous groups of cells Cell swelling and cell lysis accompanied by loss of cell membrane integrity and lysosomal leakage Necrosis usually precipitates an inflammatory response

Types of Cell Death: Apoptosis

In contrast to the passive pathological process of necrosis, a second type of cell death is now recognised which is an active process and which may occur as a physiological regulatory mechanism. This process is known as apoptosis. May be induced by physiological influences e.g. glucocorticoids or pathological influences e.g. ionising radiation or viral infections Active process characterised by specific biochemical mechanisms- DNA fragmentation, vitronectin expression Causes deletion of individual cells in the midst of others Cell shrinkage, preservation of membrane integrity, nuclear fragmentation with dense chromatin No inflammatory response but rapid phagocytosis Apoptosis important in inflammation, neoplasia, AIDS and neurodegenerative disorders

6-SORU YOK 7-SORU YOK

8-Traumatic Shock
Shock is the systemic disease that results from any process that impairs the systemic delivery of oxygen to the cells of the body, or that prevents its normal uptake and utilization. Hemorrhage with decreased cardiac output is the most common cause of shock in trauma patients (Table 1), although it is not unusual for shock to result from a combination of events. Hemorrhage, tension pneumothorax, and cardiac contusion can all coexist in the patient with chest trauma, for example, with each contributing to systemic hypoperfusion. Iatrogenic contributors to shock may include anemia following vigorous crystalloid infusion, the use of tourniquets, and the use of systemic pressor agents. Underlying medical conditions can also play a part, with myocardial ischemia

potentially contributing to decreased oxygen delivery, especially in older trauma patients. The effects of alcohol, medications, and illicit drugs may contribute to a state of hypoperfusion and may block normal compensatory mechanisms. It is important to recognize that the traumatic shock seen clinically in severely injured patients may be quite different from the induced shock seen in laboratory animals hemorrhaged under controlled conditions. Stages of Shock Traumatic shock as occurring in four stages, based on arbitrary levels of blood loss and vital signs. Better approximation of the degree of shock, based on the patients symptoms, response to therapy, and prognosis. In compensated traumatic shock, an increase in heart rate and vasoconstriction of nonessential and ischemia-tolerant vascular beds will allow prolonged survival and easy recovery once hemostasis is achieved and resuscitation is completed. Decompensated traumatic shock, also known as progressive shock, is a transitory state in which lack of perfusion is creating cellular damage that will produce toxic effects. Shock is still reversible at this stage. In subacute irreversible shock, the patient is resuscitated to normal vital signs but succumbs at a later time to multiple organ system failure (MOSF) as the result of tissue ischemia and reperfusion. Finally, acute irreversible shock is the condition of ongoing hemorrhage, acidosis, and coagulopathy that spirals downward to early death from exsanguination. Progression from compensated to uncompensated shock (usually due to ongoing hemorrhage) is a surgical and metabolic emergency. Successful recovery requires rapid diagnosis and control of the inciting event (i.e., hemostasis) facilitated by resuscitative therapy directed toward minimizing the overall dose of shock. A patient who experiences substantial blood loss and massive transfusion will experience some degree of organ system failure thereafter (i.e., edema, pulmonary dysfunction). This is due to the systemic effects of tissue ischemia. Bleeding may be controlled and vital signs may be normal or even hypernormal, but the damage has been done on the cellular level. Ischemia can persist because of no reflow caused by cellular swelling and microcirculatory obstruction, while effects in nonischemic organ systems such as the lungs are actually a form of reperfusion injury. The Systemic Response to Shock The stages of traumatic shock are directly related to the physiologic response to hemorrhage. The initial response is on the macrocirculatory level and is mediated by the neuroendocrine system.Decreased blood pressure leads to vasoconstriction and catecholamine release. Heart and brain blood flow is preserved, while other regional beds are constricted. Pain, hemorrhage, and cortical perception of traumatic injuries lead to the release of a number of hormones as part of the fight or flight response, including reninangiotensin, vasopressin, antidiuretic hormone, growth hormone, glucagon, cortisol, epinephrine and norepinephrine.This rush of chemicals sets the stage for the microcirculatory responses that follow. On the cellular level the body responds to hemorrhage by takingup interstitial fluid, causing cells to swell.Edematous cells obstruct adjacent capillaries, resulting in the "no-reflow" phenomenon that can prevent the reversal of ischemia even in the presence of adequate macro flow. The Central Nervous System The central nervous system is exquisitely sensitive to hypoperfusion and is thus the prime trigger of the neuroendocrine response to shock, which maintains oxygen supply to the heart and brain at the expense of other tissues.Regional glucose uptake in the brain changes during shock. Cardiovascular

The heart has little capacity to function anaerobically, and is relatively preserved from ischemia during hemorrhage because of maintenance or even increase of nutrient blood flow driven by the fight or flight response. Kidney and Adrenal Glands The kidney and adrenal glands are prime responders to the neuroendocrine changes of shock, producing renin, angiotensin, aldosterone, cortisol, erythropoietin, and catecholamines.The kidney itself maintains glomerular filtration in the face of hypotension by selective vasoconstriction and concentration of blood flow in the medulla and deep cortical area. The Lung The lung is almost never the trigger of the shock syndrome because it cannot itself become ischemic. The lung is nonetheless the downstream filter for the inflammatory byproducts of the ischemic body, and is itself an active immune organ.downstream filter for the inflammatory byproducts of the ischemic body, and is itself an active immune organ. The Gut Splanchnic perfusion is very strongly controlled by the autonomic nervous system, and the gut becomes vasoconstricted early in the course of hemorrhagic shock. The intestine is one of the earliest organs affected by hypoperfusion and may be a primary trigger of MOSF(Multi-Organ System Failure) The Liver The liver has a complex microcirculation and has been demonstrated to suffer both no reflow and reperfusion injury during recovery from shock. Hepatic cells are also metabolically active and contribute to the inflammatory response to decompensated shock. Skeletal Muscle, Bone, and Skin Vasoconstrictive mechanisms in peripheral tissue are important to spontaneous hemostasis and tissues of the musculoskeletal system are ischemia-tolerant as long as motor function is not required. Conclusion Traumatic shock is a disease of tissue ischemia, and is characterized by a trigger that produces tissue ischemia (usually hemorrhage) and the inflammatory disease that follows. Surgical hemostasis and precision resuscitation can restore normal blood volume quickly after major trauma, but the patient can still die as a result of the systemic effects of shock. The future management of this disease will depend on a clear understanding of the effects of shock in different organ systems, the ways in which inflammatory mediators can exacerbate ongoing ischemic distress, and our ability to support multiple failing organ systems simultaneously.

9-SORU YOK 10-Pathogenic Effect Of Electric Current

The passage of an electric current through the body may be without effect; may cause sudden death by disruption of neural regulatory impulses, producing, for example, cardiac arrest; or may cause thermal injury to organs interposed in the pathway of the current. Many variables are involved, but most important are the resistance of the tissues to the conductance of the electric current and the intensity of the current. The greater the resistance of tissues, the greater the heat generated. Although all tissues of the body are conductors of electricity, their resistance to flow varies inversely with their water content. Dry skin is particularly resistant, but when skin is wet or immersed in water, its resistance is greatly decreased. Thus, an electric current may cause only a surface burn of dry skin 7

but may cause death by disruption of regulatory pathways when it is transmitted through wet skin, producing, for example, ventricular fibrillation or respiratory paralysis without injury to the skin. The thermal effects of the passage of the electric current depend on its intensity. High-intensity current, such as lightning coursing along the skin, produces linear arborizing burns known as lightning marks. Sometimes intense current is conducted around the victim (so-called flashover), blasting and disrupting the clothing but doing little injury. When lightning is transmitted internally, it may produce sufficient heat and steam to explode solid organs, fracture bones, or char areas of organs. Focal hemorrhages from rupture of small vessels may be seen in the brain. Sometimes, death is preceded by violent convulsions related to brain damage. Less intense voltage may heat, coagulate, or rupture vessels and cause hemorrhages or, in solid organs such as the spleen and kidneys, cause infarctions or ruptures.

11-Pathogenic effect of radiation

INJURY PRODUCED BY IONIZING RADIATION Radiation is energy that travels in the form of waves or high-speed particles. Radiation has a wide range of energies that span the electromagnetic spectrum; it can be divided into non-ionizing and ionizing radiation. The energy of non-ionizing radiation such as UV and infrared light, microwave, and sound waves, can move atoms in a molecule or cause them to vibrate, but is not sufficient to displace bound electrons from atoms. By contrast, ionizing radiation has sufficient energy to remove tightly bound electrons. Collision of electrons with other molecules releases electrons in a reaction cascade, referred to as ionization. The main sources of ionizing radiation are x-rays and gamma rays (electromagnetic waves of very high frequencies), high-energy neutrons, alpha particles (composed of two protons and two neutrons), and beta particles, which are essentially electrons. At equivalent amounts of energy, alpha particles induce heavy damage in a restricted area, whereas x-rays and gamma rays dissipate energy over a longer, deeper course, and produce considerably less damage per unit of tissue. About 25% of the total dose of ionizing radiation received by the US population is human-made, mostly originated in medical devices and radioisotopes.

Effects.Cells surviving radiant energy damage show a wide range of structural changes in chromosomes, including deletions, breaks, translocations, and fragmentation. The mitotic spindle often becomes disorderly, and polyploidy and aneuploidy may be encountered. Nuclear swelling and condensation and clumping of chromatin may appear; sometimes the nuclear membrane breaks down. Apoptosis may occur. All forms of abnormal nuclear morphology may be seen. Giant cells with pleomorphic nuclei or more than one nucleus may appear and persist for years after exposure. At extremely high doses of radiant energy, markers of cell death, such as nuclear pyknosis, and lysis appear quickly. In addition to affecting DNA and nuclei, radiant energy may induce a variety of cytoplasmic changes, including cytoplasmic swelling, mitochondrial distortion, and degeneration of the endoplasmic reticulum. Plasma membrane breaks and focal defects may be seen. The histologic constellation of cellular pleomorphism, giant-cell formation, conformational changes in nuclei, and abnormal mitotic figures creates a more than passing similarity between radiation-injured cells and cancer cells, a problem that plagues the pathologist when evaluating post-irradiation tissues for the possible persistence of tumor cells.

At the light microscopic level, vascular changes and interstitial fibrosis are prominent in irradiated tissues .During the immediate post-irradiation period, vessels may show only dilation. With time, or with higher doses, a variety of degenerative changes appear, including endothelial cell swelling and vacuolation, or even dissolution with total necrosis of the walls of small vessels such as capillaries and venules. Affected vessels may rupture or thrombose. Still later, endothelial cell proliferation and collagenous hyalinization with thickening of the media are seen in irradiated vessels, resulting in marked narrowing or even obliteration of the vascular lumens. At this time, an increase in interstitial collagen in the irradiated field usually becomes evident, leading to scarring and contractions.

12- SORU YOK 13- SORU YOK 14- SORU YOK 15- SORU YOK 16 -SORU YOK 17. Allergy. Essence and classification. Humorally mediated allergy.
Mechanism Exposure to an antigen results in the formation of IgE. The antigen reacts with CD4+ cells, which differentiate to TH2 cells. TH2 cells release interleukin-3 (IL-3), IL-4, and IL-5. IL-5 stimulates eosinophils, and IL-4 activates IgE-producing B cells. The IgE binds to mast cells. Subsequent exposure to the same antigen results in binding of the antigen to IgE bound to mast cells, with the consequence of degranulation of the mast cells and release of mediators (e.g., histamine). The release of mediators causes increased vascular permeability, leading to edema and increased smooth muscle contraction and eventuallyto bronchoconstriction. Sequence of events in type I hypersensitivity reaction; 1. Early phase (occurs within 530 minutes of exposure to antigen): Characterized by vasodilation, increased vascular permeability, and increased smooth muscle contraction. The early phase is due to binding of antigen to IgE bound to mast cells, with subsequent degranulation of the mast cells and release of mediators. 2. Late phase (occurs after 224 hours and lasts for days): Characterized by infiltration by neutrophils, eosinophils, basophils, and monocytes, and results in mucosal damage due to release of mediators by these recruited inflammatory cells. Immediate Response Vasodilation Vascular Leakage Smooth Muscle Spasm Forms of type I hypersensitivity reactions Systemic anaphylaxis: Due to parenteral administration of antigen; for example, a bee sting or a reaction to penicillin. Local reaction: Urticaria (hives). Causes: Penicillin, angiotensin-converting enzyme (ACE) inhibitors, intravenous (IV) contrast and other drugs, proteins (e.g., insect venoms), and food. Clinical and Pathologic Manifestations An immediate hypersensitivity reaction may occur as a systemic disorder or as a local reaction. The nature of the reaction is often determined by the route of antigen exposure. Systemic (parenteral) 9

administration of protein antigens (e.g., in bee venom) or drugs (e.g., penicillin) may result in systemic anaphylaxis. Within minutes of an exposure in a sensitized host, itching, urticaria (hives), and skin erythema appear, followed in short order by profound respiratory difficulty caused by pulmonary bronchoconstriction and accentuated by hypersecretion of mucus. Laryngeal edema may exacerbate matters by causing upper airway obstruction. In addition, the musculature of the entire gastrointestinal tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea. Without immediate intervention, there may be systemic vasodilation with fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes. Local reactions generally occur when the antigen is confined to a particular site, such as skin (contact, causing urticaria), gastrointestinal tract (ingestion, causing diarrhea), or lung (inhalation, causing bronchoconstriction). The common forms of skin and food allergies, hay fever, and certain forms of asthma are examples of localized allergic reactions. Susceptibility to localized type I reactions is genetically controlled, and the term atopy is used to imply familial predisposition to such localized reactions. Patients who suffer from nasobronchial allergy (including hay fever and some forms of asthma) often have a family history of similar conditions. Linkage studies have identified several chromosomal regions that are associated with susceptibility to asthma and other allergic diseases. Among the candidate genes that are present close to these chromosomal loci are genes that encode HLA molecules (which may confer immune responsiveness to particular allergens), cytokines (which may control TH2 responses), a component of the FcRI, and ADAM33, a metalloproteinase that may be involved in tissue remodeling in the airways. Type I Clinical allergy represents IgE-mediated hypersensitivity response arising from deleterious inflammation in response to the presence of normally harmless environmental antigens. Anaphylactic or immediate hypersensitivity reactions occur after binding of antigen to IgE antibodies attached to the surface of the mast cell or basophil and result in the release of preformed and newly generated inflammatory mediators that produce the clinical manifestations. Examples of type I mediated reactions include anaphylactic shock, allergic rhinitis, allergic asthma, and allergic drug reactions. Type II Cytotoxic reactions involve the binding of either IgG or IgM antibody to antigens covalently bound to cell membrane structures. Antigen-antibody binding activates the complement cascade and results in destruction of the cell to which the antigen is bound. Examples of tissue injury by this mechanism include immune hemolytic anemia and Rh hemolytic disease in the newborn. Another example of the type IImediated disease process without cell death is autoimmune hyperthyroidism, a disorder in which thyroid-stimulating antibodies stimulate thyroid tissue. Type III Immune complexmediated reactions occur when immune complexes are formed by the binding of antigens to antibodies with fixation of complement. Complement-bound immune complexes facilitate opsonization by phagocytes and ADCC. Complexes are usually cleared from the circulation in the reticuloendothelial system. However, deposition of these complexes in tissues or in vascular endothelium can produce immune complexmediated tissue injury by leading to complement activation, anaphylatoxin generation, chemotaxis of polymorphonuclear leukocytes, mediator release and tissue injury. Cutaneous Arthus reaction, systemic serum sickness, some aspects of clinical autoimmunity, and certain features of infective endocarditis are clinical examples of type III mediated diseases. Type IV Cell-mediated immunity is responsible for host defenses against intracellular pathogenic organisms, although abnormal regulation of this system may result in delayed-type hypersensitivity. Type IV

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hypersensitivity reactions are mediated not by antibody but by antigen-specific T lymphocytes. Classic examples are tuberculin skin test reactions and contact dermatitis.

18) Cell-mediated allergy Allergies

Immunologists, as well as the general public, use the term allergy in several different ways. An allergy is a harmful immune response elicited by an antigen that is not itself intrinsically harmful. Examples:

The windblown pollen released by orchard grass has no effect on me but produces a violent attack of hay fever (known to physicians as allergic rhinitis) in my wife. She, on the other hand, can safely handle the leaves of poison ivy while if I do so, I break out in a massive skin rash a day or two later.

Antigens that trigger allergies are often called allergens. Four different immune mechanisms can result in allergic responses. 1. Immediate Hypersensitivities. These occur quickly after exposure to the allergen. They are usually mediated by antibodies of the IgE class. Examples:

hay fever hives asthma

2. Antibody-Mediated Cytotoxicity Cell damage caused by antibodies directed against cell surface antigens. Hence a form of autoimmunity. Examples:

Hemolytic disease of the newborn (Rh disease). Myasthenia gravis (MG)

3. Immune Complex Disorders Damage caused by the deposit in the tissues of complexes of antigen and their antibodies. Examples:

Serum sickness Systemic lupus erythematosus (SLE)

4. Cell-Mediated Hypersensitivities These reactions are mediated by CD4+ T cells. Examples:

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The rash produced following exposure to poison ivy. Because it takes a day or two for the T cells to mobilize following exposure to the antigen, these responses are called delayed-type hypersensitivities (DTH). Those, like poison ivy, that are caused by skin contact with the antigen are also known as contact sensitivities or contact dermatitis. certain autoimmune diseases, including o Type 1 diabetes mellitus o Multiple sclerosis (MS) o Rheumatoid arthritis (RA)

Immediate Hypersensitivities Local Anaphylaxis The constant region of IgE antibodies (shown in blue) has a binding site for a receptor present on the surface of basophils and their tissue-equivalent the mast cell. These cell-bound antibodies have no effect until and unless they encounter allergens (shown in red) with epitopes that can bind to their antigen-binding sites. When this occurs, the mast cells to which they are attached

explosively discharge their granules by exocytosis. The granules contain a variety of active agents including histamine; synthesize and secrete other mediators including leukotrienes and prostaglandins.

Release of these substances into the surrounding tissue causes local anaphylaxis: swelling, redness, and itching. In effect, each IgE-sensitized mast cell is a tiny bomb that can be exploded by a particular antigen. The most common types of local anaphylaxis are:

allergic rhinitis (hay fever) in which airborne allergens react with IgE-sensitized mast cells in the nasal mucosa and the tissues around the eyes; bronchial asthma in which the allergen reaches the lungs either by inhalation or in the blood [Further discussion of asthma]; hives (physicians call it urticaria) where the allergen usually enters the body in food.

ome people respond to environmental antigens (e.g., pollen grains, mold spores) with an unusually vigorous production of IgE antibodies. Why this is so is unclear; heredity certainly plays a role. In any case, the immune system of these people is tilted toward the production of T helper cells of the Th2 subtype. These release interleukin 4 (IL-4) and interleukin 13 (IL-13) on the B cells that they "help". These lymphokines promote class switching in the B cell causing it to synthesize IgE antibodies. An inherited predisposition to making IgE antibodies is called atopy. Atopic people are apt to have higher levels of circulating IgE (up to 12 g/ml) than is found usually (about 0.3 g/ml). Whereas only 2050% of the receptors on mast cells are normally occupied by IgE, all the receptors may be occupied in atopic individuals.

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Systemic Anaphylaxis Some allergens can precipitate such a massive IgE-mediated response that a life-threatening collapse of the circulatory and respiratory systems may occur. Frequent causes:

insect (e.g., bee) stings many drugs (e.g., penicillin) a wide variety of foods. Egg white, cow's milk, and nuts are common offenders in children; in fact, some school systems in the U. S. now ban peanuts and peanut-butter sandwiches when they have a student at risk of systemic anaphylaxis from exposure to peanuts. Fish and shellfish are frequent causes of anaphylaxis in adults.

Treatment of systemic anaphylaxis centers on the quick administration of adrenaline, antihistamines, and if shock has occurred intravenous fluid replacement. Anti-IgE Antibodies IgE molecules bind to mast cells and basophils through their constant region. If you could block this region, you could interfere with binding hence sensitization of these cells. Humanized monoclonal antibodies specific for the constant region of IgE are in clinical trials. They have shown some promise against asthma and peanut allergy, but such treatment will probably have to be continued indefinitely (and will be very expensive).

19. Autoimmune response essence and mechanism of generation.

The evidence is compelling that an immune reaction to self-antigens (i.e., autoimmunity) is the cause of certain human diseases; a growing number of entities have been attributed to this process. However, in many of these disorders the proof is not definitive, and an important caveat is that the simple presence of autoreactive antibodies or T cells does not equate to autoimmune disease. For example, low-affinity antibodies and T cells reactive with self-antigens can be readily demonstrated in most otherwise healthy individuals; presumably, these antibodies and T cells are not pathogenic and are of little consequence. Moreover, similar innocuous autoantibodies to selfantigens are frequently generated following other forms of injury (e.g., ischemia) and may even serve a physiologic role in the removal of products of tissue breakdown. Thus, the presence of a multiplicity of autoantibodies accounts for many of the clinical and pathologic manifestations of SLE. Moreover, these autoantibodies can be identified within lesions by immunofluorescence and electron-microscopic techniques. In many other disorders, an autoimmune etiology is suspected but is unproven. Indeed, in some cases of apparent autoimmunity the response may be directed against an exogenous antigen, such as a microbial protein; such is the probable pathogenesis of the vasculitis in many cases of polyarteritis nodosa. Presumed autoimmune diseases range from those in which specific immune responses are directed against one particular organ or cell type and result in localized tissue damage, to multisystem diseases characterized by lesions in many organs and associated with multiple autoantibodies or cellmediated reactions against numerous self-antigens. In the systemic diseases, the lesions affect principally the connective tissue and blood vessels of the various organs involved. Thus, even though the systemic reactions are not specifically directed against constituents of connective tissue or blood vessels, the diseases are often referred to as "collagen vascular" or "connective tissue" disorders. It is obvious that autoimmunity implies loss of self-tolerance, and the question arises as to how this happens. To understand the pathogenesis of autoimmunity, it is important to first familiarize ourselves with the mechanisms of normal immunologic tolerance.

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Immunological tolerance is unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that antigen. Self-tolerance refers to a lack of immune responsiveness to one's own tissue antigens. During the generation of billions of antigen receptors in developing T and B lymphocytes, it is not surprising that receptors are produced that can recognize self-antigens. Since these antigens cannot all be concealed from the immune system, there must be means of eliminating or controlling self-reactive lymphocytes. Several mechanisms work in concert to select against selfreactivity and to thus prevent immune reactions against one's own antigens. These mechanisms are broadly divided into two groups: central tolerance and peripheral tolerance.Central tolerance. This refers to deletion of self-reactive T and B lymphocytes during their maturation in central lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). Many autologous (self) protein antigens are processed and presented by thymic APCs in association with self-MHC. Any developing T cell that expresses a receptor for such a self-antigen is negatively selected (deleted by apoptosis), and the resulting peripheral T-cell pool is thereby depleted of self-reactive cells. An exciting recent advance has been the identification of putative transcription factors that induce the expression of apparently peripheral tissue antigens in the thymus. One such factor is called the autoimmune regulator (AIRE); mutations in the AIRE gene are responsible for an autoimmune polyendocrine syndrome in which T cells specific for multiple self-antigens escape deletion, presumably because these self-antigens are not expressed in the thymus. Some T cells that encounter self-antigens in the thymus are not killed but differentiate into regulatory T cells. Immature B cells that recognize, with high affinity, self-antigens in the bone marrow may also die by apoptosis. Some self-reactive B cells may not be deleted but may undergo a second round of rearrangement of antigen receptor genes and express new receptors that are no longer self-reactive (a process called "receptor editing").Unfortunately, the process of deletion of self-reactive lymphocytes is far from perfect. Many self-antigens may not be present in the thymus, and hence T cells bearing receptors for such autoantigens escape into the periphery. There is similar "slippage" in the B-cell system as well, and B cells that bear receptors for a variety of self-antigens, including thyroglobulin, collagen, and DNA, can be found in healthy individuals.Peripheral tolerance. Selfreactive T cells that escape negative selection in the thymus can potentially wreak havoc unless they are deleted or effectively muzzled. Several mechanisms in the peripheral tissues that silence such potentially autoreactive T cells have been identified: Anergy: This refers to functional inactivation (rather than death) of lymphocytes induced by encounter with antigens under certain conditions. Recall that activation of T cells requires two signals: recognition of peptide antigen in association with self-MHC molecules on APCs, and a set of second costimulatory signals (e.g., via B7 molecules) provided by the APCs. If the second costimulatory signals are not delivered, or if an inhibitory receptor on the T cell (rather than the costimulatory receptor) is engaged when the cell encounters self-antigen, the T cell becomes anergic and cannot respond to the antigen. Because costimulatory molecules are not strongly expressed on most normal tissues, the encounter between autoreactive T cells and self-antigens in tissues may result in anergy. B cells can also become anergic if they encounter antigen in the absence of specific helper T cells.Suppression by regulatory T cells: The responses of T lymphocytes to self-antigens may be actively suppressed by regulatory T cells. The best-defined populations of regulatory T cells express CD25, one of the chains of the receptor for IL-2, and require IL-2 for their generation and survival. These cells also express a unique transcription factor called FoxP3, and this one protein seems to be both necessary and sufficient for the development of regulatory cells. Mutations in the FOXP3 gene are responsible for a systemic autoimmune disease called IPEX (immune dysregulation, 14

polyendocrinopathy, enteropathy, X-linked syndrome), which is associated with deficiency of regulatory T cells. The probable mechanism by which regulatory T cells control immune responses is by secreting immunosuppressive cytokines (e.g., IL-10 and TGF-), which can dampen a variety of Tcell responses.Activation-induced cell death: Another mechanism of peripheral tolerance involves apoptosis of mature lymphocytes as a result of self-antigen recognition. T cells that are repeatedly stimulated by antigens in vitro undergo apoptosis. One mechanism of apoptosis is the death receptor Fas (a member of the TNF receptor family) being engaged by its ligand coexpressed on the same cells. The same pathway is important for the deletion of self-reactive B cells by Fas ligand expressed on helper T cells. The importance of this pathway of self-tolerance is illustrated by the discovery that mutations in the FAS gene are responsible for an autoimmune disease called the autoimmune lymphoproliferative syndrome, characterized by lymphadenopathy and multiple autoantibodies including anti-DNA. Defects in Fas and Fas ligand are also the cause of similar autoimmune diseases in mice. Mechanisms of Autoimmunity Now that we have summarized the principal mechanisms of self-tolerance, we can ask how these mechanisms might break down to give rise to pathologic autoimmunity. Unfortunately, there are no simple answers to this question, and we still do not understand the underlying causes of most human autoimmune diseases. We referred above to mutations that compromise one or another pathway of self-tolerance and cause pathologic autoimmunity. These single-gene mutations are extremely informative, and they help to establish the biologic significance of the various pathways of selftolerance. The diseases caused by such mutations are rare, however, and most autoimmune diseases cannot be explained by defects in single genes. The breakdown of self-tolerance and the development of autoimmunity are probably related to the inheritance of various susceptibility genes and changes in tissues, often induced by infections or injury, that alter the display and recognition of self-antigens. Genetic Factors in Autoimmunity There is abundant evidence that susceptibility genes play an important role in the development of autoimmune diseases. Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins.Several autoimmune diseases are linked with the HLA locus, especially class II alleles. Two genetic polymorphisms have recently been shown to be quite strongly associated with certain autoimmune diseases. One, called PTPN22, encodes a phosphatase, and particular variants are associated with rheumatoid arthritis and several other autoimmune diseases. Another, called NOD2, encodes an intracellular receptor for microbial peptides, and certain variants or mutants of this gene are present in as many as 25% of patients with Crohn's disease in some populations. How these genes contribute to autoimmunity is not established.

20)IMMUNODEFCENCY STATES.PRIMARY IMMUNODEFICIENCY DISEASE

Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired ("secondary") but some people are born with defects in their immune system, or primary immunodeficiency. Transplant patients take medications to suppress their immune system as an anti-rejection measure, as do some patients suffering from an over-active immune system. A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised 15

person may be particularly vulnerable to opportunistic infections, in addition to normal infections that could affect everyone. Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function properly. To be considered a primary immunodeficiency, the cause of the immune deficiency must not be secondary in nature (i.e., caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. About 1 in 500 people is born with a primary immunodeficiency. Types of immunodeficiencies:

a primary immunodeficiency results from a genetic or developmental defect in the immune system. a secondary or acquired immunodeficiency is a loss of immune function due to exposure to an external agent.

Primary immunodeficiences:

may affect either adaptive or innate immune functions. categorized by the type of cells involved or the developmental stage at which the defect occurs . defects generally affect either the lymphoid or myeloid cell lineages and involve specific genes Depending on the affected component of the immune system, there will be increased susceptibility to infection by different pathogens.

Lymphoid immunodeficiencies:

may involve B cells, T cells or both B and T cells. B cell defects range from a complete absence of B cells, plasma cells, and immunoglobulin to a selective loss of certain immunoglobulin classes. Serious B cell defects cause frequent bacterial infections due to the absence of humoral immunity. T cell defects cause frequent viral and fungal infections due to the absence of cell-mediated immunity. Humoral immunity to T-dependent antigens is also affected.

T cell immunodeficiencies:

can affect humoral, as well as cell-mediated immunity since many antigens are T-dependent, leading to a form of SCID. Although there is some decrease in antibody levels, the main result is increased susceptibility to viral, fungal and protozoal infections. DiGeorge Syndrome (congenital thymic aplasia) is the result of a developmental defect in which children are born without a thymus or parathyroids (in some cases the thymus is not completely absent). Because few functional T cells are present, cell-mediated immunity is undetectable, although a diminished humoral response is able to deal with most common bacterial infections. However, viral, fungal and protozoal infections are often fatal. A fetal thymus transplant can provide a source of thymic hormones and an environment for T cell maturation.

B cell immunodeficiencies:

may range from a complete absence of mature B cells, plasma cells and immunoglobulin to a selective deficiency in one class of immunoglobulin. 16

patients suffer from recurrent bacterial infections (especially by encapsulated bacteria because antibodies are critical for the opsonization and clearance of these microbes), although immunity to most viral and fungal infections is normal. X-linked agammaglobulinemia occurs in 1 in 103 to 106 males (X chromosome-linked). Pre-B cells in the bone marrow fail to differentiate into mature B cells because of a defect in a tyrosine kinase (Brutons tyrosine kinase) that is required to couple the pre-B cell receptor to nuclear events that lead to light chain gene rearrangement and B cell maturation. These individuals have little or no circulating antibody because of arrested B cell development at the pre-B cell stage. The condition can be treated with injections of purified pooled human IgG, although sinopulmonary infections persist due to lack of secretory IgA. X-linked hyper-IgM syndrome results from a defect in the gene coding for CD40 ligand. Since CD40 on B cells must interact with CD40 ligand on T cells for B cell activation to occur, these individuals fail to respond to T-dependent antigens. The response to T-independent antigens is normal, leading to heightened IgM production. selective immunoglobulin deficiencies result when one class or subclass of antibody is missing. The most common is an IgA deficiency due to a failure of IgA-committed B cells to differentiate into plasma cells. These patients suffer frequent bacterial and viral sinopulmonary infections, and increased allergies due to excessive IgE production. Treatment is with broad-spectrum antibiotics.

Myeloid immunodeficiencies:

congenital agranulocytosis results from decreased production of G-CSF and a failure of myeloid stem cells to differentiate into neutrophils and other granulocytes. Frequent bacterial infections are common. chronic granulomatous disease is caused by a defect in the oxidative pathway that phagocytes use to generate hydrogen peroxide. As a result phagocytes are unable to kill many types of phagocytosed bacteria, leading to excessive inflammatory responses and susceptibility to bacterial and fungal infections. Antigen processing and presentation by macrophages is also impaired. leukocyte adhesion deficiency (LAD) is caused by a failure to express the subunit of the adhesion molecules LFA-1, MAC-1 (CR3), and p150,90 (CR4). These adhesion molecules, which are required for cellular interactions (Table 19-2), are nearly absent from the cell membrane. Individuals with this defect exhibit impaired extravasation of neutrophils, monocytes and lymphocytes; impaired ability of CTL and NK cells to adhere to target cells; and failure of T helper cells and B cells to form conjugates. Frequent bacterial infections and impaired wound healing are major problems.

21. Immunodeficient states. Acquired immunodeficiency syndrome (AIDS).

Clinical Presentation AIDS is the most common immunodeficiency disorder worldwide, and HIV infection is one of the greatest epidemics in human history. AIDS is the consequence of a chronic retroviral infection that produces severe, life-threatening CD4 helper T lymphocyte dysfunction, opportunistic infections, and malignancy. Retroviruses contain viral RNA that is transcribed by viral reverse transcriptase into double-stranded DNA, which is integrated into the host genome. Cellular activation leads to transcription of HIV gene products and viral replication. AIDS is defined by serologic evidence of HIV infection with the presence of a variety of indicator diseases associated with clinical immunodeficiency. Table 3-7 lists criteria for defining and 17

diagnosing AIDS. HIV is transmitted by exposure to infected body fluids or sexual or perinatal contact. Transmissibility of the HIV virus is related to subtype virulence, viral load, and immunologic host factors. Acute HIV infection may present as an acute, self-limited, febrile viral syndrome characterized by fatigue, pharyngitis, myalgias, rash, lymphadenopathy, and significant viremia without detectable anti-HIV antibodies. Over time, there is a progressive decline in CD4 T lymphocytes, a reversal of the normal CD4:CD8 T lymphocyte ratio, and numerous other immunologic derangements. The clinical manifestations are directly related to HIV tissue tropism and defective immune function. Development of neurologic complications, opportunistic infections, or malignancy signal marked immune deficiency. The time course for progression of the disease varies; the majority of individuals remain asymptomatic for as long as 5-10 years. Typically, up to 70% of individuals will develop AIDS after a decade of subclinical HIV infection. Pathology & Pathogenesis Chemokines (chemoattractant cytokines) regulate leukocyte trafficking to sites of inflammation and have been discovered to play a significant role in the pathogenesis of HIV disease. During the initial stages of infection and viral proliferation, virion entry and cellular infection requires binding to two coreceptors on target T lymphocytes and monocyte/macrophages. All HIV strains express the envelope protein gp120 that binds to CD4 molecules, but different viral strains display tissue tropism or specificity based on the coreceptor they recognize. These coreceptors belong to the chemokine receptor family. Changes in viral phenotype during the course of HIV infection may lead to changes in tropism and cytopathology at different stages of disease. Viral strains isolated in early stages of infection (eg, R5 viruses) demonstrate tropism toward macrophages. X4 strains of HIV are more commonly seen in later stages of disease. X4 viruses bind to chemokine receptor CXCR4, more broadly expressed on T cells, and are associated with syncytium formation. A small percentage of individuals possessing nonfunctional alleles for the polymorphic chemokine receptor CCR5 appear to be highly resistant to HIV infection or display delayed progression of disease. Mathematical models estimate that during HIV infection billions of virions are produced and cleared each day. The reverse transcription step of HIV replication is error prone; mutations are frequent, and even within an individual patient HIV heterogeneity develops rapidly. The development of antigenically and phenotypically distinct strains contributes to progression of disease, clinical drug resistance, and lack of efficacy of early vaccines. Cellular activation is critical for viral infectivity and reactivation of integrated proviral DNA. Although only 2% of mononuclear cells are found peripherally, lymph nodes from HIV-infected individuals can contain large amounts of virus sequestered among infected follicular dendritic cells in the germinal centers. With HIV infection there is an absolute reduction of CD4 T lymphocytes, an accompanying deficit in CD4 T lymphocyte function, and an associated increase in CD8 cytotoxic T lymphocytes (CTLs). CTL activity is initially brisk and effective at controlling viremia through elimination of virus and virus-infected cells. Ultimately, viral proliferation outpaces host responses, and HIV-induced immunosuppression leads to disease progression. Loss of viral containment occurs with diminution of CD8+ T-cell dependent cytotoxic responses, lack of adequate helper T function, accumulation of viral escape mutations, and general cytokine dysregulation detrimental to effective immune responses. In addition to the cell-mediated immune defects, B-lymphocyte function is altered such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses. Both anamnestic responses and those to neoantigens can be impaired. However, the role of humoral immunity in controlling viremia or slowing disease progression is unclear. The development of assays to measure viral burden (plasma HIV-RNA quantification) has led to a better understanding of HIV dynamics and has provided a tool for assessing response to therapy. It is now well recognized that viral replication continues throughout the disease, and immune deterioration occurs despite clinical latency. The risk of progression to AIDS appears correlated with 18

an individual's viral load after seroconversion. The marked decline in CD4 T lymphocyte counts characterizing HIV infectionis due to several mechanisms, including (1) direct HIV-mediated destruction of CD4 T lymphocytes, (2) autoimmune destruction of virus-infected T cells, (3) depletion by fusion and formation of multinucleated giant cells (syncytium formation), (4) toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors, and (5) induction of apoptosis (programmed cell death). Data from several large clinical cohorts have shown that there is a direct correlation between the CD4 T-lymphocyte count number and the risk of AIDS-defining opportunistic infections. Thus, the viral load and the degree of CD4 T-lymphocyte depletion serve as important clinical indicators of immune status in HIV-infected individuals. Prophylaxis for opportunistic infections such as pneumocystis pneumonia is started when CD4 T lymphocyte counts reach the 200-250 cells/L range. Similarly, patients with HIV infection with fewer than 50 CD4 T lymphocytes/L are at significantly increased risk for cytomegalovirus (CMV) retinitis and Mycobacterium avium complex (MAC) infection. Cells other than CD4 T lymphocytes contribute to the pathogenesis of HIV infection. Monocytes, macrophages, and dendritic cells can be infected with HIV and facilitate transfer of virus to lymphoid tissues and immunoprivileged sites, such as the CNS. HIV-infected monocytes will also release large quantities of the acute-phase reactant cytokines, including IL-1, IL-6, and TNF, contributing to constitutional symptomatology. TNF, in particular, has been implicated in the severe wasting syndrome seen in patients with advanced disease. Clinical Manifestations The clinical manifestations of AIDS are the direct consequence of the progressive and severe immunologic deficiency induced by HIV. Patients are susceptible to a wide range of atypical or opportunistic infections with bacterial, viral, protozoal, and fungal pathogens. Common nonspecific symptoms include fever, night sweats, and weight loss. Weight loss and cachexia can be due to nausea, vomiting, anorexia, or diarrhea. They often portend a poor prognosis. The incidence of infection increases as the CD4 T lymphocyte number declines. Lung infection with Pneumocystis jiroveci is the most common opportunistic infection, affecting 75% of patients. Patients present clinically with fevers, cough, shortness of breath, and hypoxemia ranging in severity from mild to life threatening. A diagnosis of pneumocystis pneumonia can be made by substantiation of the clinical and radiographic findings with Wright-Giemsa or silver methenamine staining of induced sputum samples. A negative sputum stain does not rule out disease in patients in whom there is a strong clinical suspicion of disease, and further diagnostic maneuvers such as bronchoalveolar lavage or fiberoptic transbronchial biopsy may be required to establish the diagnosis. Complications of pneumocystis pneumonia include pneumothoraces, progressive parenchymal disease with severe respiratory insufficiency, and, most commonly, adverse reactions to the medications used for treatment and prophylaxis. For reasons that are not clear, HIV-infected patients have an unusually high rate of adverse reactions to a wide variety of antibiotics and frequently develop severe debilitating cutaneous reactions. As a consequence of chronic immune dysfunction, HIV-infected individuals are also at high risk for other pulmonary infections, including bacterial infections with S pneumoniae and H influenzae; mycobacterial infections with M tuberculosis or M avium-intracellulare (MAC); and fungal infections with C neoformans, H capsulatum, or C immitis. Clinical suspicion followed by early diagnosis of these infections should lead to aggressive treatment. The development of active tuberculosis is significantly accelerated in HIV infection as a result of compromised cellular immunity. The risk of reactivation is estimated to be 5-10% per year in HIVinfected patients compared with a lifetime risk of 10% in those without HIV. Furthermore, diagnosis may be delayed because of anergic skin responses. Extrapulmonary manifestations occur in up to 70% of HIV-infected patients with tuberculosis, and the emergence of multidrug resistance may 19

compound the problem. MAC is a less virulent pathogen than M tuberculosis, and disseminated infections usually occur only with severe clinical immunodeficiency. Symptoms are nonspecific and typically consist of fever, weight loss, anemia, and GI distress with diarrhea. The presence on physical examination of oral candidiasis (thrush) and hairy leukoplakia is highly correlated with HIV infection and portends rapid progression to AIDS. Abnormal outgrowth of Candida from normal mouth flora is the cause of persistent oral candidiasis, whereas Epstein-Barr virus is the cause of hairy leukoplakia. HIV-infected individuals with oral candidiasis are at much greater risk for esophageal candidiasis, which may present as substernal pain and dysphagia. This infection and its characteristic clinical presentation are so common that most practitioners treat with empiric oral antifungal therapy. Should the patient not respond rapidly, other explanations for the esophageal symptoms should be explored, including herpes simplex and CMV infections. Persistent diarrhea, especially when accompanied by high fevers and abdominal pain, may signal infectious enterocolitis. The list of potential pathogens in such cases is long and includes bacteria, MAC, protozoans (cryptosporidium, microsporidia, Isospora belli, Entamoeba histolytica, Giardia lamblia), and even HIV itself. HIV-associated gastropathy and malabsorption are commonly noted in these patients. Because of their reduced gastric acid concentrations, patients have an increased susceptibility to infection with Campylobacter, Salmonella, and Shigella. Skin lesions commonly associated with HIV infection are typically classified as infectious (viral, bacterial, fungal), neoplastic, or nonspecific. Herpes simplex virus (HSV) and herpes zoster virus (HZV) may cause chronic persistent or progressive lesions in patients with compromised cellular immunity. HSV commonly causes oral and perianal lesions but can be an AIDS-defining illness when involving the lung or esophagus. The risk of disseminated HSV or HZV infection and the presence of molluscum contagiosum appear to be correlated with the extent of immunoincompetence. Seborrheic dermatitis caused by Pityrosporum ovale and fungal skin infections (Candida albicans, dermatophyte species) are also commonly seen in HIV-infected patients. Staphylococcus can cause the folliculitis, furunculosis, and bullous impetigo commonly observed in HIV-infected patients, which require aggressive treatment to prevent dissemination and sepsis. Bacillary angiomatosis is a potentially fatal dermatologic disorder of tumor-like proliferating vascular endothelial cell lesions, the result of infection by Bartonella quintana or Bartonella henselae. The lesions may resemble those of Kaposi's sarcoma but respond to treatment with erythromycin or tetracycline. CNS manifestations in HIV-infected patients include infections and malignancies. Toxoplasmosis frequently presents with space-occupying lesions, causing headache, altered mental status, seizures, or focal neurologic deficits. Cryptococcal meningitis commonly manifests as headache and fever. Up to 90% of patients with cryptococcal meningitis exhibit a positive serum test for Cryptococcus neoformans antigen. HIV-associated cognitive-motor complex, or AIDS dementia complex, is the most frequently diagnosed cause of altered mental status in HIV-infected patients. Patients typically have difficulty with cognitive tasks, poor short-term memory, slowed motor function, personality changes, and waxing and waning dementia. Up to 50% of AIDS patients suffer from this disorder, perhaps caused by glial or macrophage infection by HIV resulting in destructive inflammatory changes within the CNS. The differential diagnosis can be broad, including metabolic disturbances and toxic encephalopathy resulting from drugs. Other causes of altered mental status include neurosyphilis, CMV or herpes simplex encephalitis, lymphoma, and progressive multifocal leukoencephalopathy, a progressive demyelinating disease caused by a JC papovavirus. Peripheral nervous system manifestations of HIV infection include sensory, motor, and inflammatory polyneuropathies. Almost 33% of patients with advanced HIV disease develop peripheral tingling, numbness, and pain in their extremities. These symptoms are likely to be due to loss of nerve axons from direct neuronal HIV infection. Alcoholism, thyroid disease, syphilis, vitamin B12 deficiency, drug toxicity (ddI, ddC), CMV-associated ascending polyradiculopathy, and transverse myelitis also cause peripheral neuropathies. Less commonly, HIV-infected patients can develop an inflammatory demyelinating polyneuropathy similar to Guillain-Barr syndrome; however, unlike 20

the sensory neuropathies, this inflammatory demyelinating polyneuropathy typically presents before the onset of clinically apparent immunodeficiency. The origin of this condition is not known, although an autoimmune reaction is suspected because the disease typically responds favorably to treatment with plasmapheresis. Retinitis resulting from CMV infection is the most common cause of rapidly progressive visual loss in HIV infection. The diagnosis can be difficult to make because Toxoplasma gondii infection, microinfarction, and retinal necrosis can all cause visual loss. HIV-related malignancies commonly seen in AIDS include Kaposi's sarcoma, non-Hodgkin's lymphoma, primary CNS lymphoma, invasive cervical carcinoma, and anal squamous cell carcinoma. Impairment of immune surveillance and defense and increased exposure to oncogenic viruses appear to contribute to the development of neoplasms. Kaposi's sarcoma is the most common HIV-associated cancer. In San Francisco, 15-20% of HIVinfected homosexual men develop this tumor during the progression of their disease. Kaposi's sarcoma is uncommon in women and children for reasons that are not clear. Unlike classic Kaposi's sarcoma, which affects elderly men in the Mediterranean, the disease in HIV-infected patients may present with either localized cutaneous lesions or disseminated visceral involvement. It is often a progressive disease, and pulmonary involvement can be fatal. Histologically, the lesions of Kaposi's sarcoma consist of a mixed cell population that includes vascular endothelial cells and spindle cells within a collagen network. Human herpesvirus 8 is associated with Kaposi's sarcoma in AIDS patients. HIV itself appears to induce cytokines and growth factors that stimulate tumor cell proliferation rather than causing malignant cellular transformation. Clinically, cutaneous Kaposi's sarcoma typically presents as a purplish nodular skin lesion or painless oral lesion. Sites of visceral involvement include the lung, lymph nodes, liver, and GI tract. In the GI tract, Kaposi's sarcoma can produce chronic blood loss or acute hemorrhage. In the lung it often presents as coarse nodular infiltrates bilaterally, frequently associated with pleural effusions. These infiltrates can be difficult to distinguish from opportunistic infections. Non-Hodgkin's lymphoma is particularly aggressive in HIV-infected patients and usually indicative of significant immune compromise. The majority of these tumors are high-grade B-cell lymphomas with a predilection for dissemination. The CNS is frequently involved either as a primary site or as an extranodal site of widespread disease. Anal dysplasia and squamous cell carcinoma are also more commonly found in HIV-infected homosexual men. These tumors appear to be associated with concomitant anal or rectal infection with human papillomavirus (HPV). In HIV-infected women, the incidence of HPV-related cervical dysplasia is as high as 40%, and dysplasia can progress rapidly to invasive cervical carcinoma. Other complications of HIV-infection include arthritides, myopathy, GI syndromes, dysfunction of the adrenal and thyroid glands, hematologic cytopenias, and nephropathy. Since the disease was first described in 1981, medical knowledge of the underlying pathogenesis of AIDS has increased at a rate unprecedented in medical history. This knowledge has led to the rapid development of therapies directed at controlling HIV infection as well as the multitude of complicating opportunistic infections and cancers.

22)DISTURBANCES OF PERIPHERAL CIRCULATION.ARTERIAL HYPEREMIA

Blood circulation in the area of peripheral vascular bed, but the movement of blood, ensuring the exchange water, electrolytes, gases, essential nutrients and metabolites in system of blood - tissue - blood. Peripheral arterial disease (P.A.D.) is a disease in which plaque (plak) builds up in the arteries that carry blood to your head, organs, and limbs. Plaque is made up of fat, cholesterol, calcium, fibrous tissue, and other substances in the blood.

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When plaque builds up in the body's arteries, the condition is called atherosclerosis . Over time, plaque can harden and narrow the arteries. This limits the flow of oxygen-rich blood to your organs and other parts of your body.P.A.D. usually affects the arteries in the legs, but it also can affect the arteries that carry blood from your heart to your head, arms, kidneys, and stomach. PVD, also known as arteriosclerosis obliterans, is primarily the result of atherosclerosis. The atheroma consists of a core of cholesterol joined to proteins with a fibrous intravascular covering. The atherosclerotic process may gradually progress to complete occlusion of medium and large arteries. The disease typically is segmental, with significant variation from patient to patient. Vascular disease may manifest acutely when thrombi, emboli, or acute trauma compromises perfusion. Thromboses are often of an atheromatous nature and occur in the lower extremities more frequently than in the upper extremities. Multiple factors predispose patients for thrombosis. These factors include sepsis, hypotension, low cardiac output, aneurysms, aortic dissection, bypass grafts, and underlying atherosclerotic narrowing of the arterial lumen. Arterial hyperemia is the enhanced blood filling of an organ because of the reinforced blood inflowing through arterial vessels.There are the physiological and pathological arterial hyperemia. The typical example of the physiological hyperemia is work hyperemia, which develops during the reinforced organ function. Pathological arterial hyperemia is observed when the part of body or all organism exposes to the influence of unusual factors of external or internal environment microbe toxins, chemical substances, biologically active substances etc. ngioneurotic hyperemia is displayed in two forms the neuroparalytic and neurotonic types. The first one arises due to paralysis of vasoconstrictor nerves, the other one at the stimulation of vasodilatator nerves. Collateral hyperemia arises in connection with the difficulty of blood flowing in the magistral artery, the lumen of which is closed by thrombus, mbol or is narrowed by tumor. Blood comes to the bloodless place through the collateral vessels, which reflexly expand. Hyperemia after anemia arises in the cases, when a factor, that pressed the artery, quickly liquidates. For such conditions the vessels of before bloodless organ sharply expand and become overflowed by blood what can bring about their break and bleeding. Also from the blood redistribution in the blood streem anemia of other organs appeares. The redistributory ischemia of the cerebrum can bring about the loss of consciousness. To avoid such complication, it is necessary to let the liquid out from abdominal cavity slowly.The vacate hyperemia develops in connection with the decreasing of the barometric pressure, for example into divers at their fast lifting from the depth.Arterial hyperemia is a permanent inflammation satellite.

23)VENOUS HYPEREMA.STASIS
Passive Hyperemia Passive Hyperemiais an excess of venous blood in a part. It is the result of a distention of a vein on account of some obstruction to the outflow of the blood. This can be caused by obstruction within the veins or capillaries, as by thickening of their walls, by thrombi, or by pressure from without, as from atumor. A common cause for general passivehyperemiais a lesion of the heart-valves. The circulation will continue slowly unless the venous pressure becomes as great as the arterial, when it will stop, a condition known as stasis.

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A part that is the seat of passive hyperemia becomes cyanotic, swollen, edematous, cooler than normal, and its function less. The rate of blood-flow is lessened. Theedemais due to the escape of fluid from the blood. If severe, red corpuscles may escape. Following long-continued passive hyperemia the tissues will undergo afatty degenerationon account of the decreased nutrition, or evennecrosisandgangrenemay result. There may also be some increase in the amount of connective tissue. Pigmentation from escapedhemoglobinis not uncommon -brown atrophy. When stasis occurs the blood-corpuscles slowly collect in the smaller vessels, the plasma is exuded, and the cells become packed closely together. Finally, the outline of the cells cannot be seen and the vessels appear to be filled with coagulated blood. Such is not the case, as when the circulation is reestablished the corpuscles separate and move along as usual. Localanemiaor ischemia is the condition in which the part contains less than its normal amount of blood. It is most commonly due to obstruction by pressure of the flow of arterial blood into a part. This may be due to tight bandaging, pressure from a tumor, or to thrombi or emboli, or to changes in the wall of the vessel. Disturbances of the vasomotor system may bring about marked lesions. If there is a good collateral circulation the area to which the obstructed vessel goes may show very slight change. If such is not the case,infarctionmay follow. An anemic area is pale in color,temperaturelower, and functional activity decreased.

24)ISCHEMIA. INFARCTION
Ischemia, is a restriction in blood supply to tissues, causing a shortage of oxygenand glucose needed for cellular metabolism Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue. Since oxygen is carried to tissues in the blood, insufficient blood supply causes tissue to become starved of oxygen. In the highly aerobic tissues of the heart and brain, irreversible damage to tissues can occur in as little as 34 minutes at body temperature. Ischemia results in tissue damage in a process known as ischemic cascade. The damage is the result of the build-up of metabolic waste products, inability to maintain cell membranes, mitochondrial damage, and eventual leakage of autolyzing proteolytic enzymes into the cell and surrounding tissues. Restoration of blood supply to ischemic tissues can cause additional damage known as reperfusion injury that can be more damaging than the initial ischemia. Reintroduction of blood flow brings oxygen back to the tissues, causing a greater production of free radicals and reactive oxygen species that damage cells. It also brings more calcium ions to the tissues causing further calcium overloading and can result in potentially fatal cardiac arrhythmias and also accelerates cellular selfdestruction. The restored blood flow also exaggerates the inflammation response of damaged tissues, causing white blood cells to destroy damaged cells that may otherwise still be viable. Cardiac ischemia Cardiac ischemia may be asymptomatic or may cause chest pain, known as angina pectoris. It occurs when the heart muscle, or myocardium, receives insufficient blood flow. This most frequently results from atherosclerosis, which is the long-term accumulation of cholesterol-rich plaques in the coronary arteries. Classification By histopathology

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Infarctions are divided into 2 types according to the amount of blood present: White infarctions (anemic infarcts) affect solid organs such as the spleen and kidneys wherein the solidity of the tissue substantially limits the amount of nutrients that can flow into the area of ischemic necrosis Red infarctions (hemorrhagic infarcts), generally affect the lungs or other loose organs (testis, ovary, small intestines). The occlusionconsists more of red blood cells and fibrin strands. By localization Heart: Myocardial infarction (MI), commonly known as a heart attack, is an infarction of the heart, causing some heart cells to die. This is most commonly due to occlusion (blockage) of a coronary artery following the rupture of a vulnerable atherosclerotic plaque, which is an unstable collection of lipids and white blood cells in the wall of an artery. The resulting ischemia and oxygen shortage, if left untreated for a sufficient period of time, can cause damage or death of heart muscle tissue Causes. If the myocardial ischemia lasts for some time (even at rest [unstable angina]; tissue necrosis, i.e., myocardial infarction ,occurs within about an hour. In 85% of cases this is due to acute thrombus formation in the region of the atherosclerotic coronary stenosis. This development is promoted by turbulence, and atheroma rupture with collagen exposure. Both events activate thrombocytes. Thrombosis is also encouraged through abnormal functions of the endothelium, thus its vasodilators (NO, prostacyclin) and antithrombotic substances are not present Rare causes of MI are inflammatory vascular diseases, embolism ,severe coronary spasm, increased blood viscosity as well as a markedly raised O2 demand at rest Brain: Cerebral infarction is the ischemic kind of stroke due to a disturbance in the blood vessels supplying blood to the brain. It can be atherothrombotic or embolic.[6] Stroke caused by cerebral infarction should be distinguished from two other kinds of stroke: cerebral hemorrhage and subarachnoid hemorrhage. Cerebral infarctions vary in their severity with one third of the cases resulting in death.

Lung: Pulmonary infarction or lung infarction Spleen: Splenic infarction occurs when the splenic artery or one of its branches are occluded, for example by a blood clot. Although it can occur asymptomatically, the typical symptom is severe pain in the left upper quadrant of the abdomen, sometimes radiating to the left shoulder. Fever and chills develop in some cases.[7] It has to be differentiated from other causes of acute abdomen. Limb: Limb infarction is an infarction of an arm or leg. Causes include arterial embolisms and skeletal muscle infarction as a rare complication of long standing, poorly controlled diabetes mellitus.[8] A major presentation is painful thigh or leg swelling.[8] Bone: Infarction of bone results in avascular necrosis. Without blood, the bone tissue dies and the bone collapses.[9] If avascular necrosis involves the bones of a joint, it often leads to destruction of the joint articular surfaces Testicle: an infarction of a testicle may be caused by testicular torsion.

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Eye: an infarction can occur to the central retinal artery which supplies the retina causing sudden visual loss.

25. Thrombosis.
Pathogenesis There are three primary influences on thrombus formation (called Virchow's triad): (1) endothelial injury, (2) stasis or turbulence of blood flow, and (3) blood hypercoagulability. Endothelial Injury This is a dominant influence, since endothelial loss by itself can lead to thrombosis. It is particularly important for thrombus formation occurring in the heart or in the arterial circulation, where the normally high flow rates might otherwise hamper clotting by preventing platelet adhesion or diluting coagulation factors. Thus, thrombus formation within the cardiac chambers (e.g., after endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely a function of endothelial injury. Clearly, physical loss of endothelium leads to exposure of subendothelial ECM, adhesion of platelets, release of tissue factor, and local depletion of PGI2 and plasminogen activators. However, it is important to note that endothelium need not be denuded or physically disrupted to contribute to the development of thrombosis; any perturbation in the dynamic balance of the prothrombotic and antithrombotic activities of endothelium can influence local clotting events. Thus, dysfunctional endothelium may elaborate greater amounts of procoagulant factors (e.g., platelet adhesion molecules, tissue factor, plasminogen activator inhibitors) or may synthesize fewer anticoagulant effectors (e.g., thrombomodulin, PGI2, t-PA). Significant endothelial dysfunction (in the absence of endothelial cell loss) may occur with hypertension, turbulent flow over scarred valves, or by the action of bacterial endotoxins. Even relatively subtle influences, such as homocystinuria, hypercholesterolemia, radiation, or products absorbed from cigarette smoke, may be sources of endothelial dysfunction. Alterations in Normal Blood Flow Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis; stasis is a major contributor to the development of venous thrombi. Normal blood flow is laminar, such that platelets flow centrally in the vessel lumen, separated from the endothelium by a slower moving clear zone of plasma. Stasis and turbulence therefore: Disrupt laminar flow and bring platelets into contact with the endothelium. Prevent dilution of activated clotting factors by fresh-flowing bloodRetard the inflow of clotting factor inhibitors and permit the buildup of thrombiPromote endothelial cell activation, resulting in local thrombosis, leukocyte adhesion, etc. Turbulence and stasis contribute to thrombosis in several clinical settings. Ulcerated atherosclerotic plaques not only expose subendothelial ECM but also cause turbulence. Abnormal aortic and arterial dilations, called aneurysms, create local stasis and consequently a fertile site for thrombosis. Acute myocardial infarction results in focally noncontractile myocardium; ventricular remodeling after more remote infarction can lead to aneurysm formation. In both cases cardiac mural thrombi

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form more easily because of the local blood stasis. Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial dilation. In conjunction with atrial fibrillation, a dilated atrium is a site of profound stasis and a prime location for development of thrombi. Hyperviscosity syndromes increase resistance to flow and cause small vessel stasis; the deformed red cells in sickle cell anemia cause vascular occlusions, with the resultant stasis also predisposing to thrombosis. Fate of the Thrombus If a patient survives the initial thrombosis, in the ensuing days or weeks thrombi undergo some combination of the following four events: 1 Propagation. Thrombi accumulate additional platelets and fibrin, eventually causing vessel obstruction. 2 Embolization. Thrombi dislodge or fragment and are transported elsewhere in the vasculature. 3 Dissolution. Thrombi are removed by fibrinolytic activity 4 Organization and recanalization. Thrombi induce inflammation and fibrosis (organization). These can eventually recanalize (re-establishing some degree of flow), or they can be incorporated into a thickened vessel wall. Clinical Correlations: Venous versus Arterial Thrombosis Thrombi are significant because they cause obstruction of arteries and veins and are potential sources of emboli. Which effect is most important depends on the site of thrombosis. Venous thrombi can cause congestion and edema in vascular beds distal to an obstruction, but they are most worrisome for their capacity to embolize to the lungs and cause death (see below). Conversely, while arterial thrombi can embolize and even cause downstream tissue infarction (see below), their role in vascular obstruction at critical sites (e.g., coronary and cerebral vessels) is much more significant clinically.

26)EMBOLISM
Embolus is a free mass in the blood which can occlude any vessel at any time. If it occludes an artery it will lead to tissue necrosis.Embolism: an embolism occurs when an object migrates from one part of the body andcausesa blockage of a blood vessel in another part of the body. MATERIAL 1.Thromboembolism embolism of thrombus or blood clot. 2.Fat embolism embolism of fat droplets. 3.Air embolism (also known as a gas embolism) embolism of air bubbles. 4.Septic embolism embolism of pus-containing bacteria. 5.Tissue embolism embolism of small fragments of tissue. 6.Foreign body embolism embolism of foreign materials such as talc and other smallobjects. 7.Amniotic fluid embolism embolism of amniotic fluid, foetal cells, hair, or other debristhat enters the mother's bloodstream via the placental bed of the uterus and triggers anallergic reaction PATHWAY 1.Anterograde 2.Retrograde 3.Paradoxica CAUSES & Pathophysiology A.Thromboembolism ,This is when a part of a blood clot (thrombus) blocks blood flow to a major organ such asthe heart or lungs. Itsthe most common type of embolism. B.Fat embolism usually occurs when 26

Endogenous :1.Thefracture of tubular bones (such as the femur), which will lead to theleakage of fat tissue within the bone marrow into ruptured vessels.2.Trauma of burns of a fatty area. Exogenous:(from sources of external origin) causes such as intravenousinjection of emulsions. C. Air embolism is usually always caused by exogenic factors. the rupture of alveoli, and inhaled air can be leaked into the blood vessels. The puncture of the subclavian vein by accident or during operation where thereis negative pressure.Air is then sucked into the veins by the negative pressure caused by thoracicexpansion during the inhalation phase of respiration.Intravenoustherapy, when air is leaked into the system (however this iatrogenicerror in modern medicine is extremely rare).

Gas embolism is a common concern for deep-sea divers because the gasesin our blood (usually nitrogen and helium) can be easily dissolved at higheramounts during the descent into deep sea. However, when the diver ascends tothe normal atmospheric pressure, the gases become insoluble, causing theformation of small bubbles in the blood. This is also known as decompressionsickness or the Bends. D.Septic embolism happens when a purulent tissue (pus-containing tissue) is dislodged fromits original focus. E.Tissue embolism is a near-equivalent to cancer metastasis, which happens when cancertissue infiltrates blood vessels, and small fragments of them are released into the blood stream. F. Foreign-body embolism happens when exogenousand only exogenousmaterials suchas talc enter the blood stream and cause occlusion or obstruction of blood circulation. G. Amniotic-fluid embolism is a rare complication of childbirth ANEMBOLISM IN AN ARTERY causes symptoms in the affected area and may includethe following:pain,numbness,tingling,coldness,mottled or pale skin,and muscular spasms (twitches)or paralysis (unable to move). AN EMBOLISM IN A VEIN doesn't always cause symptoms. However, there may be:tenderness in the calf or upper leg, which may get gradually more painful,amild fever, with the skinfeeling hot in the area where the embolism is,swelling in one leg and not the other,redness of the leg,andswollen veins. DEEP VEIN THROMBOSIS is an example of an embolism that forms in a vein in this case, ablood clot. If the blood clot breaks away, it can be carried in the bloodstream up to and through the heart,before entering one of the main arteries to the lungs. This can cause the following symptoms:chest pain,rapid heart beat,shortness of breath and fast breathing, andcoughing (sometimes bringing up blood).

27-Abnormalities of Lipid Digestion and Absorption In Gastro....

The mechanisms for lipid digestion and absorption are more complex and involve more steps than those for carbohydrate and protein. Thus, there are also more steps at which an abnormality of lipid digestion or absorption can occur. Each step in the normal process is essential: pancreatic enzyme secretion and function, bile acid secretion, emulsification, micelle formation, diffusion of lipids into 27

intestinal epithelial cells, chylomicron formation, and transfer of chylomicrons into lymph. An abnormality at any one of the steps will interfere with lipid absorption and result in steatorrhea (fat excreted in feces).

Pancreatic insufficiency. Diseases of the exocrine pancreas (e.g., chronic pancreatitis and cystic fibrosis) result in failure to secrete adequate amounts of pancreatic enzymes, including those involved in lipid digestion, pancreatic lipase and colipase, cholesterol ester hydrolase, and phospholipase A2. For example, in the absence of pancreatic lipase, triglycerides cannot be digested to monoglycerides and free fatty acids. Undigested triglycerides are not absorbable and are excreted in feces. Acidity of duodenal contents. If the acidic chyme delivered to the duodenum is not adequately neutralized by the HCO3--containing pancreatic secretions, then pancreatic enzymes are inactivated (i.e., the pH optimum for pancreatic lipase is 6). The gastric chyme, which is delivered to the duodenum, has a pH ranging from 2 at the pylorus to 4 at the duodenal bulb. Sufficient HCO3- must be secreted in pancreatic juice to neutralize the H+ and increase the pH to the range where pancreatic enzymes function optimally. There are two reasons that all of the H+ delivered from the stomach might not be neutralized: (1) Gastric parietal cells may be secreting excessive quantities of H+, causing an overload to the duodenum; or (2) the pancreas may fail to secrete sufficient quantities of HCO3- in pancreatic juice. The first reason is illustrated by Zollinger-Ellison syndrome, in which a tumor secretes large quantities of gastrin. The elevated levels of gastrin stimulate excessive secretion of H+ by the gastric parietal cells, and this H+ is delivered to the duodenum, overwhelming the ability of pancreatic juices to neutralize it. The second reason is illustrated by disorders of the exocrine pancreas (e.g., pancreatitis) in which there is impaired HCO3- secretion (in addition to impaired enzyme secretion). Deficiency of bile salts. Deficiency of bile salts interferes with the ability to form micelles, which are necessary for solubilization of the products of lipid digestion. Ileal resection (removal of the ileum) interrupts the enterohepatic circulation of bile salts, which then are excreted in feces rather than being returned to the liver. Because the synthesis of new bile salts cannot keep pace with the fecal loss, the total bile salt pool is reduced. Bacterial overgrowth. Bacterial overgrowth reduces the effectiveness of bile salts by deconjugating them. In other words, bacterial actions remove glycine and taurine from bile salts, converting them to bile acids. Recall that at intestinal pH, bile acids are primarily in the nonionized form (since their pKs are higher than intestinal pH); the nonionized form is lipid soluble and readily absorbed by diffusion across the intestinal epithelial cells. For this reason, the bile acids are absorbed "too early" (before reaching the ileum), before micelle formation and lipid absorption is completed. Similarly, decreased pH in the intestinal lumen promotes "early" absorption of bile acids by converting them to their nonionized form. Decreased intestinal cells for absorption. In conditions such as tropical sprue, the number of intestinal epithelial cells is reduced, which reduces the microvillar surface area. Since lipid absorption across the apical membrane occurs by diffusion, which depends on surface area, lipid absorption is impaired because the surface area for absorption is decreased. Failure to synthesize apoproteins. Failure to synthesize Apo B (-lipoprotein) causes abetalipoproteinemia. In this disease, chylomicrons either do not form or are unable to be transported out of intestinal cells into lymph. In either case, there is decreased absorption of lipids into blood and a buildup of lipid within the intestinal cells.

28. Disturbances in lipids transport. Hyperlipidemia. Fatty liver

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Lipoproteins are large, mostly spherical complexes that transport lipids (triglycerides, cholesteryl esters, and fat-soluble vitamins) through body fluids (plasma, interstitial fluid, and lymph) to and from tissues.Lipids such as free fatty acids (FFAs), cholesterol, and triglycerides are hydrophobic molecules that bind protein for transport. Nonesterified FFAs travel as anions complexed to albumin. Esterified complex lipids are transported in lipoprotein particles. Lipoproteins have a hydrophobic core (cholesteryl esters and triglycerides) and an amphiphilic surface monolayer (phospholipids, unesterified cholesterol, and apolipoproteins). Proteins on the surface of lipoproteins, apolipoproteins (apo), activate enzymes and receptors that guide lipid metabolism. Ultracentrifugation separates lipoproteins into five classes based on their density: chylomicrons, very low density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). The density of a lipoprotein is determined by the amount of lipid and protein per particle. HDL is the smallest and most dense lipoprotein, whereas chylomicrons and VLDL are the largest and least dense lipoprotein particles.Most triglyceride is transported in chylomicrons or VLDL, and most cholesterol is carried as cholesteryl esters in LDL and HDL. ApoA-I, which is synthesized in the liver and intestine, is found on virtually all HDL particles. ApoA-II is the second most abundant HDL apolipoprotein. ApoB is the major structural protein of chylomicrons, VLDL, IDL, and LDL; one molecule of apoB, either apoB-48 (chylomicrons) or apoB-100 (VLDL, IDL, or LDL), is present on each lipoprotein particle. The human liver makes only apoB-100, and the intestine makes apoB-48. ApoE is present in multiple copies on chylomicrons, VLDL, and IDL and plays a critical role in the metabolism and clearance of triglyceride-rich particles. Three apolipoproteins of the C-series (apoC-I, -II, and -III) also participate in the metabolism of triglyceride-rich lipoproteins. Transport of Dietary Lipids (Exogenous Pathway): The exogenous pathway of lipoprotein metabolism permits efficient transport of dietary lipids. Dietary triglycerides are hydrolyzed by pancreatic lipases within the intestinal lumen and are emulsified with bile acids to form micelles. Dietary cholesterol and retinol are esterified (by the addition of a fatty acid) in the enterocyte to form cholesteryl esters and retinyl esters, respectively. Longer-chain fatty acids (12 carbons) are incorporated into triglycerides and packaged with apoB- 48, cholesteryl esters, retinyl esters, phospholipids, and cholesterol to form chylomicrons. Nascent chylomicrons are secreted into the intestinal lymph and delivered directly to the systemic circulation, where they are extensively processed by peripheral tissues before reaching the liver. The particles encounter lipoprotein lipase (LPL), which is anchored to proteoglycans that decorate the capillary endothelial surfaces of adipose tissue, heart, and skeletal muscle. The triglycerides of chylomicrons are hydrolyzed by LPL, and free fatty acids are released; apoC-II, which is transferred to circulating chylomicrons, acts as a cofactor for LPL in this reaction. The released free fatty acids are taken up by adjacent myocytes or adipocytes and either oxidized or reesterified and stored as triglyceride. Some free fatty acids bind albumin and are transported to other tissues, especially the liver. The chylomicron particle progressively shrinks in size as the hydrophobic core is hydrolyzed and the hydrophilic lipids (cholesterol and phospholipids) on the particle surface are transferred to HDL. The resultant smaller, more cholesterol esterrich particles are referred to as chylomicron remnants. 29

The remnant particles are rapidly removed from the circulation by the liver in a process that requires apoE. Transport of Hepatic Lipids (Endogenous Pathway): The endogenous pathway of lipoprotein metabolism refers to the hepatic secretion and metabolism of VLDL to IDL and LDL. VLDL particles resemble chylomicrons in protein composition but contain apoB-100. The triglycerides of VLDL are derived predominantly from the esterification of long-chain fatty acids. The packaging of hepatic triglycerides with the other major components of the nascent VLDL particle (apoB-100, cholesteryl esters, phospholipids, and vitamin E) requires the action of the enzyme microsomal transfer protein (MTP). After secretion into the plasma, VLDL acquires multiple copies of apoE and apolipoproteins of the C series. The triglycerides of VLDL are hydrolyzed by LPL, especially in muscle and adipose tissue. As VLDL remnants undergo further hydrolysis, they continue to shrink in size and become IDL, which contain similar amounts of cholesterol and triglyceride. The liver removes approximately 40 to 60% of VLDL remnants and IDL by LDL receptormediated endocytosis via binding to apoE. The remainder of IDL is remodeled by hepatic lipase (HL) to form LDL; during this process, most of the triglyceride in the particle is hydrolyzed and all apolipoproteins except apoB-100 are transferred to other lipoproteins. The cholesterol in LDL accounts for70% of the plasma cholesterol in most individuals. Approximately 70% of circulating LDLs are cleared by LDL receptormediated endocytosis in the liver. Familial Hypercholesterolemia: Mutations in the gene that encodes the LDL (apo B/E) receptor results in familial hypercholesterolemia (FH). Impairment in LDL receptor synthesis or function decreases the clearance of LDL and increases circulating LDL levels. Excess LDL then enters macrophages through scavenger receptors resulting in foam cell and cholesterol plaque formation. These plaques deposit in arteries (atheroma), skin or tendons (xanthoma), eyelids (xanthelasma), and iris (corneal arcus). Homozygous form (rare): Affected individuals present early in life with elevated total cholesterol (600 to 1000 mg/dL) and LDL (550 to 950 mg/dL). Triglyceride and HDL levels are normal. They develop CHD, aortic stenosis due to atherosclerosis of the aortic root, and tendon xanthomas. These xanthomas commonly involve the Achilles tendon and present as tendonitis. If untreated, patients with HM FH typically die from myocardial infarction before age 20 years. The heterozygous (HZ) form: Partial receptor defect resulting in cells displaying half the normal number of fully functional LDL receptors. These individuals have lower elevated total cholesterol (>300 to 600 mg/dL) and LDL (250 to 500 mg/dL) levels. Premature CHD and tendon xanthomas are characteristic clinical findings. FH can be established by identifying one of the many known gene mutations in the LDL receptor or by demonstrating diminished LDL receptor function. The diagnosis of FH usually is made on the basis of clinical features. Elevated total cholesterol (>300 mg/dL) and LDL (>250 mg/dL) in an individual with personal or family history of premature CHD and tendon xanthomas identifies individuals at risk for FH. Treatment requires a low-fat (<20% of total calories), low cholesterol (<100 mg per day) diet in combination with drug therapy. Familial Defective Apolipoprotein B-100: In this autosomal dominant disorder, a defect in the apo B-100 protein results in impaired binding of LDL particles to the LDL receptor. Most cases are linked to a single mutation (glutamine for arginine substitution) in the apo B-100 gene.

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The clinical presentation is similar to FH, with elevated total cholesterol and LDL levels associated with premature CHD and tendon xanthomas but are milder than in FH because apo Emediated clearance of remnant particles is still functional. Total cholesterol ranges from 350 to 550 mg/dL in HM and 200 to 350 mg/dL in HZ. Polygenic Hypercholesterolemia: Apo E play a role in the pathogenesis. Apo E4 on chylomicron and VLDL remnants has a high affinity for the LDL receptor. Elevated binding of apo E4containing lipoproteins to LDL receptors downregulate LDL receptor synthesis and increase circulating LDL levels. Environmental factors such as diet can influence chylomicron and VLDL production, resulting in downregulation of the LDL receptor in high apo E4 conditions. This leads to an increased propensity for CHD. Familial Hypertriglyceridemia: Familial hypertriglyceridemia is an autosomal dominant disorder characterized by overproduction of hepatic VLDL. Secondary factors that increase VLDL, such as diabetes, alcohol ingestion, and estrogen therapy, appear to exacerbate this condition. Low HDL associated with familial hypertriglyceridemia is related to increased catabolism. Individuals with this condition present with hypertriglyceridemia (200 to 500 mg/dL) and low HDL (<35 mg/dL). The decrease in HDL increases the risk for CHD. Secondary factors can exacerbate the problem by raising triglyceride levels above 1000 mg/dL and increasing the risk for pancreatitis and xanthomas. This diagnosis is considered in individuals with a family and personal history of hypertriglyceridemia, CHD, and normal LDL levels. A cloudy infranant noted after overnight refrigeration of plasma identifies a disorder of VLDL metabolism. Treatment starts with management of secondary factors that may exacerbate the condition. Dietary fat restriction (<10% of calories) and drug therapy with niacin and fibric acid derivates should be initiated. Lipoprotein Lipase Deficiency: Mutations in the LPL gene resulting in deficiency of LPL synthesis or function lead to increased circulating chylomicron and VLDL particles and severe hypertriglyceridemia. Homozygous (rare): It presents in childhood with triglycerides higher than 1000 mg/dL. Heterozygous: Usually requires a precipitating factor such as uncontrolled diabetes to manifest the phenotype. These individuals have moderate hypertriglyceridemia (250 to 750 mg/dL) that can increase to levels above 1000 mg/dL with secondary factors, such as insulin resistance or estrogen therapy. This can result in the chylomicronemia syndrome, characterized by marked hypertriglyceridemia (>1000 to 2000 mg/dL), pancreatitis, eruptive xanthomas, lipemia retinalis, and hepatosplenomegaly.

Visual inspection demonstrates lipemic plasma. After refrigeration for 12 hours, a creamy top layer (increased chylomicrons) or turbid plasma infranatant (increased VLDL), or both, can be demonstrated. A diet low in fat (<10% of total calories or <20 to 25 g per day) is the primary treatment. Secondary factors such as uncontrolled diabetes and alcohol use should be addressed. 31

 Apolipoprotein C-II Deficiency: Apo C-II is an activating cofactor for lipoprotein lipase. Deficiency of apo C-II is a rare autosomal recessive disorder that leads to increased chylomicrons and VLDL particles in the circulation, resulting in severe hypertriglyceridemia.Clinical manifestations are similar to LPL deficiency, including hypertriglyceridemia (>1000 mg/dL) and symptoms of pancreatitis, eruptive xanthomas, lipemia retinalis, and hepatosplenomegaly. Familial Combined Hyperlipoproteinemia: is an autosomal dominant polygenic disorder. In FCHL, excess VLDL is synthesized in the liver. VLDL is hydrolyzed by LPL to produce LDL. Mutations in the LPL gene affecting its expression or function can decrease the efficiency of VLDL catabolism. Diminished LPL activity increases circulating VLDL triglyceride. Furthermore, fewer VLDL remnant particles are available for HDL synthesis. Therefore, FCHL needs to be considered in all patients with total cholesterol level higher than 250 mg/dL, triglycerides higher than 175 mg/dL, or HDL lower than 35 mg/dL. Patients typically have high apo B (>120 mg/dL) and a low LDL cholesteroltoapo B-100 ratio (<1.2). They accumulate small dense LDL particles, which are thought to be atherogenic and contribute to premature coronary artery disease. Affected individuals require a low-fat, lowcholesterol diet plus multiple lipid-lowering drugs. Primary Hypoalphalipoproteinemia: Hypoalphalipoproteinemia is defined as a plasma HDL-C level below the 10th percentile in the setting of relatively normal cholesterol and triglyceride levels. This syndrome is often referred to as isolated low HDL. The metabolic etiology of this disease appears to be primarily accelerated catabolism of HDL and its apolipoproteins. There is an increased incidence of premature atherosclerosis. Fatty liver is characterized by the accumulation of fat in hepatocytes, a condition called steatosis. The liver becomes yellow and enlarges owing to excessive fat accumulation. The pathogenesis of fatty liver can depend on the amount of alcohol consumed, dietary fat content, body stores of fat, hormonal status, and other factors.

29. Disturbances in lipids metabolism in fat tissue. Obesity

Fat cells, residing within widely distributed adipose tissue depots, are adapted to store excess energy efficiently as triglyceride and, when needed, to release stored energy as free fatty acids for use at other sites. This physiologic system, orchestrated through endocrine and neural pathways, permits humans to survive starvation for as long as several months. Definition and Measurement: Obesity is a state of excess adipose tissue mass.Although not a direct measure of adiposity, the most widely used method to gauge obesity is the body mass index (BMI), which is equal to weight/height2 (in kg/m2). Other approaches to quantifying obesity include anthropometry (skin-fold thickness), densitometry (underwater weighing), computed tomography (CT) or magnetic resonance imaging (MRI), and electrical impedance. Based on unequivocal data of substantial morbidity, a BMI of 30 is most commonly used as a threshold for obesity in both men and women.Individuals with BMIs between 25 and 30 are termed overweight and should be viewed as medically significant and worthy of therapeutic intervention, especially in the presence of risk factors that are influenced by adiposity, such as hypertension and glucose intolerance. The distribution of adipose tissue in different anatomic depots also has substantial implications for morbidity. Specifically, intraabdominal and abdominal subcutaneous fat have more significance than subcutaneous fat present in the buttocks and lower extremities. This distinction is most easily made by determining the waist-to-hip ratio, with a ratio >0.9 in women and >1.0 in men being abnormal. 32

Intraabdominal adipocytes are more lipolytically active than those from other depots. Release of free fatty acids into the portal circulation has adverse metabolic actions, especially on the liver. Body weight is regulated by both endocrine and neural components that ultimately influence the effector arms of energy intake and expenditure. This exquisite regulation of energy balance cannot be monitored easily by calorie-counting in relation to physical activity. Rather, body weight regulation or dysregulation depends on a complex interplay of hormonal and neural signals. Alterations in stable weight by forced overfeeding or food deprivation induce physiologic changes that resist these perturbations: with weight loss, appetite increases and energy expenditure falls; with overfeeding, appetite falls and energy expenditure increases. This latter compensatory mechanism frequently fails, however, permitting obesity to develop when food is abundant and physical activity is limited. A major regulator of these adaptative responses is the adipocyte-derived hormone leptin, which acts through brain circuits (predominantly in the hypothalamus)to influence appetite, energy expenditure, and neuroendocrine function. Appetite is influenced by many factors that are integrated by the brain, most importantly within the hypothalamus. Signals that impinge on the hypothalamic center include neural afferents, hormones, and metabolites. Vagal inputs are particularly important, bringing information from viscera, such as gut distention. Hormonal signals include leptin, insulin, cortisol, and gut peptides such as ghrelin, peptide YY (PYY), and cholecystokinin, which signal to the brain through direct action on hypothalamic control centers and/ or via the vagus nerve. Metabolites, including glucose, can influence appetite, as seen by the effect of hypoglycemia to induce hunger. These diverse hormonal, metabolic, and neural signals act by influencing the expression and release of various hypothalamic peptides [e.g., neuropeptide Y (NPY), Agouti-related peptide (AgRP), melanocyte-stimulating hormone (-MSH), and melanin-concentrating hormone (MCH)] that are integrated with serotonergic, catecholaminergic, and opioid signaling pathways. Energy expenditure includes the following components: (1) resting or basal metabolic rate; (2) the energy cost of metabolizing and storing food; (3) the thermic effect of exercise; and (4) adaptive thermogenesis, which varies in response to chronic caloric intake (rising with increased intake). Basal metabolic rate accounts for about 70% of daily energy expenditure, whereas active physical activity contributes 5 to 10%. The Adipocyte And Adipose Tissue: Adipose tissue is composed of the lipid-storing adipose cell and a stromal/vascular compartment in which preadipocytes reside. Adipose mass increases by enlargement of adipose cells through lipid deposition, as well as by an increase in the number of adipocytes. The process by which adipose cells are derived from a mesenchymal preadipocyte involves an orchestrated series of differentiation steps mediated by a cascade of specific transcription factors. One of the key transcription factors is peroxisome proliferator-activated receptor (PPAR ), a nuclear receptor.The adipocyte is also an endocrine cell that releases numerous molecules in a regulated fashion. These include the energy balance-regulating hormone leptin, cytokines such as tumor necrosis factor (TNF ), complement factors such as factor D (also 33

known as adipsin), prothrombotic agents such as plasminogen activator inhibitor I, and a component of the blood pressure regulating system, angiotensinogen. Adiponectin enhances insulin sensitivity and lipid oxidation, whereas resistin may induce insulin resistance. These factors play a role in the physiology of lipid homeostasis, insulin sensitivity, blood pressure control, and coagulation and are likely to contribute to obesity-related pathologies.Etiology of Obesity: Obesity is a heterogeneous group of disorders.Obesity is commonly seen in families, and the heredibility of body weight is similar to that for height. Inheritance is usually not Mendelian, however, and it is difficult to distinguish the role of genes and environmental factors.The environment plays a key role in obesity, as evidenced by the fact that famine prevents obesity in even the most obesity-prone individual. Cultural factors are also important these relate to both availability and composition of the diet and to changes in the level of physical activity.Leptin is secreted by adipose cells and acts primarily through the hypothalamus. Its level of production provides an index of adipose energy stores. High leptin levels decrease food intake and increase energy expenditure.The OB gene is present in humans and expressed in fat. Obesity caused by inactivating mutations in either leptin or the leptin receptor have been described, thus demonstrating the biologic relevance of leptin in humans. The obesity in these individuals begins shortly after birth, is severe, and is accompanied by neuroendocrine abnormalities. The most prominent of these is hypogonadotropic hypogonadism, which is reversed by leptin replacement.Central hypothyroidism and growth retardation are seen in the mouse model, but their occurrence in leptin-deficient humans is less clear.Some disorders contribute to generation of obesity including; Cushings syndrome, Hypothyroidism (not common), Insulinoma (overeating to avoid hypoglycemia symptoms), some hypothalamic disorders. Pathogenesis of Common Obesity: Obesity can result from increased energy intake, decreased energy expenditure, or a combination of the two. Thus, identifying the etiology of obesity should involve measurements of both parameters. There is increased interest in the concept of a body weight set point. There is a sensing system in adipose tissue that reflects fat stores and a receptor, or adipostat, that is in the hypothalamic centers. When fat stores are depleted, the adipostat signal is low, and the hypothalamus responds by stimulating hunger and decreasing energy expenditure to conserve energy. Conversely, when fat stores are abundant, the signal is increased, and the hypothalamus responds by decreasing hunger and increasing energy expenditure. Average energy expenditure increases as people get more obese, due primarily to the fact that metabolically active lean tissue mass increases with obesity. Given the laws of thermodynamics, the obese person must therefore eat more than the average lean person to maintain their increased weight. Leptin in Typical Obesity: The vast majority of obese people have increased leptin levels but do not have mutations of either leptin or its receptor. They appear, therefore, to have a form of functional leptin resistance. Pathologic Consequences of Obesity: Obesity has major adverse effects on health. Morbidly obese individuals have as much as a twelvefold increase in mortality. Insulin Resistance and Type 2 Diabetes Mellitus: Hyperinsulinemia and insulin resistance are pervasive features of obesity, increasing with weight gain and diminishing with weight loss. Insulin resistance is more strongly linked to intraabdominal fat than to fat in other depots. 34

The molecular link between obesity and insulin resistance in tissues such as fat, muscle, and liver include: (1) insulin itself, by inducing receptor downregulation; (2) free fatty acids, known to be increased and capable of impairing insulin action; (3) intracellular lipid accumulation; and (4) various circulating peptides produced by adipocytes, including the cytokines TNF- and interleukin (IL)6 , and the adipokines adiponectin and resistin, which are produced by adipocytes, have altered expression in obese adipocytes, and are capable of modifying insulin action. Reproductive Disorders: Male hypogonadism is associated with increased adipose tissue. In men, plasma testosterone and sex hormonebinding globulin (SHBG)are often reduced, and estrogen levels (derived from conversion of adrenal androgens in adipose tissue) are increased. Gynecomastia may be seen. However, masculinization, libido, potency, and spermatogenesis are preserved in most of these individuals. Obesity is associated with menstrual abnormalities in women, particularly in women with upper body obesity. Common findings are increased androgen production, decreased SHBG, and increased peripheral conversion of androgen to estrogen. Most obese women with oligomenorrhea have the polycystic ovarian syndrome (PCOS), with its associated anovulation and ovarian hyperandrogenism. The increased conversion of androstenedione to estrogen, which occurs to a greater degree in women with lower body obesity, may contribute to the increased incidence of uterine cancer in postmenopausal women with obesity. Cardiovascular Disease: When the additional effects of hypertension and glucose intolerance associated with obesity are included, the adverse impact of obesity is even more evident. Obesity, especially abdominal obesity, is associated with an atherogenic lipid profile, with increased lowdensity lipoprotein (LDL) cholesterol, very low density lipoprotein, and triglyceride, and decreased high-density lipoprotein cholesterol. Obesity is also associated with hypertension. Obesity-induced hypertension is associated with increased peripheral resistance and cardiac output, increased sympathetic nervous system tone, increased salt sensitivity, and insulin-mediated salt retention; it is often responsive to modest weight loss. Pulmonary Disease: These include reduced chest wall compliance, increased work of breathing, increased minute ventilation due to increased metabolic rate, and decreased total lung capacity and functional residual capacity. Severe obesity may be associated with obstructive sleep apnea and the obesity hypoventilation syndrome. Gallstones: Obesity is associated with enhanced biliary secretion of cholesterol, supersaturation of bile, and a higher incidence of gallstones, particularly cholesterol gallstones. Paradoxically, fasting increases supersaturation of bile by decreasing the phospholipid component. Cancer: Obesity in males is associated with higher mortality from cancer, including cancer of the esophagus, colon, rectum, pancreas, liver, and prostate; obesity in females is associated with higher mortality from cancer of the gallbladder, bile ducts, breasts, endometrium, cervix, and ovaries. Bone, Joint, and Cutaneous Disease: Obesity is associated with an increased risk of osteoarthritis, partly due to the trauma of added weight bearing and joint malalignment. The prevalence of gout may also be 35

increased. Among the skin problems is acanthosis nigricans, manifested by darkening and thickening of the skin folds on the neck, elbows, and dorsal interphalangeal spaces. Friability of skin may be increased, especially in skin folds, enhancing the risk of fungal and yeast infections. Finally, venous stasis is increased in the obese.

30. Disturbances in intermediary lipid metabolism. Ketosis

In humans and most other mammals, acetyl-CoA formed in the liver during oxidation of fatty acids can either enter the citric acid cycle or undergo conversion to the ketone bodies, acetone, acetoacetate, and D--hydroxybutyrate, for export to other tissues. (these compounds are quite soluble in blood and urine.) Acetone, produced in smaller quantities than the other ketone bodies, is exhaled. Acetoacetate and D--hydroxybutyrate are transported by the blood to tissues other than the liver (extrahepatic tissues), where they are converted to acetyl-CoA and oxidized in the citric acid cycle, providing much of the energy required by tissues such as skeletal and heart muscle and the renal cortex. The brain, which preferentially uses glucose as fuel, can adapt to the use of acetoacetate or D--hydroxybutyrate under starvation conditions, when glucose is unavailable. Ketone Bodies, Formed in the Liver, Are Exported to Other Organs as Fuel The first step in the formation of acetoacetate, occurring in the liver, is the enzymatic condensation of two molecules of acetyl-CoA. In healthy people, acetone is formed in very small amounts from acetoacetate, which is easily decarboxylated, either spontaneously or by the action of acetoacetate decarboxylase. Because individuals with untreated diabetes produce large quantities of acetoacetate, their blood contains significant amounts of acetone, which is toxic. Acetone is volatile and imparts a characteristic odor to the breath, which is sometimes useful in diagnosing diabetes.In extrahepatic tissues, D--hydroxybutyrate is oxidized to acetoacetate by D--hydroxybutyrate dehydrogenase. The acetoacetate is activated to its coenzyme A ester by transfer of CoA from succinyl-CoA, an intermediate of the citric acid cycle, in a reaction catalyzed by -ketoacyl-CoA transferase. The acetoacetyl-CoA is then cleaved by thiolase to yield two acetyl-CoAs, which enter the citric acid cycle. Thus the ketone bodies are used as fuels.The production and export of ketone bodies by the liver allow continued oxidation of fatty acids with only minimal oxidation of acetyl-CoA. When intermediates of the citric acid cycle are being siphoned off for glucose this is simply the reversal of the last step of oxidation.The acetoacetyl-CoA then condenses with acetyl-CoA to form-hydroxy-methylglutaryl-CoA (HMG-CoA), which is cleaved to free acetoacetate and acetyl-CoA.The acetoacetate is reversibly reduced by D--hydroxybutyrate dehydrogenase, a mitochondrial enzyme, to D--hydroxybutyrate. This enzyme is specific for the synthesis by gluconeogenesis, for example, oxidation of cycle intermediates slowsand so does acetyl-CoA oxidation.Moreover, the liver contains only a limited amount of coenzyme A, and when most of it is tied up in acetyl-CoA, oxidation slows for want of the free coenzyme. The production and export of ketone bodies free coenzyme A, allowing continued fatty acid oxidation. Ketone Bodies Are Overproduced in Diabetes and during Starvation Starvation and untreated diabetes mellitus lead to overproduction of ketone bodies. During starvation, gluconeogenesis depletes citric acid cycle intermediates, diverting acetyl-CoA to ketone body production. In untreated diabetes, when the insulin level is insufficient, extrahepatic tissues cannot take up glucose efficiently from the blood, either for fuel or for conversion to fat. Under these conditions, levels of malonyl-CoA (the starting material for fatty acid synthesis) fall, inhibition of carnitine acyltransferase I is relieved, and fatty acids enter mitochondria to be degraded to acetyl36

CoAwhich cannot pass through the citric acid cycle because cycle intermediates have been drawn off for use as substrates in gluconeogenesis. The resulting accumulation of acetyl-CoA accelerates the formation of ketone bodies beyond the capacity of extrahepatic tissues to oxidize them. The increased blood levels of acetoacetate and D--hydroxybutyrate lower the blood pH, causing the condition known as acidosis. Extreme acidosis can lead to coma and in some cases death. Ketone bodies in the blood and urine of untreated diabetics can reach extraordinary levelsa blood concentration of 90 mg/100 mL (compared with a normal level of <3 mg/100 mL) and urinary excretion of 5,000 mg/24 hr (compared with a normal rate of 125 mg/24 hr). This condition is called ketosis.

Individuals on very low-calorie diets, using the fats stored in adipose tissue as their major energy source, also have increased levels of ketone bodies in their blood and urine.

31) LIPOPROTEIN METABOLISM

The handling of lipoproteins in the body is referred to as lipoprotein metabolism. It is divided into two pathways, exogenous and endogenous, depending in large part on whether the lipoproteins in question are composed chiefly of dietary (exogenous) lipids or whether they originated in the liver (endogenous). Exogenous pathway Epithelial cells lining the small intestine readily absorb lipids from nutritive substances. These lipids, including triglycerides, phospholipids, and cholesterol, are assembled with apolipoprotein B-48 into chylomicrons. These nascent chylomicrons are secreted from the intestinal epithelial cells into the lymphatic circulation in a process that depends heavily on apolipoprotein B-48. As they circulate through the lymphatic vessels, nascent chylomicrons bypass the liver circulation and are drained via the thoracic duct into the bloodstream.In the bloodstream, HDL particles donate apolipoprotein C-II and apolipoprotein E to the nascent chylomicron; the chylomicron is now considered mature. Via apolipoprotein C-II, mature chylomicrons activate lipoprotein lipase (LPL), an enzyme on endothelial cells lining the blood vessels. LPL catalyzes the hydrolysis of triacylglycerol (i.e., glycerol covalently joined to three fatty acids) that ultimately releases glycerol and fatty acids from the chylomicrons. Glycerol and fatty acids can then be absorbed in peripheral tissues, especially adipose and muscle, for energy and storage.The hydrolyzed chylomicrons are now considered chylomicron remnants. The chylomicron remnants continue circulating until they interact via apolipoprotein E with chylomicron remnant receptors, found chiefly in the liver. This interaction causes the endocytosis of the chylomicron remnants, which are subsequently hydrolyzed within lysosomes. Lysosomal hydrolysis releases glycerol and fatty acids into the cell, which can be used for energy or stored for later use. Endogenous pathway The liver is another important source of lipoproteins, principally VLDL. Triacylglycerol and cholesterol are assembled with apolipoprotein B-100 to form VLDL particles. Nascent VLDL particles are released into the bloodstream via a process that depends upon apolipoprotein B-100.As in chylomicron metabolism, the apolipoprotein C-II and apolipoprotein E of VLDL particles are acquired from HDL particles. Once loaded with apolipoproteins C-II and E, the nascent VLDL particle is considered mature.Again like chylomicrons, VLDL particles circulate and encounter LPL expressed on endothelial cells. Apolipoprotein C-II activates LPL, causing hydrolysis of the VLDL particle and the release of 37

glycerol and fatty acids. These products can be absorbed from the blood by peripheral tissues, principally adipose and muscle. The hydrolyzed VLDL particles are now called VLDL remnants or intermediate-density lipoproteins (IDLs). VLDL remnants can circulate and, via an interaction between apolipoprotein E and the remnant receptor, be absorbed by the liver, or they can be further hydrolyzed by hepatic lipase. Hydrolysis by hepatic lipase releases glycerol and fatty acids, leaving behind IDL remnants, called low-density lipoproteins (LDL), which contain a relatively high cholesterol content . LDL circulates and is absorbed by the liver and peripheral cells. Binding of LDL to its target tissue occurs through an interaction between the LDL receptor and apolipoprotein B-100 or E on the LDL particle. Absorption occurs through endocytosis, and the internalized LDL particles are hydrolyzed within lysosomes, releasing lipids, chiefly cholesterol.

32. Atherosclerosis
Prevalence & Significance: A condition that afflicts the large and medium-sized arteries of almost every human, at least in societies in which cholesterol-rich foodstuffs are abundant and cheap, is atherosclerosis. This condition begins in childhood and, in the absence of accelerating factors, develops slowly until it is widespread in old age. However, it is accelerated by a wide variety of genetic and environmental factors. It is characterized by localized fibrous thickenings of the arterial wall associated with lipid-infiltrated plaques that may eventually calcify. Old plaques are also prone to ulceration and rupture, triggering the formation of thrombi that obstruct flow. Therefore, atherosclerosis leads to vascular insufficiency in the limbs, abnormalities of the renal circulation, and dilations (aneurysms) and even rupture of the aorta and other large arteries. It also leads to common severe and life-threatening diseases of the heart and brain because of formation of intravascular clots at the site of the plaques. Pathogenesis: The initial event in atherosclerosis is infiltration of low-density lipoproteins (LDLs) into the subendothelial region. The endothelium is subject to shear stress, the tendency to be pulled along or deformed by flowing blood. This is most marked at points where the arteries branch, and this is where the lipids accumulate to the greatest degree.The LDLs are oxidized or altered in other ways. Thus, altered LDLs activate various components of innate immune system including macrophages, natural antibodies, and innate effector proteins such as C-reactive protein and complement. Altered LDLs are recognized by a family of scavenger receptors expressed on macrophages. These scavenger receptors mediate uptake of the oxidized LDL into macrophages and the formation of foam cells. The foam cells form fatty streaks. The streaks appear in the aorta in the first decade of life, in the coronary arteries in the second decade, and in the cerebral arteries in the third and fourth decades.Oxidized LDLs have a number of deleterious effects, including stimulation of release of cytokines and inhibition of NO production. Vascular smooth muscle cells in the vicinity of foam cells are stimulated and move from the media to the intima, where they proliferate, lay down collagen and other matrix molecules, and contribute to the bulk of the lesion. Smooth muscle cells also take up oxidized LDL and become foam cells. Lipids accumulate both intracellularly and extracellularly. As the atherosclerotic lesions age, T cells of the immune system as well as macrophages are attracted to them. The plaques contains a variety of cell-damaging substances, including ozone. Growth factors and cytokines involved in cell migration and proliferation are also produced by smooth muscle cells and endothelial cells, and there is evidence for shear stress response elements in the flanking DNA of relevant genes in the endothelial cells.As plaques mature, a fibrous cap forms 38

over them. The plaques with defective or broken caps are most prone to rupture. The lesions alone may distort vessels to the point that they are occluded, but it is usually rupture or ulceration of plaques that triggers thrombosis, blocking blood flow.Oxidized LDLs inhibit NO production. If acetylcholine is infused via catheter into normal coronary arteries, the vessels dilate; however, if it is infused when atherosclerosis is present, the vessels constrict. This indicates that endothelial secretion of NO is defective. Relation to Dietary Cholesterol & Other Lipids: Transforming a monocyte into a lipid-ingesting macrophage involves the appearance on its surface of a unique type of oxidized LDL receptor, the scavenger receptor, and monocytes are stimulated to produce these receptors by the action of macrophage colony-stimulating factor secreted by endothelial cells and vascular smooth muscle cells. When oxidized LDL-receptor complexes are formed, they are internalized and the receptors recycle to the membrane while the lipid is stored.Because lipids are relatively insoluble, they are transported as special lipoprotein particles that increase their solubility. Dietary cholesterol and triglycerides are packaged in the protein-coated chylomicrons in intestinal epithelial cells. Under the influence of lipoprotein lipase, these particles release triglycerides to fat depots and muscles, and the resulting chylomicron remnants are taken up by the liver. The liver also synthesizes cholesterol and packages it with specific proteins to form very-low-density lipoproteins (VLDLs). These lipoprotein particles enter the circulation and under the influence of lipoprotein lipase donate triglycerides to tissues. In this way, they become cholesterol-rich intermediate-density lipoproteins (IDLs) and low-density lipoproteins (LDLs). The LDL supply cholesterol to the tissues. They provide all cells with the cholesterol for production of cell membranes and other uses. They also provide most of the cholesterol that is the precursor for all steroid hormones. Oxidized LDLs are taken up by macrophages and smooth muscle cells in atherosclerotic lesions. On the other hand, high-density lipoproteins (HDLs) take cholesterol from peripheral cells and transport it to the liver where it is metabolized, keeping plasma and tissue cholesterol low. Clinical Manifestations: In general, atherosclerosis is asymptomatic until one of its complications develops. In coronary arteries, atherosclerotic narrowing that reduces the lumen of a coronary artery more than 75% causes angina pectoris, the chest pain that results when pain-producing substances accumulate in the myocardium. Typically, the pain comes on during exertion and disappears with rest, as the substances are washed out by the blood. When atherosclerotic lesions cause clotting and occlusion of a coronary artery, the myocardium supplied by the artery dies (myocardial infarction). In the cerebral circulation, arterial blockage at the site of atherosclerotic plaques causes thrombotic strokes. In the abdominal aorta, extensive atherosclerosis can lead to aneurysmal dilation and rupture of the vessel. In the renal vessels, localized constriction of one or both renal arteries causes renovascular hypertension. In the circulation to the legs, vascular insufficiency causes intermittent claudication (fatigue and usually pain on walking that is relieved by rest). If the circulation of a limb is severely compromised, the skin can ulcerate, producing lesions that are slow to heal. Frank gangrene of the extremities may also occur. Less frequently, clot formation and obstruction may occur in vessels supplying the intestines or other parts of the body. Risk Factors: The progression of atherosclerosis is accelerated by a wide variety of genetic and 39

environmental factors (risk factors).Estrogen increases cholesterol removal by the liver, and the progression of atherosclerosis is less rapid in premenopausal women that in men. On the other hand, large doses of estrogens increase the incidence of blood clots, and even small doses produce a slight increase in clotting.The effect of increased plasma levels of homocysteine and related molecules such as homocystine and homocysteine thiolactone are associated with accelerated atherosclerosis, and the magnitude of the plasma elevation is positively correlated with the severity of the atherosclerosis. Homocysteine is a significant source of H2O2 and other reactive forms of oxygen, and this may accelerate the oxidation of LDL.Homocysteine is an intermediate in the synthesis of methionine. It is metabolized by enzymes that are dependent on vitamin B6, vitamin B12, and folic acid. Supplementation of the diet with these vitamins reduces plasma homocysteine, usually to normal.Lowering plasma cholesterol and triglyceride levels and increasing plasma HDL levels slows, and in some cases reverses, the atherosclerotic process. When dietary treatment is not adequate, reducing conversion of mevalonate to cholesterol with statins, drugs that inhibit hepatic 3methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes this reaction, is beneficial. In cases in which there is severe hypercholesterolemia because of congenitally defective LDL receptors, gene therapy may be an option.The deleterious effects of smoking include endothelial damage caused by carbon monoxide-induced hypoxia.Because of the increased shear stress imposed on the endothelium by an elevated blood pressure, hypertension is another important modifiable risk factor for atherosclerosis. In diabetics, there are microvascular complications and macrovascular complications. The latter are primarily related to atherosclerosis. There is a twofold increase in the incidence of myocardial infarction compared with nondiabetics; severe circulatory deficiency in the legs with gangrene is relatively common; there are more thrombotic strokes; and renal failure is a serious problem.The nephrotic syndrome and hypothyroidism also accelerate the progression of atherosclerosis.

33. Disturbances in carbohydrates digestion, absorption and transport. Hyper- and hypoglycemia.
Abnormalities of carbohydrate metabolism are usually caused by enzymopathies or abnormal regulation. Galactosaemia Galactose is normally converted to glucose. However, a deficiency of the enzyme galactose-1phosphate uridyltransferase or, less commonly, uridine diphosphate galactase-4-epimerase, results in accumulation of galactose- 1-phosphate in the blood. The transferase deficiency, inherited as an autosomal recessive, is due in 70% of patients to a glutamine to arginine missense mutation in Q188R. Galactose ingestion (i.e. milk) leads to inanition, failure to thrive, vomiting, hepatomegaly and jaundice, diabetes, cataracts and developmental delay. A lactose-free diet stops the acute toxicity but poor growth and problems with speech and mental development still occur with the transferase deficiency. A newborn screening programme to detect galactosaemia is used in almost all countries. Prenatal diagnosis and diagnosis of the carrier state are possible by measurement of the level of galactose-1- phosphate in the blood. Galactokinase deficiency also results in galactosaemia and early cataract formation. Defects of fructose metabolism Absorbed fructose is chiefly metabolized in the liver to lactic acid or glucose. Three defects of

40

metabolism in the liver and intestine occur; all are inherited as autosomal recessivetraits: Fructosuria is due to fructokinase deficiency. It is a benign asymptomatic condition. Hereditary fructose intolerance is due to fructose-1- phosphate aldolase deficiency. Fructose-1phosphate accumulates after fructose ingestion, inhibiting both glycogenolysis and gluconeogenesis, resulting in symptoms of severe hypoglycaemia. Hepatomegaly and renal tubular defects occur but are reversible on a fructose- and sucrose-free diet. Intelligence is normal and there is an absence of dental caries. Hereditary fructose-1,6-diphosphatase deficiency leads to a failure of gluconeogenesis. Infants present with hypoglycaemia, ketosis and lactic acidosis. Dietary control can lead to normal growth. Glycogen storage diseases. Glucose is stored in muscles and liver as glycogen. Breakingit down provides glucose that is used locally or reaches other organs. If the breakdown of glycogen is blocked, glycogen overloading and hypoglycemia result. This is caused by enzyme deficiencies. All glycogen storage diseases shown below in the table.

Hyperglycemia or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than (200 mg/dl). Reference ranges for blood tests are 11.1 mmol/l, but symptoms may not start to become noticeable until even higher values such as 250300 mg/dl or 1520 mmol/l. A subject with a consistent range above 126 mg/dl or 7 mmol/l is generally held to have hyperglycemia. Chronic levels exceeding 7 mmol/l (125 mg/dl) can produce organ damage. It is critical for patients who monitor glucose levels at home to be aware of which units of measurement their testing kit uses. Glucose levels are measured in either:Milligrams per decilitre (mg/dl), in the United States and other countries (e.g., Japan, France, Egypt, Colombia); or Millimoles per litre (mmol/l), which can be acquired by dividing (mg/dl) by factor of 18.[1] Glucose levels vary before and after meals, and at various times of day; the definition of "normal" varies among medical professionals. In general, the normal range for most people (fasting adults) is about 80 to 110 mg/dl or 4 to 6 mmol/l. A subject with a consistent range above 126 mg/dl or 7 mmol/l is generally held to have hyperglycemia, whereas a consistent range below 70 mg/dl or 4 mmol/l is considered hypoglycemic. In fasting adults, blood plasma glucose should not exceed 126 mg/dL. Sustained higher levels of blood sugar cause damage to the blood vessels and to the organs they supply, leading to the complications of diabetes. Chronic hyperglycemia can be measured via the HbA1c test. The definition of acute hyperglycemia varies by study, with mmol/l levels from 8 to 15. Temporary hyperglycemia is often benign and asymptomatic. Blood glucose levels can rise well above normal for significant periods without producing any permanent effects or symptoms. However, chronic hyperglycemia at levels more than slightly above normal can produce a very wide variety of serious complications over a period of years, including kidney damage, neurological damage, cardiovascular damage, damage to the retina or damage to feet and legs. Diabetic neuropathy may be a result of long-term hyperglycemia. In diabetes mellitus (by far the most common cause of chronic hyperglycemia), treatment aims at maintaining blood glucose at a level as close to normal as possible, in order to avoid these serious long-term complications.

41

Acute hyperglycemia involving glucose levels that are extremely high is a medical emergency and can rapidly produce serious complications (such as fluid loss through osmotic diuresis). It is most often seen in persons who have uncontrolled insulin-dependent diabetes. The following symptoms may be associated with acute or chronic hyperglycemia, with the first three composing the classic hyperglycemic triad: Polyphagia - frequent hunger, especially pronounced hunger Polydipsia - frequent thirst, especially excessive thirst Polyuria - frequent urination Blurred vision Fatigue (sleepiness). Weight loss Poor wound healing (cuts, scrapes, etc.) Dry mouth Seizures Frequent hunger without other symptoms can also indicate that blood sugar levels are too low. This may occur when people who have diabetes take too much oral hypoglycemic medication or insulin for the amount of food they eat. The resulting drop in blood sugar level to below the normal range prompts a hunger response. This hunger is not usually as pronounced as in Type I diabetes, especially the juvenile onset form, but it makes the prescription of oral hypoglycemic medication difficult to manage. Polydipsia and polyuria occur when blood glucose levels rise high enough to result in excretion of excess glucose via the kidneys (glycosuria), producing osmotic diuresis. Causes The following conditions can also cause hyperglycemia in the absence of diabetes. 1) Dysfunction of the thyroid, adrenal, and pituitary glands 2) Numerous diseases of the pancreas 3) Severe increases in blood glucose may be seen in sepsis and certain infections 4) Intracranial diseases (frequently overlooked) can also cause hyperglycemia. Encephalitis, brain tumors (especially those located near the pituitary gland), brain bleeds, and meningitis are prime examples. 5) Mid to high blood sugar levels are often seen in convulsions and terminal stages of many diseases. Prolonged, major surgeries can temporarily increase glucose levels. Certain forms of severe stress and Physical trauma can increase levels for a brief time as well yet rarely exceeds 120 mg/dl. Hypoglycemia ( <2.8mmol/L) Causes Glucose underproduction (hormone deficiency) Enzyme abnormalities Damage to the liver Drugs or chemicals (salicylates, alcohol) ncreased insulin activity If the amount of glucose supplied by the blood falls, the brain is one of the first organs affected. In most people, subtle reduction of mental efficiency can be observed when the glucose falls below 65 mg/dl (3.6 mM). Impairment of action and judgment usually becomes obvious below 40 mg/dl (2.2 42

mM). Seizures may occur as the glucose falls further. As blood glucose levels fall below 10 mg/dl (0.55 mM), most neurons become electrically silent and nonfunctional, resulting in coma. These brain effects are collectively referred to as neuroglycopenia.The importance of an adequate supply of glucose to the brain is apparent from the number of nervous, hormonal and metabolic responses to a falling glucose level. Most of these are defensive or adaptive, tending to raise the blood sugar via glycogenolysis and gluconeogenesis or provide alternative fuels. If the blood sugar level falls too low the liver converts a storage of glycogen into glucose and releases it into the bloodstream, to prevent the person going into a diabetic coma, for a short period of time. Brief or mild hypoglycemia produces no lasting effects on the brain, though it can temporarily alter brain responses to additional hypoglycemia. Prolonged, severe hypoglycemia can produce lasting damage of a wide range. This can include impairment of cognitive function, motor control, or even consciousness. The likelihood of permanent brain damage from any given instance of severe hypoglycemia is difficult to estimate, and depends on a multitude of factors such as age, recent blood and brain glucose experience, concurrent problems such as hypoxia, and availability of alternative fuels. It has been frequently found that those Type 1 diabetics found "dead in bed" in the morning after suspected severe hypoglycemia had some underlying coronary pathology that led to an induced fatal heart attack. Recently, several of these individuals found "dead in bed" were wearing Continuous Glucose Monitors, which provided a history of glucose levels prior to the fatal event.

34)DISTURBANCES IN PROTEIN DIGESTION AND ABSORPTION:

Protein intolerance occurs when your body is unable to digest certain proteins found in that food, according to the American College of Gastroenterology. For example, if you're intolerant to milk proteins, your body lacks the appropriate enzymes needed to break down the proteins. Proteins are too complex for the body to absorb them. They require enzymes to break them down into a more simple form that the body can absorb. If you cannot digest certain proteins, inflammation and swelling will occur in your intestines. This can lead to gas, diarrhea, stomach pain, cramping, bloating and nausea.Most food allergies are the result of an immune system malfunction from the proteins found in the food. The immune system mistakes the proteins in the food as a dangerous substance when they are actually safe. This mistake triggers the immune system to create immunoglobulin E antibodies that attempt to fight off the proteins, according to the Mayo Clinic. The creation of IgE antibodies causes cells in your soft tissue to produce histamine. Histamine released in your intestines leads to inflammation. The digestive tract is one of the most common parts of the body affected by a food allergy. Absorption disorders, also sometimes called malabsorption syndromes, are characterized by problems digesting or absorbing substances (called nutrients) in the diet. Nutrients include vitamins, minerals, carbohydrates (e.g., sugars, starches), fats, and proteins. The term, "absorption disorder," does not refer to a specific diseasein most cases, the disorders are related to another medical condition.Digestion, which occurs in the gastrointestinal (GI) tract or digestive system, is the process of breaking down food into a form that can be absorbed into the bloodstream and used by the body. The digestive tract consists of the following organs: Mouth Esophagus (muscular tube that carries food to the stomach) 43

Stomach Small intestine (small bowel) Large intestine (large bowel or colon) Biliary system (i.e., liver, pancreas, gallbladder, bile ducts) During digestion, most nutrients in food are absorbed in the small intestine. The lining of the small intestine (called the mucosa) contains folds, creases, and finger-like projections (called villi and microvilli) that increase the surface area of the intestinal lining, providing a larger surface with which to absorb nutrients. The mucosa also contains special cells that increase the absorption of nutrients. Types of Absorption Disorders There are a number of different types of absorption disorders, most of which result in a decreased ability to absorb nutrients (i.e., malabsorption). Disorders that increase the absorption of certain nutrients include hemochromatosis (increased iron absorption; also called iron overload disease) and Wilson's disease (increased copper absorption).Common absorption disorders include celiac disease (caused by intolerance to gluten, a protein in wheat, barley, and rye) and lactose intolerance. Lactose intolerance is an inability to break down a sugar in dairy products (lactose). It is caused by a lack of a certain enzyme (called lactase) that helps convert lactose into a form that can be used by the body (i.e., dextrose and galactose). Lactose intolerance also is called primary or secondary lactase deficiency. Primary lactase deficiency is a common condition that develops over time as the body produces less lactase. This process begins around 2 years of age, but symptoms usually develop much later in life. Secondary lactase deficiency occurs when damage to the small intestine reduces the production of lactase. Conditions that can cause secondary lactase deficiency include celiac disease and inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis). Other types of absorption disorders include tropical sprue and Whipple's disease. Tropical sprue is more common in tropical and subtropical areas of the world, including the Caribbean and Southeast Asia. The exact cause for the condition is unknown, but it may be related to an infection that damages the lining of the small intestine. Symptoms include anemia, diarrhea, weight loss, and malnutrition. Tropical sprue is treated with antibiotics.

35. Disturbances in intermediary protein metabolism and amino acid catabolism.

Hyperphenylalaninemia is broadly defined as the presence of blood phenylalanine levels that exceed the limits of the upper reference range (2 mg/dL or 120 mmol/L) but trail the levels found in patients with phenylketonuria (PKU). Phenylalanine levels that exceed 20 mg/dL (1200 mmol/L) are considered diagnostic for PKU. Pathophysiology Hyperphenylalaninemia is caused by defects in the gene that encodes the enzyme phenylalanine hydroxylase, impairing the conversion of phenylalanine to tyrosine. Defects in the same gene also result in classic PKU. Broad genotype/phenotype correlations have been made (ie, mild or hyperphenylalaninemia alleles vs severe or PKU alleles), although phenylalanine tolerance may vary in unrelated individuals with identical mutations. A small percentage of individuals with elevated phenylalanine levels have normal phenylalanine hydroxylase activity but lack tetrahydrobiopterin, a crucial cofactor. Phenylalanine hydroxylase (also called phenylalanine- 4-monooxygenaseis) one of a general class of

44

enzymes called mixed-function oxidase, all of which catalyze simultaneous hydroxylation of a substrate by an oxygen atom of O2 and reduction of the other oxygen atom to H2O. Phenylalanine hydroxylase requires the cofactor tetrahydrobiopter in which carries electrons from NADPH to 02 and becomes oxidized to dihydrobiopterinin the process.The accumulation of phenylalanine or its metabolites in early life impairs normal development of the brain, causing severe mental retardation. This may be caused by excess phenylalanine competing with other amino acids for transport across the blood-brain barrier, resulting in a deficit of required metabolites. Alkaptonuria The defect lies in the catabolic pathway of tyrosine, which contains a parahydroxylated ring structure. In a poorly understood complex reaction, the enzyme phenylpyruvic acid oxidase is thought simultaneously to move the pyruvic acid side chain, to decarboxylate it, and to add an additional hydroxyl group to the ring. The product, homogentisic acid, is actually ortho-metadihydroxyphenylacetic acid. A deficiency of the hepatic enzyme homogentisate 1,2-dioxygenase (HGO) forces the accumulation of homogentisic acid, which is rapidly cleared in the kidney and excreted. Upon contact with air, homogentisic acid is oxidized to form a pigmentlike polymeric material responsible for the black color of standing urine. Although homogentisic acid blood levels are kept very low through rapid kidney clearance, over time homogentisic acid is deposited in cartilage throughout the body and is converted to the pigmentlike polymer through an enzymemediated reaction that occurs chiefly in collagenous tissues. As the polymer accumulates within cartilage, a process that takes many years, the normally transparent tissues become slate blue, an effect ordinarily not seen until adulthood. The earliest sign of the disorder is the tendency for diapers to stain black. Throughout childhood and most of early adulthood, an asymptomatic, slowly progressive deposition of pigmentlike polymer material into collagenous tissues occurs. In the fourth decade of life, external signs of pigment deposition, called ochronosis, begin to appear. Upon microscopic examination, amber-colored, oval-shaped structures are detected in the mid-to-upper dermal tissues (hematoxylin and eosin, original magnification X40). The slate blue, gray, or black discoloration of sclerae and ear cartilage is indicative of widespread staining of the body tissues, particularly cartilage. The hips, knees, and intervertebral joints are affected most commonly and show clinical symptoms resembling rheumatoid arthritis. Because of calcifications that occur in these sites, however, the radiologic picture is more consistent with osteoarthritis. Despite many speculations that this polymer deposition is associated with cardiac pathology, no reports of mortality directly related to the homozygous state for alkaptonuria exist. Reports exist of calcification and stenosis of the aortic annulus leading to coronary artery disease, and the risk of myocardial infarction is higher than normal in older patients with ochronosis. Molecular analysis of the HGO gene shows a wide spectrum of mutation. Although no correlation has so far been made between the molecular nature of the HGO mutation and its clinical phenotype, the wide variability of mutational phenomena could certainly help explain the clinical variability in this disease. Approximately 70 separate mutations have thus far been reported.

36)DISTURBANCES IN THE FINAL STEP PROTEIN METABOLISM:

Metabolic disorders, or inborn errors of metabolism, are inherited genetic diseases in which a baby is unable to metabolize a specific nutrient. Without appropriate dietary management, the 45

unmetabolized nutrient and metabolic by-products will accumulate in the body, and may result in adverse effects that inhibit normal growth and development. However, many infants who start treatment early in life can grow and develop normally. Mead Johnson Nutrition is a pioneer in the field of specialized nutrition for metabolic disorders and has been a leader in the development of science-based metabolic products for more than 50 years. Protein Metabolism Disorders Protein is a key constituent of most foods we eat, including meat, beans, milk products and grains. Infants with protein metabolism disorders cannot drink human milk because it also contains proteins and amino acids that cannot be metabolized. Infants with protein metabolism disorders are unable to metabolize certain amino acids and require specialized formulas without the offending amino acid, allowing the baby to receive essential nutrients for growth. Examples of protein metabolism disorders include: Phenylketonuria (PKU) Maple Syrup Urine Disease (MSUD) Tyrosinemia Homocystinuria A Closer Look at Phenylketonuria (PKU) Phenylketonuria, often referred to as PKU, is one of the most common protein metabolism disorders. Normally, the human body metabolizes the essential amino acid phenylalanine into tyrosine. Infants with PKU do not have the enzyme needed to make this conversion. Consequently, their bodies have excess amounts of phenylalanine and low tyrosine levels. The following symptoms may result from untreated PKU: Lethargy Light pigment Eczema Intellectual disability Seizures Hyperactivity Dietary management is critical for individuals with PKU to assure normal growth and development, as well as to support normal neurocognitive function. Fortunately, PKU can be diagnosed early in life through genetic disorders screenings, which are mandatory in many countries. Once diagnosed, the dietary management of PKU can start right away. PKU management involves a highly restrictive diet that minimizes the amount of phenylalanine consumed and regular monitoring by healthcare professionals experienced in the dietary management of metabolic diseases. For infants with PKU, special phenylalanine-free formulas act as their primary source of protein. Regular clinic visits allow monitoring phenylalanine in the blood and the growth of the infant to ensure that the dietary management is successful.

37. Disturbances in purine metabolism. Gout

Gout develops in the setting of excessive stores of uric acid in the form of monosodium urate. Uric acid is an end-stage by-product of purine metabolism. Humans remove uric acid primarily by renal excretion. When excretion is insufficient to maintain serum urate levels below the saturation level of 46

6.8 mg/dL (with some variability depending on temperature and pH), hyperuricemia may develop, and urate can crystallize and deposit in soft tissues. Purine metabolism Ninety percent of patients with gout develop excess urate stores due to an inability to excrete sufficient amounts of normally produced uric acid in the urine (underexcretion). The remaining patients either overconsume purines or produce excessive amounts of uric acid endogenously (overproduction). In rare cases, overproduction of uric acid is primary, due to a genetic disorder. These disorders include hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome), glucose-6-phosphatase deficiency (von Gierke disease), fructose 1-phosphate aldolase deficiency, and PP-ribose-P synthetase variants. It has been suggested that a link exists between several autosomal dominant disorders and the development of gout. However, there has not been a specific genetic marker for those predisposed to developing gout. Overproduction of uric acid may also occur in disorders that cause high cell turnover with release of purines, which are present in high concentration in cell nuclei. These disorders include myeloproliferative and lymphoproliferative disorders, psoriasis, hemolytic anemias, pernicious anemia, and ineffective erythropoiesis (as in B-12 deficiency). Cell lysis from chemotherapy for malignancies, especially those of the hematopoietic or lymphatic systems, can raise uric acid levels, as can excessive exercise and obesity. Common causes of secondary gout due to underexcretion of uric acid include renal insufficiency, lead nephropathy (saturnine gout), starvation or dehydration, hypothyroidism, hyperparathyroidism, drugs, and chronic ethanol (especially beer and hard liquor) abuse. These disorders should be identified and corrected, if possible. Comorbidities, including hypertension, diabetes, renal insufficiency, hypertriglyceridemia, hypercholesterolemia, diabetes, obesity, and early menopause, are associated with a higher incidence of gout. Foods that are rich in purines include anchovies, sardines, sweetbread, kidney, liver, and meat extracts. Consumption of fructose-rich foods and beverages (eg, those sweetened with high-fructose corn syrup) are associated with an increased risk of gout in both men and women. Pathophysiology Gout can be considered a disorder of metabolism that allows uric acid/urate to accumulate in blood and tissues. When tissues become supersaturated, the urate salts precipitate, forming crystals. In addition, the crystals also are less soluble under acid conditions, so any condition predisposing to acidosis also precipitates urate crystals. Urate initially precipitates in the form of needlelike crystals. Many conditions and drugs have been associated with an increase in plasma (and subsequent synovial) urate levels. A genetic predisposition for the disease exists. The CPP crystals that produce pseudogout are produced by nucleoside triphosphate pyrophosphohydrolase (NTPPPH), a catalytic enzyme found in vesicles that develop within osteoarthritic cartilage. A genetic predisposition exists for the condition, but any process that leads to osteoarthritis also can be associated with subsequent pseudogout. Although the presence of urate crystals in the soft tissues and synovial tissues is a prerequisite for a gouty attack, the fact that these crystals can also be found in synovial fluid in the absence of joint inflammation suggests that the mere presence of intrasynovial urate crystals is not sufficient to cause flares of gouty arthritis. One explanation for this may lie in the observation that clumps or microtophi of highly negatively charged and reactive urate crystals are normally coated with serum proteins (apolipoprotein [apo] E or apo B) that physically inhibit the binding of the crystals to cell receptors. A gout attack may be 47

triggered by either a release of uncoated crystals (eg, due to partial dissolution of a microtophus caused by changing serum urate levels) or precipitation of crystals in a supersaturated microenvironment (eg, release of urate due to cellular damage). From either source, naked urate crystals are then believed to interact with intracellular and surface receptors of local dendritic cells and macrophages, serving as a danger signal to activate the innate immune system.This interaction may be enhanced by immunoglobulin G (IgG) binding.Triggering of these receptors, including Toll-like receptors, NALP3 inflammasomes, and the triggering receptors expressed on myeloid cells (TREMs) by MSU, results in the production of interleukin (IL)1, which in turn initiates the production of a cascade of pro-inflammatory cytokines, including IL-6, IL-8, neutrophil chemotactic factors, and tumor necrosis factor (TNF)alpha.[16, 17] Neutrophil phagocytosis leads to another burst of inflammatory mediator production. Subsidence of an acute gout attack is due to multiple mechanisms, including the clearance of damaged neutrophils, recoating of urate crystals, and the production of anti-inflammatory cytokines including, IL-1RA, IL10, and transforming growth factor (TGF)beta.

38. Disturbances in water-electrolyte balance

The movement of body fluids between the ICF and ECF compartments occurs at the cell membrane and depends on regulation of ECF water and sodium. Water provides approximately 90% to 93% of the volume of body fluids and sodium salts approximately 90% to 95% of extracellular solutes. Normally, equivalent changes in sodium and water are such that the volume and osmolality of ECF are maintained within a normal range. Because it is the concentration of sodium (in milligrams per liter) that controls ECF osmolality, changes in sodium are usually accompanied by proportionate changes in water volume. Protection of the circulatory volume can be viewed as the single most important characteristic of body fluid homeostasis. In situations in which multiple physiologic variables are threatened simultaneously, the homeostatic response protects the vascular volume even at the expense of aggravating another electrolyte disorder. Two mechanisms protect the ECF (and vascular fluid) volume: (1) alterations in hemodynamic variables such as vasoconstriction and an increase in heart rate, and (2) alterations in sodium and water balance. Tachycardia, peripheral arterial vasoconstriction, and venoconstriction occur within minutes of external fluid losses, whereas salt and water retention take hours to become effective. Alterations of sodium and water balance can be divided into two main categories: (1) isotonic contraction or expansion of ECF volume, and (2) hypotonic dilution (dilutional hyponatremia) or hypertonic concentration (hypernatremia) of extracellular sodium brought about by changes in extracellular water. Isotonic disorders usually are confined to the ECF compartment producing a contraction (fluid volume deficit) or expansion (fluid volume excess) of the interstitial and vascular fluids. Regulation of Water Balance: Total body water (TBW) varies with gender and weight. These differences can be explained by differences in body fat, which is essentially water free. In men, body 48

water approximates 60% of body weight during young adulthood and decreases to approximately 50% in old age; in young women, it is approximately 50%, and in elderly women, approximately 40%. Obesity produces further decreases in body water, sometimes reducing these levels to values as low as 30% to 40% of body weight in adults. Infants and young children have a greater water content than adults. In addition to having proportionately more body water than adults have, infants have relatively more water in their ECF compartment and a greater water turnover. Infants have more than half of their TBW in the ECF compartment, whereas adults have only approximately one third. Because ECF is more readily lost from the body, infants are more vulnerable to fluid deficit than are older children and adults. As an infant grows older, TBW decreases, and by the second year of life, the percentages and distribution of body water approach those of an adult. Gains and Losses: All healthy persons require approximately 100 mL of water per 100 calories metabolized for dissolving and eliminating metabolic wastes. The metabolic rate increases with fever. Fever also increases the respiratory rate, resulting in additional loss of water vapor through the lungs. The main source of water gain is through oral intake and metabolism of nutrients. Water, including that obtained from liquids and solid foods, is absorbed from the gastrointestinal tract. Metabolic processes also generate a small amount of water. The amount of water gained from these processes varies from 150 to 300 mL/day, depending on metabolic rate.Normally, the largest loss of water occurs through the kidneys, with lesser amounts being lost through the skin, lungs, and gastrointestinal tract. Even when oral or parenteral fluids are withheld, the kidneys continue to produce urine as a means of ridding the body of metabolic wastes. The urine output that is required to eliminate these wastes is called the obligatory urine output. The obligatory urine loss is approximately 300 to 500 mL/day. Water losses that occur through the skin and lungs are referred to as insensible water losses because they occur without a persons awareness. Mechanisms of Regulation: There are two main physiologic mechanisms that assist in regulating body water: thirst and antidiuretic hormone (ADH). Thirst is primarily a regulator of water intake and ADH a regulator of water output. - Thirst: Thirst and drinking behavior are two separate entities. Thirst is a conscious sensation of the need to obtain and drink fluids high in water content. Thirst is basically an emergency response. Thirst is controlled by the thirst center in the hypothalamus. There are two stimuli for true thirst based on water need: (1) cellular dehydration caused by an increase in extracellular osmolality, and (2) a decrease in blood volume, which may or may not be associated with a decrease in serum osmolality. Sensory neurons, called osmoreceptors, which are located in or near the thirst center in the hypothalamus, respond to changes in extracellular osmolality by swelling or shrinking. Stretch receptors in the vascular system that are sensitive to changes in arterial blood pressure (highpressure baroreceptors located in the carotid sinus and aorta) and central blood volume (lowpressure baroreceptors located in the left atrium and major thoracic veins) also aid in the regulation of thirst. Thirst is one of the earliest symptoms of hemorrhage and is often present before other signs of blood loss appear. Dryness of the mouth produces a sensation of thirst that is not necessarily associated with the bodys hydration status. Thirst sensation also occurs in those who breathe through their mouths, such as smokers and persons with chronic respiratory disease or

49

hyperventilation syndrome. A third important stimulus for thirst is angiotensin II, which becomes increased in response to low blood volume and low blood pressure. The renin-angiotensin mechanism contributes to nonosmotic thirst. This system is considered a backup system for thirst should other systems fail. Elevated levels of angiotensin II may lead to thirst in conditions, such as chronic renal failure and congestive heart failure, in which renin levels may be elevated. Thirst and elevated renin levels are also found in persons with primary hyperaldosteronism and in those with secondary hyperaldosteronism accompanying anorexia nervosa, hemorrhage, and sodium depletion. - Adipsia and Hypodipsia: Adipsia represents an absence, and hypodipsia a decrease, in the ability to sense thirst. The inability to perceive and respond to thirst is compounded in elderly persons who have had a stroke and may be further influenced by confusion and sensory disturbances. - Polydipsia: Polydipsia, or excessive thirst, is normal when it accompanies conditions of water deficit. Increased thirst and drinking behavior can be classified into three categories: symptomatic or true thirst, inappropriate or false thirst that occurs despite normal levels of body water and serum osmolality, and compulsive water drinking. Symptomatic thirst develops when there is a loss of body water and resolves after the loss has been replaced. Among the most common causes of symptomatic thirst are water losses associated with diarrhea, vomiting, diabetes mellitus, and diabetes insipidus. Inappropriate or excessive thirst may persist despite adequate hydration. It is a common complaint in persons with renal failure and congestive heart failure. It may result from increased angiotensin levels. Thirst is also a common complaint in persons with dry mouth caused by decreased salivary function or treatment with drugs with an anticholinergic action (e.g., antihistamines, atropine) that lead to decreased salivary flow. Psychogenic polydipsia involves compulsive water drinking and is usually seen in persons with psychiatric disorders, most commonly schizophrenia. Persons with the disorder drink large amounts of water and excrete large amounts of urine. The compulsive water drinking may share the same pathology as the psychosis because persons with the disorder often increase their water drinking during periods of exacerbation of their psychotic symptoms. The condition may be compounded by antipsychotic medications that increase ADH levels and interfere with water excretion by the kidneys.Cigarette smoking, which is common among persons with psychiatric disorders, also stimulates ADH secretion. Excessive water ingestion coupled with impaired water excretion (or rapid ingestion at a rate that exceeds renal excretion) in persons with psychogenic polydipsia can lead to water intoxication. - Antidiuretic Hormone: The reabsorption of water by the kidneys is regulated by ADH, also known as vasopressin. ADH is synthesized by cells in the supraoptic and paraventricular nuclei of the hypothalamus. ADH from neurons in the supraoptic and paraventricular nuclei is transported along a neural pathway (i.e., hypothalamohypophysial tract) to the neurohypophysis (i.e., posterior pituitary) and then stored for future release. ADH exerts its effects through two types of vasopressin (V) receptorsV1 and V2 receptors. V1 receptors, which are located in vascular smooth muscle, cause vasoconstriction hence the name vasopressin. Although ADH can increase blood pressure through V1 receptors, this response occurs only when ADH levels are very high. The V2 receptors, which are located on the tubular cells of the cortical collecting duct, control water reabsorption by the kidney.

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Binding of ADH to the V2 receptors increases water reabsorption by increasing the permeability of the collecting duct to water (i.e., the antidiuretic effect). In the absence of ADH, the permeability of the collecting duct to water is very low, and reabsorption of water decreases, leading to polyuria. ADH stimulates V2 receptors (and through cyclic AMP) results in the movement of water channels known as aquaporins. Aquaporin-2 water channels move from the cytoplasm of cells in the collecting duct to the luminal surface of these cells. The aquaporin-2 channels then allow free movement of water from the tubular lumen into the cell along a concentration gradient. At the basolateral membrane, water exits the cell through aquaporin-3 and -4 water channels. The basolateral water channels are continually being synthesized and always present. However, in the absence of ADH, the aquaporin-2 channels readily move out of the apical membrane so that water is no longer transferred out of the collecting duct. The synthesis of aquaporin-2, as well as the movement in and out of the collecting duct membrane, is regulated by ADH stimulation.ADH levels are controlled by extracellular volume and osmolality. Osmoreceptors in the hypothalamus sense changes in extracellular osmolality and stimulate the production and release of ADH. Acute conditions produce greater changes in ADH levels than do chronic conditions; long-term changes in blood volume or blood pressure may exist without affecting ADH levels.The effect of changes in glucose concentration on ADH secretion depends on the presence or absence of insulin. In nondiabetic persons, insulin facilitates glucose entry into the osmoreceptors, rendering it an ineffective osmole. In contrast, glucose stimulates ADH secretion in persons with diabetes, presumably because insulin is required for glucose uptake by the osmoreceptors. Responsiveness to osmolality changes with age, with older persons being more responsive to changes in serum osmolality. Osmoregulation is also altered in normal pregnancy and the menstrual cycle.The abnormal synthesis and release of ADH occurs in a number of stress situations. Severe pain, nausea, trauma, surgery, certain anesthetic agents, and some analgesic drugs increase ADH levels. Among the drugs that affect ADH are nicotine, which stimulates its release, and alcohol, which inhibits it. Alterations in Isotonic Fluid Volume Isotonic fluid volume disorders represent an expansion or contraction of the ECF brought about by proportionate changes in both sodium and water. - Isotonic Fluid Volume Deficit: Characterized by a decrease in the ECF, including the circulating blood volume. Unless other fluid and electrolyte imbalances are present, the concentration of plasma electrolytes remains essentially unchanged. When the effective circulating blood volume is compromised, the condition is often referred to as hypovolemia. Causes: Isotonic fluid volume deficit results when water and electrolytes are lost in isotonic proportions. It is almost always caused by a loss of body fluids and is often accompanied by a decrease in fluid intake. It can occur because of a loss of gastrointestinal fluids, polyuria, or sweating due to fever and exercise. Fluid intake may be reduced because of a lack of access to fluids, impaired thirst, unconsciousness, oral trauma, impaired swallowing, or neuromuscular problems that prevent fluid access In a single day, 8 to 10 L of ECF is secreted into the gastrointestinal tract. Most of it is reabsorbed in the ileum and proximal colon, and only approximately 150 to 200 mL/ day is eliminated in the feces. Vomiting and diarrhea interrupt the reabsorption process and, in some situations, lead to increased secretion of fluid into the intestinal tract.Excess sodium and water losses also can occur through the kidney. Certain forms of kidney disease are characterized by salt wasting due to impaired sodium 51

reabsorption. Fluid volume deficit also can result from osmotic diuresis or injudicious use of diuretic therapy. Glucose in the urine filtrate prevents reabsorption of water by the renal tubules, causing a loss of sodium and water. In Addison disease, a condition of chronic adrenocortical insufficiency, there is unregulated loss of sodium in the urine with a resultant loss of ECF. This is accompanied by increased potassium retention.The skin acts as an exchange surface for heat and as a vapor barrier to prevent water from leaving the body. Body surface losses of sodium and water increase when there is excessive sweating or when large areas of skin have been damaged. Hot weather and fever increase sweating. The respiratory rate and sweating usually are in creased as body temperature rises. Burns are another cause of excess fluid loss. Third-space losses cause sequestering of ECF in the serous cavities, extracellular spaces in injured tissues, or lumen of the gut. Because the fluid remains in the body, fluid volume deficit caused by third spacing does not usually cause weight loss. Manifestations: The manifestations of fluid volume deficit reflect a decrease in ECF volume. They include thirst, loss of body weight, signs of water conservation by the kidney, impaired temperature regulation, and signs of reduced interstitial and vascular volume. A loss in fluid volume is accompanied by a decrease in body weight. Because ECF is trapped in the body in persons with thirdspace losses, their body weight may not decrease.Thirst develops as the effective circulating volume decreases to a point sufficient to stimulate the thirst mechanism. Urine output decreases and urine osmolality and specific gravity increase as ADH levels rise because of a decrease in vascular volume. Although there is an isotonic loss of fluid from the vascular compartment, blood components such as red blood cells and BUN become more concentrated. The fluid content of body tissues decreases as fluid is removed from the interstitial spaces. The eyes assume a sunken appearance and feel softer than normal as the fluid content in the anterior chamber of the eye is decreased. Fluids add resiliency to the skin and underlying tissues that is referred to as skin or tissue turgor. Tissue turgor is assessed by pinching a fold of skin between the thumb and forefinger. The skin should immediately return to its original configuration when the fingers are released. A loss of body water causes the resiliency of the skin to be lost, and the tissue remains raised for several seconds. There may be a rise in body temperature that accompanies fluid volume deficit. Interstitial fluids insulate the body against changes in the external temperature, and vascular fluids transport heat from the inner core of the body to the periphery, where it can be released into the external environment. Arterial and venous volumes decline during periods of fluid deficit, as does filling of the capillary circulation. As the volume in the arterial system declines, the blood pressure decreases, heart rate increases, and the pulse becomes weak and thready. Postural hypotension is an early sign of fluid deficit, characterized by a blood pressure that is at least 10 mm Hg lower when the patient is sitting or standing than when the patient is lying down. When volume depletion becomes severe, signs of hypovolemic shock and vascular collapse appear. On the venous side of the circulation, the veins become less prominent, and venous refill time increases. Diagnosis and Treatment: Measurement of heart rate and blood pressure provides useful information about vascular volume. Treatment of fluid volume deficit consists of fluid replacement and measures to correct the underlying cause. Usually, isotonic electrolyte solutions are used for fluid replacement. Acute hypovolemia and hypovolemic shock can cause renal damage. - Isotonic Fluid Volume Excess: Fluid volume excess represents an isotonic expansion of the ECF compartment. It occurs secondary to an increase in total body sodium, which in turn leads to an increase in body water. Fluid volume excess involves an increase in interstitial and vascular volumes. 52

 Causes: Isotonic fluid volume excess almost always results from an increase in total body sodium that is accompanied by a proportionate increase in body water. It is most commonly caused by a decrease in sodium and water elimination by the kidney. Among the causes of decreased sodium and water elimination are disorders of renal function, heart failure, liver failure, and corticosteroid excess.Heart failure produces a decrease in renal blood flow and a compensatory increase in sodium and water retention. Even small increases in sodium intake can precipitate a state of fluid volume excess and a worsening of heart failure. A condition called circulatory overload results from an increase in intravascular blood volume; it can occur during infusion of intravenous fluids or transfusion of blood if the amount or rate of administration is excessive. Liver failure (e.g., cirrhosis of the liver) impairs aldosterone metabolism and alters renal perfusion, leading to increased salt and water retention.Cushings syndrome is a condition of glucocorticoid excess. Because cortisol has weak mineralocorticoid activity, Cushings syndrome predisposes to increased sodium retention. Manifestations: Isotonic fluid volume excess is manifested by an increase in interstitial and vascular fluids. It is characterized by weight gain over a short period of time. Edema is characteristic of isotonic fluid excess. When the fluid excess accumulates gradually, as often happens in debilitating diseases and starvation, edema fluid may mask the loss of tissue mass. The edema associated with ECF excess may be generalized, or it may be confined to dependent areas of the body, such as the legs and feet.The eyelids often are puffy when the person awakens. There may be a decrease in BUN and hematocrit as a result of dilution due to expansion of the plasma volume. An increase in vascular volume may be evidenced by distended neck veins, slow-emptying peripheral veins, a full and bounding pulse, and an increase in central venous pressure. When excess fluid accumulates in the lungs (i.e., pulmonary edema), there are complaints of shortness of breath and difficult breathing, respiratory crackles, and a productive cough. Ascites and pleural effusion may occur with severe fluid volume excess. Diagnosis and Treatment: The treatment of fluid volume excess focuses on providing a more favorable balance between sodium and water intake and output. A sodium-restricted diet is often prescribed as a means of decreasing extracellular sodium and water levels. Diuretic therapy is commonly used to increase sodium elimination. When there is a need for intravenous fluid administration or transfusion of blood components, the procedure requires careful monitoring to prevent fluid overload.

39)EDEMA
Edema is the medical term for excessive fluid accumulation within the interstitial space (between cells) or within the cavities of the body. This does not include fluid within the bladder or in the gastrointestinal tract (gut). Edema may be localized, affecting only one organ or area of the body or it can be generalized where it affects many areas or the whole body simultaneously. Edema Pathophysiology -Fluid in the body exists within cells (intracellular fluid), within the tissue space between cells (interstitial fluid), within the blood vessels (blood) or lymphatic vessels (lymph or lymphatic fluid). This fluid is not just water but there are also cells, nutrients, electrolytes and waste products existing with water in these areas. -Two forces are responsible for maintaining the fluid in specific areas or pulling and pushing fluid into other areas. These forces are known as hydrostatic pressure and osmotic pressure. Hydrostatic pressure is the force that pushes fluid from an area of high pressure to low pressure. Osmotic 53

pressure is the force that draws fluid from an area of low electrolyte concentration to one of a higher electrolyte concentration. Fluid within our blood vessels are at a higher pressure than the fluid in the tissue spaces. This is due to the pumping heart that pushes the blood with force within the vessels. Blood does not just ooze out of the vessels unless the vessel wall becomes permeable and allows it to exit. -Fluid within the tissue spaces also have a hydrostatic force but this is usually smaller than the pressure within the vessels so very little fluid flow from the tissues spaces into the vessel due to hydrostatic pressure. Usually fluid from the tissue spaces enters the blood vessel due to a difference in osmotic pressure. -Fluid is pushed away from an area of high hydrostatic pressure but is pulled into an area of high osmotic pressure. Therefore the blood vessels which have a higher hydrostatic and a higher osmotic pressure will push out some fluid into the tissue spaces and draw other fluids from the tissue spaces. This allows for the exchange of nutrients, gases and wastes. The lymphatic system also plays an essential part here as the interstitial fluid is pulled from the tissue spaces into the lymphatic vessels which then empties into the blood vessels. Causes of Edema Edema will occur under these circumstances : Increased hydrostatic pressure will push fluid out of the vessels into tissue spaces. This results in edema. Reduced osmotic pressure within the vessels will not pull fluid from the tissue spaces into the vessel. The fluid accumulates within the tissue space and results in edema. Fluid retention (water retention) where there is excessive fluid within the blood vessel and tissue spaces. If the body is not able to pass out this excess fluid, it will be retained within the tissue spaces thereby resulting in edema. Increased vascular permeability is when blood vessel wall allows fluid to pass out of the blood vessel unabated. Fluid from the tissue spaces are not drawn into the blood vessel fast enough and fluid remains in the tissue space thereby resulting in edema. .Lymphatic obstruction is where the lymph vessels are blocked at some point and the interstitial fluid cannot be drained from the tissue spaces. Fluid accumulates in the tissue space and the result is edema. Types of Edema There are two types of edema that can be identified upon examination. 1. Pitting edema is the swelling of a body part where an indentation will persist after pressure is applied to the area. This indentation will slowly disappear over time. 2. Non-pitting edema is where there is swelling of a body part with no indentation upon applying pressure.

40. Disturbances in mineral metabolism sodium, potassium, chlorides

Sodium Sodium is the most abundant cation in the body, averaging approximately 60 mEq/kg of body weight. Most of the bodys sodium is in the ECF compartment (135 to 145 mEq/L), with only a small amount 54

(10 to 14 mEq/L) located in the ICF compartment. The resting cell membrane is relatively impermeable to sodium. Sodium that enters the cell is transported out of the cell against an electrochemical gradient by the energy-dependent Na+/K+-ATPase membrane pump. Sodium functions mainly in regulating extracellular and vascular volume. As the major cation in the ECF compartment, Na+ and its attendant anions (Cl and HCO3) account for the osmotic activity in the ECF. Because sodium is part of the sodium bicarbonate molecule, it is important in regulating acid-base balance. As a current-carrying ion, Na+ contributes to the function of the nervous system and other excitable tissue. Gains and Losses: Sodium normally enters the body through the gastrointestinal tract and is eliminated by the kidneys or lost from the gastrointestinal tract or skin. Sodium intake normally is derived from dietary sources. Body needs for sodium usually can be met by as little as 500 mg/day. Other sources of sodium are intravenous saline infusions and medications that contain sodium. Most sodium losses occur through the kidney. When sodium intake is limited or conservation of sodium is needed, the kidneys are able to reabsorb almost all the sodium that has been filtered by the glomerulus. This results in an essentially sodium-free urine. Usually, less than 10% of sodium intake is lost through the gastrointestinal tract and skin. Sodium losses increase with conditions such as vomiting, diarrhea, fistula drainage, and gastrointestinal suction that remove sodium from the upper gastrointestinal tract. Mechanisms of Regulation: The kidney is the main regulator of sodium. The kidney monitors arterial pressure and retains sodium when arterial pressure is decreased and eliminates it when arterial pressure is increased. The rate at which the kidney excretes or conserves sodium is coordinated by the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS). Another possible regulator of sodium excretion by the kidney is atrial natriuretic peptide (ANP), which is released from cells in the atria of the heart. ANP, which is released in response to atrial stretch and overfilling, increases sodium excretion by the kidney. - The Sympathetic Nervous System: The sympathetic nervous system responds to changes in arterial pressure and blood volume by adjusting the glomerular filtration rate and thus the rate at which sodium is filtered from the blood. Sympathetic activity also regulates tubular reabsorption of sodium and renin release. - The Renin-Angiotensin-Aldosterone System: Renin is a small protein enzyme that is released by the kidney in response to changes in arterial pressure, the glomerular filtration rate, and the amount of sodium in the tubular fluid. Most of the renin that is released leaves the kidney and enters the bloodstream, where it interacts enzymatically to convert a circulating plasma protein called angiotensinogen to angiotensin I. Angiotensin I is rapidly converted to angiotensin II by the angiotensin-converting enzyme in the small blood vessels of the lung. Angiotensin II acts directly on the renal tubules to increase sodium reabsorption. It also acts to constrict renal blood vessels, thereby decreasing the glomerular filtration rate and slowing renal blood flow so that less sodium is filtered and more is reabsorbed. Angiotensin II is also a powerful regulator of aldosterone, a hormone secreted by the adrenal cortex. Aldosterone acts at the level of the cortical collecting tubules of the kidneys to increase sodium reabsorption while increasing potassium elimination.

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Alterations in Sodium Concentration Hyponatremia: Hyponatremia represents a decrease in plasma sodium concentration below 135 mEq/L (135 mmol/L). Unlike hypernatremia, which is always associated with hypertonicity, hyponatremia may be associated with high, normal, or low tonicity because of the effects of other osmotically active particles in the ECF such as glucose. Hypertonic (translocational) hyponatremia results from an osmotic shift of water from ICF to the ECF as occurs with hyperglycemia. In this case, the sodium in the ECF becomes diluted as water moves out of cells in response to the osmotic effects of the elevated blood glucose level. A normotonic hyponatremia, termed pseudohyponatremia, can be detected in plasma samples from persons with hyperlipidemia and hyperproteinemia because of laboratory methods. This disturbance is caused by laboratory methods that include excess lipids or proteins in the water volume of the sample, causing an artifactual dilution of sodium. Hypotonic (dilutional) is by far the most common form of hyponatremia. It is caused by water retention and characterized by a decrease in serum osmolality. Dilutional hyponatremia can present as a hypervolemic, euvolemic, or hypovolemic condition: - Hypervolemic hyponatremia involves an increase in ECF volume and is seen when hyponatremic conditions are accompanied by edema-forming disorders such as congestive heart failure, cirrhosis, and advanced kidney disease. - Euvolemic hyponatremia represents a retention of water with dilution of sodium while maintaining the ECF volume within a normal range. It is usually the result of inappropriate thirst or SIADH. Hypovolemic hyponatremia occurs when water is lost along with sodium, but to a lesser extent. It occurs with diuretic use, excessive sweating in hot weather, and vomiting and diarrhea. Causes: Hypotonic, or dilutional, hyponatremia represents a decreased sodium concentration and tonicity of the ECF. The most common causes of acute dilutional hyponatremia in adults are drug therapy (diuretics and drugs that increase ADH levels), inappropriate fluid replacement during heat exposure or following heavy exercise, SIADH, and polydipsia in persons with psychotic disorder.Among the causes of hypovolemic hyponatremia is the loss of salt and water from excessive sweating in hot weather, particularly during heavy exercise; hyponatremia develops when water rather than electrolyte-containing liquids is used to replace the fluids lost in sweating. Another potential cause of hypovolemic hyponatremia is the loss of sodium from the gastrointestinal tract due to repeated tap-water enemas or frequent gastrointestinal irrigations with distilled water. Gastrointestinal fluid loss and ingestion of excessively diluted formula are common causes of acute hyponatremia in infants and children.Hypovolemic hyponatremia is a common complication of adrenal insufficiency and is due to the effects of aldosterone and cortisol deficiency. A lack of aldosterone increases renal losses of sodium, and a cortisol deficiency leads to increased release of ADH with water retention.The risk for euvolemic hyponatremia is increased during the postoperative period. During this time, ADH levels are often high, producing an increase in water reabsorption by the kidney. The hyponatremia becomes exaggerated when electrolyte-free fluids (e.g., 5% glucose in water) are used for fluid replacement. Excessive water drinking during this period can also increase the risk for hyponatremia.

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Manifestations: The manifestations of hypotonic hyponatremia are largely related to sodium dilution. Serum osmolality is decreased, and cellular swelling occurs owing to the movement of water from the ECF to the ICF compartment. The signs and symptoms may be acute, as in severe water intoxication, or more insidious in onset and less severe, as in chronic hyponatremia. Because of water movement, hyponatremia causes ICF hypoosmolality. Fingerprint edema is a sign of excess intracellular water. Muscle cramps, weakness, and fatigue reflect the hypoosmolality of skeletal muscle cells and are often early signs of hyponatremia. These effects commonly are observed in persons with hyponatremia that occurs during heavy exercise in hot weather. Gastrointestinal manifestations such as nausea and vomiting, abdominal cramps, and diarrhea may develop. The brain and nervous system are the most seriously affected by increases in intracellular water. Symptoms include apathy, lethargy, and headache, which can progress to disorientation, confusion, gross motor weakness, and depression of deep tendon reflexes. Seizures and coma occur when plasma sodium levels reach extremely low levels. These severe effects, which are caused by brain swelling, may be irreversible. If the condition develops slowly, signs and symptoms do not develop until plasma sodium levels approach 125 mEq/L. Progressive neurologic symptoms occur when the plasma sodium falls below this level. The term water intoxication is often used to describe the neurologic effects of acute hypotonic hyponatremia. Diagnosis and Treatment: The treatment of hyponatremia with water excess focuses on the underlying cause. When hyponatremia is caused by water intoxication, limiting water intake or discontinuing medications that contribute to SIADH may be sufficient. The administration of a saline solution orally or intravenously may be needed when hyponatremia is caused by sodium deficiency. Symptomatic hyponatremia (i.e., neurologic manifestations) is often treated with hypertonic saline solution and a loop diuretic, such as furosemide, to increase water elimination. In the case of prolonged water intoxication, brain cells reduce their concentration of organic osmoles as a means of preventing an increase in cell volume. It takes several days for brain cells to restore the organic osmoles lost during hyponatremia. Rapid changes in serum osmolality when brain cells have already undergone volume regulation may cause a dramatic change in brain cell volume. One of the reported effects of rapid treatment of hyponatremia is an osmotic demyelinating condition called central pontine myelosis, which produces serious neurologic sequelae and sometimes causes death.

Hypernatremia: Hypernatremia implies a plasma sodium level above 145 mEq/L and a serum osmolality greater than 295 mOsm/kg. Because sodium is functionally an impermeable solute, it contributes to tonicity and induces movement of water across cell membranes. Hypernatremia is characterized by hypertonicity of ECF and almost always causes cellular dehydration. Causes: Hypernatremia represents a deficit of water in relation to the bodys sodium stores. It can be caused by net loss of water or sodium gain. Net water loss can occur through the urine, gastrointestinal tract, lungs, or skin. A defect in thirst or inability to obtain or drink water can interfere with water replacement. Rapid ingestion or infusion of sodium with insufficient time or opportunity for water ingestion can produce a disproportionate gain in sodium. 57

Hypernatremia almost always follows a loss of body fluids that have a lower than normal concentration of sodium, so that water is lost in excess of sodium. This can result from increased losses from the respiratory tract during fever or strenuous exercise, from watery diarrhea, or when osmotically active tube feedings are given with inadequate amounts of water. With pure water loss, each body fluid compartment loses an equal percentage of its volume. Because the two thirds of the water is in the intracellular compartment, more actual water volume is lost from the ICF than the ECF compartment. Normally, water deficit stimulates thirst and increases water intake. Therefore, hypernatremia is more likely to occur in infants and in persons who cannot express their thirst or obtain water to drink. With hypodipsia, or impaired thirst, the need for fluid intake does not activate the thirst response. Hypodipsia is particularly prevalent among the elderly population. The therapeutic administration of sodium containing solutions may also cause hypernatremia. Manifestations: The clinical manifestations of hypernatremia caused by water loss are largely those of ECF loss and cellular dehydration. The severity of signs and symptoms is greatest when the increase in plasma sodium is large and occurs rapidly. Because blood plasma is roughly 90% to 93% water, the concentrations of blood cells and other blood components increase as ECF water decreases.Thirst is an early symptom of water deficit, occurring when water losses are equal to 0.5% of body water. Urine output is decreased and urine osmolality increased because of renal waterconserving mechanisms. Body temperature frequently is elevated, and the skin becomes warm and flushed. The vascular volume decreases, the pulse becomes rapid and thready, and the blood pressure drops.Hypernatremia produces an increase in serum osmolality and results in water being pulled out of body cells. As a result, the skin and mucous membranes become dry, and salivation and lacrimation are decreased. The mouth becomes dry and sticky, and the tongue becomes rough and fissured. Swallowing is difficult. The subcutaneous tissues assume a firm, rubbery texture. Most significantly, water is pulled out of the cells in the CNS, causing decreased reflexes, agitation, headache, and restlessness. Coma and seizures may develop as hypernatremia progresses. Diagnosis and Treatment: The treatment of hypernatremia includes measures to treat the underlying cause of the disorder and fluid replacement therapy to treat the accompanying dehydration. Replacement fluids can be given orally or intravenously. Oral glucoseelectrolyte replacement solutions contains glucose (2.0 g/L), sodium (90 mEq/L), potassium (20 mEq/L), chloride (80 mEq/L), and bicarbonate (30 mEq/L)are available for the treatment of infants with diarrhea.One of the serious aspects of fluid volume deficit is dehydration of brain and nerve cells. Serum osmolality should be corrected slowly in cases of chronic hypernatremia. This is because brain cells synthesize osmotically active organic solutes to protect against volume changes. These organic solutes serve to produce a gradual increase in intracellular osmolality, allowing osmotic flow of water back into the cell and restoring cell volume. This response begins within 4 to 6 hours of increased serum osmolality and takes several days to become fully effective. Changes in brain water content are greatest during acute hypernatremia but only slightly reduced in chronic hypernatremia. If hypernatremia is corrected too rapidly before the organic osmoles have had a chance to dissipate, the plasma may become relatively hypotonic in relation to brain cell osmolality. When this occurs, water moves into the brain cells, causing cerebral edema and potentially severe neurologic impairment. Potassium

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Potassium is the major cation in the ICF compartment, with an intracellular concentration of 140 to 150 mEq/L.30 The potassium content of the ECF (3.5 to 5.0 mEq/L) is considerably less. Because potassium is an intracellular ion, total body stores of potassium are related to body size and muscle mass. Thus, potassium content declines with age, mainly as a result of a decrease in muscle mass. Gains and Losses: Potassium intake is normally derived from dietary sources. In healthy persons, potassium balance usually can be maintained by a daily dietary intake. Additional amounts of potassium are needed during periods of trauma and stress. The kidneys are the main source of potassium loss. Most of potassium losses occur in the urine, with the remainder being lost in stools or sweat. Mechanisms of Regulation: An increase in potassium of only 0.3 to 0.4 mEq/L can cause serious cardiac dysrhythmias and even death. Plasma potassium is largely regulated through two mechanisms: (1) renal mechanisms that conserve or eliminate potassium, and (2) a transcellular shift between the intracellular and extracellular compartments. Normally, it takes 6 to 8 hours to eliminate 50% of potassium intake. To avoid an increase in ECF potassium during this time, excess potassium is temporarily shifted in cells such as those of muscle, liver, red blood cells, and bone. - Renal Regulation: The regulation of potassium elimination is controlled by secretion from the blood into the tubular filtrate. Potassium is filtered in the glomerulus, reabsorbed along with sodium and water in the proximal tubule and with sodium and chloride in the thick ascending loop of Henle, and then secreted into the late distal and cortical collecting tubules for elimination in the urine. The effects of aldosterone on potassium elimination are mediated through a sodiumpotassium exchange system located in the late distal and cortical collecting tubules of the kidney. In the presence of aldosterone, sodium is transported back into the blood, and potassium is secreted in the tubular filtrate for elimination in the urine. The rate of aldosterone secretion by the adrenal gland is strongly controlled by plasma potassium levels. In the absence of aldosterone, as occurs in persons with Addison disease, renal elimination of potassium is impaired, causing plasma potassium levels to rise to dangerously high levels. There is also a potassiumhydrogen ion exchange mechanism in the cortical collecting tubules of the kidney. When plasma potassium levels are increased, potassium ions (K+) are secreted into the urine, and hydrogen ions (H+) are reabsorbed into the blood, producing a decrease in pH and metabolic acidosis. Conversely, when potassium levels are low, K+ ions are reabsorbed, and H+ ions are secreted in the urine, leading to metabolic alkalosis. - ExtracellularIntracellular Shifts: The transcellular shift of potassium between the ECF and ICF compartments allows potassium to move into body cells when plasma levels are high and move out when the plasma levels are low. This movement is controlled by the function of the Na+/K+-ATPase membrane pump and the permeability of ion channels in the cell membrane.

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Both insulin and -adrenergic catecholamines increase cellular uptake of potassium by increasing the activity of the Na+/K+-ATPase membrane pump. The plasma potassium concentration directly affects insulin release from beta cells in the pancreas. The catecholamines, particularly epinephrine, facilitate the movement of potassium into muscle tissue. The osmolality of the ECF also influences transcellular shifts in potassium. Acute increases in serum osmolality cause potassium to move out of cells. When serum osmolality increases because of the presence of impermeable extracellular solutes such as mannitol or glucose (without insulin), water leaves the cell. The loss of cell water produces an increase in ICF potassium concentration, causing potassium to diffuse out of the cell. The exchange of K+ and H+ ions between the ICF and ECF plays a significant role in regulating the ECF concentration of both ions. In acidosis, H+ ions move into the cell as a means of preventing large changes in ECF pH. As H+ ions move into the cell, other positively charged ions, such as K+, must move out as a means of maintaining electrical neutrality. Exercise also produces compartmental shifts in potassium. Repeated muscle contraction releases potassium into the ECF. Although the increase usually is small with modest exercise, it can be considerable during exhaustive exercise. Alterations in Potassium Balance: Potassium is involved in a wide range of body functions, including the maintenance of the osmotic integrity of cells, acid-base balance, and the kidneys ability to concentrate urine. Potassium is necessary for growth, and it contributes to the intricate chemical reactions that transform carbohydrates into energy, change glucose into glycogen, and convert amino acids to proteins. Potassium also plays a critical role in conducting nerve impulses and the excitability of skeletal, cardiac, and smooth muscle. It does this by regulating the resting membrane potential, the opening of the sodium channels that control the flow of current during the action potential, and the rate of membrane repolarization. Changes in nerve and muscle excitability are particularly important in the heart, where alterations in serum potassium can produce serious dysrhythmias and conduction defects. Changes in plasma potassium also affect skeletal muscles and the smooth muscle in blood vessels and the gastrointestinal tract. A decrease in serum potassium causes the resting membrane potential to become more negative (hyperpolarization), moving further from the threshold for excitation. An increase in serum potassium has the opposite effect; it causes the resting membrane potential to become more positive (hypopolarized), moving closer to threshold. With severe hyperkalemia, the resting membrane approaches the threshold potential, causing sustained subthreshold depolarization. This inactivates the sodium channels and produces a net decrease in excitability. Hypokalemia: Hypokalemia refers to a decrease in plasma potassium levels below 3.5 mEq/L (3.5 mmol/L). Causes: The causes of potassium deficit can be grouped into three categories: (1) inadequate intake; (2) excessive gastrointestinal, renal, and skin losses; and (3) redistribution between the ICF and ECF compartments. - Inadequate Intake: A potassium intake of at least 10 to 30 mEq/day is needed to compensate for obligatory urine losses. Potassium intake is often inadequate in persons on fad diets and those who have eating disorders. Elderly persons are particularly likely to have potassium deficits. - Excessive Losses: The kidneys are the main source of potassium loss. Most of potassium losses occur in the urine, with the remaining losses occurring in the stool and sweat. The kidneys do not have the homeostatic mechanisms needed to conserve potassium during periods of insufficient 60

intake. After trauma and in stress situations, urinary losses of potassium are greatly increased. Renal losses also can be increased by medications, metabolic alkalosis, magnesium depletion, and increased levels of aldosterone. Some antibiotics, particularly amphotericin B and gentamicin, are impermeable anions that require the presence of positively charged cations for elimination in the urine; this causes potassium wasting. Diuretic therapy, with the exception of potassium-sparing diuretics, is the most common cause of hypokalemia. Magnesium depletion causes renal potassium wasting. Magnesium deficiency often coexists with potassium depletion due to diuretic therapy or disease processes such as diarrhea. Renal losses of potassium are accentuated by aldosterone and cortisol. Increased potassium losses occur in situations such as trauma and surgery that produce a stress-related increase in these hormones.Although potassium losses from the skin and the gastrointestinal tract usually are minimal, these losses can become excessive under certain conditions. For example, burns increase surface losses of potassium. Losses due to sweating increase in persons who are acclimated to a hot climate, partly because increased secretion of aldosterone during heat acclimatization increases the loss of potassium in urine and sweat. Gastrointestinal losses also can become excessive; this occurs with vomiting and diarrhea and when gastrointestinal suction is being used. - Transcellular Shifts: Because of the high ratio of intracellular to extracellular potassium, a redistribution of potassium from the ECF to the ICF compartment can produce a marked decrease in the plasma concentration. One cause of potassium redistribution is insulin. After insulin administration, there is increased movement of glucose and potassium into cells. Manifestations: The manifestations of hypokalemia include alterations in renal, gastrointestinal, cardiovascular, and skeletal muscle function. The signs and symptoms are typically gradual in onset; therefore, the disorder may go undetected for some time.The renal processes that conserve potassium during hypokalemia interfere with the kidneys ability to concentrate urine. Urine output and plasma osmolality are increased, urine specific gravity is decreased, and complaints of polyuria, nocturia, and thirst are common. Metabolic alkalosis and renal chloride wasting are signs of severe hypokalemia. Gastrointestinal signs and symptoms include anorexia, nausea, and vomiting. Atony of the gastrointestinal smooth muscle can cause constipation, abdominal distention, and, in severe hypokalemia, paralytic ileus. When gastrointestinal symptoms occur gradually and are not severe, they often impair potassium intake and exaggerate the condition. The most serious effects of hypokalemia are those affecting cardiovascular function. Postural hypotension is common. There is an increased risk for ventricular dysrhythmias, particularly in persons with underlying heart disease. Most persons with plasma potassium levels below 3.0 mEq/L demonstrate electrocardiographic (ECG) changes typical of hypokalemia. These changes include prolongation of the PR interval, depression of the ST segment, flattening of the T wave, and appearance of a prominent U wave. Normally, potassium leaves the cell during the repolarization phase of the action potential, returning the membrane potential to its normal resting value. Hypokalemia produces a decrease in potassium efflux that prolongs the rate of repolarization and lengthens the relative refractory period. The U wave normally may be present on the ECG but should be of lower amplitude than the T wave. With hypokalemia, the amplitude of the T wave decreases as the U-wave amplitude increases. Although these ECG changes usually are not serious, they may predispose to sinus bradycardia and ectopic ventricular dysrhythmias. Complaints of weakness, fatigue, and muscle cramps, particularly during exercise, are common in 61

moderate hypokalemia (plasma potassium, 3.0 to 2.5 mEq/L). Muscle paralysis with life-threatening respiratory insufficiency can occur with severe hypokalemia (plasma potassium <2.5 mEq/L). Leg muscles, particularly the quadriceps, are most prominently affected. Some persons complain of muscle tenderness and paresthesias rather than weakness. In chronic potassium deficiency, muscle atrophy may contribute to muscle weakness. At least three defects in skeletal muscle function occur with potassium deficiency: alterations in the resting membrane potential, alterations in glycogen synthesis and storage, and impaired ability to increase blood flow during strenuous exercise. In hypokalemia, the resting membrane potential becomes more negative, resulting in a decrease in neuromuscular excitability. Normal concentrations of intracellular potassium are necessary for glycogen synthesis in muscle cells. Therefore, hypokalemia can interfere with muscle metabolism, especially under exercise conditions that rely heavily on anaerobic pathways that use glycogen as fuel. Potassium released from muscle normally contributes to the autoregulation of blood flow during exercise.Thus, potassium deficiency lead to impaired blood flow with increased risk for ischemic injury to muscle cells during intense physical exercise. Treatment: When possible, hypokalemia caused by potassium deficit is treated by increasing the intake of foods high in potassium contentmeats, dried fruits, fruit juices (particularly orange juice), and bananas. Magnesium deficiency may impair potassium correction; in such cases, magnesium replacement is indicated. The rapid infusion of a concentrated potassium solution can cause death from cardiac arrest. Hyperkalemia Hyperkalemia refers to an increase in plasma levels of potassium in excess of 5.0 mEq/L (5.0 mmol/L). Causes: The three major causes of potassium excess are decreased renal elimination, excessively rapid administration, and movement of potassium from the intracellular to extracellular compartment. The most common cause of hyperkalemia is decreased renal function. Chronic hyperkalemia is almost always associated with renal failure. Some renal disorders, such as sickle cell nephropathy, lead nephropathy, and systemic lupus nephritis, can selectively impair tubular secretion of potassium without causing renal failure. Acidosis diminishes potassium elimination by the kidney. Persons with acute renal failure accompanied by lactic acidosis or ketoacidosis are at increased risk for development of hyperkalemia. Aldosterone acts at the level of the distal tubular sodiumpotassium exchange system to increase potassium excretion while facilitating sodium reabsorption. A decrease in aldosterone-mediated potassium elimination can result from adrenal insufficiency (i.e., Addisons disease), depression of aldosterone release due to a decrease in renin or angiotensin II, or impaired ability of the kidneys to respond to aldosterone. Potassium-sparing diuretics (e.g., spironolactone, amiloride, triamterene, eplerenone) can produce hyperkalemia. Because of their ability to decrease aldosterone levels, angiotensinconverting enzyme inhibitors and angiotensin II receptor blockers can also produce an increase in plasma potassium levels. Potassium excess can result from excessive oral ingestion or intravenous administration of potassium. In some cases, severe and fatal incidents of hyperkalemia have occurred when intravenous potassium solutions were infused too rapidly. Because the kidneys control potassium elimination, intravenous solutions that contain potassium should never be started until urine output has been assessed and renal function has been deemed to be adequate.

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The movement of potassium out of body cells into the ECF also can lead to elevated plasma potassium levels. Tissue injury causes release of intracellular potassium into the ECF compartment. For example, burns and crushing injuries cause cell death and release of potassium into the ECF. The same injuries often diminish renal function, which contributes to the development of hyperkalemia. Transient hyperkalemia may be induced during extreme exercise or seizures, when muscle cells are permeable to potassium. Manifestations: The signs and symptoms of potassium excess are closely related to the alterations in neuromuscular excitability. The effect that potassium has on membrane excitability is determined by the ratio of K+ ions inside the cell membrane to those outside the cell membrane. As the ECF potassium concentration rises, there is a decrease in the potassium ratio. This change produces an initial increase in membrane excitability because it brings the resting membrane potential closer to the threshold potential. However, with persistent depolarization, as occurs with severe hyperkalemia, the Na+ ion channels become inactivated, producing a net decrease in excitability. The first symptom associated with hyperkalemia typically is paresthesia. There may be complaints of generalized muscle weakness or dyspnea secondary to respiratory muscle weakness. The most serious effect of hyperkalemia is on the heart. As potassium levels increase, disturbances in cardiac conduction occur. The earliest changes are peaked, narrow T waves and widening of the QRS complex. If plasma levels continue to rise, the PR interval becomes prolonged and is followed by disappearance of P waves. The heart rate may be slow. Ventricular fibrillation and cardiac arrest are terminal events. Diagnosis and Treatment: The treatment of potassium excess varies with the degree of increase in plasma potassium and whether there are ECG and neuromuscular manifestations. Calcium antagonizes the potassium-induced decrease in membrane excitability, restoring excitability toward normal. In persons with severe hyperkalemia, calcium gluconate is given intravenously over a period of 2 to 3 minutes.38 The protective effect of calcium administration is usually rather rapid and should be used only in persons in whom the P wave is absent or the QRS is widened. Insulin lowers plasma potassium concentration by driving potassium into cells. Intravenous infusions of insulin and glucose are used for this purpose. Less emergent measures focus on decreasing or curtailing intake or absorption, increasing renal excretion, and increasing cellular uptake. Decreased intake can be achieved by restricting dietary sources of potassium. Increasing potassium output often is more difficult. Patients with renal failure may require hemodialysis or peritoneal dialysis to reduce plasma potassium levels. Sodium polystyrene sulfonate, a cation exchange resin, also may be used to remove K+ ions from the colon. The sodium ions in the resin are exchanged for K+ ions, and then the potassium-containing resin is eliminated in the stool.

41)DISTURBANCES IN CALCIUM AND PHOSPHATE METABOLISM

Disorders of calcium metabolism occur when the body has too little or too much calcium. The serum level of calcium is closely regulated within a fairly limited range in the human body. In a healthy physiology, extracellular calcium levels are maintained within a tight range through the actions of parathyroid hormone, vitamin D and the calcium sensing receptor [1] . Disorders in calcium metabolism can lead to hypocalcemia, decreased plasma levels of calcium or hypercalcemia, 63

elevated plasma calcium levels. Hypocalcemia Hypocalcemia is common and can occur unnoticed with no symptoms or, in severe cases, can have dramatic symptoms and be life-threatening . Hypocalcemia can be parathyroid related or vitamin D related. Parathyroid related hypocalcemia includes post-surgical hypoparathyroidism, inherited hypoparathyroidism, pseudohypoparathyroidism, and pseudo-pseudohypoparathyroidism [1]. Postsurgical hypoparathyroidism is the most common form, and can be temporary (due to suppression of tissue after removal of a malfunctioning gland) or permanent, if all parathyroid tissue has been removed [1]. Inherited hypoparathyroidism is rare and is due to a mutation in the calcium sensing receptor. Pseudohypoparathyroidism is maternally inherited and is categorized by hypocalcemia and hyperphosphatemia. Finally, pseudo-pseudohypoparathyroidism is paternally inherited. Patients display normal parathyroid hormone action in the kidney, but exhibit altered parathyroid hormone action in the bone [1]. Vitamin D related hypocalcemia may be associated with a lack of vitamin D in the diet, a lack of sufficient UV exposure, or disturbances in renal function. Low vitamin D in the body can lead to a lack of calcium absorption and secondary hyperparathyroidism (hypocalcemia and raised parathyroid hormone) [1].Symptoms of hypocalcemia include numbness in fingers and toes, muscle cramps, irritability, impaired mental capacity and muscle twitching . Hypercalcemia Hypercalcemia is suspected to occur in approximately 1 in 500 adults in the general adult population . Like hypocalcemia, hypercalcemia can be non-severe and present with no symptoms, or it may be severe, with life-threatening symptoms. Hypercalcemia is most commonly caused by hyperparathyroidism and by malignancy, and less commonly by vitamin D intoxication, familial hypocalciuric hypercalcemia and by sarcoidosis [2]. Hyperparathyroidism occurs most commonly in postmenopausal women. Hyperparathyroidism can be caused by a tumor, or adenoma, in the parathyroid gland or by increased levels of parathyroid hormone due to hypocalcemia [2]. Approximately 10% of cancer sufferers experience hypercalcemia due to malignancy [2]. Hypercalcemia occurs most commonly in breast cancer, lymphoma, prostate cancer, thyroid cancer, lung cancer, myeloma, and colon cancer [2]. It may be caused by secretion of parathyroid hormonerelated peptide by the tumor (which has the same action as parathyroid hormone), or may be a result of direct invasion of the bone, causing calcium release. Symptoms of hypercalcemia include anorexia, nausea, vomiting, constipation, abdominal pain, lethargy, depression, confusion, polyuria, polydipsia and generalized aches and pains. A variety of genetic diseases and disorders due to therapeutic agents affect phosphate homeostasis. Not surprisingly, since the kidney is the primary regulatory site for phosphate homeostasis, aberrant phosphate metabolism results most commonly from altered renal Pi handling. Moreover, the majority of the primary diseases are phosphate losing disorders in which renal Pi wasting and hypophosphatemia predominate and osteomalacia and rickets are characteristic. Osteomalacia and rickets are disorders of calcification characterized by defects of bone mineralization in adults and bone and cartilage mineralization during growth. In osteomalacia, there is a failure to normally mineralize the newly formed organic matrix (osteoid) of bone. In rickets, a disease of children, there is not only abnormal mineralization of bone but defective cartilage growth plate calcification at the epiphyses as well. Apoptosis of chondrocytes in the hypertrophic zone is reduced, typically resulting in an expanded hypertrophic zone, delayed mineralization and vascularization of the calcification front, with an overall appearance of a widened and disorganized growth plate.

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42)Disturbances in trace elements metabolism

Copper Menkes Disease (Kinky Hair Syndrome) Pathogenesis This is an X-linked neurodegenerative disease due to a defect in copper transport and utilisation. The gene responsible (ATP7A), unlike the related Wilsons Disease protein ATP7B which is expressed predominantly in the liver, kidney and basal ganglia, is expressed in the gut, blood brain barrier and in fact in all cells in the body apart from those in which ATP7B is expressed. It is involved in the transport of copper out of the cells. The net effect of a defect in the gene is low plasma copper concentrations secondary to the impaired gut absorption. This leads to low concentrations in the brain and, paradoxically, increased copper concentrations in some tissues due to the inability to remove copper from the cells. Wilsons Disease Pathogenesis This is an autosomal recessive disorder due to mutations in the copper-transporting protein ATP7B which is expressed predominantly in the liver, kidney and parts of the brain. The protein facilitates the transport of copper out of the liver cell (the main site for copper storage in the body) for incorporation into caeruloplasmin and excretion in the bile. Hence the net effect of a defect in the gene is a failure of excretion from the liver leading to a build up in the liver, overspill into the blood and deposition in other tissues with consequential damage.

Iron Hereditary Haemochromatosis Pathogenesis Hereditary Haemochromatosis (HH) is an autosomal recessive disorder characterized by abnormal accumulation of iron in the liver, heart, pancreas, pituitary, joints and skin with consequential dysfunction in these tissues. The iron accumulation is thought to be due to defective cellular iron binding, uptake and utilisation.The gene responsible is called HFEand is located on Chromosome 6. Most, but not all, individuals with HH have a detectable mutation in the HFEgene Zinc Acrodermatitis Enteropathica (AE) Pathogenesis AE is a rare autosomal recessive disorder causing profound zinc deficiency thought to be caused by mutations in the SLC39A4gene. The protein product of the SLC39A4gene is a transmembrane protein that is part of the zinc / iron-regulated transporterlike protein (ZIP) family required for zinc uptake. The protein is preferentially expressed in the enterocytes of the duodenum and the jejunum and ZIP deficiency leads to impaired gut uptake of dietary zinc. Presentation Patients generally present after weaning with hair loss, intractable diarrhoea, failure to thrive, irritability and a characteristic skin rash.

43)Basic disturbances in acid-base equilibrium. Acidosis:

Acidosis is an increased acidity in the blood. (i.e., an increased hydronium ion concentration). If not 65

further qualified, it usually refers to acidity of the blood plasma.Acidosis is said to occur when arterial pH falls below 7.35 (except in the fetus- see below), while its counterpart (alkalosis) occurs at a pH over 7.45. Arterial blood gas analysis and other tests are required to separate the main causes. The term acidemia describes the state of low blood pH, while acidosis is used to describe the processes leading to these states. Nevertheless, the terms are sometimes used interchangeably. The distinction may be relevant where a patient has factors causing both acidosis and alkalosis, wherein the relative severity of both determines whether the result is a high or a low pH. The rate of cellular metabolic activity affects and, at the same time, is affected by the pH of the body fluids. In mammals, the normal pH of arterial blood lies between 7.35 and 7.50 depending on the species (e.g., healthy human-arterial blood pH varies between 7.35 and 7.45). Blood pH values compatible with life in mammals are limited to a pH range between 6.8 and 7.8. Changes in the pH of arterial blood (and therefore the extracellular fluid) outside this range result in irreversible cell damage. Metabolic acidosis Metabolic acidosis may result from increased production of metabolic acids or disturbances in the ability to excrete acid via the kidneys. Renal acidosis is associated with an accumulation of urea and creatinine as well as metabolic acid residues of protein catabolism. An increase in the production of other acids may also produce metabolic acidosis. For example, lactic acidosis may occur from 1) severe (PaO2 <36mm Hg) hypoxemia causing a fall in the rate of oxygen diffusion from arterial blood to tissues, or 2) hypoperfusion (e.g., hypovolemic shock) causing an inadequate blood delivery of oxygen to tissues. A rise in lactate out of proportion to the level of pyruvate, e.g., in mixed venous blood, is termed "excess lactate", and may also be an indicator of fermention due to anaerobic metabolism occurring in muscle cells, as seen during strenuous exercise. Once oxygenation is restored, the acidosis clears quickly. Another example of increased production of acids occurs in starvation and diabetic acidosis. It is due to the accumulation of ketoacids (ketosis) and reflects a severe shift from glycolysis to lipolysis for energy needs.Acid consumption from poisoning, elevated levels of iron in the blood, and chronically decreased production of bicarbonate may also produce metabolic acidosis.Metabolic acidosis is compensated for in the lungs, as increased exhalation of carbon dioxide promptly shifts the buffering equation to reduce metabolic acid. This is a result of stimulation to chemoreceptors, which increases alveolar ventilation, leading to respiratory compensation, otherwise known as Kussmaul breathing (a specific type of hyperventilation). Should this situation persist, the patient is at risk for exhaustion leading to respiratory failure.Mutations to the V-ATPase 'a4' or 'B1' isoforms result in distal renal tubular acidosis, a condition that leads to metabolic acidosis, in some cases with sensorineural deafness. Arterial blood gases will indicate low pH, low blood HCO3, and normal or low PaCO2. In addition to arterial blood gas, an anion gap can also differentiate between possible causes. The Henderson-Hasselbalch equation is useful for calculating blood pH, because blood is a buffer solution. The amount of metabolic acid accumulating can also be quantitated by using buffer base deviation, a derivative estimate of the metabolic as opposed to the respiratory component. In hypovolemic shock for example, approximately 50% of the metabolic acid accumulation is lactic acid, which disappears as blood flow and oxygen debt are corrected. Treatment of uncompensated metabolic acidosis is focused upon correcting the underlying problem. When metabolic acidosis is severe and can no longer be compensated for adequately by the lungs, neutralizing the acidosis with infusions of bicarbonate may be required. 66

Fetal metabolic acidemia In the fetus, the normal range differs based on which umbilical vessel is sampled (umbilical vein pH is normally 7.25 to 7.45; umbilical artery pH is normally 7.18 to 7.38).[4] Fetal metabolic acidemia is defined as an umbilical vessel pH of less than 7.20 and a base excess of less than -8] Respiratory acidosis Respiratory acidosis results from a build-up of carbon dioxide in the blood (hypercapnia) due to hypoventilation. It is most often caused by pulmonary problems, although head injuries, drugs (especially anaesthetics and sedatives), and brain tumors can cause this acidemia. Pneumothorax, emphysema, chronic bronchitis, asthma, severe pneumonia, and aspiration are among the most frequent causes. It can also occur as a compensatory response to chronic metabolic alkalosis. One key to distinguish between respiratory and metabolic acidosis is that in respiratory acidosis, the CO2 is increased while the bicarbonate is either normal (uncompensated) or increased (compensated). Compensation occurs if respiratory acidosis is present, and a chronic phase is entered with partial buffering of the acidosis through renal bicarbonate retention. However, in cases where chronic illnesses that compromise pulmonary function persist, such as latestage emphysema and certain types of muscular dystrophy, compensatory mechanisms will be unable to reverse this acidotic condition. As metabolic bicarbonate production becomes exhausted, and extraeneous bicarbonate infusion can no longer reverse the extreme buildup of carbon dioxide associated with uncompensated respiratory acidosis, mechanical ventilation will usually be applied. Fetal respiratory acidemia In the fetus, the normal range differs based on which umbilical vessel is sampled (umbilical vein pH is normally 7.25 to 7.45; umbilical artery pH is normally 7.20 to 7.38). In the fetus, the lungs are not used for ventilation. Instead, the placenta performs ventilatory functions (gas exchange). Fetal respiratory acidemia is defined as an umbilical vessel pH of less than 7.20 and an umbilical artery PCO2of 66 or higher or umbilical vein PCO2 of 50 or higher.

44. Basic disturbances in acid-base equilibrium. Alkalosis

Metabolic activities of the body require the precise regulation of acid-base balance, which is reflected in the pH of extracellular fluids. Membrane excitability, enzyme systems, and chemical reactions depend on acid-base balance being regulated within a narrow physiologic range to function in an optimal way.Normally, the concentration of body acids and bases is regulated so that the pH of extracellular body fluids is maintained within a very narrow range of 7.35 to 7.45. This balance is maintained through mechanisms that generate, buffer, and eliminate acids and bases. An acid is a molecule that can release a hydrogen ion (H+), and a base is a molecule that can accept or combine with an hydrogen ion.1,2 When an acid (HA) is added to water, it dissociates reversibly to form H+ and anions (A); for example, HA H+ + A. Acids are continuously generated as byproducts of metabolic processes. Physiologically, these acids fall into two groups: the volatile acid H2CO3 and all other nonvolatile or fixed acids. The difference between the two types of acids arises because H2CO3 is in equilibrium with the volatile gas CO2, which leaves the body by way of the lungs. The fixed acids (e.g., sulfuric,hydrochloric, phosphoric) are nonvolatile and are not eliminated by the lungs. Instead, they 67

are buffered by body proteins or extracellular buffers, such as HCO3, and then excreted by the kidney.Carbon Dioxide and Bicarbonate Production: Body metabolism results in the production of approximately 15,000 mmol of CO2 each day. Carbon dioxide is transported in the circulation in three forms: attached to hemoglobin, as dissolved CO2 in the plasma, and as HCO3. Although CO2 is not an acid, a small percentage of the gas combines with water in the bloodstream to form H2CO3.The reaction that generates H2CO3 from CO2 and water is catalyzed by an enzyme called carbonic anhydrase, which is present in large quantities in red blood cells, renal tubular cells, and other tissues in the body. Production of Noncarbonic Acids and Bases: The metabolism of dietary proteins and other substances results in the generation of noncarbonic acids and bases. Oxidation of the sulfurcontaining amino acids (e.g., methionine, cysteine, cystine) results in the production of sulfuric acid. Oxidation of arginine and lysine produces hydrochloric acid, and oxidation of phosphorus-containing nucleic acids yields phosphoric acid. Incomplete oxidation of glucose results in the formation of lactic acid, and incomplete oxidation of fats results in the production of ketoacids. The major source of base is the metabolism of amino acids such as aspartate and glutamate and the metabolism of certain organic anions (e.g., citrate, lactate, acetate).The plasma pH can be calculated using an equation called the Henderson-Hasselbalch equation. This equation uses the negative logarithm of the dissociation constant and the logarithm of the HCO3 to CO2 (HCO3/CO2) ratio to calculate pH. Intracellular and Extracellular Buffer Systems: The moment-by-moment regulation of pH depends on intracellular and extracellular buffer systems. A buffer system consists of a weak acid and the base salt of that acid or of a weak base and its acid salt. In the process of preventing large changes in pH, the system trades a strong acid for a weak acid or a strong base for a weak base.The two major buffer systems that protect the pH of body fluids are proteins and the bicarbonate buffer system. These buffer systems are immediately available to combine with excess acids or bases and prevent large changes in pH from occurring during the time it takes for respiratory and renal mechanisms to become effective. Bone also represents an important site for buffering of acids and bases. One consequence of bone buffering is the release of calcium from bone and increased renal excretion of calcium. In addition to causing demineralization of bone, it also predisposes to kidney stones. Protein Buffer Systems: Proteins are the largest buffer system in the body. Proteins are amphoteric, meaning that they can function as acids or bases. They contain many ionizable groups that can release or bind H+. The protein buffers are largely located in cells, and H+ ions and CO2 diffuse across cell membranes for buffering by intracellular proteins. Albumin and plasma globulins are the major protein buffers in the vascular compartment. Bicarbonate Buffer System: The bicarbonate buffer system uses H2CO3 as its weak acid and a bicarbonate salt such as sodium bicarbonate (NaHCO3) as its weak base. It substitutes the weak H2CO3 for a strong acid such as hydrochloric acid (HCl + NaHCO3 H2CO3 + NaCl) or the weak bicarbonate base for a strong base such as sodium hydroxide (NaOH + H2CO3 NaHCO3 + H2O). Metabolism provides an ample supply of CO2, which can replace any H2CO3 that is lost when excess base is added, and CO2 can be readily eliminated when excess acid is added. Likewise, the kidney can conserve or form new HCO3 when excess acid is added, and it can excrete HCO3 when excess base is added. Plasma PotassiumHydrogen Exchange: Potassium ions (K+) and H+ ions interact in important ways in the regulation of acid-base balance. Both ions are positively charged, and both ions move freely between the intracellular and extracellular compartments. In situations of acidosis, excess H+ ions move into the intracellular compartment for buffering. When this happens, another cation, in this 68

case the K+ ion, must leave the cell and move into the extracellular fluid. When extracellular potassium levels fall, K+ ions move out of the cell and are replaced by H+ ions. Thus, alterations in extracellular potassium levels can affect acid-base balance, and changes in acid-base balance can influence extracellular potassium levels. Potassium shifts tend to be more pronounced in metabolic acidosis than respiratory acidosis. Also, metabolic acidosis caused by an accumulation of nonorganic acids (e.g., HCl that occurs in diarrhea, phosphoric acid that occurs in renal failure) produces a greater increase in extracellular potassium than does acidosis caused by an accumulation of organic acids (e.g., lactic acid, ketoacids). Respiratory Control Mechanisms: The second line of defense against acid-base disturbances is the control of CO2 by the respiratory system. Excess CO2 or excess H+ ions in the blood mainly act directly on the respiratory center in the brain to control ventilation. Although H+ ions do not easily cross the bloodbrain barrier, CO2 crosses with ease and in the process reacts with water to form carbonic acid, which dissociates into H+ and HCO3 ions. It is the H+ ion that stimulates the respiratory center, causing an increase or decrease in ventilation.The respiratory control of pH is rapid, occurring within minutes, and is maximal within 12 to 24 hours. Although the respiratory response is rapid, it does not completely return the pH to normal. In acting rapidly, however, it prevents large changes in pH from occurring while waiting for the much more slowly reacting kidneys to respond.Although CO2 readily crosses the bloodbrain barrier, there is a lag for entry of the HCO3 ion. Thus, blood pH and HCO3 levels drop more rapidly than cerebrospinal fluid (CSF) levels. When metabolic acid-base disorders are corrected rapidly, the respiratory response may persist because of a delay in CSF adjustments. Renal Control Mechanisms: The kidneys regulate acid-base balance by excreting either an acidic or an alkaline urine. Excreting an acidic urine reduces the amount of acid in the extracellular fluid, and excreting an alkaline urine removes base from the extracellular fluid. Hydrogen Ion Elimination and Bicarbonate Conservation: The kidney regulates pH by excreting excess H+ ions and reabsorbing or regenerating HCO3 ions. Bicarbonate is freely filtered in the glomerulus and reabsorbed in the tubules. Because H+ ions are not filtered in adequate amounts to maintain acid-base balance, they are secreted from blood in the peritubular capillaries into the urine filtrate in the renal tubules. Most of the H+ ion secretion and reabsorption of HCO3 ions takes place in the proximal tubule. The process begins with a coupled Na+/H+ transport system in which a H+ ion is secreted into the tubular fluid and a Na+ ion is reabsorbed into the tubular cell. The secreted H+ ion combines with a filtered HCO3 ion to yield CO2 and H2O. The water is eliminated in the urine, and the CO2 diffuses into the tubular cell, where it combines with water, in a carbonic anhydrasemediated reaction to form a HCO3 ion and a H+ ion. The HCO3 ion is then reabsorbed into the blood along with the Na+ ion, and the newly generated H+ ion is secreted into the tubular fluid to begin another cycle. Tubular Buffer Systems: Because an extremely acidic urine would be damaging to structures in the urinary tract, the pH of the urine is maintained within a range from 4.5 to 8.0. This limits the number of unbuffered H+ ions that can be excreted by the kidney. When the number of free H+ ions secreted into the tubular fluid threatens to cause the pH of the urine to become too acidic, they must be carried in some other form. This is accomplished by combining H+ ions with intratubular buffers before they are excreted in the urine. There are two important intratubular buffer systems: the phosphate buffer system and the ammonia buffer system.

69

The phosphate buffer system uses HPO42 and H2PO4 that are present in the tubular filtrate. Both become concentrated in the tubular fluid because of their relatively poor absorption and because of reabsorption of water from the tubular fluid. The combination of H+ with HPO42 to form H2PO4 allows the kidneys to increase their secretion of H+ ions. The excretion of H+ and generation of HCO3 by the ammonia buffer system occurs in three major steps: (1) the synthesis of ammonium (NH4+) from the amino acid glutamine in the proximal tubule, thick ascending loop of Henle, and distal tubules; (2) the reabsorption and recycling of NH3 within the medullary portion of the kidney; and (3) the buffering of H+ ions by NH3 in the collecting tubules. The metabolism of glutamate in the proximal tubule results in the formation of two NH4+ and two HCO3 ions. The two NH4+ ions are secreted into the tubular fluid by a countertransport mechanism in exchange for a Na+ ion. The two HCO3 ions move out of the tubular cell along with the reabsorbed Na+ ion to enter the peritubular capillaries system. Thus, for each molecule of glutamine metabolized in the proximal tubule, two NH4+ ions are secreted into the tubular filtrate, and two HCO3 ions are reabsorbed into the blood. The HCO3 generated by this process constitutes new HCO3. A second buffering mechanism involves the recycling of NH4+ by tubular cells in the medullary portion of the kidney. Here, NH4+ is converted to NH3 and secreted into the tubular lumen. In the collecting tubules, H+ ions that are secreted into the tubular lumen combine with NH3 to form NH4+ ions. However, this part of the tubule is relatively impermeable to NH4+; therefore, once the H+ has reacted with NH3 to NH4+, it becomes trapped in the tubular lumen and is eliminated in the urine. In the process of being converted to NH3, the H+ from the recycled NH4+ promotes the reabsorption of HCO3 by combining with HCO3 delivered from the proximal tubule. Thus, an additional new HCO3 is generated and added to the blood for each NH4 + that is recycled. Hydrogen and Potassium Ions Compete for Elimination in the Urine: Plasma K+ levels influence renal elimination of H+ ions, and vice versa. When plasma K+ levels fall, there is movement of K+ ions from body cells into the extracellular fluid and a reciprocal movement of H+ ions from the extracellular fluid into body cells. In the kidney, these movements lower the intracellular pH of tubular cells, causing an increase in H+ ion secretion. Potassium depletion also stimulates ammonia synthesis by the kidney as a means of buffering the excess H+ ions. The net result is an increased reabsorption of the filtered HCO3 ions and the development of metabolic alkalosis. An elevation in plasma K+ levels has the opposite effect. Plasma K+ levels are similarly altered by acid-base balance. Acidosis tends to increase H+ ion elimination and decrease K+ ion elimination, with a resultant increase in plasma potassium levels. Alkalosis has the opposite effect. Aldosterone also influences H+ ion elimination by the kidney. It acts in the collecting duct to stimulate H+ ion secretion indirectly, while increasing Na+ ion reabsorption and K+ ion secretion. Hyperaldosteronism tends to lead to a decrease in plasma K+ levels and increased pH and alkalosis because of increased H+ ion secretion. Hypoaldosteronism has the opposite effect. It leads to

70

increased K+ levels, decreased H+ ion secretion, and acidosis. Influence of Sodium ChlorideBicarbonate Exchange on pH: Body sodium levels can indirectly influence acid-base balance by way of the Cl/HCO3 exchange system. Sodium reabsorption in the kidneys requires the reabsorption of an accompanying anion. The two major anions in the extracellular fluid are Cl and HCO3. One of the mechanisms that the kidneys use in regulating the pH of the extracellular fluids is to conserve or eliminate HCO3 ions; in the process, it often is necessary to shuffle anions. Chloride is the most abundant anion in the extracellular fluid and can substitute for HCO3 when an anion shift is needed. Metabolic Alkalosis Metabolic alkalosis is a systemic disorder caused by an increase in pH due to a primary excess of plasma HCO3 ions. It can be caused by a loss of H+ ions, net gain in HCO3 ions, or loss of Cl ions in excess of HCO3 ions. Causes: Most of the bodys plasma HCO3 is obtained from three sources: from CO2 that is produced during metabolic processes, from reabsorption of filtered HCO3, or from generation of new HCO3 by the kidney. Usually, HCO3 production and renal reabsorption are balanced in a manner that prevents alkalosis from occurring. The proximal tubule reabsorbs 99.9% of the filtered HCO3. When the plasma levels of HCO3 rise above the threshold for tubular reabsorption, the excess is excreted in the urine. Many of the conditions that increase plasma HCO3 also raise the level for HCO3 reabsorption; thus, an increase in HCO3 contributes not only to the generation of metabolic alkalosis but also to its maintenance. Metabolic alkalosis involves both the factors that generate the loss of H+ or gain of HCO3 ions and those that maintain it by interfering with excretion of the excess HCO3. Factors that serve to maintain metabolic alkalosis include extracellular fluid volume contraction accompanied by hypokalemia and hypochloremia and mineralocorticoid (aldosterone) excess. - Excess Alkali Intake: Excessive alkali ingestion, as in the use of bicarbonate-containing antacids or NaHCO3 administration during cardiopulmonary resuscitation, can cause metabolic alkalosis. Other sources of alkali intake are acetate in hyperalimentation solutions, lactate in parenteral solutions such as Ringers lactate, and citrate used in blood transfusions. A condition called the milkalkali syndrome may develop in persons who consume excessive amounts of milk along with an antacid such as calcium carbonate. The most common cause at present is the use of calcium carbonate as a phosphate buffer in persons with renal failure. - Hydrogen, Chloride, and Potassium Ion Loss Associated With Bicarbonate Ion: Vomiting, removal of gastric secretions through use of nasogastric suction, and low potassium levels resulting from diuretic therapy are the most common causes of metabolic alkalosis in hospitalized patients. Gastric secretions contain high concentrations of HCl and lesser concentrations of potassium chloride (KCL). Under normal conditions, each 1 mEq of H+ ion that is secreted into the stomach generates 1 mEq of plasma HCO3. Because the entry of acid into the duodenum stimulates an equal amount of pancreatic HCO3 secretion, the increase in plasma HCO3 concentration is usually transient, and pH returns to normal within a matter of hours. However, loss of H+ and Cl ions from the stomach due 71

to vomiting or gastric suction stimulates continued production of gastric acid and thus the addition of more bicarbonate into the blood. - Maintenance of Metabolic Alkalasis by Volume Contraction, Hypokalemia, and Hypochloremia: Vomiting also results in the loss of water, sodium, and potassium. The resultant volume depletion and hypokalemia maintain the generated metabolic alkalosis by increasing the renal reabsorption of HCO3 ion. Administration of diuretics (e.g., loop and thiazide diuretics) is often associated with metabolic alkalosis. Loop diuretics decrease Na+, K+, and Cl reabsorption, leading to volume contraction and hypokalemia. The thiazide diuretics increase renal K+ loss, leading to increased HCO3 reabsorption. Extracellular volume depletion is one of the most important factors affecting HCO3 reabsorption in the proximal tubule. A decrease in extracellular fluid volume activates the renin-angiotensinaldosterone system, which increases Na+ reabsorption as a means of maintaining extracellular fluid volume. The reabsorption of Na+ requires concomitant anion reabsorption; because there is a Cl deficit, HCO3 is reabsorbed along with Na+. Hypokalemia is a potent stimulus for H+ secretion and HCO3 reabsorption. In hypokalemia, K+ moves out of the tubular cell into the blood and is replaced by the H+ ion. This results in intracellular acidosis and increased HCO3 reabsorption. Hypochloremia and the reduced delivery of Cl to the distal tubule of the kidney are responsible for maintaining metabolic alkalosis, rather than volume depletion per se. A low intraluminal concentration of Cl ion is interpreted by the kidney as a sign of low extracellular fluid volume, thereby serving as a stimulus for activation of the renin-angiotensin-aldosterone system. Low intraluminal concentrations of Cl ion also reduce the driving force for bicarbonate reabsorption. Metabolic alkalosis can also result from excessive adrenocorticosteroid hormones (e.g., hyperaldosteronism, Cushings syndrome). The hormone aldosterone increases H+ ion secretion as it increases Na+ and HCO3 ion reabsorption. In hyperaldosteronism, the concurrent loss of K+ in the urine serves to perpetuate the alkalosis. Chronic respiratory acidosis produces a compensatory loss of H+ and Cl ions in the urine along with HCO3 retention. When respiratory acidosis is corrected abruptly, as with mechanical ventilation, a posthypercapneic metabolic alkalosis may develop because of a rapid drop in PCO2; however, the concentration of HCO3 ions, which are eliminated renally, remains elevated. Manifestations: Metabolic alkalosis is characterized by a plasma pH above 7.45, plasma HCO3 level above 29 mEq/L (29 mmol/L), and base excess above 3.0 mEq/L (3 mmol/L). Persons with metabolic alkalosis often are asymptomatic or have signs related to volume depletion or hypokalemia. When neurologic manifestations do occur, as in acute and severe metabolic alkalosis, they include mental confusion, hyperactive reflexes, tetany, and carpopedal spasm. Metabolic alkalosis also leads to a compensatory hypoventilation with development of various degrees of hypoxemia and respiratory acidosis. Significant morbidity occurs with severe metabolic alkalosis (pH >7.55), including respiratory failure, dysrhythmias, seizures, and coma. Treatment: The treatment of metabolic alkalosis usually is directed toward correcting the cause of the condition. A chloride deficit requires correction. Potassium chloride usually is the treatment of choice for metabolic alkalosis when there is an accompanying K+ deficit. When KCl is used as a therapy, the Cl anion replaces the HCO3 anion, and correcting the potassium deficit allows the 72

kidney to conserve the H+ ion while eliminating the K+ ion. Fluid replacement with normal saline or one half normal saline often is used in the treatment of patients with volume contraction alkalosis. Respiratory Alkalosis Respiratory alkalosis is a systemic acid-base disorder characterized by a primary decrease in plasma PCO2, also referred to as hypocapnia, which produces an elevation in pH and a subsequent decrease in HCO3. Causes: Respiratory alkalosis is caused by hyperventilation or a respiratory rate in excess of that needed to maintain normal plasma PCO2 levels. It may occur as the result of central stimulation of the medullary respiratory center or stimulation of peripheral (e.g., carotid chemoreceptor) pathways to the medullary respiratory center. Mechanical ventilation may produce respiratory alkalosis if the rate and tidal volume are set so that CO2 elimination exceeds CO2 production. Carbon dioxide crosses the alveolar capillary membrane 20 times more rapidly than oxygen. Therefore, the increased minute ventilation may be necessary to maintain adequate oxygen levels while producing a concomitant decrease in CO2 levels. In some cases, respiratory alkalosis may be induced medically as a means of controlling disorders such as severe intracranial hypertension. Central stimulation of the medullary respiratory center occurs with anxiety, pain, pregnancy, febrile states, sepsis, encephalitis, and salicylate toxicity. Progesterone increases ventilation in women; during the progesterone phase of the menstrual cycle, normal women increase their PCO2 values by 2 to 4 mm Hg and their pH by 0.01 to .02.3 Women also develop substantial hypocapnia during pregnancy, most notably during the last trimester, with PCO2 values of 29 to 32 mm Hg.One of the most common causes of respiratory alkalosis is the hyperventilation syndrome, which is characterized by recurring episodes of overbreathing often associated with anxiety. Persons experiencing panic attacks frequently present in the emergency room with manifestations of acute respiratory alkalosis.Hypoxemia exerts its effect on pH through the peripheral chemoreceptors in the carotid bodies. Stimulation of peripheral chemoreceptors occurs in conditions that cause hypoxemia with relatively unimpaired CO2 transport such as exposure to high altitudes, asthma, and respiratory disorders that decrease lung compliance. Manifestations: Respiratory alkalosis manifests with a decrease in PCO2 and a deficit in H2CO3. In respiratory alkalosis, the pH is above 7.45, arterial PCO2 is below 35 mm Hg, and plasma HCO3 levels usually are below 24 mEq/L (24 mmol/L).The signs and symptoms of respiratory alkalosis are associated with hyperexcitability of the nervous system and a decrease in cerebral blood flow. Alkalosis increases protein binding of extracellular calcium. This reduces ionized calcium levels, causing an increase in neuromuscular excitability. A decrease in the CO2 content of the blood causes constriction of cerebral blood vessels. Because CO2 crosses the bloodbrain barrier rather quickly, the manifestations of acute respiratory alkalosis are usually of sudden onset. The person often experiences light-headedness, dizziness, tingling, and numbness of the fingers and toes. These manifestations may be accompanied by sweating, palpitations, panic, air hunger, and dyspnea. Because CO2 provides the stimulus for short-term regulation of respiration, short periods of apnea may occur in persons with acute episodes of hyperventilation. Treatment: The treatment of respiratory alkalosis focuses on measures to correct the underlying cause. Hypoxia may be corrected by administration of supplemental oxygen. 73

45)Interrelationships between intracellular and extracellular pH.

All cells contain an intracellular fluid whose pH value is known as the intracellular pH (pHi). The pHi plays a critical role in the function of the cell, and close regulation is required for cells to survive. There are numerous mechanisms that can cause pHi to change, including metabolic acid production, leakage of acid across plasma and organelle membranes and membrane transport processes. The mechanisms that regulate pHi are usually considered to be plasma membrane transporters of which two main types exist those independent of HCO3 and those requiring HCO3. The normal extracellular pH is 7.4 +/- Intracellular pH is around 6.8 due to acid production. It contains low HCO3levels and thereby at pCO2 above 45 mmHg, the pH can not be 7.4 but much lower. The intracellular pH of HEK cells (HEK 293) is 7.3.In the pH range between 6.8 and 7.4, lymphocytes maintain a constant internal pH of 7.17 0.06 pH unit. Out side this range, intracellular pH changes with extracelular pH. Extracellular fluid (ECF) or extracellular fluid volume (ECFV) usually denotes all body fluid outside of cells. The remainder is called intracellular fluid. In some animals, including mammals, the extracellular fluid can be divided into two major subcompartments, interstitial fluid and blood plasma. The extracellular fluid also includes the transcellular fluid; making up only about 2.5 percent of the ECF. In humans, the normal glucose concentration of extracellular fluid that is regulated by homeostasis is approximately 5 mM.The pH of extracellular fluid is tightly regulated by buffers around 7.4. The volume of ECF is typically 15L (of which 12L is interstitial fluid and 3L is plasma)

46)Hypoxia definition, essence, and classification.

Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole (generalized hypoxia) or a region of the body (tissue hypoxia) is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise. A mismatch between oxygen supply and its demand at the cellular level may result in a hypoxic condition. Hypoxia in which there is complete deprivation of oxygen supply is referred to as anoxia.Hypoxia differs from hypoxemia in that, in the latter, the oxygen concentration within the arterial blood is abnormally low.[1] It is possible to experience hypoxia and have a low oxygen content (e.g., due to anemia) but maintain high oxygen partial pressure (pO2). Incorrect use of these terms can easily lead to confusion, especially as hypoxemia is among the causes of hypoxia.Generalized hypoxia occurs in healthy people when they ascend to high altitude, where it causes altitude sickness leading to potentially fatal complications: high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE).Hypoxia also occurs in healthy individuals when breathing mixtures of gases with a low oxygen content, e.g. while diving underwater especially when using closed-circuit rebreather systems that control the amount of oxygen in the supplied air. A mild and non-damaging intermittent hypoxia is used intentionally during altitude trainings to develop an athletic performance adaptation at both the systemic and cellular level. Hypoxia is also a serious consequence of preterm birth in the neonate. The main cause for this is that the lungs of the human fetus are among the last organs to develop during pregnancy. To assist the lungs to distribute oxygenated blood throughout the body, infants at risk of hypoxia are often placed inside an incubator capable of providing continuous positive airway pressure (also known as a humidicrib). In humans, hypoxia is detected by chemoreceptors in the carotid body. This response does not 74

control ventilation rate at normal pO2, but below normal the activity of neurons innervating these receptors increases dramatically, so much so to override the signals from central chemoreceptors in the hypothalamus, increasing pO2 despite a falling pCO2. Classification Hypoxemic hypoxia is a generalized hypoxia, with an inadequate supply of oxygen to the body as a whole. The term "hypoxemic hypoxia" specifies hypoxia caused by low partial pressure of oxygen in arterial blood. In the other causes of hypoxia that follow, the partial pressure of oxygen in arterial blood is normal. Hypoxemic hypoxia may be due to: Hypoventilation. Inadequate pulmonary minute ventilation (e.g., respiratory arrest or by drugs such as opiates)Shunts in the pulmonary circulation or a right-to-left shunt in the heart. Shunts can be caused by collapsed alveoli that are still perfused or a block in ventilation to an area of the lung. Whatever the mechanism, blood meant for the pulmonary system is not ventilated and so no gas exchange occurs (the ventilation/perfusion ratio is decreased).Normal anatomical shunt occur due to Thebesian veins which empty into the left ventricle and the bronchial circulation which supplies the bronchi with oxygen.Normal physiological shunts occur due to the effect of gravity. The highest concentration of blood in the pulmonary circulation occurs in the bases of the pulmonary tree compared to the highest pressure of gas in the apices of the lungs.V/Q mismatch. When the ventilation does not match the perfusion through the paranchyema of the lung. This can occur for a variety of reasons, the commonest being a Pulmonary embolism.Diffusing defects such as pulmonary fibrosis where the Aa gradient has increased.Decreased concentration of oxygen in inspired air. Low partial pressure of atmospheric oxygen such as found at high altitude[4] or by reduced replacement of oxygen in the breathing mix.Low partial pressure of oxygen in the lungs when switching from inhaled anesthesia to atmospheric air, due to the Fink effect, or diffusion hypoxia.Anemia in which arterial oxygen pressure is normal, but total oxygen content of the blood is reduced. This is due to a decreased total carrying capacity, such as a reduced Hemoglobin content.Hypoxia when the blood fails to deliver oxygen to target tissues.Carbon monoxide poisoning which inhibits the ability of hemoglobin to release the oxygen bound to it.Methemoglobinemia in which an abnormal version of hemoglobin accumulates in the blood.Histotoxic hypoxia in which quantity of oxygen reaching the cells is normal, but the cells are unable to use the oxygen effectively, due to disabled oxidative phosphorylation enzymes. Cyanide toxicity is one example. Signs and symptoms The symptoms of generalized hypoxia depend on its severity and acceleration of onset. In the case of altitude sickness, where hypoxia develops gradually, the symptoms include headaches, fatigue, shortness of breath, a feeling of euphoria and nausea. In severe hypoxia, or hypoxia of very rapid onset, changes in levels of consciousness, seizures, coma, priapism, and death occur. Severe hypoxia induces a blue discoloration of the skin, called cyanosis. Because hemoglobin is a darker red when it is not bound to oxygen (deoxyhemoglobin), as opposed to the rich red color that it has when bound to oxygen (oxyhemoglobin), when seen through the skin it has an increased tendency to reflect blue light back to the eye. In cases where the oxygen is displaced by another molecule, such as carbon monoxide, the skin may appear 'cherry red' instead of cyanotic. Pathophysiology After mixing with water vapor and expired CO2 in the lungs, oxygen diffuses down a pressure gradient to enter arterial blood where its partial pressure is around 100 mmHg (13.3 kPa).[4] Arterial blood flow delivers oxygen to the peripheral tissues, where it again diffuses down a pressure gradient into the cells and into their mitochondria. These bacteria-like cytoplasmic structures strip hydrogen 75

from fuels (glucose, fats and some amino acids) to burn with oxygen to form water. The fuel's carbon is oxidized to CO2, which diffuses down its partial pressure gradient out of the cells into venous blood to be exhaled finally by the lungs. Experimentally, oxygen diffusion becomes rate limiting (and lethal) when arterial oxygen partial pressure falls to 40 mmHg (5.3 kPa) or below.If oxygen delivery to cells is insufficient for the demand (hypoxia), hydrogen will be shifted to pyruvic acid converting it to lactic acid. This temporary measure (anaerobic metabolism) allows small amounts of energy to be released. Lactic acid build up (in tissues and blood) is a sign of inadequate mitochondrial oxygenation, which may be due to hypoxemia, poor blood flow (e.g., shock) or a combination of both.[6] If severe or prolonged it could lead to cell death. Vasoconstriction and vasodilation In most tissues of the body, the response to hypoxia is vasodilation. By widening the blood vessels, the tissue allows greater perfusion.By contrast, in the lungs, the response to hypoxia is vasoconstriction. This is known as "Hypoxic pulmonary vasoconstriction", or "HPV".

47)Hypoxic hypoxia
Hypoxic hypoxia is a result of insufficient oxygen available to the lungs. A blocked airway, a drowning or a reduction in partial pressure (high altitude above 10,000 feet) are obvious examples of how lungs can be deprived of oxygen. Some medical examples are abnormal pulmonary function or respiratory obstruction, or a right-to-left shunt in the heart. Hypoxic hypoxia is seen in patients suffering from chronic obstructive pulmonary diseases (COPD), neuromuscular diseases or interstitial lung disease. Some symptoms of hypoxic hypoxia are: Cyanosis Headache Decreased reaction time Impaired judgment time Euphoria Visual impairment Drowsiness Lightheaded or dizzy sensation Tingling in fingers and toes Numbness

48.Hypoxemic hypoxia
Hypoxemia (or hypoxaemia) was originally defined as a deficiency of oxygen in arterial blood, and standard manuals take this to mean an abnormally low partial pressure of oxygen (mm Hg), content of oxygen (ml oxygen per dl blood) or percent saturation of hemoglobin with oxygen, either found singly or in combination.[1][2] One simple rule is that hypoxemia becomes very serious when the decreased partial pressure of oxygen in blood is less than 60 mm Hg, because that point is the beginning of the steep portion of the hemoglobin dissociation curve, where a small decrease in the partial pressure of oxygen results in a large decrease in the oxygen content of the blood.[3] or when hemoglobin oxygen saturation is less than 90%. Many of the causes for hypoxemia fall into the general category of problems that concern the lung 76

and heart.The most common source of an individual's hypoxemia is the lung, where inspired air is wasted by going to regions that are poorly supplied with blood and (conversely) blood is perfusing areas of the lung that receive little of the inspired air; this is termed ventilation-perfusion mismatch. A second category includes those causes where the ventilatory drive is inadequate for some reason. Finally, the blood might be incapable of carrying sufficient oxygen for the body's needs for reasons such as anemia or carbon monoxide poisoning; remember, this final category is for those whose definition of hypoxemia includes situations where the quantity of oxygen is deficient, as well as when the partial pressure and/or the percent saturation is reduced. Shunt Some venous blood never circulates by alveoli before returning to the arterial vasculature, thus diluting the freshly oxygenated blood and reducing its oxygen content. The shunt may be intracardiac or may be intrapulmonary, and cannot be corrected by administering 100% oxygen. Some anatomic shunting is normal, as the bronchial circulation provides nutrition to the lung and is not oxygenated before it returns to the left heart. Additionally, some of the through the smallest cardiac veins empty back into the left heart directly. Shunting of blood from the right side to the left side of the circulation (right-to-left shunt) through a still patent atrial or ventricular septal defect or other congenital malformation is a powerful cause of hypoxemia. In the fetus, this is the normal circulation; newborn babies with a large anatomic shunt are cyanotic and fail to thrive.Blood passing through alveoli that have a ventilation/perfusion ratio of zero is a physiologic shunt. The physiologic shunt grows much larger in acute lung injury and especially in adult respiratory distress syndrome. Administering 100% oxygen can convert regions of the lung that have especially low ventilation to regions with physiologic shunt as affected alveoli collapse.Recently, the anatomic use of the term intrapulmonary shunt has returned.[20] In this use, an intrapulmonary shunt is defined according to its ability to pass micro-bubbles or microspheres through the lung, signifying that some fraction of the bloodflow is passing through vessels larger than capillaries. Such a shunt is normally absent at rest or when exercising while breathing 100% oxygen, but appears during strenuous exercise or when breathing air low in oxygen. The quantitative and functional importance of bubble-defined shunts is being vigorously debated, as is the relationship between physiologic shunt and these bubble-defined shunts. Impaired diffusion Impaired diffusion across the blood-gas barrier in the lung can cause hypoxemia. However this is a rare cause as it is a problem only in extremely unusual circumstances. Most of the past cases once thought to be due to a diffusion problem are now recognized as being due to ventilation-perfusion inequality.Mount Everest presents its climbers with the lowest oxygen partial pressure on earth. Blood gas determinations obtained from subjects breathing ambient air at Camp 2, above the Ice Fall (6300 M) demonstrated hypoxemia due to a diffusion limitation in the uptake of oxygen. Hypoxemia developing during vigorous exercise. It is possible to become hypoxemic during exercise with certain lung diseases due to impaired diffusion of oxygen across the alveolar-capillary membrane.This is particularly true with idiopathic pulmonary fibrosis, where even at rest a fifth of the hypoxemia is due to diffusion limitations (on average). During exercise, almost half of the hypoxemia is due to diffusion limitations (again, on average). Inadequate ventilation If the alveolar ventilation is insufficient, there will not be enough oxygen delivered to the alveoli for the body's use. This can cause hypoxemia even if the lungs are normal, as the cause is in the brainstem's control of ventilation or in the body's inability to breathe effectively. 77

Reduced ventilatory drive The rate of breathing and the depth of each breath is controlled by the brainstem and are generally controlled by the blood level of carbon dioxide, as determined by chemoreceptors in the aorta. Hypoxia occurs when the breathing center doesn't function correctly or when the signal is not appropriate.Central sleep apnea. During sleep, the breathing centers of the brain can pause their activity, leading to prolonged periods of apnea with potentially serious consequences. Infants also have periods of apnea during their sleep.Prolonged breath-holding post-hyperventilation. The duration of breath-holding during swimming or diving is greatly prolonged by first hyperventilating to blow off the carbon dioxide, thus reducing the urge to breathe. However, this maneuver is dangerous as it can lead to death because the falling blood oxygen levels are not sensed, and tissue hypoxia can ensue. Mechanical blockade of the airflow A variety of conditions that physically limit airflow can lead to hypoxemia.Suffocation can occur in many ways; for instance, temporary interruption of breathing can occur during sleep when the upper airways fall shut (obstructive sleep apnea), while bedclothes may interfere with breathing in infants (SIDS).Structural deformities of the chest (scoliosis an kyphosis) can severely restrict breathing, leading to hypoxemia towards the end of life.Congenital and acquired causes of muscle weakness may be severe enough to limit breathing and cause hypoxemia, as can muscle weakness and then fatigue in extreme cases of COPD.

49.Circulatory hypoxia. Disturbed oxygen utilization.

In this form of hypoxia the lungs are working just fine and the blood can carry sufficient oxygen. However, the tissue is not receiving sufficient oxygen because the heart cannot pump the blood to the tissue (or the arteries leading to the tissue have been blocked by clots etc...). Sickle cell anemia can lead to circulatory hypoxia as the cells sickle in the blood vessels and block them. In freshwater or marine systems apparent oxygen utilisation (AOU) is the difference between the measured dissolved oxygen concentration and its equilibrium saturation concentration in water with the same physical and chemical properties.[1] Such differences typically occur when biological activity acts to change the ambient concentration of oxygen. For example, primary production liberates oxygen and increases its concentration, while respiration consumes it and decreases its concentration.Consequently, the AOU of a water sample represents the sum of the biological activity that the sample has experienced since it was last in equilibrium with the atmosphere. In shallow water systems (e.g. lakes), the full water column is generally in close contact with the atmosphere, so oxygen concentrations are typically close to saturation: AOU values are low. In deep water systems (e.g. oceans), water can be out of contact with the atmosphere for extremely long periods of time (years, decades, centuries) and large AOU values are possible.

50-Tissue hypoxia.
Tissue hypoxia is a condition in which tissue cells experience inadequate oxygen utilization due to a number of causes such as decreased partial pressure of oxygen (PO2) in a given tissue. Endotoxins associated with sepsis or other critical conditions may also inhibit cellular metabolism and decrease oxygen consumption. Cellular utilization of oxygen may be inhibited by some metabolic poisons, such as cyanide. Learn more about Aerobic Cellular Respiration...Releasing various toxins 78

and/or mediators one organ affected by tissue hypoxia can lead indirectly to a dysfunction or even failure of other organs. Measurement of changes in oxygen consumption in response to changes in oxygen delivery is one of the methods used to determine existence of tissue hypoxia. Some regulatory mechanisms involved in the stimulation and regulation of angiogenesis are comparable to those implicated in collagen synthesis and deposition. Oxygen stimulates macrophages to produce angiogenic substances (like vascular endothelial growth factor [VEGF]) that attract and stimulate endothelial cells.264 Therefore, hypoxia weakens the neovascularization process. A decrease in venous oxygen saturation can be caused by either decrease in oxygen delivery, increase of oxygen demand or both. Metabolic acidosis developed in hypoxic tissues is one of the common abnormalities associated with tissue hypoxia. Injuries that damage the microvasculature attract inflammatory cells that consume large amounts of oxygen and concentrate potentially damaging products at the hypoxic tissues of wound site. This creates a low-oxygen environment with low pH, high lactate, increased oxidant production and poor local perfusion.261 The macrophages respond to this environment by releasing growth factors that induce angiogenesis, multiplication of fibroblasts and collagen synthesis. Therefore, acute wound hypoxia is, to a certain extent, necessary for leukocyte adherence, neovascularization, collagen formation and bone formation.However, oxygen availability becomes essential in 2 steps of collagen biosynthesis proline and lysine are incorporated into growing peptides and hydroxylated when they enter the endoplasmic reticulum. When the PO2 is 20 mm Hg, this process evolves at half the normal rate; when the PO2 is 200 mm Hg, this process evolves at 90% of the optimal rate. Moreover, cell multiplication also requires oxygen. An oxygen environment of 40 mm Hg is needed to ensure fibroblast activity.263 Therefore, chronic wound hypoxia weakens the collagen synthesis process.262, 264 Analyzing the underlying causes and clinical manifestations of tissue hypoxia in each individual case is crucial, because different conditions may promote tissue hypoxia in different ways. Maintaining an adequate blood supply to the oxygen-sensitive tissues should be among primary corrective measures when treating tissue hypoxia. There is a tremendous need for treatments that will reduce the human and economic burden and loss associated with diabetic foot ulcers and lower extremity ulcerations. As tissue hypoxia is one of the pathophysiological characteristics of diabetic ulcers, Hyperbaric Oxygen Therapy (HBOT) has been considered as a therapeutic strategy to reduce tissue hypoxia and enhance wound healing.

51-BULUNAMADI 52-BULUNAMADI
53. Inflammation etiology, phases, and main clinical signs.
The survival of all organisms requires that they eliminate foreign invaders, such as infectious pathogens, and damaged tissues. These functions are mediated by a complex host response called inflammation. Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult. Inflammation accomplishes its protective mission by diluting, destroying, or otherwise neutralizing harmful agents (e.g., microbes and toxins). It then sets into motion the events that eventually heal and repair the sites of injury. Without inflammation, infections would go unchecked and wounds would never heal. In the context of infections, inflammation is part of a broader protective response that immunologists refer to as 79

innate immunity. Although inflammation helps clear infections and other noxious stimuli and initiates repair, the inflammatory reaction and the subsequent repair process can cause considerable harm. The components of the inflammatory reaction that destroy and eliminate microbes and dead tissues are capable of also injuring normal tissues. Therefore, injury may accompany entirely normal, beneficial inflammatory reactions, and the pathology may even become the dominant feature if the reaction is very strong (e.g., when the infection is severe), prolonged (e.g., when the eliciting agent resists eradication), or inappropriate (e.g., when it is directed against self-antigens in autoimmune diseases. or against usually harmless environmental antigens in allergic disorders). Some of the most vexing diseases of humans are disorders in which the pathophysiologic basis is inappropriate, often chronic, inflammation. This is why the process of inflammation is fundamental to virtually all of clinical medicine. The cells and molecules of host defense normally circulate in the blood, and the goal of the inflammatory reaction is to bring them to the site of infection or tissue damage. Several types of cells and molecules play important roles in inflammation. These include blood leukocytes and plasma proteins, cells of vascular walls, and cells and extracellular matrix (ECM) of the surrounding connective tissue.

The steps of the inflammatory response can be remembered as the five Rs: (1) Recognition of the injurious agent, (2) Recruitment of leukocytes, (3) Removal of the agent, (4) Regulation (control) of the response, and (5) Resolution (repair). The outcome of acute inflammation is either elimination of the noxious stimulus followed by decline of the reaction and repair of the damaged tissue, or persistent injury resulting in chronic inflammation. Systemic Effects of Inflammation Fever: cytokines (TNF, IL-1) stimulate production of prostaglandins in hypothalamus. Fever, characterized by an elevation of body temperature, usually by 1 to 4C, is one of the most prominent manifestations of the acute-phase response, especially when inflammation is caused by infection. Fever is produced in response to substances called pyrogens that act by stimulating prostaglandin (PG) synthesis in the vascular and perivascular cells of the hypothalamus. Bacterial products, such as lipopolysaccharide (LPS; called exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens) that increase the levels of cyclooxygenases that convert AA into prostaglandins. In the hypothalamus the PGs, especially PGE2, stimulate the production of neurotransmitters, which function to reset the temperature set point at a higher level. Chronic inflammation is associated with a wasting syndrome called cachexia, which is mainly the result of TNF-mediated appetite suppression and mobilization of fat stores.In severe bacterial infections (sepsis), the large amounts of organisms and LPS in the blood or extravascular tissue 80

stimulate the production of enormous quantities of several cytokines, notably TNF, as well as IL-12 and IL-1. As a result, circulating levels of these cytokines increase, and the nature of the host response changes. High levels of TNF cause disseminated intravascular coagulation (DIC), hypoglycemia, and hypotensive shock. Production of acute-phase proteins: C-reactive protein, others; synthesis stimulated by cytokines (IL6, others) acting on liver cells. Leukocytosis: cytokines (colony-stimulating factors) stimulate production of leukocytes from precursors in the bone marrow. In some severe infections, septic shock: fall in blood pressure, disseminated intravascular coagulation, metabolic abnormalities; induced by high levels of TNF.

54. Vascular changes in inflammation

In inflammation, blood vessels undergo a series of changes that are designed to maximize the movement of plasma proteins and circulating cells out of the circulation and into the site of injury or infection. Changes in Vascular Flow and Caliber Vasodilation; sometimes, it follows a transient constriction of arterioles, lasting a few seconds. Comes about increased blood flow, which is the cause of the heat and the redness. Vasodilation is induced by the action of several mediators, notably histamine and nitric oxide, on vascular smooth muscle. Vasodilation is quickly followed by increased permeability of the microvasculature, with the outpouring of protein-rich fluid into the extravascular tissues. The loss of fluid results in concentration of red cells in small vessels and increased viscosity of the blood, reflected by the presence of dilated small vessels packed with red cells and slower blood flow, a condition termed stasis. As stasis develops, leukocytes, principally neutrophils, accumulate along the vascular endothelium. Leukocytes then stick to the endothelium, and soon afterward they migrate through the vascular wall into the interstitial tissue. Increased Vascular Permeability (Vascular Leakage) A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich fluid (exudate) into the extravascular tissue. The loss of protein from the plasma reduces the intravascular osmotic pressure and increases the osmotic pressure of the interstitial fluid. Together with the increased hydrostatic pressure owing to increased blood flow through the dilated vessels, this leads to a marked outflow of fluid and its accumulation in the interstitial tissue. The net increase of extravascular fluid results in edema. Leakage is as follows: Formation of endothelial gaps in venules. This is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other classes of chemical mediators. It occurs rapidly after exposure to the mediator and is usually reversible and short-lived (15 to 30 minutes); it is thus known as the immediate transient response. This type of leakage affects venules leaving capillaries and arterioles unaffected because there is a greater density of receptors for the mediators in venular 81

endothelium. Binding of mediators, such as histamine, to their receptors on endothelial cells activates intracellular signaling pathways that lead to phosphorylation of contractile and cytoskeletal proteins, such as myosin. These proteins contract, leading to contraction of the endothelial cells and separation of intercellular junctions. Thus, the gaps in the venular endothelium are largely intercellular or close to the intercellular junctions. Cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon-y (IFN-y) also increase vascular permeability by inducing a structural reorganization of the cytoskeleton, such that the endothelial cells retract from one another. Direct endothelial injury, resulting in endothelial cell necrosis and detachment. This effect is due to direct damage to the endothelium by the injurious stimulus, as, for example, in severe burns or lytic bacterial infections. Neutrophils that adhere to the endothelium may also injure the endothelial cells. In most instances, leakage starts immediately after injury and is sustained at a high level for several hours until the damaged vessels are thrombosed or repaired. The reaction is known as the immediate sustained response. All levels of the microcirculation are affected, including venules, capillaries, and arterioles. Endothelial cell detachment is often associated with platelet adhesion and thrombosis. Delayed prolonged leakage, a delay of 2 to 12 hours, lasts for several hours or even days, and involves venules as well as capillaries. Such leakage is caused, for example, by mild to moderate thermal injury, radiation or ultraviolet radiation, and certain bacterial toxins. Leukocyte-mediated endothelial injury. Leukocytes adhere to endothelium relatively early in inflammation. Such leukocytes may be activated in the process, releasing toxic oxygen species and proteolytic enzymes, which then cause endothelial injury or detachment, resulting in increased permeability. This form of injury is largely restricted to vascular sites, such as venules and pulmonary and glomerular capillaries, where leukocytes adhere for prolonged periods to the endothelium. Increased transcytosis across the endothelial cytoplasm. Transcytosis occurs across channels consisting of clusters of interconnected, uncoated vesicles and vacuoles called the vesiculovacuolar organelle, many of which are located close to intercellular junctions. Certain factors, for example, vascular endothelial growth factor (VEGF), appear to cause vascular leakage by increasing the number and perhaps the size of these channels. Leakage from new blood vessels. During repair, endothelial cells proliferate and form new blood vessels, a process called angiogenesis. New vessel sprouts remain leaky until the endothelial cells mature and form intercellular junctions. In addition, certain factors that cause angiogenesis (e.g., VEGF) also increase vascular permeability, and endothelial cells in foci of angiogenesis have increased density of receptors for vasoactive mediators, including histamine, substance P, and VEGF. All these factors account for the edema that is characteristic of the early phases of healing that follow inflammation. In acute inflammation, fluid loss from vessels with increased permeability occurs in distinct phases: (1) an immediate transient response lasting for 30 minutes or less, mediated mainly by the actions of histamine and leukotrienes on endothelium; (2) a delayed response starting at about 2 hours and lasting for about 8 hours, mediated by kinins, complement products, and other factors; and (3) a prolonged response that is most noticeable after direct endothelial injury, for example, after burns.

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55. Cell response in inflammation.

When a microorganism crosses the epidermis or the epithelial surface of the mucous membranes, it encounters other components of the host constitutive defenses. These responses are constitutive because they are nonspecific and do not require prior contact with the organism to be effective. Clinically, signs of inflammation (heat, erythema, pain, and swelling) are the characteristic features of localized infection, secondary tissue injury, and the body's response to this injury. Blood supply to the affected area increases in response to vasodilation, and the capillaries become more permeable, allowing antibodies, complement, and white blood cells to cross the endothelium and reach the site of injury. An important consequence of inflammation is that the pH of the inflamed tissues is lowered, creating an inhospitable environment for the microbe. The increased blood flow to the area allows continued recruitment of inflammatory cells as well as the necessary components for tissue repair and recovery.When a microorganism enters host tissue, it activates the complement system and components of the coagulation cascade and induces the release of chemical mediators of the inflammatory response. These mediators result in the increased vascular permeability and vasodilation characteristic of inflammation. For example, the anaphylatoxins C3a, C4a, and C5a, produced by the activation of complement, stimulate the release of histamine from mast cells. Histamine dilates the blood vessels and further increases their permeability. Bradykinin is also released, increasing vascular permeability.Proinflammatory cytokines include interleukin-1 (IL-1), IL6, tumor necrosis factor, and interferon-.These factors, singly or in combination, promote fever, produce local inflammatory signs, and trigger catabolic responses. During severe infection, hepatic synthesis of proteins is altered, leading to an increase in proteins described as "acute-phase reactants." Typically, serum albumin concentration is reduced, whereas rheumatoid factor, Creactive protein, ferritin, and various proteinase inhibitors increase. Serum levels of zinc and iron decrease at the same time, and the erythrocyte sedimentation rate, a nonspecific marker of inflammation, rises. A catabolic state is further augmented by simultaneous increases in levels of circulating cortisol, glucagon, catecholamines, and other hormones.Mild to moderate inflammatory responses serve important host defense functions. For example, elevated body temperature may inhibit viral replication. Inflammatory hyperemia and systemic neutrophilia optimize phagocyte delivery to sites of infection. The decreased availability of iron inhibits the growth of microbes such as Yersinia that require this element as a nutrient. However, when the inflammatory responses become extreme, extensive tissue damage can result, as in the case of sepsis. Complement System The complement system is composed of a series of plasma protein and cell membrane receptors that are important mediators of host defenses and inflammation (Figure below). Most of the biologically significant effects of the complement system are mediated by the third component (C3) and the terminal components (C59). To carry out their host defense and inflammatory functions, C3 and C5 9 must first be activated. Two pathways of complement activation have been recognized and have been termed the classic and alternative pathways. The classic pathway is activated by antigen-antibody complexes or antibodycoated particles, and the alternative pathway is activated by mechanisms independent of antibodies, usually by interaction with bacterial surface components. Both pathways form C3 convertase, which cleaves the C3 component of complement, a key protein common to both pathways. The two pathways then proceed in identical fashion to bind late-acting components to form a membrane attack complex (C59), which results in target cell lysis. Once activated, complement functions to enhance the antimicrobial defenses in several ways. Complement facilitates phagocytosis through proteins called opsonins, which coat invading 83

microorganisms, making them susceptible to engulfment and destruction by neutrophils and macrophages. The complement-derived membrane attack complex inserts itself into the membrane of a target organism, leading to increased permeability and subsequent lysis of the cell. Complement also acts indirectly through production of substances that are chemotactic for white blood cells and through promotion of the inflammatory response.Inherited disorders of complement are associated with an increased risk of bacterial infection. The specific infections seen in complement-deficient patients relate to the biologic functions of the missing component. Patients with a deficiency of C3 or of a component in either of the two pathways necessary for the activation of C3 typically have increased susceptibility to infections with encapsulated bacteria such as S pneumoniae and Haemophilus influenzae. In contrast, patients with deficiencies of C59 have normal resistance to encapsulated bacteria because C3b-mediated opsonization is intact. These patients, however, are unusually susceptible to life-threatening infections with N meningitidis and N gonorrhoeae because they are unable to form a membrane attack complex and, therefore, cannot lyse the Neisseria cell membrane. Phagocytosis After the natural barriers of the skin or mucous membranes have been penetrated, the phagocytic cellsneutrophils, monocytes, and macrophagesconstitute the next line of host defense. The process of internalizing organisms by these cells (phagocytosis) involves attachment of the organism to the cell surface. This triggers extension of a pseudopod to enclose the bacterium in an endocytic vesicle, or phagosome. The circulating polymorphonuclear neutrophil (PMN) is an important component of the host immune response that in the absence of infection circulates in a quiescent state. When chemotactic factors, arachidonic acid metabolites, or complement cleavage fragments interact with specific PMN membrane receptors, the neutrophil rapidly becomes activated and moves toward the chemoattractants. After phagocytosis, the mechanisms by which the phagolysosome destroys the microorganism can be divided into oxygen-independent and oxygendependent processes. Functional defects or quantitative deficiencies of neutrophils are important risk factors for infection.

56. Mediators of inflammation

- Mediators may be produced locally by cells at the site of inflammation, or they may be circulating in the plasma (typically synthesized by the liver) as inactive precursors that are activated at the site of inflammation. - Cell-derived mediators are normally sequestered in intracellular granules and are rapidly secreted upon cellular activation (e.g., histamine in mast cells) or are synthesized de novo in response to a stimulus (e.g., prostaglandins and cytokines). - Plasma-protein-derived mediators (complement proteins, kinins) typically undergo proteolytic cleavage to acquire their biologic activities. - Most mediators induce their effects by binding to specific receptors on target cells. Some mediators have direct enzymatic and/or toxic activities (e.g., lysosomal proteases and ROS). Mediators may stimulate target cells to release secondary effector molecules. - Different mediators may have similar actions, or they may have opposing effects, thus serving to control the response.

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- The actions of most mediators are tightly regulated. Once activated and released from the cell, mediators quickly decay (e.g., arachidonic acid metabolites), are inactivated by enzymes (e.g., kininase inactivates bradykinin), are eliminated (e.g., antioxidants scavenge toxic oxygen metabolites), or are inhibited (complement-inhibitory proteins). Cell-Derived Mediators: Tissue macrophages, mast cells, endothelial cells and leukocytes are all capable of producing different mediators of inflammation. - Vasoactive Amines: The two vasoactive amines histamine and serotonin are stored as preformed molecules in mast cells and other cells and are among the first mediators to be released in acute inflammatory reactions. Preformed histamine is released from mast cell granules in response to a variety of stimuli: (1) physical injury such as trauma or heat; (2) immune reactions involving binding of IgE antibodies to Fc receptors on mast cells; (3) C3a and C5a fragments of complement, the so-called anaphylatoxins; (4) leukocyte-derived histamine-releasing proteins; (5) neuropeptides (e.g., substance P); and (6) certain cytokines (e.g., IL-1 and IL-8). Histamine causes arteriolar dilation and is the principal mediator of the immediate phase of increased vascular permeability, inducing venular endothelial contraction and interendothelial gaps. Soon after its release, histamine is inactivated by histaminase. Serotonin is also a preformed vasoactive mediator, with effects similar to those of histamine. It is found primarily within platelet dense body granules (along with histamine, adenosine diphosphate, and calcium) and is released during platelet aggregation. - Arachidonic Acid (AA) Metabolites: Prostaglandins, Leukotrienes, and Lipoxins: Leukocytes, mast cells, endothelial cells, and platelets are the major sources of AA metabolites in inflammation. AA is a 20-carbon polyunsaturated fatty acid derived from dietary linoleic acid and present in the body mainly in its esterified form as a component of cell membrane phospholipids. It is released from these phospholipids via cellular phospholipases that have been activated by mechanical, chemical, or physical stimuli, or by inflammatory mediators such as C5a. AA metabolism proceeds along one of two major enzymatic pathways: - Cyclooxygenase stimulates the synthesis of prostaglandins and thromboxanes, and - Lipoxygenase is responsible for production of leukotrienes and lipoxins. Cyclooxygenase pathway: Products of this pathway include prostaglandin E2 (PGE2), PGD2, PGF2, PGI2 (prostacyclin), and thromboxane A2 (TXA2), each derived by the action of a specific

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enzyme on an intermediate. PGD2 is the major metabolite of the cyclooxygenase pathway in mast cells; along with PGE2 and PGF2 (which are more widely distributed), it causes vasodilation and potentiates edema formation. The PGs are also involved in the pathogenesis of pain and fever in inflammation; PGE2 augments pain sensitivity to a variety of other stimuli and interacts with cytokines to cause fever. Lipoxygenase pathway: 5-Lipoxygenase is the predominant AA-metabolizing enzyme in neutrophils. The 5-hydroperoxy derivative of AA, is quite unstable and is either reduced or converted into leukotrienes. The first leukotriene generated is called leukotriene A4 (LTA4), which in turn gives rise to LTB4 or LTC4. LTB4 is produced by neutrophils and some macrophages and is a potent chemotactic agent for neutrophils. LTC4 and its subsequent metabolites, LTD4 and LTE4, are produced mainly in mast cells and cause vasoconstriction, bronchospasm, and increased vascular permeability. Lipoxins function mainly as inhibitors of inflammation. Once leukocytes enter tissues, they gradually change their major lipoxygenase-derived AA products to lipoxins, which inhibit neutrophil chemotaxis and adhesion to endothelium, thus serving as endogenous antagonists of leukotrienes. Platelets that are activated and adherent to leukocytes are also important sources of lipoxins. - Platelet-Activating Factor: PAF is generated from the membrane phospholipids of neutrophils, monocytes, basophils, endothelial cells, and platelets (and other cells) by the action of phospholipase A2. PAF acts directly on target cells via a specific G-protein-coupled receptor. In addition to stimulating platelets, PAF causes vasoconstriction and bronchoconstriction and is more potent than histamine in inducing vasodilation and increased vascular permeability. PAF can elicit most of the reactions of inflammation, including enhanced leukocyte adhesion, chemotaxis, leukocyte degranulation, and the oxidative burst; it also stimulates the synthesis of other mediators, particularly eicosanoids. - Cytokines: Polypeptide products of many cell types. Some cytokines stimulate bone marrow precursors to produce more leukocytes, thus replacing the ones that are consumed during inflammation and immune responses. Molecularly characterized cytokines are called interleukins (IL), referring to their ability to mediate communications between leukocytes. The major cytokines in acute inflammation are TNF and IL-1, as well as a group of chemoattractant cytokines called chemokines. Other cytokines that are more important in chronic inflammation include interferon- (IFN-) and IL-12. Tumor Necrosis Factor and Interleukin-1: TNF and IL-1 are produced by activated macrophages, as well as mast cells, endothelial cells, and some other cell types. Their secretion is stimulated by microbial products, such as bacterial endotoxin, immune complexes, and products of T lymphocytes generated during adaptive immune responses. The principal role of these cytokines in inflammation is in endothelial activation. Both TNF and IL-1 stimulate the expression of adhesion molecules on endothelial cells, resulting in increased leukocyte binding and recruitment, and enhance the production of additional cytokines (notably chemokines) and eicosanoids. TNF also increases the thrombogenicity of endothelium and causes aggregation and activation of neutrophils, and IL-1 activates tissue fibroblasts, resulting in increased proliferation and production of ECM.

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 Chemokines: Proteins that act as chemoattractants for different subsets of leukocytes. The two main functions of chemokines are in leukocyte recruitment in inflammation and in the normal anatomic organization of cells in lymphoid and other tissues. Chemokines also activate leukocytes; one consequence of such activation, is increased affinity of leukocyte integrins for their ligands on endothelial cells. Some chemokines are produced constitutively in tissues and are responsible for the anatomic segregation of different cell populations in tissues. Chemokines mediate their activities by binding to specific G-protein-coupled receptors on target cells; two of these chemokine receptors (called CXCR4 and CCR5) are important coreceptors for the binding and entry of the human immunodeficiency virus into lymphocytes. The two major groups are the CXC and CC chemokines: - CXC chemokines act primarily on neutrophils. IL-8 is typical of this group; it is produced by activated macrophages, endothelial cells, mast cells, and fibroblasts, mainly in response to microbial products and other cytokines such as IL-1 and TNF. - CC chemokines include monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1 (MIP-1) (both chemotactic predominantly for monocytes), RANTES (regulated on activation normal T expressed and secreted) (chemotactic for memory CD4+ T cells and monocytes), and eotaxin (chemotactic for eosinophils). - Reactive Oxygen Species: ROS are synthesized via the NADPH oxidase (phagocyte oxidase) pathway and are released from neutrophils and macrophages that are activated by microbes, immune complexes, cytokines, and a variety of other inflammatory stimuli. When the ROS are produced within lysosomes they function to destroy phagocytosed microbes and necrotic cells. At high levels, these mediators are responsible for tissue injury by several mechanisms, including (1) endothelial damage, with thrombosis and increased permeability; (2) protease activation and antiprotease inactivation, with a net increase in breakdown of the ECM; and (3) direct injury to other cell types (e.g., tumor cells, erythrocytes, parenchymal cells). Fortunately, various antioxidant protective mechanisms (e.g., catalase, superoxide dismutase, and glutathione) are present in tissues and blood to minimize the toxicity of the oxygen - Nitric Oxide: In the central nervous system it regulates neurotransmitter release as well as blood flow. Macrophages use it as a cytotoxic metabolite for killing microbes and tumor cells. When produced it causes: (1) relaxation of vascular smooth muscle (vasodilation), (2) antagonism of all stages of platelet activation (adhesion, aggregation, and degranulation), (3) reduction of leukocyte recruitment at inflammatory sites, and (4) action as a microbicidal (cytotoxic) agent (with or without superoxide radicals) in activated macrophages.

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- Lysosomal Enzymes of Leukocytes: These may be released after cell death, by leakage during the formation of the phagocytic vacuole, or during futile attempts to phagocytose large, indigestible surfaces. Acid proteases have acidic pH optima and are generally active only within phagolysosomes, whereas neutral proteases, including elastase, collagenase, and cathepsin, are active in the ECM and cause destructive, deforming tissue injury by degrading elastin, collagen, basement membrane, and other matrix proteins. Neutral proteases can also cleave the complement proteins C3 and C5 directly to generate the vasoactive mediators C3a and C5a and can generate bradykinin-like peptides from kininogen. - Neuropeptides: These are small proteins, such as substance P, that transmit pain signals, regulate vessel tone, and modulate vascular permeability. Plasma Protein-Derived Mediators The complement, kinin, and coagulation systems. - Complement: Consists of plasma proteins. Upon activation, different complement proteins coat (opsonize) particles, such as microbes, for phagocytosis and destruction, and contribute to the inflammatory response by increasing vascular permeability and leukocyte chemotaxis. Complement activation ultimately generates a porelike membrane attack complex (MAC) that punches holes in the membranes of invading microbes.

Complement components (numbered C1 to C9) are present in plasma in inactive forms, and many of them are activated by proteolysis to themselves acquire proteolytic activity, thus setting up an enzymatic cascade. The critical step in the generation of biologically active complement products is the activation of the third component, C3. C3 cleavage occurs (1) via the classical pathway, triggered by fixation of the first complement component C1 to antigenantibody complexes; (2) through the alternative pathway, triggered by bacterial polysaccharides (e.g., endotoxin) and other microbial cell-wall components, and involving a distinct set of plasma proteins; and (3) by the lectin pathway, in which a plasma lectin binds to mannose residues on microbes and activates an early component of the classical pathway. All three pathways lead to the formation of a C3 convertase that cleaves C3 to C3a and C3b. The complement-derived factors affect a variety of phenomena: Vascular effects: C3a and C5a increase vascular permeability and cause vasodilation by inducing mast cells to release histamine (anaphylatoxins). C5a also activates the lipoxygenase pathway of AA metabolism in neutrophils and macrophages, causing release of more inflammatory mediators. Leukocyte activation, adhesion, and chemotaxis: C5a activates leukocytes, increasing their adhesion to endothelium, and is a potent chemotactic agent for neutrophils, monocytes, eosinophils, and basophils.

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 Phagocytosis: When fixed to a microbial surface, C3b acts as opsonin, augmenting phagocytosis by neutrophils and macrophages. Inappropriate or excessive complement activation can overwhelm the regulatory systems, and be responsible for serious tissue injury in a variety of immunologic disorders. - Coagulation and Kinin Systems: A central event is activation of Hageman factor. Activated Hageman factor (factor XIIa) initiates four systems involved in the inflammatory response:

(1) the kinin system, producing vasoactive kinins; (2) the clotting system, inducing the activation of thrombin, fibrinopeptides, and factor X, all with inflammatory properties; (3) the fibrinolytic system, producing plasmin and inactivating thrombin; and (4) the complement system, producing the anaphylatoxins C3a and C5a. Hageman factor in an inactive form until it encounters collagen, basement membrane, or activated platelets (e.g., at a site of endothelial injury). With the assistance of a high-molecular-weight kininogen (HMWK) cofactor, factor XII then undergoes a conformational change (becoming factor XIIa), that can cleave several protein substrates of the kinin and coagulation systems. In the clotting system, the factor XII leads to activation of thrombin, which then cleaves circulating soluble fibrinogen to generate an insoluble fibrin clot. Factor Xa, an intermediate in the clotting cascade, causes increased vascular permeability and leukocyte emigration. Binding of thrombin to protease-activated receptors that are expressed on platelets, endothelial cells, and many other cell types, leads to their activation and enhanced leukocyte adhesion on endothelial cells. In addition, thrombin generates fibrinopeptides that increase vascular permeability and are chemotactic for leukocytes. While activated Hageman factor is inducing clotting, it is concurrently activating the fibrinolytic system. This mechanism exists to limit clotting by cleaving fibrin, thereby solubilizing the fibrin clot. Without fibrinolysis and other regulatory mechanisms, initiation of the coagulation cascade, even by trivial injury, would culminate in continuous and irrevocable clotting of the entire vasculature. Kinin system activation leads ultimately to the formation of bradykinin from its circulating precursor, HMWK. Like histamine, bradykinin causes increased vascular permeability, arteriolar dilation, and bronchial smooth muscle contraction. It also causes pain when injected into the skin. The actions of bradykinin are short-lived because it is rapidly degraded by kininases present in plasma and tissues.

57. Metabolic changes and proliferative processes during inflammation.

The cellular phase of inflammation follows and is evidenced by the migration of phagocytic white blood cells that digest and remove invading organisms, fibrin, extracellular debris, and other foreign matter. The neutrophils or PMNs are the first cells to arrive and are usually gone by day 3 or 4. They ingest bacteria and cellular debris. Approximately 24 hours after the arrival of the PMNs, a larger and

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less specific phagocytic cell, the macrophage, which is an essential cell in the healing process, enters the wound area and remains for an extended period. Its functions include phagocytosis and release of growth factors that stimulate epithelial cell growth, angiogenesis (i.e., growth of new blood vessels), and attraction of fibroblasts. When a large defect occurs in deeper tissues, PMNs and macrophages are required to remove the debris and facilitate wound closure. Although a wound may heal in the absence of PMNs, it cannot heal in the absence of macrophages. The proliferative phase of healing usually begins within 2 to 3 days of injury and may last as long as 3 weeks in wounds healing by primary intention. The primary processes during this time focus on the building of new tissue to fill the wound space. The key cell during this phase is the fibroblast. The fibroblast is a connective tissue cell that synthesizes and secretes collagen and other intercellular elements needed for wound healing. Fibroblasts also produce a family of growth factors that induce the growth of blood vessels (angiogenesis) and endothelial cell proliferation and migration. As early as 24 to 48 hours after injury, fibroblasts and vascular endothelial cells begin proliferating to form a specialized type of soft, pink granular tissue, called granulation tissue, that serves as the foundation for scar tissue development. This tissue is fragile and bleeds easily because of the numerous, newly developed capillary buds. Wounds that heal by secondary intention have more necrotic debris and exudate that must be removed, and they involve larger amounts of granulation tissue. The newly formed blood vessels are leaky and allow plasma proteins and white blood cells to leak into the tissues. At approximately the same time, epithelial cells at the margin of the wound begin to regenerate and move toward the center of the wound, forming a new surface layer that is similar to that destroyed by the injury. In wounds that heal by primary intention, these epidermal cells proliferate and seal the wound within 24 to 48 hours.8 When a scab has formed on the wound, the epithelial cells migrate between it and the underlying viable tissue; when a significant portion of the wound has been covered with epithelial tissue, the scab can be easily removed. At times, excessive granulation tissue, sometimes referred to as proud flesh, may form and extend above the edges of wound, preventing re-epithelialization. Surgical removal or chemical cauterization of the defect allows healing to proceed. As the proliferative phase progresses, there is continued accumulation of collagen and proliferation of fibroblasts. Collagen synthesis reaches a peak within 5 to 7 days and continues for several weeks, depending on wound size. By the second week, the white blood cells have largely left the area, the edema has diminished, and the wound begins to blanch as the small blood vessels become thrombosed and degenerate. Inflammatory and immune mechanisms function in wound healing. Inflammation is essential to the first phase of wound healing, and immune mechanisms prevent infections that impair wound healing. Among the conditions that impair inflammation and immune function are disorders of phagocytic function, diabetes mellitus, and therapeutic administration of corticosteroid drugs. Phagocytic disorders may be divided into extrinsic and intrinsic defects. Extrinsic disorders are those that impair attraction of phagocytic cells to the wound site, prevent engulfment of bacteria and

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foreign agents by the phagocytic cells (i.e., opsonization), or cause suppression of the total number of phagocytic cells (e.g., immunosuppressive agents). Intrinsic phagocytic disorders are the result of enzymatic deficiencies in the metabolic pathway for destroying the ingested bacteria by the phagocytic cell.

58- Types of inflammation. Development, going out, and biological significance of inflammation
The survival of all organisms requires that they eliminate foreign invaders, such as infectious pathogens, and damaged tissues. These functions are mediated by a complex host response called inflammation. Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult. Inflammation accomplishes its protective mission by diluting, destroying, or otherwise neutralizing harmful agents (e.g., microbes and toxins). The components of the inflammatory reaction that destroy and eliminate microbes and dead tissues are capable of also injuring normal tissues. Therefore, injury may accompany entirely normal, beneficial inflammatory reactions, and the pathology may even become the dominant feature if the reaction is very strong (e.g., when the infection is severe), prolonged (e.g., when the eliciting agent resists eradication), or inappropriate (e.g., when it is directed against self-antigens in autoimmune diseases. or against usually harmless environmental antigens in allergic disorders).The cells and molecules of host defense normally circulate in the blood, and the goal of the inflammatory reaction is to bring them to the site of infection or tissue damage. Blood leukocytes and plasma proteins, cells of vascular walls, and cells and extracellular matrix (ECM) of the surrounding connective tissue play important roles in inflammation. Inflammation can be acute or chronic. Acute inflammation is rapid in onset and of short duration, lasting from a few minutes to as long as a few days, and is characterized by fluid and plasma protein exudation and a predominantly neutrophilic leukocyte accumulation. Chronic inflammation may be more insidious, is of longer duration (days to years), and is typified by influx of lymphocytes and macrophages with associated vascular proliferation and fibrosis (scarring). When a host encounters an injurious agent (e.g., a microbe) or dead cells, phagocytes that reside in tissues try to eliminate these agents. At the same time, phagocytes and other host cells react to the presence of the foreign or abnormal substance by liberating several protein and lipid molecules that function as chemical mediators of inflammation. Mediators are also produced from plasma proteins that react with the microbes or to injured tissues. Some of these mediators act on small blood vessels in the vicinity and promote the efflux of plasma and the recruitment of circulating leukocytes to the site where the offending agent is located. The recruited leukocytes are activated by the injurious agent and by locally produced mediators, and the activated leukocytes try to remove the offending agent by phagocytosis. The external manifestations of inflammation, often called its cardinal signs, result from the vascular changes and cell recruitment: heat (calor), redness (rubor), and swelling (tumor) and pain (dolor) and loss of function (functio laesa), occur as consequences of mediator elaboration and leukocytemediated damage. As the injurious agent is eliminated and anti-inflammatory mechanisms become 91

active, the process subsides and the host returns to a normal state of health. If the injurious agent cannot be quickly eliminated, the result may be chronic inflammation.

59. Chronic inflammation

Acute infections usually are self-limiting and rapidly controlled by the host defenses. In contrast, chronic inflammation is selfperpetuating and may last for weeks, months, or even years. It may develop during a recurrent or progressive acute inflammatory process or from low-grade, smoldering responses that fail to evoke an acute response.Characteristic of chronic inflammation is an infiltration by mononuclear cells (macrophages) and lymphocytes, instead of the influx of neutrophils commonly seen in acute inflammation. Chronic inflammation also involves the proliferation of fibroblasts instead of exudates. As a result, the risk of scarring and deformity usually is considered greater than in acute inflammation. Agents that evoke chronic inflammation typically are low-grade, persistent irritants that are unable to penetrate deeply or spread rapidly. Among the causes of chronic inflammation are foreign bodies such as talc, silica, asbestos, and surgical suture materials. Many viruses provoke chronic inflammatory responses, as do certain bacteria, fungi, and larger parasites of moderate to low virulence. Examples are the tubercle bacillus, the treponema of syphilis, and the actinomyces. The presence of injured tissue such as that surrounding a healing fracture also may incite chronic inflammation.Immunologic mechanisms are thought to play an important role in chronic inflammation. The two patterns of chronic inflammation are a nonspecific chronic inflammation and granulomatous inflammation.

Nonspecific Chronic Inflammation Nonspecific chronic inflammation involves a diffuse accumulation of macrophages and lymphocytes at the site of injury. Ongoing chemotaxis causes macrophages to infiltrate the inflamed site, where they accumulate because of prolonged survival and immobilization. These mechanisms lead to fibroblast proliferation, with subsequent scar formation that in many cases replaces the normal connective tissue or the functional parenchymal tissues of the involved structures. For example, scar tissue resulting from chronic inflammation of the bowel causes narrowing of the bowel lumen. A granulomatous lesion results from chronic inflammation. A granuloma typically is a small, 1- to 2mm lesion in which there is a massing of macrophages surrounded by lymphocytes. These modified macrophages resemble epithelial cells and sometimes are called epithelioid cells. Like other macrophages, these epithelioid cells are derived originally from blood monocytes. Granulomatous inflammation is associated with foreign bodies such as splinters, sutures, silica, and asbestos and with microorganisms that cause tuberculosis, syphilis, sarcoidosis, deep fungal infections, and brucellosis. These types of agents have one thing in common: they are poorly digested and usually are not easily controlled by other inflammatory mechanisms. The epithelioid cells in granulomatous inflammation may clump in a mass (granuloma) or coalesce, forming a large, multinucleated giant cell that attempts to surround the foreign agent. A dense membrane of connective tissue eventually encapsulates the lesion and isolates it.

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60.Fever etiology and pathogenesis

Fever (also known as pyrexia) is a common medical sign characterized by an elevation of temperature above the normal range of 36.537.5 C (98100 F) due to an increase in the body temperature regulatory set-point.[2] This increase in set-point triggers increased muscle tone and shivering. As a person's temperature increases, there is, in general, a feeling of cold despite an increasing body temperature. Once the new temperature is reached, there is a feeling of warmth. A fever can be caused by many different conditions ranging from benign to potentially serious. There are arguments for and against the usefulness of fever, and the issue is controversial. With the exception of very high temperatures, treatment to reduce fever is often not necessary; however, antipyretic medications can be effective at lowering the temperature, which may improve the affected person's comfort. Fever differs from uncontrolled hyperthermia,[1] in that hyperthermia is an increase in body temperature over the body's thermoregulatory set-point, due to excessive heat production and/or insufficient thermoregulation. fever might be caused by: A virus A bacterial infection Heat exhaustion Extreme sunburn Certain inflammatory conditions such as rheumatoid arthritis inflammation of the lining of your joints (synovium) A malignant tumor Some medications, such as antibiotics and drugs used to treat high blood pressure or seizures Some immunizations, such as the diphtheria, tetanus and acellular pertussis (DTaP) or pneumococcal vaccines Temperature is ultimately regulated in the hypothalamus. A trigger of the fever, called a pyrogen, causes a release of prostaglandin E2 (PGE2). PGE2 then in turn acts on the hypothalamus, which generates a systemic response back to the rest of the body, causing heat-creating effects to match a new temperature level. In many respects, the hypothalamus works like a thermostat.[20] When the set point is raised, the body increases its temperature through both active generation of heat and retaining heat. Vasoconstriction both reduces heat loss through the skin and causes the person to feel cold. If these measures are insufficient to make the blood temperature in the brain match the new setting in the hypothalamus, then shivering begins in order to use muscle movements to produce more heat. When the fever stops, and the hypothalamic setting is set lower; the reverse of these processes (vasodilation, end of shivering and nonshivering heat production) and sweating are used to cool the body to the new, lower setting. This contrasts with hyperthermia, in which the normal setting remains, and the body overheats through undesirable retention of excess heat or over-production of heat.[20] Hyperthermia is usually the result of an excessively hot environment (heat stroke) or an adverse reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances surrounding it and its response to antipyretic medications.

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61. Stages of fever. Types of temperature curves

Manifestations The physiologic behaviors that occur during the development of fever can be divided into four successive stages: a prodrome; a chill, during which the temperature rises; a flush; and defervescence.During the first or prodromal period, there are nonspecific complaints, such as mild headache and fatigue, general malaise, and fleeting aches and pains. During the second stage or chill, there is the uncomfortable sensation of being chilled and the onset of generalized shaking, although the temperature is rising. Vasoconstriction and piloerection usually precede the onset of shivering. At this point the skin is pale and covered with goose flesh. There is a feeling of being cold and an urge to put on more clothing or covering and to curl up in a position that conserves body heat. When the shivering has caused the body temperature to reach the new set point of the temperature control center, the shivering ceases, and a sensation of warmth develops. At this point, the third stage or flush begins, during which cutaneous vasodilation occurs and the skin becomes warm and flushed. The fourth, or defervescence, stage of the febrile response is marked by the initiation of sweating. Not all persons proceed through the four stages of fever development. Sweating may be absent, and fever may develop gradually, with no indication of a chill or shivering. Common manifestations of fever are anorexia, myalgia, arthralgia, and fatigue. These discomforts are worse when the temperature rises rapidly or exceeds 39.5C (103.1F). Respiration is increased, and the heart rate usually is elevated. Dehydration occurs because of sweating and the increased vapor losses caused by the rapid respiratory rate. The occurrence of chills commonly coincides with the introduction of pyrogen into the circulation. This is one of the reasons that blood cultures to identify the organism causing the fever are usually drawn during the first signs of a chill. A number of infectious processes have typical temperature curves characterizing the manifestations of fever. The following forms of fever are distinguished, according to the elevation of the temperature: a) subfebrile (not above 38 C, b) moderate (up to 39 C) , c) high (39-41), and d) excessively high - hyperpyretic (41 C and higher). The body temperature very rarely rises above 41 C. The following main forms of fever are distinguished according to the character of the temperature curves: 1 Continuous fever (febris continua) in which the elevated temperature for some time persists on a high level, the difference between the morning and evening temperature not exceeding 1 C. The fever may end abruptly (crisis) or gradually (lysis) . This form includes typhoid fever early in the course of the disease, the fever in croupous pneumonia, typhus and certain other infectious disease. 2. Remittent fever (febris remittens) in which the difference between the morning and evening temperature exceeds 1 C. It includes the temperature curves observed during the late course to typhoid fever, sepsis and catarrhal pneumonia. 3 Intermittent fever (febris intermittens) which is characterized by regular alternation of brief attacks of fever (paroxysms) with feverless periods (apyrexia). High temperature persists for several hours, drops to normal and then rises again. The length to the feverless periods may vary. This form of temperature curve is characteristic of malaria. Attacks of fever may occur every third day (febris quartana), every second day (febris tertina ) or every day (febris quotidiana) 4 Recurrent fever (febris recurrents) which is characterized by longer periods of pyrexia than in intermittent fever (5-8 days). The duration of these periods corresponds to that of the periods corresponds to that of the periods of normal temperature. Such a curve is characteristic of replasing fever. 94

There are fevers- which at first run the course of febris continua and then change to febris remittens (for example, in typhoid fever). There are also fevers of short duration (ephemeral) with an indefinite or irregular course (considerable diurnal variations in body temperature) and fevers with a perverted course, for example, an elevation of temperature in the morning and a drop in the evening (in some forms of sepsis and tuberculosis) . The aforementioned types of temperature curves dc not exhaust their variety. The type of temperature curve is determined not only by the character of the infection, but also by the reactivity of the characterized by increased heat loss and its predominance over heat production which may relatively even increase. Heat lass increases as a result of excessive perspiration (sometimes very profuse) and considerable dilatation of the peripheral vessels. The ratio of heat production to heat loss is the reverse of that observed during the first stage of fever. Then heat production, heat loss and body temperature return to normal. At this stage the temperature is often unstable. The temperature drops either rapidly (crisis) or slowly, gradually (lysis). A critical drop in temperature, especially in cases of cardiovascular insufficiency, in dangerous because it requires a rapid adjustment of the organism to the new conditions of the internal environment. This may result in a shock reaction (collapse). In all the aforedescribed stages physical and chemical thermoregulation functions concertedly. In man the disturbance in physical thermoregulation is of the utmost importance. The different stages of the febrile reaction may be characterized by noticeable fluctuations in the heat balance due to compensation for the disturbed functions, which is in its turn connected with the physiologic defence role of the central nervous system. Thus the course of the different stages of the febrile process is determined, not only by the etioiogic factor, but also by the general state of the organism, its reactivity, metabolism and intensity of the oxidative processes

62-Metabolic And Functional Changes During Fever.Biological Significance Of Fever.

Fever (also known as pyrexia) is a common medical sign characterized by an elevation of temperature above the normal range of 36.537.5 C (98100 F) due to an increase in the body temperature regulatory set-point.[2] This increase in set-point triggers increased muscle tone and shivering. As a person's temperature increases, there is, in general, a feeling of cold despite an increasing body temperature. Once the new temperature is reached, there is a feeling of warmth. A fever can be caused by many different conditions ranging from benign to potentially serious. There are arguments for and against the usefulness of fever, and the issue is controversial. With the exception of very high temperatures, treatment to reduce fever is often not necessary; however, antipyretic medications can be effective at lowering the temperature, which may improve the affected person's comfort. Fever differs from uncontrolled hyperthermia,[1] in that hyperthermia is an increase in body temperature over the body's thermoregulatory set-point, due to excessive heat production and/or insufficient thermoregulation. fever might be caused by: A virus A bacterial infection Heat exhaustion Extreme sunburn Certain inflammatory conditions such as rheumatoid arthritis inflammation of the lining of your

95

joints (synovium) A malignant tumor Some medications, such as antibiotics and drugs used to treat high blood pressure or seizures Some immunizations, such as the diphtheria, tetanus and acellular pertussis (DTaP) or pneumococcal vaccines Temperature is ultimately regulated in the hypothalamus. A trigger of the fever, called a pyrogen, causes a release of prostaglandin E2 (PGE2). PGE2 then in turn acts on the hypothalamus, which generates a systemic response back to the rest of the body, causing heat-creating effects to match a new temperature level. In many respects, the hypothalamus works like a thermostat.[20] When the set point is raised, the body increases its temperature through both active generation of heat and retaining heat. Vasoconstriction both reduces heat loss through the skin and causes the person to feel cold. If these measures are insufficient to make the blood temperature in the brain match the new setting in the hypothalamus, then shivering begins in order to use muscle movements to produce more heat. When the fever stops, and the hypothalamic setting is set lower; the reverse of these processes (vasodilation, end of shivering and nonshivering heat production) and sweating are used to cool the body to the new, lower setting. This contrasts with hyperthermia, in which the normal setting remains, and the body overheats through undesirable retention of excess heat or over-production of heat.[20] Hyperthermia is usually the result of an excessively hot environment (heat stroke) or an adverse reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances surrounding it and its response to antipyretic medications.

63.The molecular & biochemical basis of neoplasia. Genetic changes, oncogenes & tumor suppressor genes.
Neoplasia is the abnormal proliferation of cells.The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the stimuli. It usually causes a lump or tumor. Neoplasms may be benign, pre-malignant or malignant. Benign neoplasms include uterine fibroids and skin moles. They are circumscribed and localized and do not transform into cancer.Potentially malignant neoplasms include carcinoma in situ. They do not invade and destroy but, given enough time, will transform into a cancer.Malignant neoplasms are commonly called cancer. They invade and destroy the surrounding tissue, may form metastases and eventually kill the host. Pathophysiology Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.Cancer is fundamentally a disease of failure of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, the genes which regulate cell growth and differentiation must be altered.The affected genes are divided into two broad categories. Oncogenes are genes which promote cell growth and reproduction. Tumor suppressor genes are genes which inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, 96

the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes.Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase. Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and resulting in the expression of viral oncogenes in the affected cell and its descendants. Replication of the enormous amount of data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention is built into the process, and safeguards the cell against cancer. If significant error occurs, the damaged cell can "self-destruct" through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells. Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called carcinogens, repeated physical injury, heat, ionising radiation, or hypoxia.The errors which cause cancer are self-amplifying and compounding, for example: A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly. A further mutation in an oncogene might cause the cell to reproduce more rapidly and more frequently than its normal counterparts. A further mutation may cause loss of a tumour suppressor gene, disrupting the apoptosis signalling pathway and resulting in the cell becoming immortal.

64. The molecular & biochemical basis of neoplasia. Hormones, growth factors & inhibitors, and stromal, adhesive & proteolytic proteins
Hormones, Growth Factors, & Other Cellular Genes in Neoplasia Signaling proteins of all kinds may drive the oncogenic process through abnormal signaling: abnormal in time, duration, or intensity; abnormal tissue expression; or abnormal subcellular compartment localization. The regulation of growth in complex organisms requires specialized proteins for the normal growth, maturation, development, and function of cells and specialized tissue. An essential component of this regulation is the system of hormones, growth factors, and growth inhibitors. On binding to specific receptor proteins on the cell surface or in the cytoplasm, these factors lead to mitogenesis, growth inhibition, changes in cell cycle regulation, apoptosis, differentiation, and induction of a secondary set of genes. The actual end effects are dependent not only on the particular type of interacting factor and receptor but also on the cell type and milieu in which factor 97

receptor coupling occurs. This system allows for cell-to-cell interactions, whereby a factor secreted by one cell or tissue can enter the bloodstream and influence another set of distant cells (endocrine action) or act on adjacent cells (paracrine action). An autocrine action is when a cell produces a factor that binds to a receptor on or in the same cell. Altered concentration of these growth factors as well as overexpression or mutations of the receptors can change the signaling behavior, contributing to a malignant phenotype. Only a subset of growth factor receptors are proto-oncogenes. Many additional growth factors and growth factor receptors appear to be important in tumor growth and progression, although not classified as protooncogenes, because they serve tumorigenic causes without incurring mutations or without overexpression. An important class of growth factor signaling molecules are the growth factor receptor tyrosine kinases (RTKs). Most are capable of transforming cells if activated or overexpressed. Members of the HER family of RTKs are commonly mutated or amplified in human tumors and exemplify the important role of RTKs in human neoplasia. In many other tumors, they likely play an important role despite having a normal sequence and expression level. For example, HER1 (also called EGFR) is not mutated or overexpressed in colon cancers, but it is sometimes activated by autocrine signaling in the cancer cells. The platelet-derived growth factor (PDGF) receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, and insulin-like growth factor receptor are all families of RTKs that function similar to HER family RTKs. These receptors are, in general, not reported to be mutated or amplified in human tumors. However, there is increased expression in many tumors or aberrant expression in tumors from tissue types that ordinarily would not be expected to express that receptor. Alternatively, excessive production of receptor ligands is due to a variety of mechanisms. Some growth factor signaling pathways function to inhibit cell growth and provide negative regulation in response to extracellular stimuli. Desensitization of cells to such growth inhibitors is common in tumors. An example of this is the transforming growth factor- (TGF-). TGF- potently inhibits cell proliferation but also stimulates the production and deposition of extracellular matrix (ECM) and adhesion factors. Continued secretion, and often oversecretion, of TGF- by the tumor and stromal tissues leads to an increase in the production of ECM and adhesion factors and promotes the invasive and metastatic property of tumors.Another important class of receptors is the large superfamily of nuclear hormone receptors. These include the cellular receptors for a variety of hormones, among them estrogen and progesterone, androgens, glucocorticoids, thyroid hormone, and retinoids. The actions of estrogen are fundamentally important in the development of breast cancer. Approximately half of all breast cancers are dependent on estrogen for proliferation. Although the loss of certain tumor suppressor genes or activation of certain oncogenes leads to the development of breast cancer, continued ER (estrogen receptor) function is essential throughout this process and without ER function it cannot proceed. Alternatively, it is possible that abnormal ER signaling, perhaps as a result of altered cofactors, cross-talk, or phosphorylation status, drives breast carcinogenesis. The androgen receptor (AR), similarly, plays a critical role in the development of prostate cancer. The ability of retinoids (ligands for retinoic acid receptors) that are well known to participate in the differentiation of a variety of tissues during development to cause the differentiation of certain 98

tumors is exploited as a treatment approach for acute promyelocytic leukemia (APL). APL is characterized by a t(15;17) chromosomal translocation resulting in the fusion of the PML gene with the retinoic acid receptor- (RAR-) gene. The resulting fusion protein blocks the differentiation of hematopoietic progenitor cells and eventually leads to the development of APL. Because the fusion protein contains the ligand-binding domain of RAR-, it remains sensitive to ligand and treatment of patients with the ligand all-trans retinoic acid results in differentiation of tumor cells and complete remission in most patients with this disease.Other functional membrane proteins not related to growth can also be present on tumors cells. The MDR-1 gene product belongs to a class of ATPdependent channel transporter proteins and is present on some normal epithelial cells. Its physiologic role may be to pump toxic molecules out of the cell, but in some tumor cells, its overexpression causes efflux of certain chemotherapeutic agents, leading to drug resistance. Stromal, Adhesive, & Proteolytic Proteins The preservation of tissue structure in multicellular organisms involves the orderly arrangement of cells within an architectural framework. This higher-level order is required to maintain tissue structure and organ function, and mechanisms are in place to enable remodeling during embryogenesis or during wound repair. A number of protein families serve to constitute the ECM, to embed cells within the ECM, to attach cells to each other, and to dissolve and reestablish the ECM when necessary. Abnormalities of these proteins frequently occur in later stages of tumorigenesis, account for the loss of architecture, and mediate the invasive and metastatic phenotype of tumor cells. Integrins are a large family of membrane proteins that bind ECM ligands, anchor cells to the ECM, and activate intracellular signaling pathways in response to ECM signals. Cells have the ability to express any of a large repertoire of integrin combinations. Tumor cells can reshuffle their integrin expression profiles in favor of an invasive or metastatic phenotype. Cadherins are a family of membrane proteins that function in epithelial cell-to-cell adhesion. Loss of E-cadherin expression is seen in some human epithelial tumors leading to a more invasive phenotype. The expression and activity of many secreted and membrane-anchored proteases are increased in tumor cells. This includes the matrix metalloprotease family and the serine protease family of proteins. Increased protease activity leads to ECM degradation, triggering of the plasminogen activation cascade, and activation of transmembrane receptors through cleavage and shedding of their extracellular domains. Through abnormalities in deposition of ECM, of expression of cell adhesion proteins, and in activity of membrane and secreted proteases, cancer cells develop an invasive and ultimately a metastatic phenotype.

65. Cellular changes in neoplasia. Differences between normal and cancer cell.
The molecular changes of neoplastic cells and their phenotypic behavior is a constantly evolving process. Every cell division can result in additional genomic abnormalities and a variety of phenotypic consequences. Certain genotypes result in proliferative, survival, or other biological attributes that favor its clonal expansion. Such neoplastic clones eventually overtake the tumor cell population and change its clinical behavior. This remodeling process occurs repeatedly with repeated cell division, 99

recreating a process akin to evolution, albeit in a much faster timeframe. Attributes that are acquired early during the evolution of cancer include enhanced proliferation and survival. Changes that are acquired midpoint include the ability to overcome spacial limitations by invading surrounding tissues, the ability to survive under conditions of low oxygen and nutrients, and the ability to evade host immune defenses. Changes acquired later in the progression of neoplasia are the ability to travel to distant organs and the ability to resist anticancer treatments. The changing nature of cancer with repeated cell proliferation cycles along constantly expanding cell lineages creates heterogeneity in the whole tumor cell population. Tumor cell heterogeneity is a common characteristic of many types of cancer. Although many or most of the cells that arise from cancer cell division themselves proceed to multiply, the changes with repeated cycles of cell division often lead to the loss of some of the more fundamental properties of the ancestral cancer cells. For example, many of the cells in a tumor are unable to give rise to a new tumor if isolated. In fact, only a small proportion of cancer cells appear to be capable of starting new colonies of cancer cells if isolated or if metastasized to a new site in the body. Such cells, named cancer stem cells, typically do not proliferate as fast but are capable of self-renewal and of generating daughter cells that can proliferate much faster and produce new tumors. Current efforts explore the hypotheses that defects in normal tissue stem cells within an organ give rise to cancer stem cells terminally differentiated cells (non-stem cells) usurp the machinery used by normal stem cells in the process of becoming cancer stem cells. Cancer cells, unlike normal cells, fail to undergo normal cell proliferation and differentiation. It is thought that cancer cells develop from mutations that occur during the differentiation process. When the mutation occurs early in the process, the resulting tumor is poorly differentiated and highly malignant; when it occurs later in the process, better differentiated and less malignant tumors result. The term anaplasia is used to describe the lack of cell differentiation in cancerous tissue. Undifferentiated cancer cells are altered in appearance and nuclear size and shape from the cells in the tissue from which the cancer originated. In descending the scale of differentiation, enzymes and specialized pathways of metabolism are lost and cells undergo functional simplification. Highly anaplastic cancer cells, whatever their tissue of origin, begin to resemble each other more than they do their tissue of origin. For example, when examined under the microscope, cancerous tissue that originates in the liver does not have the appearance of normal liver tissue. Some cancers display only slight anaplasia, and others display marked anaplasia.

66. Tumor/organism relationships

The importance of neoplasms lies in their effects on patients. Although malignant tumors are of course more threatening than benign tumors, any tumor, even a benign one, may cause morbidity and mortality. Indeed, both malignant and benign tumors may cause problems because of (1) location and impingement on adjacent structures, (2) functional activity such as hormone synthesis or the development of paraneoplastic syndromes, (3) bleeding and infections when the tumor ulcerates through adjacent surfaces, (4) symptoms that result from rupture or infarction, and (5) cachexia or wasting.

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Effects of Tumor on Host: Location is crucial in both benign and malignant tumors. A small (1-cm) pituitary adenoma can compress and destroy the surrounding normal gland and give rise to hypopituitarism. A 0.5-cm leiomyoma in the wall of the renal artery may lead to renal ischemia and serious hypertension. A comparably small carcinoma within the common bile duct may induce fatal biliary tract obstruction. Hormone production is seen with benign and malignant neoplasms arising in endocrine glands. Adenomas and carcinomas arising in the -cells of the islets of the pancreas can produce hyperinsulinism, sometimes fatal. Analogously, some adenomas and carcinomas of the adrenal cortex elaborate corticosteroids that affect the patient (e.g., aldosterone, which induces sodium retention, hypertension, and hypokalemia). Such hormonal activity is more likely with a welldifferentiated benign tumor than with a corresponding carcinoma. A tumor may ulcerate through a surface, with consequent bleeding or secondary infection. Benign or malignant neoplasms that protrude into the gut lumen may become caught in the peristaltic pull of the gut, causing intussusception and intestinal obstruction or infarction. Cancer Cachexia: Many cancer patients suffer progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia, referred to as cachexia. There is some correlation between the size and extent of spread of the cancer and the severity of the cachexia. However, cachexia is not caused by the nutritional demands of the tumor. Cachexia results from the action of soluble factors such as cytokines produced by the tumor and the host rather than reduced food intake. In patients with cancer, calorie expenditure remains high, and basal metabolic rate is increased, despite reduced food intake. It is suspected that TNF produced by macrophages in response to tumor cells or by the tumor cells themselves mediates cachexia. TNF suppresses appetite and inhibits the action of lipoprotein lipase, inhibiting the release of free fatty acids from lipoproteins. Additionally, a protein-mobilizing factor called proteolysis-inducing factor, which causes breakdown of skeletal muscle proteins by the ubiquitin-proteosome pathway, has been detected in the serum of cancer patients. Other molecules with lipolytic action also have been found. There is no satisfactory treatment for cancer cachexia other than removal of the underlying cause, the tumor. Paraneoplastic Syndromes: Symptom complexes that occur in patients with cancer and that cannot be readily explained by local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue of origin of the tumor are referred to as paraneoplastic syndromes. They appear in 10% to 15% of patients with cancer, and it is important to recognize them for several reasons: They may represent the earliest manifestation of an occult neoplasm. In affected patients, they may represent significant clinical problems and may even be lethal. They may mimic metastatic disease and confound treatment. The most common syndromes are hypercalcemia, Cushing syndrome, and nonbacterial thrombotic endocarditis; the neoplasms most often associated with these and other syndromes are lung and breast cancers and hematologic malignancies. Hypercalcemia in cancer patients is multifactorial, but the most important mechanism is the synthesis of a parathyroid hormone-related protein (PTHrP) by tumor cells. Also implicated are other tumor-derived factors, such as TGF-, a polypeptide factor that activates osteoclasts, and the active form of vitamin D. Cushing syndrome as a paraneoplastic phenomenon is usually related to ectopic production of ACTH

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or ACTH-like polypeptides by cancer cells, as occurs in small-cell cancers of the lung. Sometimes one tumor induces several syndromes concurrently. For example, bronchogenic carcinomas may elaborate products identical to or having the effects of ACTH, antidiuretic hormone, parathyroid hormone, serotonin, human chorionic gonadotropin, and other bioactive substances. Paraneoplastic syndromes may also manifest as hypercoagulability leading to venous thrombosis and nonbacterial thrombotic endocarditis. Other manifestations are clubbing of the fingers and hypertrophic osteoarthropathy in patients with lung carcinomas.

67. Epithelial neoplasia. Carcinomas.

Epithelial cells are in constant turnover, arising from a basal layer that continually generates new cells. The mature and functional layer of cells performs specialized tissue or organ functions, and with senescence it is eventually sloughed off. Proliferating epithelial cells normally observe anatomic boundaries such as the basement membrane that underlies the basal layer of cells in the epithelium. The potential to divide, migrate, and differentiate is tightly controlled. The stimulus to divide may be autonomous or exogenous as a response to factors from adjacent or distant cells. Inhibitory signals and factors may also be present and serve to function as negative regulators to check uncontrolled growth. The neoplastic phenotype of epithelial cells can be seen as a spectrum from hyperplastic to preinvasive to frankly invasive and metastatic neoplasia. Because of their embryonic origins, malignancies of epithelial origin are termed carcinomas. Hyperplasia can be a normal physiologic response in some situations, such as that which occurs in the lining of the uterus in response to estrogens before the ovulatory phase of the menstrual cycle. It may also be a pathologic finding and associated with a predisposition to progress to invasive carcinoma. In such instances of hyperplasia, there are usually accompanying disorders of maturation that may be recognizable by microscopic examination. These changes are termed dysplasia, atypical hyperplasia, or metaplasia depending on the type of epithelium in which they are observed. More aggressive proliferation without the ability to invade through the basement membrane is termed preinvasive carcinoma, or carcinoma in situ. Technically, these cells do not have the capacity to invade the basement membrane and metastasize, although they may over time progress to invasive carcinoma. The term "invasive carcinoma" implies that tissue boundaries, especially the basement membrane, have been breached. Metastatic carcinoma occurs via the lymphatic system to regional lymph nodes and via the bloodstream to distant organs and other tissues. This pattern of metastasis, however, is not unique to epithelial malignancies. Epithelial neoplasms in general have a variable propensity to spread to regional nodes and distant sites. It is assumed that the natural history of most tumors is to follow this pattern of spread over time. The specific genotypic and phenotypic changes necessary to accomplish this spread are not well understood; they may, in some cases, be shared across tumor types, and in other cases they are unique to a given neoplasia. Certain molecular characteristics have been linked to clinical characteristics, although the exact mode of action is not fully understood. Colon Carcinoma The model of stepwise genetic alterations in cancer is best illustrated by observations made in colonic lesions representing different stages of progression to malignancy. Certain genetic alterations are found commonly in early-stage adenomas, whereas others tend to occur with significant frequency only after the development of invasive carcinoma. These changes are in keeping with the concept that serial phenotypic changes must occur in a cell for it to exhibit full malignant (invasive and metastatic) properties. Two principal lines of evidence support the model of stepwise genetic alterations in colon cancer. 1 The rare familial syndromes associated with predisposition to colon cancer at an early age are now 102

known to result from germline mutations. Familial adenomatous polyposis is the result of a mutation in the APC gene, which encodes a cell adhesion protein that has also been implicated in the control of -catenin, a potent transcriptional activator. In the tumors that subsequently develop, the remaining allele has been lost. Similarly, hereditary nonpolyposis colorectal cancer is associated with germline mutations in DNA repair genes such as hMSH2 and hMLH1. These genes can also be affected in sporadic cancers. 2. The carcinogenic effects of factors known to be linked to an increased risk of colon cancer constitute the second line of evidence for a genetic basis for colon cancer. Substances derived from bacterial colonic flora, ingested foods, or endogenous metabolites such as fecapentaenes, 3ketosteroids, and benzo[]pyrenes are mutagenic. Levels of these substances can be reduced by lowfat and high-fiber diets, and several epidemiologic studies confirm that such diets reduce the risk of colon cancer. Furthermore, because the risk of sporadic colon cancer in older individuals is mildly elevated in the presence of a positive family history, there may be other inherited genetic abnormalities that interact with environmental factors to cause colon cancer. The sequence of genetic changes may not need to be exact to lead to the development of an invasive cancer, although there is mounting evidence that some genetic lesions tend to develop early, whereas others may develop late in the course of the natural disease. All phenotypic changes cannot be explained by a known genetic abnormality, nor do all identified genetic alterations have a known phenotypic result. However, the stepwise nature of genotypic and phenotypic abnormalities is well established. The earliest molecular defect in the pathogenesis of colon cancer is the acquisition of somatic mutations in the APC gene in the normal colonic mucosa. This defect causes abnormal regulation of catenin, which leads to abnormal cell proliferation and the initial steps in tumor formation. Subsequent defects in the TGF- signaling pathway inactivate this important growth inhibitory pathway and lead to further tumor mucosal proliferation and the development of small adenomas. Mutational activation of the K-ras gene leads to constitutive activation of an important proliferative signaling pathway, is common at these stages, and further increases the proliferative potential of the adenomatous tumor cells. Deletion or loss of expression of the DCC gene is common in the progression to invasive colon cancers. The DCC protein is a transmembrane protein of the immunoglobulin superfamily and may be a receptor for certain extracellular molecules that guide cell growth and or apoptosis. Mutational inactivation of p53 is also a commonly observed step in the development of invasive colon cancer, seen in late adenomas and early invasive cancers, and leads to loss of an important cell cycle checkpoint and inability to activate the p53-dependent apoptotic pathways. Identification of genetic abnormalities in the progression of colon cancer to metastatic disease is currently under investigation. Breast Carcinoma The female breast is a specialized gland that undergoes repeated cycles of growth factor and hormone-induced changes that define the different stages of breast development (fetal, pubertal, menstrual, pregnancy-associated, and lactational growth together with postlactational involution). Deregulation in this complex biology leads to a diverse group of breast diseases inherently connected with growth factor or hormonal signaling. Factors associated with an increased risk of breast cancer development may provide clues to early driving forces. Prolonged usage of high doses of exogenous estrogen is a risk factor that implicates the estrogen signaling pathway. In contrast, reduced exposure to estrogen protects against the development of breast cancer. This has been demonstrated in ovariectomized animal models of breast carcinogenesis and is confirmed by clinical studies demonstrating that women who have undergone oophorectomy at a young age have a significant reduction in their lifetime risk of developing breast cancer. The clinical success of antiestrogen therapies provides proof of principle of the essential role of estrogen signaling in the pathogenesis of breast cancer. Agents that inhibit the production of estrogen or the ability of estrogen to activate the ER are highly effective in the treatment of patients with early or advanced breast cancer, are active in halting disease progression in patients with preinvasive breast cancers, 103

and are also active in the primary prevention of breast cancer in women at risk. However, although the central role of estrogen signaling in the pathogenesis of breast cancer is now well established, the evidence to date does not etiologically implicate genetic abnormalities of the ER or its downstream targets in the development of breast cancer. It appears that ER signaling is a physiological pathway existing in breast epithelial cells whose continued signaling activity is favorable to, or perhaps even necessary for, the oncogenic process. Yet the estrogen signaling pathway is intact in only one half of patients diagnosed with breast cancer; the remaining half appear to have no expression of the ER or activity of the estrogen signaling pathway. This has led some investigators to believe that ER-negative breast cancer is a different disease with an alternative pathophysiology. Most likely, there are common early molecular steps in the development of ER-positive and ER-negative breast cancers; however, at an early or intermediate step, these pathways diverge, leading to the development of breast cancers with distinctly different phenotypes.

68. Mesenchymal, neuroendocrine & germ cell neoplasia. Carcinoid tumors, testicular cancer & sarcomas
Mesenchymal, Neuroendocrine, & Germ Cell Neoplasia Mesenchymal, neuroendocrine, and germ cell neoplasms account for a large proportion of the tumors of childhood and young adulthood, ostensibly because these cells are actively dividing and more subject to mutational events. Owing to the extensive migration and convolution of embryonic cell layers during early development, these tumor types may not evolve in specific anatomic sites. Neuroendocrine tumors are derived from cells that migrate throughout the body and have developed specific enzymatic capabilities and accumulation of cytoplasmic proteins that serve a secretory function. As such, they are frequently identified by certain enzymatic markers, in particular, nonspecific esterase. Not all neuroendocrine tumors can be traced to the neural crest. Indeed tumors of this classification may not have a common embryonic ancestry. Neuroendocrine tumors can secrete biologically active peptides and produce specific clinical syndromes because of their secretory activities. Germ cell tumors can arise within the testes or in extragonadal sites through which germ cells migrate during development. Mesenchymal cells, by virtue of their function, are distributed throughout the body, and mesenchymal tumors can arise at any anatomic site. Carcinoid Tumors Carcinoid tumors are one type of neuroendocrine tumor. They arise from neural crest tissue and, more specifically, from enterochromaffin cells, whose final resting place after embryonic migration is along the submucosal layer of the intestines and pulmonary bronchi. Reflecting this embryonic origin, carcinoid cells express the necessary enzymes to produce bioactive amines such as 5hydroxytryptamine and other vasoactive serotonin metabolites as well as a variety of small peptide hormones. Cytoplasmic granules typical of neuroendocrine cells are also commonly seen. The anatomic distribution of primary carcinoid tumors is consistent with embryonic development patterns. Carcinoid tumors and other mesenchymal neoplasms have similar patterns of tissue invasion followed by local and distant spread to regional lymph nodes and distant organs. The characteristics of increased mitotic count (an indicator of rapid proliferation), nuclear pleomorphism, lymphatic and vascular invasion, and an undifferentiated growth pattern are associated with a higher rate of metastases.A frequent site of carcinoid metastasis is the liver. Testicular Germ Cell Cancer Testicular cancer arises chiefly from germ cells within the testes. Germ cells are the population of cells that give rise to spermatozoa through meiotic division and can, therefore, theoretically retain 104

the ability to differentiate into any cell type. Some testicular neoplasms arise from remnant tissue outside the testes owing to the midline migration of germ cells that occurs during early embryogenesis. This is followed by the formation of the urogenital ridge and eventually by the aggregation of germ cells in the ovary or testes. By this pattern of migration, extragonadal testicular germ cell neoplasms are found in the midline axis of the lower cranium, mediastinum, or retroperitoneum. The pluripotent ability of the germ cell is most evident in benign germ cell tumors such as mature teratomas. These tumors often contain differentiated elements from all three germ cell layers, including teeth and hair in lesions termed dermoid cysts. Malignant teratomas can also exist as a spectrum bridging other germ cell layer-derived neoplasms such as sarcomas and epithelium-derived carcinomas. Malignant testicular cancers may coexist with benign mature teratomas, and the benign component sometimes becomes apparent only after the malignancy has been eradicated with chemotherapy. Proteins expressed during embryonic or trophoblastic development such as alpha-fetoprotein and human chorionic gonadotropin can be secreted and measured in the serum. Testicular carcinoma follows a lymphatic and hematogenous pattern of spread to regional retroperitoneal nodes and distant organs such as lung, liver, bone, and brain. The testicular cancers are sensitive to radiation and chemotherapy. Sarcomas The sarcomas consist of a family of mesenchymal neoplasms whose morphologic appearance and anatomic distribution mirror the early mesenchymal elements from which they derive. They arise in structures composed of the mesenchymal cell type or in locations where remnant cells eventually come to rest in the path of early tissue migration. Several of the less mature sarcomas that resemble more primitive cells are seen in children, because this compartment of cells is usually dividing more rapidly. These sarcomas include rhabdomyosarcoma and osteosarcoma, which are less common in adults. The morphologic appearance of sarcomas does not involve perceptible architectural changes, because cell polarity and gland formation do not occur in normal mature mesenchymal cells such as muscle or cartilage. Nuclear pleomorphism and mitotic rate determine the grade of a tumor; a higher grade correlates with a higher propensity to invade local and distant structures and a poorer survival. Sarcomas also have a tendency to retain the cell appearance and repertoire of expressed proteins of the cell of origin. There is less of a propensity for direct tissue invasion by sarcomas than by epithelial malignancies. However, tissue destruction can result when a sarcoma compresses but does not invade adjacent tissue, leading to the formation of a pseudocapsule. Sarcomas exhibit metastatic dissemination to regional lymph nodes and distant organs, especially the lungs. High-grade histologic features and anatomic location are factors influencing the likelihood and timing of metastases. Mutations in the p53 tumor suppressor gene are the most commonly detected lesion. The NF1 tumor suppressor gene was originally identified through a germline mutation of this gene in patients with type 1 neurofibromatosis. This inherited syndrome is characterized by caf-au-lait hyperpigmented skin spots and multiple benign neurofibromas (benign tumors of Schwann cells) under the skin and throughout the body. These can degenerate into malignant neurofibrosarcomas (malignant schwannoma). NF1 mutations have since been detected in sporadic sarcomas of different types. Defective or absent activity of the NF1 protein is known to cause enhanced activation of the G protein-signaling pathways.

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69)SYSTEMC EFFECTS OF NEOPLASIA

The systemic effects of cancer are the general effects the cancer has on the various body systems. Weight Loss Cachexia is the term used for severe tissue wasting and resulting weight loss that occurs as a result of the altered protein and carbohydrate metabolism caused by the malignancy. Bleeding Bleeding can occur due to the tumor cells' erosion of blood vessels or ulceration of tissues. Also, bone marrow depression can contribute to poor clotting. Chronic blood loss leads to anemia. Anemia Anemia, or decreased hemoglobin, commonly occurs as a result of anorexia, loss of appetite, chronic bleeding or bone marrow depression. Anemia reduces the oxygen available to cells, which leads to fatigue, poor tissue regeneration and weakness. Infections nfections, such as pneumonia, frequently occur due to tissue breakdown which lessens the effectiveness of the immune system. Paraneoplastic Syndromes Sometimes tumors release substances that affect the body's neurological function, blood clotting or hormonal activities. These can confuse the diagnosis and complicate the monitoring of the condition.

70)Red blood cell disorders. Classification of anemias.

Blood diseases involving the red blood cells include: -Anemias are diseases characterized by low oxygen transport capacity of the blood, because of low red cell count or some abnormality of the red blood cells or the hemoglobin. Iron deficiency anemia is the most common anemia; it occurs when the dietary intake or absorption of iron is insufficient, and hemoglobin, which contains iron, cannot be formed. Sickle-cell disease is a genetic disease that results in abnormal hemoglobin molecules. When these release their oxygen load in the tissues, they become insoluble, leading to mis-shaped red blood cells. These sickle shaped red cells are less deformable and viscoelastic meaning that they have become rigid and can cause blood vessel blockage, pain, strokes, and other tissue damage. Thalassemia is a genetic disease that results in the production of an abnormal ratio of hemoglobin subunits. Spherocytosis is a genetic disease that causes a defect in the red blood cell's cytoskeleton, causing the red blood cells to be small, sphere-shaped, and fragile instead of donut-shaped and flexible. Pernicious anemia is an autoimmune disease wherein the body lacks intrinsic factor, required to absorb vitamin B12 from food. Vitamin B12 is needed for the production of hemoglobin. Aplastic anemia is caused by the inability of the bone marrow to produce blood cells.

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Pure red cell aplasia is caused by the inability of the bone marrow to produce only red blood cells. -Hemolysis is the general term for excessive breakdown of red blood cells. It can have several causes and can result in hemolytic anemia. The malaria parasite spends part of its life-cycle in red blood cells, feeds on their hemoglobin and then breaks them apart, causing fever. Both sickle-cell disease and thalassemia are more common in malaria areas, because these mutations convey some protection against the parasite. -Polycythemias (or erythrocytoses) are diseases characterized by a surplus of red blood cells. The increased viscosity of the blood can cause a number of symptoms. -Several microangiopathic diseases, including disseminated intravascular coagulation and thrombotic microangiopathies, present with pathognomonic red blood cell fragments called schistocytes. These pathologies generate fibrin strands that sever red blood cells as they try to move past a thrombus. -Inherited hemolytic anemias caused by abnormalities of the erythrocyte membrane comprise an important group of inherited disorders. These disorders are characterized by clinical and biochemical heterogeneity and also genetic heterogeneity, as evidenced by recent molecular studies. The Hereditary spherocytosis syndromes are a group of inherited disorders characterized by the presence of spherical-shaped erythrocytes on the peripheral blood smear. HS is found worldwide. It is the most common inherited anemia in individuals of northern European descent, affecting approximately 1 in 1000-2500 individuals depending on the diagnostic criteria. The primary defect in hereditary spherocytosis is a deficiency of membrane surface area. Decreased surface area may produced by two different mechanisms: 1) Defects of spectrin, ankyrin, or protein 4.2 lead to reduced density of the membrane skeleton, destabilizing the overlying lipid bilayer and releasing band 3-containing microvesicles. 2) Defects of band 3 lead to band 3 deficiency and loss of its lipidstabilizing effect. This results in the loss of band 3-free microvesicles. Both pathways result in membrane loss, decreased surface area, and formation of spherocytes with decreased deformability. These deformed erythrocytes become trapped in the hostile environment of the spleen where splenic conditioning inflicts further membrane damage, amplifying the cycle of membrane injury. -Hemolytic transfusion reaction is the destruction of donated red blood cells after a transfusion, mediated by host antibodies, often as a result of a blood type mismatch. Several blood tests involve red blood cells, including the RBC count (the number of red blood cells per volume of blood), the hematocrit (percentage of blood volume occupied by red blood cells), and the erythrocyte sedimentation rate. The blood type needs to be determined to prepare for a blood transfusion or an organ transplantation.

71)Iron deficiency anemia.

-the iron content in the body is 2 g in females,5 g in males. 2/3 is bound to hemoglobin, 1/4 is stored iron (ferritin, hemosiderin),the rest is iron with diverse functions (myoglobin,Fe-containing enzymes). -Loss of iron is 1mg/d in males and up to 2 mg/d in females(menstruation, pregnancy, birth).

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-Fe taken up in food, 315% is absorbed in the duodenum; in cases of Fe deficiency it can be up to 25%. -Fe can be absorbed relatively efficiently as heme-Fe2+ (found in meat and fish). The Fe (split off from heme) gets into the blood or remains in the mucosa as ferritinFe3+ and returns to the lumen on mucosal cell disintegration. Non-heme Fe can be absorbed only in the form of Fe2+. A low pH of the chyme is essential for absorption, because it will increase the H+ gradient that drives Fe2+ into the cell via DCT1, and release Fe from compounds in food. -Fe uptake by blood is regulated by the intestinal mucosa: in Fe deficiency mucosal ferritin translation is inhibited by binding the Fe-regulating protein IRP1 to ferritin-mRNA, so that more of the absorbed Fe2+ can reach the blood. There it is oxidized by ceruloplasmin (+copper) to Fe3+ and bound to apotransferrin, which transports Fe in plasma. -After Fe has transferred to the target cells, apotransferrin again becomes available for Fe absorption from the intestine and macrophages. -Ferritin (in the intestinal mucosa, liver, bone marrow, erythrocyte and plasma), which has a pocket for 4500 Fe3+ ions, is a rapidly available iron reserve, while Fe from hemosiderin is more difficult to mobilize. Hb-Fe and heme-Fe, released from malformed erythroblasts, and hemolyzed erythroblasts, is bound to haptoglobin and hemopexin respectively, and taken up by the macrophages in bone marrow or by liver and spleen by endocytosis. -Iron deficiency inhibits Hb synthesis so that hypochromic microcytic anemia develops: MCH < 26 pg, MCV < 70 fL, Hb < 110 g/L. Its causes are: 1-Blood loss (gastrointestinal tract, increased menstrual bleeding) in adults is the most common cause of iron deficiency. 2-Fe recycling is decreased; this form of anemia occurs with chronic infections. In this situation the Fe regained by the macrophages is no longer adequately released and thus cannot be reused.3-Fe uptake is too low. 4-Fe absorption is reduced due to: chlorhydria and malabsorption in diseases of the upper small intestine or in the presence of Fe-binding food components.

72)Pernicious anemia:
-Pernicious anemia, also known as Biermer's anemia, Addison's anemia, is one of many types of the larger family of megaloblastic anemias. -It is caused by loss of gastric parietal cells which are responsible for the secretion of intrinsic factor, a protein essential for subsequent absorption of vitamin B12 in the ileum.

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-The loss of ability to absorb vitamin B12 is the most common cause of adult B12 deficiency. Such a loss may be due to pernicious anemia or to a number of other conditions that decrease production of gastric acid, which also plays a part in absorption of B12 from foods. -Replacement of vitamin stores does not correct the defect in absorption from loss of intrinsic factor. Since the defect defines the disease, a person without the ability to absorb B12 in this way will have pernicious anemia for the remainder of his or her life. -Vitamin B12 cannot be produced by the human body, and must be obtained from the diet. Normally, dietary B12 is absorbed by the body in the small bowel only when it is bound by the intrinsic factor produced by parietal cells of the gastric mucosa. Pernicious anemia is thought to occur when the body's immune system mistakenly targets the IF, with a loss of parietal cells. Insufficient IF results in insufficient absorption of the vitamin. Although the normal body stores three to five years' worth of B12 in the liver, the usually undetected autoimmune activity in one's gut over a prolonged period of time leads to B12 depletion and the resulting anemia. Inhibition of DNA synthesis in red blood cells results in the formation of large, fragile megaloblastic erythrocytes.

73)White blood cell disorders. Leucocytosis & leucopenia. Cyclic neutropenia:

-White blood cells are an important part of our immune system that play a vital role in defending the body from various infections. -There are different types of white blood cells; neutrophils, lymphocytes, monocytes, eosinophils, and basophils. All of them are produced in the bone marrow and are found in the lymph tissues and blood. -Neutrophils, eosinophils and basophils are called granulocytes. T cells, B cells and natural killer cells are types of lymphocytes. There is a definite life span of these cells; it can be 2 weeks to 3 weeks, after which they are destroyed. The number of leukocytes present in the body changes with advancing age. -Increase or decrease in the number of leukocytes in the blood, leads to different diseases and disorders of the white blood cells. -Neutropenia: Neutrophils contribute to 70% of white blood cells in our body. They help the body to fight with bacterial and fungal infections. Neutropenia is caused due to reduced number of neutrophils in the blood. Side effects of any medication, chemotherapy, and viral infection are some of the causes. Inadequate formation of neutrophils in the bone marrow or destruction of neutrophils in the blood stream, can cause a type of neutropenia called autoimmune neutropenia. Fever or any frequent infection can be symptoms of neutropenia. Neutropenia is diagnosed by determining the white blood cell count. A normal neutrophil count is 3000 to 8000 (per microliter of blood), while neutropenia is diagnosed when the neutrophil count is 2000. The treatment for neutropenia depends on the cause. Medications that help grow the number of neutrophils are recommended to such patients. In rare cases, bone marrow transplant is performed. -HIV/AIDS: AIDS is a life-threatening disease that is caused due to the Human immunodeficiency virus (HIV). The stage when the HIV spreads almost all over the body, is called AIDS (Acquired Immunodeficiency Syndrome). This virus attacks and destroys the white blood cells, that are 109

responsible for regulating the immune system. Thus, the immune system of a HIV-infected person becomes very weak. These viruses are present in the blood and sexual fluids. Thus, unprotected sex with a HIV-infected person is the most common cause. An infected mother can pass the virus to her child, via breast-feeding or during childbirth. These days, the infection to the child can be prevented with the help of proper treatment. HIV does not show any symptoms in its early stages. Neither is there any vaccine that can prevent HIV infection nor any treatment that can cure it. Safety measures are the only way to avoid getting infected with HIV. -Lymphocytopenia: Reduced number of lymphocytes in the blood leads to lymphocytopenia. Chronic infections and hereditary disorders are some of the causes of the disease. The treatment is given depending upon the cause. -Leukemia: Leukemia, also called blood cancer, is a group of diseases that is caused due to increased number of blood cells. Uncontrolled growth of any blood cell leads to leukemia. Most forms of the disease are caused due to high white blood cell count. The bone marrow produces a large number of immature white blood cells that cannot function properly. Lymphocytic leukemia is caused due to increased number of lymphocytes. The causes that lead to growth in the number of immature cells is still unknown.The following is a list of different types of leukemia that occur due to increased white blood cells in the blood: Acute myeloid leukemia (AML) Chronic myeloid leukemia (CML) Acute lymphocytic leukemia (ALL) Chronic lymphocytic leukemia (CLL) Leukemia patients are susceptible to any kind of infection. Their immune system is not capable of fighting against infection. Chemotherapy and bone marrow transplant are some of the treatments given for leukemia. Eosinophilia, monocyte disorders, idiopathic hypereosinophilic syndrome are some other diseases related to white blood cells. Leukocytes are vital cells of our body, diseases and disorders of which, can lead to fatal consequences. A regular white blood cell count can help to give timely treatment to the patient and reduce the symptoms to a great extent.

74)Lymphoma & acute myelogenous leukemia:

-Lymphoma is a cancer of the lymphocytes, a type of cell that forms part of the immune system. Lymphoma is present as a solid tumor of lymphoid cells. -Treatment might involve chemotherapy and in some cases radiotherapy or bone marrow transplantation. -These malignant cells often originate in lymph nodes, presenting as an enlargement of the node. It can also affect other organs in which case it is referred to as extranodal lymphoma. Extranodal sites include the skin, brain, bowels and bone. Lymphomas are closely related to lymphoid leukemias, which also originate in lymphocytes but typically involve only circulating blood and the bone marrow and do not usually form static tumors. 110

-The pathophysiology of lymphoma refers to the process or processes going on inside the body that are sometimes reflected in the signs and symptoms that are identified as being indicative of lymphoma. For example, swollen, painless lymph nodes are a symptom of lymphoma. Pathophysiology of lymphoma with this symptoms is that it becomes this way when cancerous lymphocytes do not die, as they are supposed to, but rather proliferate and collect at the lymph nodes. NON-HODGKINS LYMPHOMA (NHL) 1. Commonly seen in HIV, often in brain, teenagers, get in head & neck 2. Burkitts lymphoma a. Closely related to Epstein- Barr virus (EBV) infections b. African Burkitt involves jaw/neck, US Burkitts involves abdomen 3. Cutaneous T-cell Lymphoma a. often in elderly, diffuse scaly rash or erythroderma clinically apparent malignancy by years b. Stained cells have cerebriform nuclei c. Leukemic phase of this disease is called Sezary syndrome d. UV light therapy, consider systemic chemotherapy 4. Angiocentric T-cell lymphoma a. 2 subtypes = nasal T-cell lymphoma (lethal midline granuloma) & pulmonary angiocentric lymphoma b. large mass, biopsy often non-Dx due to diffuse necrosis c. palliative radiation therapy, Px very poor HODGKINS LYMPHOMA -Occurs in a bimodal age distribution, young men & the elderly -EBV infection is present in up to 50% of cases -fevers wax & wane over weeks, chills, night sweats, weight loss, pruritus, worsen with alcohol intake -Reed-Sternberg cells seen on biopsy, appear as binucleated giant cells or mononucleated giant cell -depends on clinical staging Stage I = 1 lymph node involved radiation 111

Stage II = =2 lymph nodes on same side of diaphragm radiation Stage III = involvement on both sides of diaphragm chemo Stage IV = disseminated to organs or extranodal tissue chemo Chemo regimens MOPP = meclorethamine, oncovin (vincristine), procarbazine, prednisone ABVD = adriamycin, bleomycin, vincristine, dacarbazine

75)Platelet disorders
Platelets, or thrombocytes are small, irregularly shaped clear cell fragments, 23 m in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days. Platelets are a natural source of growth factors. They circulate in the blood of mammals and are involved in hemostasis, leading to the formation of blood clots. Platelet disorders lead to defects in primary hemostasis and produce signs and symptoms different from coagulation factor deficiencies. The body's reaction to vessel wall injury is rapid adhesion of platelets to the subendothelium. The initial hemostatic plug, composed primarily of platelets, is stabilized further by a fibrin mesh generated in secondary hemostasis. The arrest of bleeding in a superficial wound, such as the bleeding time wound, almost exclusively results from the primary hemostatic plug. Thrombocytopenia is defined as a platelet count of less than 150,000/mm3. With normal platelet function, thrombocytopenia is rarely the cause of bleeding unless the count is less than 50,000/mm3. Thrombocytopenia should always be confirmed by examination of a peripheral smear. It can be caused by decreased platelet production, increased destruction, sequestration, or a combination of these causes.

76)DRUG-ASSOCIATED IMMUNE THROBOCYTOPENIA

-Thrombocytopenia represents a defective or decreased production of platelets. -Symptoms include sudden onset of small spots of hemorrhage on the skin, or bleeding into mucous membranes. - The disorder may also be evident as blood in vomit or stools, bleeding during surgery, or heavy menstrual flow in women. Some patients show none of these symptoms, but complain of fatigue and general weakness. -There are several causes of thrombocytopenia, which is more commonly acquired as a result of another disorder. Common underlying disorders include leukemia, drug toxicity, or aplastic anemia, severe infection, disseminated intravascular coagulation, and cirrhosis of the liver. -The idiopathic form most commonly occurs in children, and is most likely the result of production of antibodies that cause destruction of platelets in the spleen and to a lesser extent the liver.

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-Von Willebrand's disease is caused by a defect in the Von Willebrand clotting factor. It is a hereditary disorder that affects both males and females.Nosebleeds and blood in the stool with a black, tarlike appearance are signs of Von Willebrand's disease. -Drug-induced thrombocytopenia can be caused by dozens, perhaps hundreds, of medications. -If the causative medication is stopped, symptoms usually resolve within 1 or 2 days, and the platelet count returns to normal in less than a week. -capable of causing drug-induced thrombocytopenia are : heparin, histamine-receptor antagonists, antimicrobial agents, diuretic agents, analgesic agents. -heparin-induced thrombocytopenia is the most common drug-related cause of a drop in the platelet count. -Quinine, which is rarely used now as an antimalarial drug but is often prescribed for nocturnal muscle cramps, may still be the most common trigger. -The hallmark of thrombocytopenia induced by quinine and many other drugs is a remarkable antibody that binds tightly to normal platelets only in the presence of the sensitizing drug. The epitopes targeted by these antibodies usually reside on glycoprotein complexes. -Acute thrombocytopenia, usually mild but occasionally life-threatening, is a common complication of treatment with the platelet inhibitors tirofiban and eptifibatide, which are widely used to prevent restenosis after coronary angioplasty. These ligand-mimetic drugs inhibit thrombosis by binding to a specific site on the platelet integrin and competitively inhibiting plateletfibrinogen interaction.

77)COAGULATION DISORDERS:
-Coagulation disorders deal with disruption of the body's ability to control blood clotting. The most commonly known coagulation disorder is hemophilia, a condition in which patients bleed for long periods of time before clotting. -Coagulation, or clotting, occurs as a complex process involving several components of the blood. Plasma, the fluid component of the blood, carries a number of proteins and coagulation factors that regulate bleeding. Platelets, small colorless fragments in the blood, initiate contraction of damaged blood vessels so that less blood is lost. They also help plug damaged blood vessels and work with plasma to accelerate blood clotting. A disorder affecting platelet production or one of the many steps in the entire process can disrupt clotting. -Normal blood clotting involves as many as 20 different plasma proteins, which are known as blood clotting or coagulation factors. These factors act together with other chemicals to form a substance called fibrin that stops bleeding. Problems can occur when certain coagulation factors are low or missing. Some bleeding disorders are present at birth and are passed through families. Others develop from: Illnesses such as vitamin K deficiency or severe liver disease

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Treatments such as the use of drugs to stop blood clots (anticoagulants) or the long-term use of antibiotics. Bleeding disorders can also result from having poorly working or too few of the blood cells that promote blood clotting (platelets). These disorders can also be either inherited or picked up (acquired). The side effects of certain drugs often lead to the acquired forms. -Some common coagulation disorders are: 1-Hemophilia, or hemophilia A (Factor VIII deficiency), an inherited coagulation disorder. This genetic disorder is carried by females but most often affects males. 2-Christmas disease, also known as hemophilia B or Factor IX deficiency, is less common than hemophilia A with similar in symptoms. 3-Disseminated intravascular coagulation disorder, also known as consumption coagulopathy, occurs as a result of other diseases and conditions. This disease accelerates clotting, which can actually cause hemorrhage. 4-Thrombocytopenia is the most common cause of coagulation disorder. It is characterized by a lack of circulating platelets in the blood. This disease also includes idiopathic thrombocytopenia. 5-Von Willebrand's disease is a hereditary disorder with prolonged bleeding time due to a clotting factor deficiency and impaired platelet function. It is the most common hereditary coagulation disorder. 6-Hypoprothrombinemia is a congenital deficiency of clotting factors that can lead to hemorrhage. 7-Other coagulation disorders include Factor XI deficiency, also known as hemophilia C, and Factor VII deficiency. Factor VII is also called serum prothrombin conversion accelerator deficiency.

78) MOTOR DISTURBANCES-CEREBLLUM AND BASAL GANGLIA:

Motor skills disorder impairs motor coordination in daily activities. It is neurological in origin. Many children with autism or Asperger syndrome experience deficits in motor skills development, which often manifests as abnormal clumsiness. The disorder has its basis in the brain, a network of neural connections that allow humans to process the information received. Motor Dyspraxia is a result of weak or disorganised connections in the brain, which then translates to trouble with motor coordination. Movements are performed because the brain sends messages to the area requiring action. The dyspraxia is a result of weak or poorly structured neural pathways to the moving parts of the body. Clumsiness and tendency to fall down are a matter of poor balance and gross motor coordination. The origin of all of these difficulties is the vestibular system of the inner ear. The vestibule is an organ responsible for maintaining balance and coordination and is located beside the cochlea, which acts as a sound receptor. Although they attend to different information, the proximity of the vestibule and cochlea allows them to complement each other. People with dyspraxia also tend to have an overly sensitive tactile system that causes them to perceive the most benign touch as unpleasant. They may also have a very low pain-threshold or have an automatic reaction of fear when touched. This is a result of a sensory integrative dysfunction, 114

which describes a problem in the way the brain interprets information received from the senses. This problem, like that of coordination, originates in the vestibule, as all sensory information is transmitted to the vestibule before being sent to the cerebellum, the part of the brain associated with movement. The causes of this disorder are unknown, but it is thought to originate with inner ear problems, possibly resultant from head injuries or childhood diseases. Basal ganglia disease refers to a group of physical dysfunctions that occur when the group of nuclei in the brain known as the basal ganglia fail to properly suppress unwanted movements or to properly prime upper motor neuron circuits to initiate motor function. Research indicates that increased output of the basal ganglia inhibits thalamocortical projection neurons. Proper activation or deactivation of these neurons is an integral component for proper movement. If something causes too much basal ganglia output, then the thalamocortical projection neurons become too inhibited and one cannot initiate voluntary movement. These disorders are known as hypokinetic disorders. However, a disorder leading to abnormally low output of the basal ganglia leads to relatively no inhibition of the thalamocortical projection neurons. This situation leads to an inability to suppress unwanted movements. These disorders are known as hyperkinetic disorders. One possible factor could be the natural accumulation of iron in the basal ganglia, causing neurodegeneration due to its involvement in toxic free-radical reactions.Though motor disorders are the most common associated with the basal ganglia, recent research shows that basal ganglia disorders can lead to other dysfunctions such as Obsessive Compulsive Disorder (OCD) and Tourette syndrome.Hypokinetic Disorders: Hypokinetic disorders are movement disorders that are described as having reduced motor function. This is generally attributed to higher than normal basal ganglia output causing inhibition of thalamocortical motor neurons. Parkinsonism: The muscle rigidity, tremor at rest, and slowness in initiation and execution of movement that are the cardinal motor symptoms of Parkinson's disease are attributed to a reduction in dopaminergic activity in the basal ganglia motor areas, particularly the putamen, due to gradually reduced innervation from SNc.

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Hyperkinetic Disorders: Hyperkinetic disorders are movement disorders characterized by increased uncontrollable motor function. They are caused by reduced basal ganglia output, which causes increased thalamocortical function which lead to the inability to stop unwanted movement. Huntington's Disease: Huntingtons disease is a hereditary disease that causes defects in behavior, cognition, and uncontrolled rapid, jerky movements. Huntingtons disease stems from a defect that consists of an expanded CAG repeat in a gene located on chromosome 4. The basal ganglias in patients with Huntingtons Disease show a decrease in activity of the mitochondrial pathway, complex II-III. Such deficiencies are often associated with basal ganglia degeneration. This degeneration of striatal neurons projecting to GPe leads to disinhibition of the indirect pathway, increased inhibition of STN, and therefore, reduced output of the basal ganglia. The neuronal degeneration eventually causes death within 10 to 20 years. Dystonia: Dystonia is hyperkinetic movement disorder that is characterized by involuntary movement and the slowing of intentional movement. Dystonia can occur as a hyperkinetic disorder or as a side effect of hypokinetic disorders such as Parkinsons disease. Hemiballismus: Hemiballismus is a hyperkinetic movement disorder that causes uncontrolled movement on one side of the body. It is generally caused by damage to the subthalamic nucleus (STN). Since the internal segment of the globus pallidus (GPi) is the link in the circuit between the STN and thalamic projection, destruction of localized brain cells in the GPi via a pallidotony has proven to serve as a useful treatment for Hemiballismus. Cerebellar disorders have numerous causes, including congenital malformations, hereditary ataxias, and acquired conditions. Symptoms vary with the cause but typically include ataxia. The cerebellum has 3 parts:

Archicerebellum (vestibulocerebellum): It includes the flocculonodular lobe, which is located in the medial zone. It helps maintain equilibrium and coordinate eye, head, and neck movements; it is closely interconnected with the vestibular nuclei. Midline vermis (paleocerebellum): It helps coordinate trunk and leg movements. Vermis lesions result in abnormalities of stance and gait. Lateral hemispheres (neocerebellum): They control quick and finely coordinated limb movements, predominantly of the arms.

79.Disturbances of the somatosensory system.

-A somatosensory deficiency may be caused by a peripheral neuropathy involving peripheral nerves of the somatosensory system. -This may present as numbness or paresthesia. -Evaluation of any suspected disease of the somatosensory system is included in a neurological examination of the peripheral nervous system. -Hypoesthesia refers to a reduced sense of touch or sensation, or a partial loss of sensitivity to sensory stimuli. -Anaphia, also known as tactile anesthesia, is a medical symptom in which there is a total or partial absence of the sense of touch. Anaphia is a common symptom of spinal cord injury and neuropathy.

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-Hyperesthesia is a condition that involves an abnormal increase in sensitivity to stimuli of the sense. Stimuli of the senses can include sound that one hears, foods that one tastes, textures that one feels, and so forth. Increased touch sensitivity is referred to as "tactile hyperesthesia", and increased sound sensitivity is called "auditory hyperesthesia". Tactile hyperesthesia may be a common symptom of many neurologic disorders such as herpes zoster, peripheral neuropathy and radiculopathies. -Dysesthesia is defined as an unpleasant, abnormal sense of touch, and it may or may not be considered as a kind of pain. It is caused by lesions of the nervous system, peripheral or central, and it involves sensations, whether spontaneous or evoked, such as burning, wetness, itching, electric shock, and pins and needles. It is sometimes described as feeling like acid under the skin. Burning dysesthesia might accurately reflect an acidotic state in the synapses and perineural space. Some ion channels will open to a low pH, the acid sensing ion channel has been shown to open at body temperature, in a model of nerve injury pain. Dysesthetic burning may be hallucinatory as to the cutaneous surface, but accurate as to what is occurring in the synapses. Causes: Dysesthesia is commonly seen in diabetic patients, and can be relieved by using creams containing capsaicin. Dysesthesia is among symptoms of neuropathy. Dysesthesia, along with polyneuropathy can be a symptom of nerve damage caused by Lyme Disease. Dysesthesia is a common symptom of a withdrawal from alcohol or other drugs. Dysesthesia is also a common symptom of Multiple Sclerosis. It is an effect of spinal cord injury.

80)PAIN:
-Pain is defined as an unpleasant sensory experience, either physical or emotional, associated with actual or potential tissue damage. From a medical point of view, pain has always been referred to as the fifth vital sign. -The pathophysiology of pain is usually divided into four distinct stages: (1) transduction, (2) transmission, (3) pain modulation, and (4) perception. -The brain can inhibit or facilitate the intensity and propagation of pain stimuli via specific neural pathways. This modulation function of the brain accounts for the variations in pain perception of different individuals who sustain identical injuries and receive the same drug therapies. Transduction occurs at the sensory level, when a stimulus is converted into a nerve signal. Transmission is the primary function of nerves that act as conduits transferring pain information from the peripheral nerves to the central nervous system. Pain modulation refers to the function of neural cells to inhibit, reduce, or dampen the intrinsic modulatory activity of the central nervous system, thus reducing the painful stimuli. Perception is the result of the three previous components of transduction, transmission and pain modulation and is the conscious awareness, usually localized in certain areas of the body. This is probably the most recognizable component of this phenomenon since it is what the sufferer consciously feels. Levels of pain perception depend on factors such as personal experiences, immediate environment, and sociocultural influences. For example, if a person has broken a limb before or has known of someone close to him who has broken an arm or leg, he might perceive the pain level through the memories of his 117

pain or the pain of the other person. When people speak of pain thresholds, they may well be referring to the pathophysiology of pain. It varies from person to person and has to do with individual brains and their processing of pain.

81 Sensory Disturbunces Hearing Visual Balance.

Causes of deafness. A tear in the eardrum, a lesion in the ossicles, or immobilization of the conduction apparatus, for example, caused by a purulent middle ear infection, dampen transmission to the fenestra vestibuli. Furthermore, if there is a hole in the drum, the fenestra cochleae is no longer protected. This results in middle ear hearing loss. While conduction through the air is impaired, bone conduction remains normal .The hair cells can be damaged by sound stress (i.e., impingement of too loud a sound for too long) and ischemia. But thanks to its high glycogen content they can survive short periods of ischemia by anaerobic glycolysis.Hair cells can also be damaged by certain drugssuch as aminoglycoside antibiotics and the chemotherapeutic agent cisplatinthat, via the stria vascularis, are accumulated in the endolymph. This results in inner ear hearing loss that affects air and bone conduction equally (!B4). Both the hearing threshold and the active component of basilar membrane displacement are affected, so that discrimination of different higher-frequency tones is impaired (!B5). Lastly, inadequate depolarization of the inner hair cells can produce an unusual and disturbing sound sensation (subjective tinnitus). This can also be caused by inadequate excitation of neurons in the auditory pathway or the auditory cortex. Stiffening of the basilar membrane disturbs the micromechanics and thus probably contributes to hearing loss in the elderly . Inner ear deafness can also be the result of abnormal endolymph secretion. Thus loop diuretics at high dosage not only inhibit renal but also auditory Na+-K+-2 Cl cotransport. In addition, there is a known (but rare) genetic defect of the luminal K+ channel. The channel, which consists of two subunits (IsK/KvLQT1), is also expressed in the heart (as well as other organs), where it participates in repolarization. The endolymph space becomes evaginated, distorting the relationship between hair cells and tectorial membrane (endolymph edema). Finally, increased permeability between the endolymph and perilymph spaces may be responsible for Mnires disease, which is characterized by attacks of deafness and vertigo. Visual disturbunces In myopia the bulb of the eye is usually too long for refraction (axial myopia). Less frequently refraction is too strong (refractivemyopia). As a result, the light that originates from distant objects does not converge onto the retina, and thus distant objects do not produce sharp images on the retina. The anomaly can be corrected by means of a concave lens. ! In hyperopia the bulb is either too short (axial hyperopia) or the refraction too low (refractive hyperopia). As a result, light that originates from a near object can no longer converge on the retina and near objects are not seen clearly. The abnormality can be corrected by means of a convex lens. Astigmatism. The surface of the eye is not perfectly spherical. In regular astigmatism the curvatures radiuses in the horizontal and vertical axes are different; and an upright square is imaged as a rectangle. This abnormality can be corrected by means of a cylindrical lens. 118

Glaucoma. The pressure within the eyeball (ca. 1020mmHg) results from the equilibrium between the secretion of fluid into the anterior chamber (ca. 4 l/min) within the ciliary body and its outflow from the chamber via the trabecular network at the edge of the chamber (the iridocorneal angle) into Schlemms canal. Cataract. The transparency of the lens is, among other factors, dependent on a strictly regulated water content. In diabetes mellitus a high glucose concentration brings about glycosylation of proteins (advanced glycation end-products [AGE]) . Similar products also accumulate with age. In diabetes mellitus there is also an accumulation of sorbitol in the lens. Electroretinogram (ERG). When light falls on the retina, potential differences can be recorded between the cornea and an indifferent electrode on the ear . Sudden exposure to light at first generates an a-wave, the summation of potential changes at the receptors. It is followed by a b-wave due to potential changes in the bipolar cells and glial cells. Night blindness. The visual pigment consists of 11-cis-retinol, a metabolite of vitamin A and a protein that is different in the rods and the three types of cones . Balance Disturbuances In order tomaintain positional equilibrium the organism requires information about the movement of the endolymph in the semicircular canals, the position of the statoliths in the inner ear (in relation to gravity), the position and tension of the bodys musculature as well as the retinal image in relation to the activity of the eye muscles (!A). On turning the head the eye muscles normally move in such a way that a stable picture is transiently maintained on the retina . As soon as maximal displacement of the head is obtained, the eye is returned in jolt-like movements of restoration and a new point in the environment is fixed (optokinetic nystagmus). All this information is processed in the vestibular nucleus and the cerebellum, and in turn such information influences the eye muscles via the oculomotor and abducens nerves. An abnormality of the sense of balance can occur in damage to the semicircular canals and the maculae of the membranous labyrinth (ischemia, trauma, inner ear infection, Mnires disease, the cerebellum (intoxication, genetic defects, degenerative disease, inflammation , the thalamus (ischemia), and the cerebral cortex (ischemia, epilepsy. False information leads to inadequate movement of the eye muscles (nystagmus), and thus to roving of the surrounding objects on the retina (the room spins). Dizziness occurs and, via connections with autonomic neurons, nausea and vomiting. However, these disturbances are usually quickly compensated if there is prolonged loss of one of the organs in the vestibular system.

82-Disturbuences in conscious,arousal,cognition.
We become conscious of only a fraction of the information reaching our brain. The conscious contents are stored in associative cortical areas that specialize in this task . Conscious awareness requires not only that the specific afferents have been transmitted to the cerebral cortex, but also nonspecific activation by the ARAS through which neurons from the reticular formation activate wide areas of the cerebral cortex via intralaminar neurons of the thalamus.Damage to large areas of the cortex and/or breakdown of the ARAS brings about loss of consciousness.Loss of consciousness can be divided into several stages: in a state of drowsiness the patient can still be roused and will respond; in a stupor (profound sleep) patientscan be awakened by vigorous stimuli; when in a coma 119

this is no longer possible. In socalled coma dpass vital functions will also have ceased (e.g., respiratory arrest.The split brain represents a special abnormality of consciousness . Uniform consciousness presupposes communication between the two cerebral hemispheres. This takes place along large commissural fiber bundles through the corpus callosum and the anterior commissure. Arousal Disturbiances. This is a state caused by withdrawal from alcohol or barbiturates, acute encephalitis, head trauma resulting in coma, partial seizures in epilepsy, metabolic disorders of electrolyte imbalance, Intra-cranial space- occupying lesions, Alzheimer's disease, rabies, hemispheric lesions in stroke and multiple sclerosis.Anatomically this is a disorder of the limbic system, hypothalamus, temporal lobes, amygdala and frontal lobes. It is not to be confused with mania. The philosophy of low arousal approaches is one of non-confrontation. In high-risk situations, responses that reduce arousal are adopted by carers and staff, especially when confronted by distressed individuals. These approaches became popular in services for people with intellectual disabilities in the UK in the mid-1990s. This humanistic and person-centred approach to crisis management was developed in response to the use of restrictive responses to crises such as restraint, seclusion, and chemical restraint. The avoidance of sanctions- and of consequence-based punishment strategies became an implicit part of the approach. The low arousal theory is a psychological theory explaining that people with attention-deficit hyperactivity disorder (ADHD) seek self-stimulation or excessive activity in order to transcend their state of abnormally low arousal.[1][2] The theory states that one with ADHD cannot self-moderate, and his or her attention can only be sustained by means of sustained external/environmental stimuli.[2] This results in an inability to sustain attention on any task of waning stimulation or novelty, as well as explaining compulsive hyperactive behavior. The low arousal theory is a psychological theory explaining that people with attention-deficit hyperactivity disorder (ADHD) seek self-stimulation or excessive activity in order to transcend their state of abnormally low arousal.[1][2] The theory states that one with ADHD cannot self-moderate, and his or her attention can only be sustained by means of sustained external/environmental stimuli.[2] This results in an inability to sustain attention on any task of waning stimulation or novelty, as well as explaining compulsive hyperactive behavior. when a person fails to be aroused in a situation that would normally produce arousal and the lack of arousal is persistent, it may be due to a sexual arousal disorder or hypoactive sexual desire disorder. There are many reasons why a person fails to be aroused, including a mental disorder, such as depression, drug use, or a medical or physical condition. The lack of sexual arousal may be due to a general lack of sexual desire or due to a lack of sexual desire for the current partner. A person may always have had no or low sexual desire or the lack of desire may have been acquired during the person's life. Cognitive disturbences : Cognitive disorders often are thought of as disorders of elderly people. Although most common in this population, cognitive disorders can occur at any age. Very young or very old people with cognitive disorders have multiple health needs. Elderly clients usually have more than one chronic illness, and psychiatric disorders can be accompanied by other comorbidities. Cognitive disorders cause a clinically significant deficit in cognition that represents a major change

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from the individuals previous baseline level of functioning. Two common disorders are Delirium Dementiarbidities. Cognitive disorders are a general medical condition, a result of substance use or abuse, a reaction to medications or other ingested agents, or a combination of all of these. In science, cognition: refers to mental processes. These processes include attention, memory, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, science and computer science. Dementia is not merely a problem of memory. It reduces the ability to learn, reason, retain or recall past experience and there is also loss of patterns of thoughts, feelings and activities. The causes of dementia depend on the age at which symptoms begin. In the elderly population (usually defined in this context as over 65 years of age), a large majority of cases of dementia are caused by Alzheimer's disease, vascular dementia or both. Dementia with Lewy bodies is another fairly common cause, which again may occur alongside either or both of the other causes. Hypothyroidism sometimes causes slowly progressive cognitive impairment as the main symptom, and this may be fully reversible with treatment. Normal pressure hydrocephalus, though relatively rare, is important to recognize since treatment may prevent progression and improve other symptoms of the condition. However, significant cognitive improvement is unusual. Delirium is a very general and nonspecific symptom of organ dysfunction, where the organ in question is the brain. Delirium may be caused by physical illness, which can be mild, or any process which interferes with the normal metabolism or function of the brain. For example, electric shock, fever, pain, poisons (including toxic drug reactions), brain injury, hypoxia, anoxia, surgery, traumatic shock, lack of food or water or sleep, and even withdrawal symptoms of certain drug and alcohol dependent states, are all known to cause delirium. In addition, there is an interaction between acute and chronic symptoms of brain dysfunction; delirious states are more easily produced in people already suffering with underlying chronic brain dysfunction.

83)MOTOR

NEURON

DSEASE

Motor neurone disease is a rare condition that progressively damages the nervous system, causing the muscles to waste away. Motor neurone disease occurs when specialist nerve cells, called motor neurones, stop working properly. Motor neurones control important muscle activity such as:

walking speaking breathing swallowing

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As the condition progresses, people with motor neurone disease will find these activities increasingly difficult, and eventually impossible, to do. Exactly what causes the motor neurones to stop working properly is unclear, but several theories have been suggested. Find out about the possible causes of motor neurone disease. In its early stages, motor neurone disease causes symptoms such as:

a weakened grip, which can cause difficulty picking up or holding objects a general feeling of tiredness muscle pains and cramps

As the damage progresses, the symptoms become more debilitating. In the final stages, a person with the condition will be unable to move their body (the medical name for this is total body paralysis) and their breathing difficulties will get worse. Read more about the symptoms of motor neurone disease. Types of motor neurone disease There are three main types of motor neurone disease, which have similar symptoms but progress in different ways:

Limb-onset disease begins with symptoms that affect the arms and legs, such as muscle weakness and loss of function. This is the most common type and accounts for 70% of cases.

Bulbar-onset disease begins with symptoms that affect the mouth and throat, such as difficulties swallowing and slurred speech. This accounts for around 25% of cases. Respiratory-onset disease begins with symptoms that affect the lungs, such as shortness of breath. This accounts for around 5% of cases.

84)PARKNSONS DISEASE
Parkinson's disease is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown. Classification The term parkinsonism is used for a motor syndrome whose main symptoms are tremor at rest, stiffness, slowing of movement and postural instability. Parkinsonian syndromes can be divided into four subtypes according to their origin: primary or idiopathic, secondary or acquired, hereditary parkinsonism, and parkinson plus syndromes or multiple system degeneration Pathophysiology The primary symptoms of Parkinson's disease result from greatly reduced activity of dopaminesecreting cells caused by cell death in thepars compacta region of the substantia nigra.[24]

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There are five major pathways in the brain connecting other brain areas with the basal ganglia. These are known as the motor, oculo-motor, associative, limbic and orbitofrontal circuits, with names indicating the main projection area of each circuit.] All of them are affected in PD, and their disruption explains many of the symptoms of the disease since these circuits are involved in a wide variety of functions including movement, attention and learning. Scientifically, the motor circuit has been examined the most intensively. A particular conceptual model of the motor circuit and its alteration with PD has been of great influence since 1980, although some limitations have been pointed out which have led to modifications. In this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output.[24] Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias

85- Epilepsy
An epileptic seizure (epileptic attack, epileptic fit) is triggered by a spontaneous, synchronized,massive excitation of a large number ofneurons, resulting in localized or generalized activation of motor (fits or seizures), sensory(sensory impressions), autonomic (e.g., salivation), or complex (cognitive, emotional) functions.The epileptic seizures can occur locally, for example, in the left precentral gyrus in the area of those neurons that control the right foot (partial seizure). They can spread from there to the entire precentral gyrus (Jacksonian epilepsy). Clonic cramps may spread, as in this example, from the right foot to the entire right half of the body (Jacksonian motor march), the patient not necessarily losing consciousness. However, should the seizures spread to the other side of the body, the patient will lose consciousness (partial seizure with secondary generalization). Primary generalized seizures are always associated with loss of consciousness. Neuronal excitation or the spread of excitation to neighboring neurons is promoted by a number of cellular mechanisms: The dendrites of the pyramidal cells contain voltage-gated Ca2+ channels that open on depolarization and thus increase depolarization.In lesions of neurons more of these Ca2+ channels are expressed. They are inhibited by Mg2+,while hypomagnesemia promotes the activity of these channels (!A2). An increased extracellular concentration of K+ reduces K+ efflux through the K+ channels, i.e., it has a depolarizing effect and thus at the same time promotes the activation of Ca2+ channels. The dendrites of pyramidal cells are also depolarized by glutamate from excitatory synapses. Glutamate acts on a cation channel that is impermeable to Ca2+ (AMPA channel) and one that is permeable to Ca2+ (NMDA channel). The NMDA channel is normally blocked by Mg2+. However, the depolarization that is triggered by activation of the AMPA channel abolishes the Mg2+ block (co-operation of the two channels). Mg2+ deficiency and depolarization thus favor activation of the NMDA channel.The membrane potential of the neurons is normally maintained by the K+ channels. A precondition for this is an adequate K+ gradient across the cell membrane. This gradient is created by Na+/K+-ATPase (!A4). A lack of available energy (e.g., due to O2 deficiency or hypoglycemia) impairs Na+/K+-ATPase and thus promotes depolarization of the cell.Normally 123

depolarizations are reduced by inhibitory neurons that activate K+ and/or Clchannels via GABA, among others (!A5).GABA is formed by glutamate decarboxylase(GD), an enzyme that needs pyridoxine (vitaminB6) as co-factor. Vitamin B6 deficiency or a reduced affinity of the enzyme for vitamin B6(genetic defect) favors the occurrence of epilepsy.Hyperpolarization of thalamic neurons can increase the readiness of T-type Ca2+ channels to be activated, thereby promoting the onset of absences.

86-Dementia Alzhimer Disease

Dementia is a serious loss of global cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging. It may be static, the result of a unique global brain injury, or progressive, resulting in long-term decline due to damage or disease in the body. Although dementia is far more common in the geriatric population, it can occur before the age of 65, in which case it is termed "early onset dementia".[1] A recent survey done by Harvard University School of Public Health and the Alzheimer's Europe consortium revealed that the second leading health concern (after cancer) among adults is Dementia. Dementia is not a single disease, but rather a non-specific illness syndrome (i.e., set of signs and symptoms) in which affected areas of cognition may be memory, attention, language, and problem solving. It is normally required to be present for at least 6 months to be diagnosed. Symptoms of dementia can be classified as either reversible or irreversible, depending upon the etiology of the disease. Fewer than 10% of cases of dementia are due to causes that may presently be reversed with treatment. Causes include many different specific disease processes, in the same way that symptoms of organ dysfunction such as shortness of breath, jaundice, or pain are attributable to many etiologies.Some of the most common forms of dementia are: Alzheimer's disease, vascular dementia, frontotemporal dementia, semantic dementia and dementia with Lewy bodies. The occurrence of Alzheimers disease, the most common cause of (senile) dementia (about 70%), is favored by a genetic disposition.However, the disease is not genetically uniform. An especially severe form of the disease has an autosomal dominant inheritance. Defects on chromosomes 1, 12, 14, 19, or 21 were found in families with Alzheimers disease. Certain mutations of the !-amyloid precursor gene promote the formation of senile plaques. Amyloid deposits can also occur under the influence of other genetic or external factors. It is thought, for example, that toxins can penetrate the brain via the olfactory nerves and cause the disease. Amyloid deposits also occur in trisomy 21 (Downs syndrome) that also leads to dementia. !-amyloid fibrils can react with receptors at the cell surface, such as the receptor for advanced glycation end products (RAGE), and a scavenger receptor (RA). Oxygen radicals formed as a result may increase the neuronal intracellular concentration of Ca2+ ("A3), possibly via depolarization of the cell membrane and activation of NMDA receptors. The O2 radicals and Ca2+ promote cell death. Cholinergic neurons in the basal nucleus of Meynert, in the hippocampus (especially CA1, the subiculum) and in the entorhinal cortex are particularly affected by cell death, but neurons also die in other cerebral areas, such as the frontal lobes, anterior temporal lobes, parietal lobes, olfactory cortex, hypothalamus, locus ceruleus, and raphe nuclei. Neuronal death is accompanied by decreased formation and concentration of neurotransmitters in the brain. Acetylcholine is markedly affected: in the cerebral cortex and the hippocampus there is an up to 90% decrease in the 124

concentration of choline-acetyl transferase, the enzyme that is necessary for the formation of acetylcholine. The concentration of other neurotransmitters is also reduced. A consequence of the degenerative changes is an increased loss of cerebral functions. The disease typically begins insidiously with subtle deficits of memory, neglect of appearance and body hygiene, phases of confusion, and taking wrong decisions. As the disease progresses, anterograde amnesia will be followed by impairment of past memories as well as procedural memory. Lesions in the limbic system express themselves alternately through restlessness and lethargy. Motor deficits (speech disorders, abnormal muscle tone, ataxia, hyperkinesia, myoclonus) occur relatively late.

87-Stroke
The two major mechanisms causing brain damage in stroke are, ischemia and hemorrhage. In ischemic stroke, which represents about 80% of all strokes, decreased or absent circulating blood deprives neurons of necessary substrates. The effects of ischemia are fairly rapid because the brain does not store glucose, the chief energy substrate and is incapable of anaerobic metabolism. Nontraumatic intracerebral hemorrhage represents approximately 10% to 15% of all strokes. Intracerebral hemorrhage originates from deep penetrating vessels and causes injury to brain tissue by disrupting connecting pathways and causing localized pressure injury. Ischemic Stroke The three main mechanisms causing ischemic strokes are: (a) thrombosis, (2) embolism and (3) global ischemia (hypotensive) stroke. All ischemic strokes do not neatly fall into these categories and the list of entities responsible for unusual stroke syndromes is very long. Atherosclerosis is the most common pathological feature of vascular obstruction resulting in thrombotic stroke. Atherosclerotic plaques can undergo pathological changes such as ulcerations, thrombosis, calcifications, and intra-plaque hemorrhage. The susceptibility of the plaque to disrupt, fracture or disrupt or ulcerate depends on the structure of the plaque, and its composition and consistency. Embolic stroke (ES) can result from embolization of an artery in the central circulation from a variety of sources. Besides clot, fibrin, and pieces of atheromatous plaque, materials known to embolize into the central circulation include fat, air, tumor or metastasis, bacterial clumps, and foreign bodies. Superficial branches of cerebral and cerebellar arteries are the most frequent targets of emboli. Most emboli lodge in the middle cerebral artery distribution because 80% of the blood carried by the large neck arteries flow through the middle cerebral arteries. Global ischemia causes the greatest damage to areas between the territories of the major cerebral and cerebellar arteries known as the boundary zone or watershed area. The parietal-temporal-occipital triangle at the junction of the anterior, middle, and posterior cerebral arteries is most commonly affected. Watershed infarction in this area causes a clinical syndrome consisting of paralysis and sensory loss predominantly involving the arm; the face is not affected and speech is spared.

88)STATIC PROPERTIES AND DYNAMC PROPERTES OF LUNGSPATHOLOGCAL CHANGES

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Lung compliance can refer to either dynamic or static lung compliance. Static lung compliance is the change in volume for any given applied pressure. Dynamic lung compliance is the compliance of the lung at any given time during actual movement of air. Pulmonary compliance is calculated using the following equation, where V is the change in volume, and P is the change in pleural pressure:

Static compliance represents pulmonary compliance during periods without gas flow, such as during an inspiratory pause. It can be calculated with the formula:

Pplat = plateau pressure. Dynamic Compliance Dynamic compliance represents pulmonary complaince during periods of gas flow, such as during active inspiration. Dynamic compliance is always less than or equal to static lung compliance. It can be calculated using the following equation, where Cdyn = Dynamic compliance; VT = tidal volume; PIP = Peak inspiratory pressure; PEEP = Positive End Expiratory Pressure:

Elastic recoil is the rebound of the lungs after having been stretched by inhalation. With inhalation, the interpleural pressure of the lungs decreases. Relaxing the diaphragm during expiration allows the lungs to recoil and regain the interpleural pressure experienced previously at rest. Elastic recoil is inversely related to lung compliance. Airway Resistance can be indirectly measured with body plethysmography. HagenPoiseuille Equation In fluid dynamics, the HagenPoiseuille equation is a physical law that gives the pressure drop in a fluid flowing through a long cylindrical pipe.

= Pressure difference between the ends of the pipe = Length of pipe = the dynamic viscosity = the volumetric flow rate = the radius of the pipe

Laminar flow versus Turbulent flow Where air is flowing in a laminar manner it has less resistance than when it is flowing in a turbulant manner. If flow becomes turbulent, and the pressure difference is increased to maintain flow, this response itself increases resistance. This means that a large increase in pressure difference is required to mainintain flow if it becomes turbulent. 126

is the Reynolds number is the diameter of the pipe. is the mean velocity. is the dynamic viscosity. is the density.

89)CHANGES N VENTILATION PERFUSION RATIO

The ventilation/perfusion ratio is a measurement used to assess the efficiency and adequacy of the matching of two variables:[1] It is defined as: the ratio of the amount of air reaching the alveoli to the amount of blood reaching the alveoli.

"V" ventilation the air which reaches the alveoli "Q" perfusion the blood which reaches the alveoli

These two variables constitute the main determinants of the blood oxygen concentration. In fact since V determines the quantity of oxygen mass reaching the alveoli per minute (g/min) and Q expresses the flow of blood in the lungs (l/min), the V/Q ratio refers to a concentration (g/l).

The actual values in the lung vary depending on the position within the lung. If taken as a whole, the typical value is approximately 0.8.[2] Because the lung is centered vertically around the heart, part of the lung is superior to the heart, and part is inferior. This has a major impact on the V/Q ratio:[3] --apex of lung higher --base of lung lower Ventilation Gravity and lungs weight act on ventilation by increasing pleural pressure at the base (making it less negative) and thus reducing the alveolar volume. The lowest part of the lung in relation to gravity is called the dependent region. At the dependent region smaller volumes mean the alveoli are more compliant (more distensible) and so capable of wider oxygen exchanges with the external environment. The apex, though showing a higher oxygen partial pressure, ventilates less efficiently since its compliance is lower and so smaller volumes are exchanged. Perfusion The impact of gravity on pulmonary perfusion expresses itself as the hydrostatic pressure of the blood passing through the branches of the pulmonary artery in order to reach the apical and basal district of the lung, acting respectively against or synergistically with the pressure developed by the right ventricle. Thus at the apex of the lung the resulting pressure can be insufficient for developing a flow (which can be sustained only by the negative pressure generated by venous flow towards the left atrium) or even for preventing the collapse of the vascular structures surrounding the alveoli,

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while the base of the lung shows an intense flow due to the higher resulting pressure. Pathophysiology A lower V/Q ratio (with respect to the expected value for a particular lung area in a defined position) impairs pulmonary gas exchange and is a cause of low arterial partial pressure of oxygen (paO2). Excretion of carbon dioxide, impaired but a rise in arterial partial pressure of carbon dioxide (paCO2), is very uncommon because this leads to respiratory stimulation and the resultant increase in alveolar ventilation returns paCO2 to within the normal range. These abnormal phenomena are usually seen in chronic bronchitis, asthma and acute pulmonary edema.

A high V/Q ratio increases paO2 and decreases paCO2. This finding is typically associated with pulmonary embolism (where blood circulation is impaired by an embolus). Ventilation is wasted, as it fails to oxygenate any blood. A high V/Q can also be observed in COPD as a maladaptive ventilatory overwork of the undamaged lung parenchyma.

90)DISTURBANCES IN THE CONTROL OF BREATHING Control of Breathing

Introduction

respiration is highly integrated with circulation allowing flexibility between individuals and between species in the best way to optimize gas exchange; control of depth and rate of breathing are essential components of respiratory control

Dyspnea

non-specific symptom of many illnesses the sensation is due to projections from the respiratory controller to higher centers, and projection of sensory information to the brainstem and cortex, and prior experience the relation of dyspnea to the actual physiologic deficits is highly varied across cultures and individuals relief of dyspnea may or may not correspond to adequate relief of the underlying physiologic causes dyspnea can be due to physiologic mechanisms, cortical mechanisms, or a combination of both the whole control system must be examined in the presence of dyspnea (from brain to lungs)

Brainstem Control of Respiration operates breath by breath to control rate and depth

metabolic control: concerns O2 and CO2 (acid/base) balance; can briefly be overridden during speech, swallowing, etc., but metabolic control is always re-asserted after a minute or so; control at brainstem level behavioral control: coordinates breathing with other complex voluntary functions (eating, talking, etc); control at thalamus and cortex; regulates use of motor systems used by both respiratory control and other activities reticular activating system: links the BS and cortex to coordinate respiration with level of alertness (i.e. sleep/wake) medullary control: basic regulation occurs even when the cortex and mid-brain are separated from the medulla o breathing pattern is controlled by the nucleus tractus solitarius and the nucleus retroambiguus o rhythm generation occurs in the pre-Botzinger complex 128

proposed mechanism: tonic inspiratory drive comes from the dorsal motor group via phasic excitatory inputs; expiration is a result of reciprocal inhibition of the tonic drive (influenced by pneumotaxic center in the pons) apneusis: gasping, prolonged inspiration; occurs when pneumotaxic center is destroyed neonates probably have an intrinsic respiratory pacemaker because tonic excitation/reciprocal inhibition systems may not yet be active

Chemoreceptor Control

central chemoreceptors: mainly located ventrolateral medulla; respond to [H+]; account for 70-80% of the CO2 induced changes in respiratory pattern peripheral chemoreceptors: mainly in carotid bodies; location of major PaO2 sensors sensitivity of chemoreceptors: o sensitivity to PaCO2 is linear and increases with hypoxia; because there is a lag time in PCO2, there is a short delay in reaching the steady-state ventilatory rate o sensitivity to O2 is hyperbolic and sensitivity increases with hypercapnea; primarily sensed in carotid bodies and carried by CN IX; if the carotid bodies are destroyed, hypoxia will actually lower ventilation due to hypoxia induced decreases in neuronal activity

Other Control systems

higher brain centers (cortex, spinal, cerebellar): cortical outputs descend to the spinal neurons, and to the brainstem; lesions in certain areas of the brainstem can knock out metabolic control, but maintain volitional control (as long as the person is awake); cerebellum helps with coordination spinal cord integration: descending impulses are modified by inter/intra-segmental neurons, and by motor reflexes o integration is lost in a hiccup when the diaphragm is able to suck in the rib cage without reflexive activation of the intercostal muscles receptors in the lungs: stretch receptors (smooth muscle layer), irritant receptors (epithelial cells), and unmyelinated C fibers (lung interstitium and alveolar walls) receptors in chest wall: joint, tendon, and muscle spindle receptors; reflex control is the same as other skeletal muscle, gamma motor neurons control the gain of the muscle stretch receptors

91)OBSTRUCTION OF AIRFLOW IN RESPRATORY PASSAGE WAY .PATHOPHSIOLOGY OF ASTHMA

Asthma is an airway disease that can be classified physiologically as a variable and partially reversible obstruction to air flow, and pathologically with overdeveloped mucus glands, airway thickening due to scarring and inflammation, andbronchoconstriction, the narrowing of the airways in the lungs due to the tightening of surrounding smooth muscle. Bronchial inflammation also causes narrowing due to edema and swelling caused by an immune response to allergens. Bronchoconstriction During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus, making it difficult to breathe. In essence, asthma is the result of an immune response in the bronchial airways.[1] 129

The airways of asthma patients are "hypersensitive" to certain triggers, also known as stimuli (see below). (It is usually classified as type I hypersensitivity.)[2][3] In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an "asthma attack").Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties. Bronchospasm may resolve spontaneously in 12 hours, or in about 50% of subjects, may become part of a 'late' response, where this initial insult is followed 312 hours later with further bronchoconstriction and inflammation.[4] The normal caliber of the bronchus is maintained by a balanced functioning of these systems, which both operate reflexively. Theparasympathetic reflex loop consists of afferent nerve endings which originate under the inner lining of the bronchus. Whenever these afferent nerve endings are stimulated (for example, by dust, cold air or fumes) impulses travel to the brain-stem vagal center, then down the vagal efferent pathway to again reach the bronchial small airways. Acetylcholine is released from the efferent nerve endings. This acetylcholine results in the excessive formation of inositol 1,4,5-trisphosphate (IP3) in bronchial smooth muscle cells which leads to muscle shortening and this initiates bronchoconstriction. Bronchial inflammation The mechanisms behind allergic asthmai.e., asthma resulting from an immune response to inhaled allergensare the best understood of the causal factors. In both people with asthma and people who are free of the disease, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen-presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system cells. In most people, these other immune cells (TH0 cells) "check" and usually ignore the allergen molecules. In asthma patients, however, these cells transform into a different type of cell (TH2), for reasons that are not well understood. The resultant TH2 cells activate an important arm of the immune system, known as the humoral immune system. The humoral immune system produces antibodies against the inhaled allergen. Later, when a patient inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results: chemicals are produced that cause the wall of the airway to thicken, cells which produce scarring to proliferate and contribute to further 'airway remodeling', causes mucus producing cells to grow larger and produce more and thicker mucus, and the cellmediated arm of the immune system is activated. Inflamed airways are more hyper-reactive, and will be more prone to bronchospasm. The "hygiene hypothesis" postulates that an imbalance in the regulation of these TH cell types in early life leads to a long-term domination of the cells involved in allergic responses over those involved in fighting infection. The suggestion is that for a child being exposed to microbes early in life, taking fewer antibiotics, living in a large family, and growing up in the country stimulate the TH1 response and reduce the odds of developing asthma.

92) OBSTRUCTON OF ARFLOW N RESPRATORY PASSAGEWAYS.PATHOPHSOLOGY OF CHRONC OBSTURUCTVE PULMONARY DSEASE(CHRONC BRONCHTS AND EMPHYSEMA)
Acute bronchitis is an inflammation of the large bronchi (medium-size airways) in the lungs that is usually caused by viruses orbacteria and may last several days or weeks.[1] Characteristic symptoms include cough, sputum (phlegm) production, and shortness of breath and wheezing related to the obstruction of the inflamed airways. Diagnosis is by clinical examination and sometimesmicrobiological examination of the phlegm. Treatment for acute bronchitis is typically symptomatic. As viruses cause most cases of acute bronchitis, antibiotics should not be used unless 130

microscopic examination of gram-stained sputum reveals large numbers of bacteria. Acute bronchitis can be caused by contagious pathogens. In about half of instances of acute bronchitis, a bacterial or viral pathogen is identified. Typical viruses include respiratory syncytial virus, rhinovirus, influenza, and others; typical bacteria include Mycoplasma pneumoniae, Chlamydophila pneumoniae, Bordetella pertussis,streptococcus pneumoniae, and haemophilus influenzae.

Damage caused by irritation of the airways leads to inflammation and leads to neutrophils infiltrating the lung tissue. Mucosal hypersecretion is promoted by a substance released by neutrophils. Further obstruction to the airways is caused by more goblet cells in the small airways. This is typical of chronic bronchitis. Although infection is not the reason or cause of chronic bronchitis, it is seen to aid in sustaining the bronchitis.

Emphysema usually refers to a long-term, progressive disease of the lungs that primarily causes shortness of breath. Subcutaneous emphysema refers to a condition when gas or air is present in the subcutaneous layer of the skin. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary disease or COPD (pulmonary refers to the lungs). Emphysema is called an obstructive lung disease because the destruction of lung tissue around smaller sacs, called alveoli, makes these air sacs unable to hold their functional shape upon exhalation. Emphysema is most often caused by tobacco smoking and long-term exposure to air pollution.

Emphysema can be classified into primary and secondary types. However, it is more commonly classified by location into panacinaryand centroacinary (or panacinar and centriacinar,[2] or centrilobular and panlobular).[3]

Panacinar (or panlobular) emphysema: The entire respiratory acinus, from respiratory bronchiole to alveoli, has expanded. Occurs more commonly in the lower lobes (especially basal segments) and in the anterior margins of the lungs.[2] Centriacinar (or centrilobular) emphysema: The respiratory bronchiole (proximal and central part of the acinus) has expanded. The distal acinus or alveoli are unchanged. Occurs more commonly in the upper lobes.[2]

Other types include distal acinar emphysema and irregular emphysema.[2] A special type is congenital lobar emphysema Congenital lobar emphysema CLE results in overexpansion of a pulmonary lobe, and resultant compression of the remaining lobes of the ipsilateral lung (and possibly also the contralateral lung). There is bronchial narrowing because of weakened or absent bronchial cartilage.[4] There may be congenitalextrinsic compression, commonly by an abnormally large pulmonary artery. This causes malformation of bronchial cartilage, making them soft and collapsible.[4] CLE is a potentially reversible (yet possibly life-threatening) cause of respiratory distress in the neonate. Paraseptal emphysema

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Paraseptal emphysema is a type of emphysema which involves the alveolar ducts and sacs at the lung periphery. The emphysematous areas are subpleural in location and often surrounded by interlobular septa (hence the name). It may be an incidental finding in young adults, and may be associated with spontaneous pneumothorax. It may also be seen in older patients with centrilobular emphysema. Both centrilobular and paraseptal emphysema may progress to bullous emphysema. A bulla is defined as being at least 1 cm in diameter, and with a wall less than 1mm thick. Bullae are thought to arise by air trapping in emphysematous spaces, causing local expansion.

93)RESTRIVTIVE DSTURBANCES OF BREATHING.IDIOPATHIC PULMONARY FIBROSIS

Restrictive lung diseases Restrictive lung diseases are a category of respiratory disease characterized by a loss of lung compliance,[2] causing incomplete lung expansion and increased lung stiffness. E.g. in infant respiratory distress syndrome Respiratory tract infections Infections can affect any part of the respiratory system. They are traditionally divided into upper respiratory tract infections and lower respiratory tract infections. Upper respiratory tract infection The most common upper respiratory tract infection is the common cold however, infections of specific organs of the upper respiratory tract such as sinusitis, tonsillitis, otitis media,pharyngitis and laryngitis are also considered upper respiratory tract infections. Lower respiratory tract infection The most common lower respiratory tract infection is pneumonia, a lung infection. Pneumonia is usually caused by bacteria, particularly Streptococcus pneumoniae in Western countries. Worldwide, tuberculosis is an important cause of pneumonia. Other pathogens such as viruses and fungi can cause pneumonia for examplesevere acute respiratory syndrome and pneumocystis pneumonia. A pneumonia may develop complications such as a lung abscess, a round cavity in the lung caused by the infection, or may spread to the pleural cavity. Idiopathic pulmonary fibrosis is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, primarily occurring in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia . Etiology Despite extensive investigation, the cause of IPF remains unknown. The condition involves abnormal and excessive deposition of collagen (fibrosis) in the pulmonary interstitium (mainly the walls of the alveoli) with minimal associated inflammation.[4] The fibrosis in IPF has been linked to cigarette smoking, gastroesophageal reflux disease and autoimmune disorders, but none of these are present in all patients with IPF, and therefore do not provide a completely satisfactory explanation for the disease. Classification Idiopathic pulmonary fibrosis is one specific presentation of idiopathic interstitial pneumonia (IIP), which is in turn a type of interstitial lung disease. Other forms of "idiopathic interstitial pneumonias" include non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP) and acute interstitial pneumonia (AIP). Examples of known causes of interstitial lung disease include sarcoidosis. hypersensitivity pneumonitis, pulmonary Langerhans cell histiocytosis, asbestosis and collagen vascular diseases such as scleroderma and rheumatoid arthritis. Pathogenesis 132

Pulmonary fibrosis involves gradual exchange of normal lung parenchyma with fibrotic tissue. The replacement of normal lung with scar tissue causes irreversible decrease inoxygen diffusion capacity.[1] In addition, decreased compliance makes pulmonary fibrosis a restrictive lung disease. It is the main cause of restrictive lung disease that is intrinsic to the lung parenchyma. In contrast, quadriplegia and kyphosis are examples of causes of restrictive lung disease that do not necessarily involve pulmonary fibrosis.

94)PULMONARY EDEMA
Pulmonary edema , is fluid accumulation in the air spaces and parenchyma of the lungs. It leads to impaired gas exchange and may cause respiratory failure. It is due to either failure of the left ventricle of the heart to adequately remove blood from the pulmonary circulation ("cardiogenic pulmonary edema"), , or an injury to the lung parenchyma or vasculature of the lung ("noncardiogenic pulmonary edema"),.[2] Whilst the range of causes are manifold the treatment options are limited, and to a large extent, the most effective therapies are used whatever the cause. Treatment is focused on three aspects, firstly improving respiratory function, secondly, treating the underlying cause, and thirdly avoiding further damage to the lung. Pulmonary edema, especially in the acute setting, can lead to respiratory failure, cardiac arrest due to hypoxia and death. Causes Pulmonary edema is an accumulation of fluid within the parenchyma and air spaces of the lungs. Classically it is cardiogenic (left ventricular) but fluid may also accumulate due to damage to the lung. This damage may be direct injury or injury mediated by high pressures within the pulmonary circulation. When directly or indirectly caused by increased left ventricular pressure pulmonary edema may form when mean pulmonary pressure rises from the normal of 15 mmHg[3] to above 25 mmHg.[4] Broadly, the causes of pulmonary oedema can be divided into cardiogenic and noncardiogenic. By convention cardiogenic refers to left ventricular causes. Cardiogenic Left ventricular failure which may be termed Congestive heart failure and may be due to a heart attack leading to left ventricular failure, arrhythmias (tachycardia/fast heartbeat orbradycardia/slow heartbeat) and fluid overload, e.g., from kidney failure or intravenous therapy which may cause dilatation and failure of the left ventricle or may cause pulmonary edema in the absence of heart failure. Non-cardiogenic

Hypertensive crisis. The cause of pulmonary edema in the presence of a hypertensive crisis is probably due to a combination of increased pressures in the right ventricle and pulmonary circulation and also increased systemic vascular resistance and left ventricle contractility increasing the hydrostatic pressure within the pulmonary capillaries leading to extravasation of fluid and edema. Upper airway obstruction (negative pressure pulmonary edema[5] ) Neurogenic causes[6] (seizures, head trauma, strangulation, electrocution).

95)PULMONARY EMBOLSM
A.Definition and Classification A pulmonary embolism most commonly occurs when a thrombus (a circulating blood clot) lodges in the pulmonary vascular bed and restricts circulation to the corresponding part of lung vasculature. 133

PEs are generally classified as small, medium or large based of the size of the obstruction. Large PEs affect 2 or more lung lobes, medium PE affect 1 lung lobe and small PE affect a fraction of a lung lobe. B. Etiology and Risk Factors There are three major risk factors for thromboemboli formation (Virchow's Triad) 1) Stasis 2) Endothelial injury 3) Hypercoagulable states PE also rarely results from embolization of tumor cells or fragments, fat, amniotic fluid, foreign bodies or air. C. Pathophysiology A thrombus that has separated from its site of origin travels through the circulation to the inferior vena cava. The right ventricle pumps this thrombus to the pulmonary arteries where the thrombus finally lodges. PE may occur singly or multiply. They can be microscopic in size or be big enough to occlude the major branches of the pulmonary artery.The embolus obstructs flow in the pulmonary arteries and thus causes an increase in resistance to blood flow in the pulmonary vessels. Severe pulmonary hypertension, RV strain, and cardiac heart failure occur when more than 50-60% decrease in perfusion. In addition, intrapulmonary reflexes stimulate the relase of humoral substances that lead to vasoconstriction throughout the lungs and thus increases pulmonary vascular resistance. 10% of PE will progress to pulmonary infarction. The lung depends on 3 sources of oxygen (airways, bronchial circulation, pulmonary circulation) and therefore the chance that all 3 sources will be compromised simultaneously are not great.Recurrent PE may gradually obstruct the pulmonary vasculature and ultimately lead to chronic obstructive pulmonary hypertension and cor pulmonale.The most important pathophysiological consequence of PE is V/Q mismatch in which there is "dead space" ventilation in some parts of the lung and overperfusion in others. "Dead space" ventilation refers to ventilation of lung segments that have obstructed vascular supply and thus no perfusion. On the other hand, overperfusion and decreased vascular resistance in other parts of the lung leads to right-to-left intrapulmonary shunting with insufficient oxygenation of a large portion of perfused blood.

96)CARDAC ARRHYTHMAS.BRADYCARDA. ATROVENTRCULAR BLOCK

Heart rhythm problems (heart arrhythmias) occur when the electrical impulses in your heart that coordinate your heartbeats don't work properly, causing your heart to beat too fast, too slow or irregularly. Sinus bradycardia can be defined as a sinus rhythm with a resting heart rate of 60 beats per minute or less. However, few patients actually become symptomatic until their heart rate drops to less than 50 beats per minute. The action potential responsible for this rhythm arises from the sinus node and causes a P wave on the surface ECG that is normal in terms of both amplitude and vector. These P waves are typically followed by a normal QRS complex and T wave. The pathophysiology of sinus bradycardia is dependent on the underlying cause. Commonly, sinus bradycardia is an incidental finding in otherwise healthy individuals, particularly in young adults or sleeping patients. Other causes of sinus bradycardia are related to increased vagal tone. Physiologic causes of increased vagal tone include the bradycardia seen in athletes. Pathologic causes include, but are not limited to, inferior wall myocardial infarction, toxic or environmental exposure, electrolyte disorders, infection, sleep apnea, drug effects, hypoglycemia, hypothyroidism, and increased intracranial pressure. Sinus bradycardia may also be caused by the sick sinus syndrome, which involves a dysfunction in the ability of the sinus node to generate or transmit an action potential to the atria. Sick sinus syndrome includes a variety of disorders and pathologic processes that are grouped within one loosely defined clinical syndrome. The syndrome includes signs and symptoms related to cerebral hypoperfusion in association with sinus bradycardia, sinus arrest, sinoatrial (SA) block, carotid hypersensitivity, or 134

alternating episodes of bradycardia and tachycardia. Sick sinus syndrome most commonly occurs in elderly patients with concomitant cardiovascular disease and follows an unpredictable course. Some studies have shown that these patients have a functional decrease in the number of nodal cells, while others have demonstrated the presence of antinodal antibodies. Although these and other developments are beginning to focus our understanding of this syndrome, most cases remain idiopathic.SA block occurs when the SA node fails to excite the atria uniformly. SA block may be associated with abnormal intrinsic nodal function, a failure of the SA junction, or a failure of propagation in the surrounding tissue. The 3 forms of SA block are first-, second-, and third-degree block.Both first- and third-degree SA blocks are essentially undiagnosable on the surface ECG. First-degree SA block is characterized by a delay in the propagation of the action potential from the SA node to the atria. Unlike first-degree atrioventricular (AV) block, this delay is not reflected in the surface ECG. In third-degree, or complete, SA block, the surface ECG is identical to that of sinus arrest, with absent P waves. Second-degree SA block is characterized by an occasional dropped P wave (analogous to the dropped QRS complex of seconddegree AV block), reflecting the inability of the SA node to consistently transmit an action potential to the surrounding myocardium. An atrioventricular block (or AV block) involves the impairment of the conduction between the atria and ventricles of the heart. Under normal conditions, SA node in the atria sets the pace for the heart, and these impulses travel down to the ventricles. In an AV block, this message does not reach the ventricles or is impaired along the way. The ventricles of the heart have their own pacing mechanisms, which can maintain a lowered heart rate in the absence of SA stimulation.

97)TACHYARRHYTHMA.WOLFF PARKINSON WHITE SYNDROME

Tachycardia typically refers to aheart rate that exceeds the normal range. A heart rate over 100 beats per minute is generally accepted as tachycardia. Tachycardia can be caused by various factors which often are benign. However, tachycardia can be dangerous depending on the speed and type of rhythm. Main types : Atrial fibrillation (AF) : In AF the electrical activity of the atria becomes very rapid and irregular, and the pumping action of the atria is lost. The rapid beating of the atria can also cause the ventricles to contract very rapidly and irregularly. This rapid beating of the ventricles can cause fatigue, lightheadedness, shortness of breath, or other manifestations of abnormal heart function. Ventricular tachycardia (VT) : In VT, a rapid heart rhythm originates in the ventricles instead of the SA node. The heart pumps less blood with each beat and, since the rhythm usually starts very suddenly, the cardiac output suddenly falls, and less blood reaches your brain and other organs Ventricular fibrillation (VF) : In VF, the electrical activity of the ventricles is very rapid and disorganized. Little or no blood is pumped, and, unless VF is rapidly terminated, it is invariably fatal. This type of event is also called a cardiac arrest. wolff-parkinson-white syndrome WPW syndrome is currently defined as a congenital abnormality involving the presence of abnormal conductive tissue between the atria and the ventricles in association with supraventricular tachycardia (SVT). Electrical activity in the normal human heart is initiated when a cardiac action potential arises in the sinoatrial (SA) node, which is located in the right atrium. From there, the electrical stimulus is transmitted via internodal pathways to the atrioventricular (AV) node. After a brief delay at the AV node, the stimulus is conducted through the bundle of His to the left and right bundle branches and then to the Purkinje fibers and the endocardium at the apex of the heart, then finally to the 135

ventricular myocardium. The bundle of Kent is an abnormal extra or accessory conduction pathway between the atria and ventricles that is present in a small percentage (between 0.1% and 0.3%) of the general population.[1][2][3] This pathway may communicate between the left atrium and the left ventricle, in which case it is termed a "type A pre-excitation", or between the right atrium and the right ventricle, in which case it is termed a "type B pre-excitation".[6] Problems arise when this pathway creates an electrical circuit that bypasses the AV node. The AV node is capable of slowing the rate of conduction of electrical impulses to the ventricles, whereas the bundle of Kent lacks this capability. When an aberrant electrical connection is made via the bundle of Kent, tachydysrhythmias may therefore result.

98) Congestive heart failure.LEFT Ventricular Failure

Congestive heart failure (CHF) is a condition in which the heart's function as a pump is inadequate to deliver oxygen rich blood to the body. Congestive heart failure can be caused by: 1)diseases that weaken the heart muscle, 2)diseases that cause stiffening of the heart muscles, or 3)diseases that increase oxygen demand by the body tissue beyond the capability of the heart to deliver adequate oxygen-rich blood. The heart has two atria (right atrium and left atrium) that make up the upper chambers of the heart, and two ventricles (left ventricle and right ventricle) that make up the lower chambers of the heart. Heart failure is caused by any condition which reduces the efficiency of the myocardium, or heart muscle, through damage or overloading. As such, it can be caused by as diverse an array of conditions as myocardial infarction (in which the heart muscle is starved of oxygen and dies), hypertension (which increases the force of contraction needed to pump blood) and amyloidosis (in which protein is deposited in the heart muscle, causing it to stiffen). Over time these increases in workload will produce changes to the heart itself:

Reduced force of contraction, due to overloading of the ventricle. In health, increased filling of the ventricle results in increased force of contraction (by the FrankStarling law of the heart) and thus a rise in cardiac output. In heart failure this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. This is due to reduced ability to cross-link actin and myosin filaments in over-stretched heart muscle.[16] A reduced stroke volume, as a result of a failure of systole, diastole or both. Increased end systolic volume is usually caused by reduced contractility. Decreased end diastolic volume results from impaired ventricular filling as occurs when the compliance of the ventricle falls (i.e. when the walls stiffen). Reduced spare capacity. As the heart works harder to meet normal metabolic demands, the amount cardiac output can increase in times of increased oxygen demand (e.g. exercise) is reduced. This contributes to the exercise intolerance commonly seen in heart failure. This translates to the loss of one's cardiac reserve. The cardiac reserve refers to the ability of the heart to work harder during exercise or strenuous activity. Since the heart has to work harder to meet the normal metabolic demands, it is incapable of meeting the metabolic demands of the body during exercise. Increased heart rate, stimulated by increased sympathetic activity[17] in order to maintain cardiac output. Initially, this helps compensate for heart failure by maintaining blood pressure and 136

perfusion, but places further strain on the myocardium, increasing coronary perfusion requirements, which can lead to worsening of ischemic heart disease. Sympathetic activity may also cause potentially fatal arrhythmias. Hypertrophy (an increase in physical size) of the myocardium, caused by the terminally differentiated heart muscle fibres increasing in size in an attempt to improve contractility. This may contribute to the increased stiffness and decreased ability to relax during diastole. Enlargement of the ventricles, contributing to the enlargement and spherical shape of the failing heart. The increase in ventricular volume also causes a reduction in stroke volume due to mechanical and contractile inefficiency. Left-sided failure Backward failure of the left ventricle causes congestion of the pulmonary vasculature, and so the symptoms are predominantly respiratory in nature. Backward failure can be subdivided into failure of the left atrium, the left ventricle or both within the left circuit. The patient will have dyspnea (shortness of breath) on exertion (dyspne d'effort) and in severe cases, dyspnea at rest. Increasing breathlessness on lying flat, called orthopnea, occurs. It is often measured in the number of pillows required to lie comfortably, and in severe cases, the patient may resort to sleeping while sitting up. Another symptom of heart failure is paroxysmal nocturnal dyspnea a sudden nighttime attack of severe breathlessness, usually several hours after going to sleep. Easy fatigueability and exercise intolerance are also common complaints related to respiratory compromise. "Cardiac asthma" or wheezing may occur. Compromise of left ventricular forward function may result in symptoms of poor systemic circulation such as dizziness, confusion and cool extremities at rest.

99) Congestive heart failure.RIGHT VENTRICULAR FAILURE

Congestive heart failure (CHF) is a condition in which the heart's function as a pump is inadequate to deliver oxygen rich blood to the body. Congestive heart failure can be caused by: 1)diseases that weaken the heart muscle, 2)diseases that cause stiffening of the heart muscles, or 3)diseases that increase oxygen demand by the body tissue beyond the capability of the heart to deliver adequate oxygen-rich blood. The heart has two atria (right atrium and left atrium) that make up the upper chambers of the heart, and two ventricles (left ventricle and right ventricle) that make up the lower chambers of the heart. Heart failure is caused by any condition which reduces the efficiency of the myocardium, or heart muscle, through damage or overloading. As such, it can be caused by as diverse an array of conditions as myocardial infarction (in which the heart muscle is starved of oxygen and dies), hypertension (which increases the force of contraction needed to pump blood) and amyloidosis (in which protein is deposited in the heart muscle, causing it to stiffen). Over time these increases in workload will produce changes to the heart itself:

Reduced force of contraction, due to overloading of the ventricle. In health, increased filling of the ventricle results in increased force of contraction (by the FrankStarling law of the heart) and thus a rise in cardiac output. In heart failure this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. This is due to reduced ability to cross-link actin and myosin filaments in over-stretched heart muscle.[16] 137

A reduced stroke volume, as a result of a failure of systole, diastole or both. Increased end systolic volume is usually caused by reduced contractility. Decreased end diastolic volume results from impaired ventricular filling as occurs when the compliance of the ventricle falls (i.e. when the walls stiffen). Reduced spare capacity. As the heart works harder to meet normal metabolic demands, the amount cardiac output can increase in times of increased oxygen demand (e.g. exercise) is reduced. This contributes to the exercise intolerance commonly seen in heart failure. This translates to the loss of one's cardiac reserve. The cardiac reserve refers to the ability of the heart to work harder during exercise or strenuous activity. Since the heart has to work harder to meet the normal metabolic demands, it is incapable of meeting the metabolic demands of the body during exercise. [17] Increased heart rate, stimulated by increased sympathetic activity in order to maintain cardiac output. Initially, this helps compensate for heart failure by maintaining blood pressure and perfusion, but places further strain on the myocardium, increasing coronary perfusion requirements, which can lead to worsening of ischemic heart disease. Sympathetic activity may also cause potentially fatal arrhythmias. Hypertrophy (an increase in physical size) of the myocardium, caused by the terminally differentiated heart muscle fibres increasing in size in an attempt to improve contractility. This may contribute to the increased stiffness and decreased ability to relax during diastole. Enlargement of the ventricles, contributing to the enlargement and spherical shape of the failing heart. The increase in ventricular volume also causes a reduction in stroke volume due to mechanical and contractile inefficiency. Right-sided failure Backward failure of the right ventricle leads to congestion of systemic capillaries. This generates excess fluid accumulation in the body. This causes swelling under the skin (termedperipheral edema or anasarca) and usually affects the dependent parts of the body first (causing foot and ankle swelling in people who are standing up, and sacral edema in people who are predominantly lying down). Nocturia (frequent nighttime urination) may occur when fluid from the legs is returned to the bloodstream while lying down at night. In progressively severe cases, ascites (fluid accumulation in the abdominal cavity causing swelling) and hepatomegaly (enlargement of the liver) may develop. Significant liver congestion may result in impaired liver function, and jaundice and even coagulopathy (problems of decreased blood clotting) may occur.

100)ENDOCARDITIS AND MYOCARDITIS

Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves (native or prosthetic valves). Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or even on intracardiac devices. Endocarditis is characterized by a prototypic lesion, the vegetation, which is a mass of platelets, fibrin, microcolonies of microorganisms, and scant inammatory cells.[1] In the subacute form of infective endocarditis, the vegetation may also include a center of granulomatous tissue, which may fibrose or calcify.[2] There are multiple ways to classify endocarditis. The simplest classification is based on etiology: either infective or non-infective, depending on whether a microorganism is the source of the inflammation or not. Regardless, diagnosis of endocarditis is based on the clinical features, investigations such as echocardiogram, as well as any blood cultures demonstrating the presence of endocarditis-causing microorganisms.

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Infective endocarditis Since the valves of the heart do not receive any dedicated blood supply, defensive immune mechanisms (such as white blood cells) cannot directly reach the valves via the bloodstream. If an organism (such as bacteria) attaches to a valve surface and forms a vegetation, the host immune response is blunted. The lack of blood supply to the valves also has implications on treatment, since drugs also have difficulty reaching the infected valve. Non-infective endocarditis Nonbacterial thrombic endocarditis (NBTE) or marantic endocarditis is most commonly found on previously undamaged valves.[2] As opposed to infective endocarditis, the vegetations in NBTE are small, sterile, and tend to aggregate along the edges of the valve or the cusps.[2] Also unlike infective endocarditis, NBTE does not cause an inflammation response from the body.[2] NBTE usually occurs during a hypercoagulable state such as system wide bacterial infection, or pregnancy, though it is also sometimes seen in patients with venous catheters.[2] NBTE may also occur in patients with cancers, particularly mucinous adenocarcinoma[2] where Trousseau syndrome can be encountered. Typically NBTE does not cause many problems on its own, but parts of the vegetations may break off and embolize to the heart or brain, or they may serve as a focus where bacteria can lodge, thus causing infective endocarditis.[2] Myocarditis or inflammatory cardiomyopathy is inflammation of heart muscle (myocardium).The pathogenesis of myocarditis is not entirely clear. However, in viral-mediated myocarditis, animal models have implicated 3 significant mechanisms An infectious organism directly invades the myocardium

Local and systemic immunological activation quickly ensues Cellular (CD4+) and humoral (B-cell clonal multiplication) activation occurs, causing worsening local inflammation, anti-heart antibody production and further myonecrosis. All 3 may occur in the same host. However, the predominant pathway may differ depending on the individual characteristics of the infectious species and the innate defenses of the host organism. The first phase is characterised by viraemia in the host organism. During this time, the cardiotropic RNA virus enters the host myocyte via receptor-mediated endocytosis. Here, the viral RNA is translated into viral protein, and the viral genome is incorporated into the host-cell DNA as doublestranded RNA. This latter mechanism has been shown to cleave dystrophin, which is thought to directly cause myocyte dysfunction. During the second and third phases, macrophages, natural killer cells, and other inflammatory cells infiltrate the myocardium. Once in the myocardium, these cells express inflammatory cytokines including interleukin-1, interleukin-2, interferon-gamma, and TNF. This results in increased cytokine production and causes endothelial cell activation resulting in further infiltration of inflammatory cells. TNF alone also acts as a negative inotrope. In addition, auto-antibodies directed against myocardial contractile and structural proteins are produced. This is thought to have cytopathic effects on energy metabolism, calcium homeostasis and signal transduction, and also to cause complement activation resulting in the lysis of myocytes.

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101)Valvular heart disease. Aortic stenosis.

-Valvular heart disease is any disease process involving one or more of the valves of the heart. Valve problems may be congenital or acquired. Treatment may be with medication but often involves valve repair or replacement. -Aortic valve stenosis is a disease of the heart valves in which the opening of the aortic valve is narrowed. The aortic valve is the valve between the left ventricle of the heart and the aorta, which is the largest artery in the body and carries the entire output of blood. symptoms: -Congestive heart failure carries a grave prognosis in patients with AS. CHF in the setting of AS is due to a combination of systolic dysfunction and diastolic dysfunction. -Syncope (fainting spells) from aortic valve stenosis is usually exertional.In the setting of heart failure it increases the risk of death.When the patient exercises, their peripheral vascular resistance will decrease as the blood vessels of the skeletal muscles dilate to allow the muscles to receive more blood to allow them to do more work. This decrease in peripheral vascular resistance is normally compensated for by an increase in the cardiac output. Since patients with severe AS cannot increase their cardiac output, the blood pressure falls and the patient will syncopize due to decreased blood perfusion to the brain. -Angina in the setting of heart failure also increases the risk of death. Angina in the setting of AS is secondary to the left ventricular hypertrophy that is caused by the constant production of increased pressure required to overcome the pressure gradient caused by the AS. The ischemia may first be evident during exercise, when the heart muscle requires increased blood supply to compensate for the increased workload. Cause: -Aortic stenosis is most commonly caused by age-related progressive calcification of a normal (threeleafed) aortic valve mean age 65 to 70 years old - most common cause. Other causes include calcification of a congenital bicuspid aortic valve most common cause and acute rheumatic fever post-inflammatory. pathophysiology: The aortic valve normally consists of three leaflets. When the left ventricle contracts, it forces blood through the valve to the aorta and then to the rest of the body. When the LV expands again, the aortic valve prevents the blood from returning to the ventricle. When the opening of the aortic valve becomes narrowed or constricted, the blood can't be pumped adequately and the pressure in the left ventricle increases.[5]Initially, the LV compensates by thickening its walls (myocardial hypertrophy) in order to maintain adequate pumping pressure. The type of hypertrophy most commonly seen in AS is concentric hypertrophy, in which the walls of the LV are equally thickened. In the later stages, the left ventricle dilates, the wall thins, and the systolic function deteriorates. Morris and Innasimuthu et al showed that different coronary anatomy is associated with different valve 140

diseases. There is more research going on to see if different coronary anatomy might lead to turbulent flow at the level of valves leading to inflammation and degeneration.

102)Valvular heart disease. Aortic regurgitation.

-Valvular heart disease is any disease process involving one or more of the valves of the heart. Valve problems may be congenital or acquired. Treatment may be with medication but often involves valve repair or replacement. -Aortic insufficiency, also known as aortic regurgitation, is the leaking of the aortic valve of the heart that causes blood to flow in the reverse direction during ventricular diastole, from the aorta into the left ventricle. Aortic insufficiency can be due to abnormalities of either the aortic valve or the aortic root. -Pathophysiology: In aortic insufficiency, when the pressure in the left ventricle falls below the pressure in the aorta, the aortic valve is not able to completely close. This causes a leaking of blood from the aorta into the left ventricle. This means that some of the blood that was already ejected from the heart is regurgitating back into the heart. The percentage of blood that regurgitates back through the aortic valve due to AI is known as the regurgitant fraction. For instance, if an individual with AI has a stroke volume of 100 ml and during ventricular diastole 25 ml regurgitates back through the aortic valve, the regurgitant fraction is 25%. This regurgitant flow causes a decrease in the diastolic blood pressure in the aorta, and therefore an increase in the pulse pressure. Thus, physical examination will reveal a bounding pulse, especially in the radial artery. Since some of the blood that is ejected during systole regurgitates back into the left ventricle during diastole, there is decreased effective forward flow in AI. -while diastolic blood pressure is diminished and the pulse pressure widens, systolic blood pressure generally remains normal or can even be slightly elevated. This is because sympathetic nervous system and the renin-angiotensin-aldosterone axis of the kidneys compensate for the decreased cardiac output. Catecholamines will increase the heart rate and increase the strength of ventricular contraction, directly increasing cardiac output. Catecholamines will also cause peripheral vasoconstriction, which causes increased systemic vascular resistance and ensures that core organs are adequately perfused. Renin, a proteolytic enzyme, cleaves angiotensinogen to angiotensin I, which is converted to angiotensin II, which is also a potent vasoconstrictor. In the case of chronic aortic insufficiency with resultant cardiac remodeling, heart failure will develop, and it is possible to see systolic pressures diminish. Aortic insufficiency causes both volume overload and pressure overload of the heart. The pressure overload (due to elevated pulse pressure and the systemic effects of neuroendocrine hormones) causes left ventricular hypertrophy. There is both concentric hypertrophy and eccentric hypertrophy 141

in AI. The concentric hypertrophy is due to the increased left ventricular systolic pressures associated with AI, while the eccentric hypertrophy is due to volume overload caused by the regurgitant fraction.

103.Valvular heart disease. Mitral stenosis.

-Valvular heart disease is any disease process involving one or more of the valves of the heart. Valve problems may be congenital or acquired. Treatment may be with medication but often involves valve repair or replacement. -Mitral stenosis is a valvular heart disease characterized by the narrowing of the orifice of the mitral valve of the heart. -Symptoms include: dyspnea, orthopnea Palpitations Chest pain Thromboembolism in later stages when the left ventricular volume is increased Ascites and edema and hepatomegaly -Cause: Almost all cases of mitral stenosis are due to disease in the heart secondary to rheumatic fever and the consequent rheumatic heart disease. Uncommon causes of mitral stenosis are calcification of the mitral valve leaflets, and as a form of congenital heart disease. However, there are primary causes of mitral stenosis that emanate from a cleft mitral valve.Other causes include infective endocarditis where the vegetations may favor increase risk of stenosis. It is the most common valvular heart disease in pregnancy. -Pathophysiology: The normal area of the mitral valve orifice is about 4 to 6 cm2. In normal cardiac physiology, the mitral valve opens during left ventricular diastole, to allow blood to flow from the left atrium to the left ventricle. A normal mitral valve will not impede the flow of blood from the left atrium to the left ventricle during diastole, and the pressures in the left atrium and the left ventricle during ventricular diastole will be equal. The result is that the left ventricle gets filled with blood during early ventricular diastole, with only a small portion of extra blood contributed by contraction of the left atrium during late ventricular diastole.

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When the mitral valve area goes below 2 cm2, the valve causes an impediment to the flow of blood into the left ventricle, creating a pressure gradient across the mitral valve. This gradient may be increased by increases in the heart rate or cardiac output. As the gradient across the mitral valve increases, the amount of time necessary to fill the left ventricle with blood increases. Eventually, the left ventricle requires the atrial kick to fill with blood. As the heart rate increases, the amount of time that the ventricle is in diastole and can fill up with blood decreases. When the heart rate goes above a certain point, the diastolic filling period is insufficient to fill the ventricle with blood and pressure builds up in the left atrium, leading to pulmonary congestion. When the mitral valve area goes less than 1 cm2, there will be an increase in the left atrial pressures.Since the normal left ventricular diastolic pressures is about 5 mmHg, a pressure gradient across the mitral valve of 20 mmHg due to severe mitral stenosis will cause a left atrial pressure of about 25 mmHg. This left atrial pressure is transmitted to the pulmonary vasculature and causes pulmonary hypertension. Pulmonary capillary pressures in this level cause an imbalance between the hydrostatic pressure and the oncotic pressure, leading to extravasation of fluid from the vascular tree and pooling of fluid in the lungs. The constant pressure overload of the left atrium will cause the left atrium to increase in size. As the left atrium increases in size, it becomes more prone to develop atrial fibrillation. When atrial fibrillation develops, the atrial kick is lost. In individuals with severe mitral stenosis, the left ventricular filling is dependent on the atrial kick. The loss of the atrial kick due to atrial fibrillation can cause a precipitous decrease in cardiac output and sudden congestive heart failure.[citation needed] Patients with mitral stenosis prompts a series of hemodynamic changes that frequently cause deterioration of the patient's clinical status. A reduction in cardiac output, associated with acceleration of heart rate and shortening of the diastolic time, frequently leads to congestive heart failure. In addition, when AF sets in, systemic embolization becomes a real danger.

104.Valvular heart disease. Mitral regurgitation.

-Valvular heart disease is any disease process involving one or more of the valves of the heart. Valve problems may be congenital or acquired. Treatment may be with medication but often involves valve repair or replacement. -Mitral regurgitation, mitral insufficiency or mitral incompetence is a disorder of the heart in which the mitral valve does not close properly when the heart pumps out blood. It is the abnormal leaking of blood from the left ventricle, through the mitral valve, and into the left atrium, when the left ventricle contracts. MR is the most common form of valvular heart disease. -symptoms: shortness of breath, pulmonary edema, orthopnea, and paroxysmal nocturnal dyspnea, palpitations, cardiogenic shock.

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-causes: The mitral valve is composed of two valve leaflets, the mitral valve annulus, the papillary muscles and the chordae tendineae. A dysfunction of any of these portions of the mitral valve apparatus can cause mitral regurgitation. The most common cause of mitral regurgitation is mitral valve prolapse, which in turn is caused by myxomatous degeneration.The most common cause of primary mitral regurgitation is myxomatous degeneration of the valve. Myxomatous degeneration of the mitral valve is more common in females, and is more common in advancing age. This causes a stretching out of the leaflets of the valve and the chordae tendineae. The elongation of the valve leaflets and the chordae tendineae prevent the valve leaflets from fully coapting when the valve is closed, causing the valve leaflets to prolapse into the left atrium, thereby causing mitral regurgitation. Ischemic heart disease causes mitral regurgitation by the combination of ischemic dysfunction of the papillary muscles, and the dilatation of the left ventricle that is present in ischemic heart disease, with the subsequent displacement of the papillary muscles and the dilatation of the mitral valve annulus. Rheumatic fever and Marfan's syndrome are other typical causes of mitral regurgitation. Secondary mitral regurgitation is due to the dilatation of the left ventricle, causing stretching of the mitral valve annulus and displacement of the papillary muscles. This dilatation of the left ventricle can be due to any cause of dilated cardiomyopathy, including aortic insufficiency, nonischemic dilated cardiomyopathy and Noncompaction Cardiomyopathy. It is also called functional mitral regurgitation, because the papillary muscles, chordae, and valve leaflets are usually normal. -Pathophysiology: 1-Acute phase Acute mitral regurgitation causes a sudden volume overload of both the left atrium and the left ventricle. The left ventricle develops volume overload because with every contraction it now has to pump out not only the volume of blood that goes into the aorta, but also the blood that regurgitates into the left atrium. In the acute setting, the stroke volume of the left ventricle is increased, this happens because of more complete emptying of heart. However, as it progresses the LV volume increases and the contractile function deteriorates and thus leading to dysfunctional LV and a decrease in ejection fraction. The regurgitant volume causes a volume overload and a pressure overload of the left atrium. The increased pressures in the left atrium inhibit drainage of blood from the lungs via the pulmonary veins. This causes pulmonary congestion. 2-Chronic phase: a)Compensated:

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If the mitral regurgitation develops slowly over months to years or if the acute phase cannot be managed with medical therapy, the individual will enter the chronic compensated phase of the disease. In this phase, the left ventricle develops eccentric hypertrophy in order to better manage the larger than normal stroke volume. The eccentric hypertrophy and the increased diastolic volume combine to increase the stroke volume so that the forward stroke volume approaches the normal levels. In the left atrium, the volume overload causes enlargement of the chamber of the left atrium, allowing the filling pressure in the left atrium to decrease. This improves the drainage from the pulmonary veins, and signs and symptoms of pulmonary congestion will decrease. b)Decompensated An individual may be in the compensated phase of mitral regurgitation for years, but will eventually develop left ventricular dysfunction, the hallmark for the chronic decompensated phase of mitral regurgitation. It is currently unclear what causes an individual to enter the decompensated phase of this disease. However, the decompensated phase is characterized by calcium overload within the cardiac myocytes. In this phase, the ventricular myocardium is no longer able to contract adequately to compensate for the volume overload of mitral regurgitation, and the stroke volume of the left ventricle will decrease.The left ventricle begins to dilate during this phase. This causes a dilatation of the mitral valve annulus, which may worsen the degree of mitral regurgitation. The dilated left ventricle causes an increase in the wall stress of the cardiac chamber as well. While the ejection fraction is less in the chronic decompensated phase than in the acute phase or the chronic compensated phase of mitral regurgitation, it may still be in the normal range and may not decrease until late in the disease course. A decreased ejection fraction in an individual with mitral regurgitation and no other cardiac abnormality should alert the physician that the disease may be in its decompensated phase.

105.Coronary artery disease. Angina pectoris.

-Coronary artery disease is the result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients,the filling up of the plaque in the lumen of artery causes narrowing of lumen of the artery by decreasing its diameter. It is sometimes also called coronary heart disease. -Pathophysiology: Limitation of blood flow to the heart causes ischemia of the myocardial cells. Myocardial cells may die from lack of oxygen and this is called a myocardial infarction. It leads to heart muscle damage, heart muscle death and later myocardial scarring without heart muscle regrowth. Chronic high-grade stenosis of the coronary arteries can induce transient ischemia which leads to the induction of a ventricular arrhythmia, which may terminate into ventricular fibrillation leading to death.

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-Angina pectoris is chest pain due to ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries. Coronary artery disease, the main cause of angina, is due to atherosclerosis of the coronary arteries. -Classification: Stable angina Typical presentations of stable angina is that of chest discomfort and associated symptoms precipitated by some activity with minimal or non-existent symptoms at rest. Unstable angina this is defined as angina pectoris that changes or worsens. It has at least one of these three features: it occurs at rest, usually lasting >10 min; it is severe and of new onset; it occurs with a crescendo pattern. UA may occur unpredictably at rest which may be a serious indicator of an impending heart attack. What differentiates stable angina from unstable angina is the pathophysiology of the atherosclerosis. The pathophysiology of unstable angina is the reduction of coronary flow due to transient platelet aggregation on apparently normal endothelium, coronary artery spasms or coronary thrombosis.The process starts with atherosclerosis, and when inflamed leads to an active plaque, which undergoes thrombosis and results in acute ischemia, which finally results in cell necrosis after calcium entry. Microvascular angina Microvascular Angina or Angina Syndrome X is characterized by angina-like chest pain.The cause of is unknown, but it appears to be the result of poor function in the tiny blood vessels of the heart, arms and legs. -symptoms: the discomfort is usually described as a pressure, heaviness, tightness, squeezing, burning, or choking sensation. Typical locations for referred pain are arms, shoulders, and neck into the jaw. Angina is typically precipitated by exertion or emotional stress. -Major risk factors: Age (= 55 years for men, = 65 for women) Cigarette smoking Diabetes mellitus Hypertension

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Kidney disease Obesity Medications vasodilators excessive thyroid replacement vasoconstrictors -Pathophysiology: Angina results when there is an imbalance between the heart's oxygen demand and supply. This imbalance can result from an increase in demand without a proportional increase in supply.

106.Coronary artery disease. Myocardial infarction.

-Coronary artery disease is the result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients,the filling up of the plaque in the lumen of artery causes narrowing of lumen of the artery by decreasing its diameter. It is sometimes also called coronary heart disease. -Myocardial infarction results from the interruption of blood supply to a part of the heart, causing heart cells to die. This is most commonly due to blockage of a coronary artery following the rupture of a vulnerable atherosclerotic plaque, which is an unstable collection of lipids and white blood cells in the wall of an artery. Classical symptoms of acute myocardial infarction include sudden chest pain, shortness of breath, nausea, vomiting, palpitations, sweating, and anxiety. Women may experience fewer typical symptoms than men, most commonly shortness of breath, weakness, a feeling of indigestion, and fatigue. -Classification: There are two basic types based on pathology: Transmural: associated with atherosclerosis involving a major coronary artery. Transmural infarcts extend through the whole thickness of the heart muscle and are usually a result of complete occlusion of the area's blood supply. Subendocardial: involving a small area in the subendocardial wall of the left ventricle, ventricular septum, or papillary muscles. The other classification: Type 1 Spontaneous myocardial infarction related to ischaemia due to a primary coronary event such as plaque erosion or rupture, fissuring.

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Type 2 Myocardial infarction secondary to ischaemia due to either increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias, hypertension, or hypotension Type 3 Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischaemia, accompanied by new ST elevation or evidence of fresh thrombus in a coronary artery by angiography or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood Type 4 Associated with coronary angioplasty or stents Type 5 Myocardial infarction associated with CABG -Pathopyhysiology: The most common triggering event is the disruption of an atherosclerotic plaque in an epicardial coronary artery, which leads to a clotting cascade, sometimes resulting in total occlusion of the artery.[60][61] Atherosclerosis is the gradual buildup of cholesterol and fibrous tissue in plaques in the wall of arteries, typically over decades.Blood stream column irregularities visible on angiography reflect artery lumen narrowing as a result of decades of advancing atherosclerosis.[63] Plaques can become unstable, rupture, and additionally promote a thrombus (blood clot) that occludes the artery; this can occur in minutes. When a severe enough plaque rupture occurs in the coronary vasculature, it leads to myocardial infarction. If impaired blood flow to the heart lasts long enough, it triggers a process called the ischemic cascade; the heart cells in the territory of the occluded coronary artery die and do not grow back. A collagen scar forms in its place. Recent studies indicate that another form of cell death called apoptosis also plays a role in the process of tissue damage subsequent to myocardial infarction. As a result, the patient's heart will be permanently damaged. This myocardial scarring also puts the patient at risk for potentially life threatening arrhythmias, and may result in the formation of a ventricular aneurysm that can rupture with catastrophic consequences.

107)PERCARDAL DSEASE. PERCARDTS, PERCARDAL EFFUSON, TAMPONADE:

Pericarditis is a swelling and irritation of the pericardium, the thin sac-like membrane that surrounds your heart. Pericarditis often causes chest pain and sometimes other symptoms. Pericarditis is usually sudden and short-lived (acute). When symptoms develop more gradually or persist, the pericarditis is considered chronic. The sharp chest pain associated with pericarditis occurs when the inflamed or irritated two layers of the pericardium rub against each other. Symptoms:

Sharp, piercing chest pain over the center or left side of chest Shortness of breath when reclining Low-grade fever

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An overall sense of weakness, fatigue or feeling sick Dry cough Abdominal or leg swelling Causes: Pericarditis can develop shortly after a major heart attack, due to the irritation of the underlying damaged heart muscle. In addition, a delayed form of pericarditis may occur weeks after a heart attack or heart surgery because of antibody formation. This delayed pericarditis is known as Dressler's syndrome. Other causes of pericarditis include:

Systemic inflammatory disorders. These include lupus and rheumatoid arthritis. Trauma. Injury to your heart or chest may occur as a result of a motor vehicle or other accident. Other health disorders. These may include kidney failure, AIDS, tuberculosis and cancer. Certain medications. Some medications can cause pericarditis, although this is unusual. Pathophysiology: The pericardium has two layers: visceral and parietal. The visceral layer is closely apposed to the heart, whilst the fibrous parietal layer provides a more rigid outer shell to the pericardial cavity. The normal volume of pericardial fluid is in the region of 50 mL. Viral pericarditis is the most common type, but in many cases either the diagnosis is never made or the viral infection is never identified. Another common presentation is characteristic pain 314 days postmyocardial infarction or postcardiac surgery, which tends to be self-limiting. Relapsing episodes are referred to as Dressler's syndrome or postcardiotomy syndrome, and are thought to represent an autoimmune process.

Pericardial effusion is an abnormal accumulation of fluid in the pericardial cavity. A pericardial effusion with enough pressure to adversely affect heart function is called cardiac tamponade. Pericardial effusion usually results from a disturbed equilibrium between the production and reabsorption of pericardial fluid. Normal levels of pericardial fluid are from 15 to 50 mL. Types It may be:

transudative (congestive heart failure, myxoedema, nephrotic syndrome), exudative (tuberculosis, spread from empyema) haemorrhagic (trauma, rupture of aneurysms, malignant effusion). malignant (due to fluid accumulation caused by metastasis)

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symptoms: Chest pain or pressure are common symptoms. Larger effusions may cause cardiac tamponade, a lifethreatening complication; signs of impending tamponade include dyspnea, low blood pressure, and distant heart sounds. Causes: Pericarditis Viral infection Infection Inflammatory disorders, such as lupus and post myocardial infarction pericarditis (Dressler's syndrome) Cancer that has spread to the pericardium Trichinosis Kidney failure with excessive blood levels of urea nitrogen Hypothyroidism The pericardium plays a pivotal role in cardiac changes during inspiration. As the right atrium and ventricle fill during normal inspiration, the pericardium, by limiting the ability of these chambers to dilate, contributes to the bowing of the atrial and ventricular septums to the left. This reduces left ventricular (LV) filling volumes, which lead to the drop in cardiac output. As intrapericardial pressures rise, this effect becomes pronounced, eventually leading to the finding of pulsus paradoxus, which heralds the development of pericardial tamponade. Cardiac tamponade is an acute type of pericardial effusion in which fluid accumulates in the pericardium. Cardiac tamponade is pressure on the heart muscle which occurs when the pericardial space fills up with fluid faster than the pericardial sac can stretch. If the amount of fluid increases slowly the pericardial sac can expand to contain a liter or more of fluid prior to tamponade occurring. If the fluid occurs rapidly as little as 100 ml can cause tamponade. Causes of increased pericardial effusion include hypothyroidism, physical trauma, pericarditis, iatrogenic trauma and myocardial rupture. One of the most common settings for cardiac tamponade is in the first 24 to 48 hours after heart surgery. After heart surgery, chest tubes are placed to drain blood. These chest tubes, however, are prone to clot formation. When a chest tube becomes occluded or clogged, the blood that should be drained can accumulate around the heart, leading to tamponade. Pathophysiology The outer layer of the heart is made of fibrous tissue which does not easily stretch, and so once fluid begins to enter the pericardial space, pressure starts to increase. If fluid continues to accumulate, then with each successive diastolic period, less and less blood enters the ventricles, as the increasing pressure presses on the heart and forces the septum to bend into the left ventricle, leading to decreased stroke volume. This causes obstructive shock to develop, and if left untreated then cardiac arrest may ocur.

108) Primary Hypertension ;

Essential hypertension remains a major modifiable risk factor for cardiovascular disease (CVD) despite important advances in our understanding of its pathophysiology and the availability of effective treatment strategies. High blood pressure (BP) increases the risk of CVD for millions of 150

people worldwide, and there is evidence that the problem is only getting worse. In the past decade, age-adjusted rates of stroke incidence have risen, and the slope of the age-adjusted rate of decline in coronary disease has leveled off. The incidence of end-stage renal disease and the prevalence of heart failure have also increased. A major contributor to these trends is inadequate control of BP in the hypertensive population. This review of current concepts regarding the definition, etiology, and treatment of essential hypertension is intended to aid the clinician in identifying those individuals at high risk who need to undergo evaluation and treatment, as well as in selecting optimal treatment strategies for hypertensive patients with comorbid conditions and/or target organ damage. The part of the review that deals with the genetic basis of hypertension and the gene/environment interaction that may lead to elevated BP is still a work in progress. Information gained from the Human Genome Project and from ongoing studies of the genetic basis of hypertension both in animal models and human populations may revolutionize the treatment of hypertension by replacing current empirical therapy with more effective, targeted treatments based on the genotype of the patient. Concepts introduced in this review form the basis for such "pharmacogenomic" approaches to antihypertensive therapy. Definition of Essential or Primary Hypertension BP is a quantitative trait that is highly variable1 ; in population studies, BP has a normal distribution that is slightly skewed to the right. There is a strong positive and continuous correlation between BP and the risk of CVD (stroke, myocardial infarction, heart failure), renal disease, and mortality, even in the normotensive range. This correlation is more robust with systolic than with diastolic BP.2 There is no specific level of BP where cardiovascular and renal complications start to occur; thus the definition of hypertension is arbitrary but needed for practical reasons in patient assessment and treatment. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) defined and classified hypertension in adults, as shown in Table 1 .3 The diagnosis of hypertension is made when the average of 2 or more diastolic BP measurements on at least 2 subsequent visits is 90 mm Hg or when the average of multiple systolic BP readings on 2 or more subsequent visits is consistently 140 mm Hg. Isolated systolic hypertension is defined as systolic BP 140 mm Hg and diastolic BP <90 mm Hg. Individuals with high normal BP tend to maintain pressures that are above average for the general population and are at greater risk for development of definite hypertension and cardiovascular events than the general population. Known Etiological Factors in Essential Hypertension Although it has frequently been indicated that the causes of essential hypertension are not known, this is only partially true because we have little information on genetic variations or genes that are overexpressed or underexpressed as well as the intermediary phenotypes that they regulate to cause high BP.4 A number of factors increase BP, including (1) obesity, (2) insulin resistance, (3) high alcohol intake, (4) high salt intake (in salt-sensitive patients), (5) aging and perhaps (6) sedentary lifestyle, (7) stress, (8) low potassium intake, and (9) low calcium intake.5 6 Furthermore, many of these factors are additive, such as obesity and alcohol intake. Inherited BP The identification of variant (allelic) genes that contribute to the development of hypertension is complicated by the fact that the 2 phenotypes that determine BP, cardiac output and total peripheral resistance, are controlled by intermediary phenotypes, including the autonomic nervous system, vasopressor/vasodepressor hormones, the structure of the cardiovascular system, body fluid volume and renal function, and many others. Furthermore, these intermediary phenotypes are also

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controlled by complex mechanisms including BP itself.12 Thus there are many genes that could participate in the development of hypertension. Glucocorticoid-Remediable Aldosteronism This is an autosomal dominant form of monogenic hypertension in which aldosterone secretion is regulated by adrenocorticotropic hormone. Glucocorticoid treatment causes BP to decrease and gives the syndrome its name. The genetic mutation that causes GRA has been identified by Lifton14 as a chimeric gene fusing nucleotide sequences of the promoter-regulatory region of 11-hydroxylase (controlled by adrenocorticotropic hormone) and the structural portion of the aldosterone synthase gene. The chimeric gene results from a meiotic mismatch and unequal crossing over. The patients are usually thought to have primary aldosteronism because they exhibit volume expansion, metabolic alkalosis with hypokalemia, low plasma renin, and high aldosterone Liddles Syndrome This is an autosomal dominant form of monogenic hypertension that results from mutations in the amiloride-sensitive epithelial sodium channel, leading to increased channel activity.17 The mutations reported to date result in the elimination of 45 to 75 amino acids from the cytoplasmic carboxyl terminus of - or -subunits of the channel; thus Liddles syndrome is genetically heterogeneous. It is characterized by the early onset of hypertension with hypokalemia and suppression of both plasma renin activity and aldosterone, the latter differentiating this syndrome from primary aldosteronism. Both the hypertension and the hypokalemia vary in severity, raising the possibility that some patients classified as having salt-sensitive essential hypertension actually have Liddles syndrome. Autosomal Dominant Hypertension With Brachydactyly In this monogenic syndrome, hypertension and brachydactyly are always inherited together (100% cosegregation).4 Affected persons are shorter than nonaffected relatives. The gene for hypertension has been mapped to the short arm of chromosome 12 (12p) in a large Turkish kindred. Two other families with this syndrome have been reported, 1 in Canada and 1 in the United States. In addition, the study of a Japanese child with hypertension and type E brachydactyly has allowed the area on 12p containing the gene mutation to be pinpointed further, although the gene responsible for this syndrome has not yet been cloned. Essential or Primary Hypertension The genetic alterations responsible for inherited "essential" hypertension remain largely unknown.4 Results from family studies suggest several possible intermediary phenotypes (genetic traits) that may be related to inherited high BP, such as high sodium-lithium countertransport, low urinary kallikrein excretion, high fasting plasma insulin concentrations, high-density LDL subfractions, fat pattern index, and body mass index (BMI).12 Jeunemaitre et al20 21 first reported a polymorphism in the angiotensinogen gene linked with essential hypertension in hypertensive siblings from Utah and France. This polymorphism consists of a substitution of thymidine for cytosine in nucleotide 704, which causes substitution of methionine for threonine at position 235 (M235T) and is associated with increased concentrations of plasma angiotensinogen. This variant appears to be in tight linkage disequilibrium with a promoter mutation in which adenine replaces guanine (-6A) upstream from the initiation side of transcription.22 Tests of promoter activity suggest that this nucleotide substitution increases the rate of gene transcription, which may explain the higher angiotensinogen concentration found in subjects with the variant M235T.22 Many studies have been published on various racial groups with regard to the association between allelic variations in angiotensinogen and hypertension.23 However, these variations explain only a small part of the BP variation (6%). Furthermore, plasma angiotensinogen concentrations, though higher in patients with the polymorphism, clearly overlap with normotensive patients. Obesity and Insulin Resistance Obesity, and especially abdominal obesity, is the main hypertensinogenic factor. It was estimated in the Framingham study that each 10% weight gain is associated with a 6.5 mm Hg increase in systolic 152

BP.24 Obesity is also the cause of insulin resistance, adult-onset diabetes mellitus, left ventricular hypertrophy, hyperlipidemia, and atherosclerotic disease. Thus obesity is an important cardiovascular health problem; its incidence and prevalence are rising in most industrialized societies and in the United States has reached epidemic proportions. The relationship between BP and body fat is not restricted to the morbidly obese but is continuous throughout the entire range of body weight. A direct association between hypertension and BMI (weight in kilograms divided by the square height in meters) has been observed in cross-sectional and longitudinal population studies from early childhood to old age.25 A BMI of <25 is considered normal or healthy, whereas a BMI of 26 to 28 (as compared with BMI <23) increases the risk of high BP by 180% and the risk of insulin resistance by >1000%. Thus insulin resistance is present in many patients with obesity and hypertension.

109-Secondary Hypertension
Secondary hypertension (secondary high blood pressure) is high blood pressure that's caused by another medical condition. Secondary hypertension differs from the usual type of high blood pressure (essential hypertension), which is often referred to simply as high blood pressure. Essential hypertension, also known as primary hypertension, has no clear cause and is thought to be linked to genetics, poor diet, lack of exercise and obesity. Diabetes complications (diabetic nephropathy). Diabetes can damage your kidneys' filtering system, which can lead to high blood pressure. Polycystic kidney disease. In this inherited condition, cysts in your kidneys prevent the kidneys from working normally, and can raise blood pressure. Glomerular disease. Your kidneys filter waste and sodium using microscopic-sized filters called glomeruli that can sometimes become swollen. If the swollen glomeruli can't work normally, you may develop high blood pressure. Renovascular hypertension. This is a type of secondary hypertension caused by narrowing (stenosis) of one or both arteries leading to your kidneys. Renovascular hypertension can cause severe hypertension and irreversible kidney damage. It's often caused by the same type of fatty plaques that can damage your coronary arteries (atherosclerosis) or a condition in which the muscle and fibrous tissues of the renal artery wall thicken and harden into rings (fibromuscular dysplasia). Cushing's syndrome. In this condition, corticosteroid medications, a pituitary tumor or other factors cause the adrenal glands to produce too much of the hormone cortisol. This raises blood pressure. Aldosteronism. In this condition, a tumor in the adrenal gland, increased growth of normal cells in the adrenal gland or other factors cause the adrenal glands to release an excessive amount of the hormone aldosterone. This makes your kidneys retain salt and water and lose too much potassium, which raises blood pressure. Pheochromocytoma. This rare tumor, usually found in an adrenal gland, increases production of the hormones adrenaline and noradrenaline, which can lead to long-term high blood pressure or shortterm spikes in blood pressure. Thyroid problems. When the thyroid gland doesn't produce enough thyroid hormone (hypothyroidism) or produces too much thyroid hormone (hyperthyroidism), high blood pressure can result. Hyperparathyroidism. The parathyroid glands regulate levels of calcium and phosphorus in your body. If the glands secrete too much parathyroid hormone, the amount of calcium in your blood rises which triggers a rise in blood pressure. 153

Coarctation of the aorta. With this defect you're born with, the body's main artery (aorta) is narrowed (coarctation). This forces the heart to pump harder to get blood through the aorta and to the rest of your body. This, in turn, raises blood pressure particularly in your arms. Sleep apnea. In this condition, often marked by severe snoring, breathing repeatedly stops and starts during sleep, meaning you don't get enough oxygen. Not getting enough oxygen may damage the lining of the blood vessel walls, which may make your blood vessels less effective in regulating your blood pressure. In addition, sleep apnea causes part of the nervous system to be overactive and release certain chemicals that increase blood pressure. Obesity. As you gain weight, the amount of blood circulating through your body increases. This puts added pressure on your artery walls, increasing your blood pressure. In addition, excess weight often is associated with an increase in heart rate and a reduction in the capacity of your blood vessels to transport blood. All of these factors can increase blood pressure. Pregnancy. Pregnancy can make existing high blood pressure worse, or may cause high blood pressure to develop (pregnancy-induced hypertension or preeclampsia). Medications and supplements. Various prescription medications from pain relievers to antidepressants and drugs used after organ transplants can cause or aggravate high blood pressure in some people. Birth control pills, decongestants and certain herbal supplements, including ginseng.

110-Circulatory Insufficiency.Shock
Circulatory failure may result from decreased myocardial contractility, arrhythmias that allow insufficient time for diastolic filling or impair atrioventricular synchrony, circulatory stresses such as increased afterload or hypovolaemia, valvular dysfunction, tamponade, or a variety of less common insults. Regardless of the aetiology, circulatory failure elicits characteristic compensatory haemodynamic adjustments, mediated in large part by activation of the sympathetic nervous system. The cause of shock is usually reduced cardiac output, with the following possible causes: In hypovolemia (hypovolemic shock) the central venous pressure is reduced, and thus the venous return decreased. As a result stroke volume falls. The cause of the hypovolemia can be bleeding (hemorrhagic shock) or some other loss of fluid to the outside. Cardiogenic shock. Primary or secondary heart failure can be caused by acutemyocardial infarction, acute decompensating heart failure,malignant arrhythmias, cardiomyopathy,acute valvar regurgitation, obstruction of the large vessels (e.g., pulmonary embolism) or by impairment of cardiac filling (mitral stenosis,pericardial tamponade, constrictive pericarditis).In these conditions, in contrast to hypovolemic shock, the central venous pressure is raised. Hormonal causes of shock include adrenal hypofunction (Addisonian crisis), diabetic coma (.), hypoglycemic shock (insulin overdosage, insulinoma;), hypothyroid or hyperthyroid coma,and coma in hypoparathyroidism or hyperparathyroidism. Reduced cardiac output may also be caused by peripheral vascular distension (no pallor) with venous pooling of blood (decreased venous return), as may happen in anaphylactic shock (food or drug allergy), in which vasoactive substances are released (histamine. In septictoxic shock the cardiac output is at first raised by the action of toxins of, usually Gramnegative bacteria (tachycardia and reduced total peripheral resistance). The initially normal blood pressure then falls, respiratory failure occurs, and finally a late stage develops with reduced cardiac output and high total peripheral resistance.

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Neurogenic shock is rare, but it may occur when, for example, brain stem or spinal cord trauma or intoxication (barbiturates, narcotics)disturb autonomic nervous system regulation of the heart and circulation and the venous return is markedly reduced. Symptoms ( left). Hypovolemic and hemorrhagic shock is often associated with a reduced blood pressure (narrow pulse amplitude), increased heart rate, pallor with cold sweat (not in shock that is due to vascular distension),diminished urine output. The resulting (blood) volumedeficit can be estimated by means of theshock index (heart rate per minute/systolicblood pressure in mmHg): 0.5 = normal or blood loss < 10%; 1.0 = blood loss < 2030% (incipient shock); 1.5 = blood loss > 3050% (manifest shock).

111-Hypotension
Hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiological state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the opposite of hypertension, which is high blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. If it is lower than normal, then it is called low blood pressure or hypotension. Hypotension is generally considered as systolic blood pressure less than 90 millimeters of mercury (mm Hg) or diastolic less than 60 mm Hg. Symptoms Chest pain Shortness of breath Irregular heartbeat Fever higher than 38.3C (101F) Headache Stiff neck Severe upper back pain Cough with phlegm Prolonged diarrhea or vomiting Dyspepsia Dysuria Blood pressure is continuously regulated by the autonomic nervous system, using an elaborate network of receptors, nerves, and hormones to balance the effects of the sympathetic nervous system, which tends to raise blood pressure, and the parasympathetic nervous system, which lowers it. The vast and rapid compensation abilities of the autonomic nervous system allow normal

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individuals to maintain an acceptable blood pressure over a wide range of activities and in many disease states. Low blood pressure[6] causes can be due to low blood volume, hormonal changes, widening of blood vessels, medicine side effects, anemia, and heart and endocrine problems. Reduced blood volume, hypovolemia, is the most common mechanism producing hypotension. This can result from hemorrhage, or blood loss; insufficient fluid intake, as in starvation; or excessive fluid losses from diarrhea or vomiting. Hypovolemia is often induced by excessive use of diuretics. Other medications can produce hypotension by different mechanisms.

112-Overview of Gastrointestinal Disorders.

Constipation is the difficult passage of stools (bowel movements) or the infrequent (less than three times a week) or incomplete passage of stools. Constipation is usually caused by inadequate "roughage" or fiber in the diet, or a disruption of the regular routine or diet. Constipation causes a person to strain during a bowel movement. It might include small, hard stools, and sometimes causes anal problems such as fissures and hemorrhoids. Constipation is rarely the sign of a more serious medical condition.Treatment of constipation includes increasing the amount of fiber you eat, exercising regularly, and moving your bowels when you have the urge.

Irritable bowel syndrome (IBS) Irritable bowel syndrome (also called spastic colon, irritable colon, or nervous stomach) is a condition in which the colon muscle contracts more readily than in people without IBS. A number of factors can trigger IBS including certain foods, medicines, and emotional stress. Symptoms of IBS include abdominal pain and cramps, excess gas, bloating, and a change in bowel habits such as harder, looser, or more urgent stools than normal. Often people with IBS have alternating constipation and diarrhea. Treatment includes avoiding caffeine, increasing fiber in the diet, monitoring which foods trigger IBS. Structural disorders Structural disorders are those in which the bowel looks abnormal and doesnt work properly. Sometimes, the structural abnormality needs to be removed surgically. Anal disorders Hemorrhoids Hemorrhoids are swollen blood vessels that line the anal opening caused by chronic excess pressure from straining during a bowel movement, persistent diarrhea, or pregnancy. There are two types of hemorrhoids: internal and external. Internal hemorrhoids Internal hemorrhoids are normal structures cushioning the lower rectum and protecting it from damage by stool. When they fall down into the anus as a result of straining, they become irritated and start to bleed. Ultimately, internal hemorrhoids can fall down enough to prolapse (sink or protrude) out of the anus. External hemorrhoids External hemorrhoids are veins that lie just under the skin on the outside of the anus. Sometimes, after straining, the external hemorrhoidal veins burst and a blood clot forms under the skin. This very painful condition is called a pile.Treatment includes removing the clot and vein under local anesthesia in the doctors office. Anal fissures Anal fissures are splits or cracks in the lining of the anal opening. The most common cause of an anal 156

fissure is the passage of very hard or watery stools. The crack in the anal lining exposes the underlying muscles that control the passage of stool through the anus and out of the body. An anal fissure is one of the most painful problems because the exposed muscles become irritated from exposure to stool or air, and leads to intense burning pain, bleeding, or spasm after bowel movements. Diverticular disease Diverticulosis is the presence of small outpouchings (diverticula) in the muscular wall of the large intestine that form in weakened areas of the bowel. They usually occur in the sigmoid colon, the high-pressure area of the lower large intestine. Diverticular disease is very common and occurs in 10 percent of people over age 40 and in 50 percent of people over age 60 in Western cultures. It is often caused by too little roughage (fiber) in the diet. Colon polyps and cancer Each year 130,000 Americans are diagnosed with colorectal cancer, the second most common form of cancer in the United States. Fortunately, with advances in early detection and treatment, colorectal cancer is one of the most curable forms of the disease. By using a variety of screening tests, it is possible to prevent, detect, and treat the disease long before symptoms appear.There are several types of colitis, conditions that cause an inflammation of the bowel. These include:

Infectious colitis Ulcerative colitis (cause not known) Crohn's disease (cause not known) Ischemic colitis (caused by not enough blood going to the colon) Radiation colitis (after radiotherapy).

113- Esophageal Achalasia

Achalasia, also known as esophageal achalasia, achalasia cardiae, cardiospasm, and esophageal aperistalsis, is an esophageal motility disorder involving the smooth muscle layer of the esophagus and the lower esophageal sphincter (LES). It is characterized by incomplete LES relaxation, increased LES tone, and lack of peristalsis of the esophagus (inability of smooth muscle to move food down the esophagus) in the absence of other explanations like cancer or fibrosis. Achalasia is characterized by difficulty swallowing, regurgitation, and sometimes chest pain. Diagnosis is reached with esophageal manometry and barium swallow radiographic studies. Various treatments are available, although none cure the condition. Certain medications or Botox may be used in some cases, but more permanent relief is brought by esophageal dilatation and surgical cleaving of the muscle.The main symptoms of achalasia are dysphagia (difficulty in swallowing), regurgitation of undigested food, chest pain behind the sternum, and weight loss.Dysphagia tends to become progressively worse over time and to involve both fluids and solids. Some people may also experience coughing when lying in a horizontal position. The chest pain experienced, also known as cardio spasm and non-cardiac chest pain can often be mistaken for a heart attack. It can be extremely painful in some sufferers. Food and liquid, including saliva, are retained in the esophagus and may be inhaled into the lungs.The cause of most cases of achalasia is unknown.LES pressure and relaxation are regulated by excitatory (e.g., acetylcholine, substance P) and inhibitory (e.g., nitric oxide, vasoactive intestinal peptide) neurotransmitters. Persons with achalasia lack nonadrenergic, noncholinergic, inhibitory ganglion cells, causing an imbalance in excitatory and inhibitory neurotransmission. The result is a hypertensive nonrelaxed esophageal sphincter. 157

Esophageal manometry Schematic of manometry in achalasia showing aperistaltic contractions, increased intraesophageal pressure and failure of relaxation of the lower esophageal sphincter.Because of its sensitivity, manometry (esophageal motility study) is considered the key test for establishing the diagnosis. A thin tube is inserted through the nose, and the patient is instructed to swallow several times. The probe measures muscle contractions in different parts of the esophagus during the act of swallowing. Pneumatic dilatation In balloon (pneumatic) dilation or dilatation, the muscle fibers are stretched and slightly torn by forceful inflation of a balloon placed inside the lower esophageal sphincter. Heller myotomy helps 90% of achalasia patients. It can usually be performed by a keyhole approach, or laparoscopically.

114-Reflux Esophagitis
The musculature in the upper third of the esophageal wall is partly made up of striated muscle, partly of smooth muscle. On swallowing (deglutition) the upper esophageal sphincter opens reflexly and a (primary) peristaltic reflex wave moves the bolus of food into the esophagus. Here the dilation by the bolus initiates further (secondary) peristaltic waves that continue until the bolus has reached the stomach.The lower esophageal sphincter is usually closed, just like its upper counterpart. This barrier against reflux of the harmful gastric juice (pepsin and HCl) is strengthened when the sphincter pressure is raised , for example, by the action of acetylcholine liberated from the ganglion cells of the myenteric plexus, or by adrenergic agonists, by hormones, such as gastrin (reflux protection during digestive gastric motility), motilin (reflux protection during interdigestive motility. Esophagitis (or oesophagitis) is inflammation of the esophagus. It may be acute or chronic. The acute esophagitis can be catarrhal or phlegmonous, whereas the chronic esophagitis may be hypertrophic or atrophic.gastro-oesophageal reflux disease (GORD), gastric reflux disease, or acid reflux disease is a chronic symptom of mucosal damage caused by stomach acid coming up from the stomach into the esophagus.GERD is caused by a failure of the cardia. In healthy patients, the "Angle of His"the angle at which the esophagus enters the stomachcreates a valve that prevents duodenal bile, enzymes, and stomach acid from traveling back into the esophagus where they can cause burning and inflammation of sensitive esophageal tissue. Factors that can contribute to GERD: Hiatal hernia, which increases the likelihood of GERD due to mechanical and motility factors. Obesity: increasing body mass index is associated with more severe GERD.In a large series of 2000 patients with symptomatic reflux disease, it has been shown that 13 % of changes in esophageal acid exposure is attributable to changes in body mass index.Zollinger-Ellison syndrome, which can be present with increased gastric acidity due to gastrin production. Hypercalcemia, which can increase gastrin production, leading to increased acidity. Scleroderma and systemic sclerosis, which can feature esophageal dysmotility.

115-Acid Peptic Ulcers.Gastric Ulser.

Excessive secretion of this acid and pepsin or a weakened stomach mucosal defense is responsible for damage to the delicate mucosa and the lining of the stomach, esophagus and duodenum resulting in ulceration which is known as Acid Peptic Disease.Physiologically, a certain amount of acid is secreted by the gastric cells lining the stomach as a natural mechanism which serves to activate the digestive enzymes and help in the digestion and assimilation of important proteins so that they can be easily absorbed by the body. Acid peptic disease is a collective term used to include 158

many conditions such as gastro-esophageal reflux disease (GERD), gastritis, gastric ulcer, duodenal ulcer, esophageal ulcer, Zollinger Ellison Syndrome (ZES) and Meckels diverticular ulcer. Symptoms of peptic ulcers include abdominal pain, nausea, water brash, vomiting, loss of appetite and weight loss. Complications include bleeding, perforation, obstruction in the digestive tract and sometimes cancer. Peptic ulcer is diagnosed using blood and stool tests, breath tests, and endoscopy and barium radiography. The patient is treated with drugs that reduce acidity and sometimes in addition with certain antibiotics. Diagnosis;An esophagogastroduodenoscopy (EGD), a form of endoscopy, also known as a gastroscopy, is carried out on patients in whom a peptic ulcer is suspected. By direct visual identification, the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD can often provide an alternative diagnosis. Urea breath test (noninvasive and does not require EGD); Direct culture from an EGD biopsy specimen; this is difficult to do, and can be expensive. Most labs are not set up to perform H. pylori cultures;Direct detection of urease activity in a biopsy specimen by rapid urease test; Measurement of antibody levels in blood An esophagogastroduodenoscopy (EGD), a form of endoscopy, also known as a gastroscopy, is carried out on patients in whom a peptic ulcer is suspected. By direct visual identification, the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD can often provide an alternative diagnosis. Gastric Ulcer; Gastric ulcers are most often localized on the lesser curvature of the stomach. The ulcer is a round to oval parietal defect ("hole"), 2 to 4 cm diameter, with a smooth base and perpendicular borders. These borders are not elevated or irregular in the acute form of peptic ulcer, regular but with elevated borders and inflammatory surrounding in the chronic form. In the ulcerative form of gastric cancer the borders are irregular. Surrounding mucosa may present radial folds, as a consequence of the parietal scarring. A gastric peptic ulcer is a mucosal defect which penetrates the muscularis mucosae and muscularis propria, produced by acid-pepsin aggression. Ulcer margins are perpendicular and present chronic gastritis. During the active phase, the base of the ulcer shows 4 zones: inflammatory exudate, fibrinoid necrosis, granulation tissue and fibrous tissue. The fibrous base of the ulcer may contain vessels with thickened wall or with thrombosis.

116-Acid Peptic Ulcers Acute Erosive Gastritis and Chronic Atrophic.

Excessive secretion of this acid and pepsin or a weakened stomach mucosal defense is responsible for damage to the delicate mucosa and the lining of the stomach, esophagus and duodenum resulting in ulceration which is known as Acid Peptic Disease.Physiologically, a certain amount of acid is secreted by the gastric cells lining the stomach as a natural mechanism which serves to activate the digestive enzymes and help in the digestion and assimilation of important proteins so that they can be easily absorbed by the body. Acid peptic disease is a collective term used to include many conditions such as gastro-esophageal reflux disease (GERD), gastritis, gastric ulcer, duodenal ulcer, esophageal ulcer, Zollinger Ellison Syndrome (ZES) and Meckels diverticular ulcer. Symptoms of peptic ulcers include abdominal pain, nausea, water brash, vomiting, loss of appetite and weight loss. Complications include bleeding, perforation, obstruction in the digestive tract and 159

sometimes cancer. Peptic ulcer is diagnosed using blood and stool tests, breath tests, and endoscopy and barium radiography. The patient is treated with drugs that reduce acidity and sometimes in addition with certain antibiotics. Diagnosis;An esophagogastroduodenoscopy (EGD), a form of endoscopy, also known as a gastroscopy, is carried out on patients in whom a peptic ulcer is suspected. By direct visual identification, the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD can often provide an alternative diagnosis. Urea breath test (noninvasive and does not require EGD); Direct culture from an EGD biopsy specimen; this is difficult to do, and can be expensive. Most labs are not set up to perform H. pylori cultures; Direct detection of urease activity in a biopsy specimen by rapid urease test; Measurement of antibody levels in blood. An esophagogastroduodenoscopy (EGD), a form of endoscopy, also known as a gastroscopy, is carried out on patients in whom a peptic ulcer is suspected. By direct visual identification, the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD can often provide an alternative diagnosis. Gastritis; Gastritis is an inflammation of the lining of the stomach, and has many possible causes.The main acute causes are excessive alcohol consumption or prolonged use of nonsteroidal antiinflammatory drugs (also known as NSAIDs) such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic injury, burns, or severe infections. Many people with gastritis experience no symptoms at all. However, upper central abdominal pain is the most common symptom; the pain may be dull, vague, burning, aching, gnawing, sore, or sharp. Nausea,Vomiting (if present, may be clear, green or yellow, blood-streaked, or completely bloody, depending on the severity of the stomach inflammation),Belching (if present, usually does not relieve the pain much) ,Bloating. Erosive and hemorrhagic gastritis can have many causes, for example: intake of nonsteroidal antiinflammatory drugs (NSAIDs), whose local and systemic mucosa-damaging effect is described in greater detail on p.146; ischemia (e.g., vasculitis or while running a marathon) stress (multi-organ failure, burns, surgery, central nervous system trauma), in which the gastritis is probably in part caused by ischemia; alcohol abuse, corrosive chemicals; trauma (gastroscope, swallowed foreignbody, retching, vomiting, etc.); radiation trauma. This type of gastritis can quickly produce an acute ulcer (e.g., through stress or NSAIDs), with the risk of massive gastric bleeding or perforation of the stomach wall Nonerosive, chronic active gastritis is usually restricted to the antrum. It has become increasingly clear in the last decade that its determining cause is a bacterial colonization of the antrum with Helicobacter pylori, which can be effectively treated with antibiotics.

160

Helicobacter colonization not only diminishes mucosal protection, but can also stimulate antral gastrin liberation and thus gastric juice secretion in the fundus, a constellation that favors the development of chronic ulcer.A fourth type, reactive gastritis, occurs in the surroundings of erosive gastritis (see above), of ulcers or of operative wounds. The latter may partly be caused after operations on the antrum or pylorus by enterogastric reflux (reflux gastritis), resulting in pancreatic and intestinal enzymes and bile salts attacking the gastric mucosa. On the other hand, the alkaline milieu of the intestinal juice counteracts gastrin release and is also a hostile medium for Helicobacter pylori.

117-Acid-Peptic Disease.Duedonal ulcer

Excessive secretion of this acid and pepsin or a weakened stomach mucosal defense is responsible for damage to the delicate mucosa and the lining of the stomach, esophagus and duodenum resulting in ulceration which is known as Acid Peptic Disease.Physiologically, a certain amount of acid is secreted by the gastric cells lining the stomach as a natural mechanism which serves to activate the digestive enzymes and help in the digestion and assimilation of important proteins so that they can be easily absorbed by the body. Acid peptic disease is a collective term used to include many conditions such as gastro-esophageal reflux disease (GERD), gastritis, gastric ulcer, duodenal ulcer, esophageal ulcer, Zollinger Ellison Syndrome (ZES) and Meckels diverticular ulcer.Symptoms of peptic ulcers include abdominal pain, nausea, water brash, vomiting, loss of appetite and weight loss. Complications include bleeding, perforation, obstruction in the digestive tract and sometimes cancer.Peptic ulcer is diagnosed using blood and stool tests, breath tests, and endoscopy and barium radiography. The patient is treated with drugs that reduce acidity and sometimes in addition with certain antibiotics. Diagnosis;An esophagogastroduodenoscopy (EGD), a form of endoscopy, also known as a gastroscopy, is carried out on patients in whom a peptic ulcer is suspected. By direct visual identification, the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD can often provide an alternative diagnosis. Urea breath test (noninvasive and does not require EGD);Direct culture from an EGD biopsy specimen; this is difficult to do, and can be expensive. Most labs are not set up to perform H. pylori cultures; Direct detection of urease activity in a biopsy specimen by rapid urease test; Measurement of antibody levels in blood An esophagogastroduodenoscopy (EGD), a form of endoscopy, also known as a gastroscopy, is carried out on patients in whom a peptic ulcer is suspected. By direct visual identification, the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD can often provide an alternative diagnosis. Duedonum Ulcers; A duodenal ulcer is a type of peptic ulcer that occurs in the duodenum, the beginning of the small intestine. Peptic ulcers are eroded areas in the lining of stomach and duodenum, which result in abdominal pain, possible bleeding, and other gastrointestinal symptoms. The most common cause of duodenal ulcer is a stomach infection associated with the Helicobacter pylori (H pylori) bacteria. Symptoms; abdominal pain, classically epigastric with severity relating to mealtimes, after around 161

three hours of taking a meal (duodenal ulcers are classically relieved by food, while gastric ulcers are exacerbated by it);bloating and abdominal fullness;waterbrash (rush of saliva after an episode of regurgitation to dilute the acid in esophagus - although this is more associated with gastroesophageal reflux disease);nausea, and copious vomiting;loss of appetite and weight loss. Cause; Another major cause is the use of NSAIDs (see above). The gastric mucosa protects itself from gastric acid with a layer of mucus, the secretion of which is stimulated by certain prostaglandins. NSAIDs block the function of cyclooxygenase 1 (cox-1), which is essential for the production of these prostaglandins. COX-2 selective anti-inflammatories (such as celecoxib or the since withdrawn rofecoxib) preferentially inhibit cox-2, which is less essential in the gastric mucosa, and roughly halve the risk of NSAID-related gastric ulceration. As the prevalence of H. pylori-caused ulceration declines in the Western world due to increased medical treatment, a greater proportion of ulcers will be due to increasing NSAID use among individuals with pain syndromes as well as the growth of aging populations that develop arthritis.

118-Disorders of the Gallbladder

Cholelithiasis - Gallstones Solid crystalline precipitates in the BILIARY TRACT, usually formed in the GALLBLADDER. Gallstones, derived from the BILE, consist mainly of calcium, cholesterol, or bilirubin. Biliary Dyskinesia;Acalculous cholecystopathy which means disease or condition of the gallbladder without the presence of gallstones. You might also call it functional gallbladder disorder or impaired gallbladder emptying. Some causes may be chronic inflammation, stress, a problem with the smooth muscles of the gallbladder or the muscle of the Sphincter of Oddi being too tight. Inflammation of the gallbladder. Acute cholecystitis is nearly always due to gallstones but may be due to infection (bacterial). It can also be due to chemical irritation. Chronic cholecystitis occurs with or without stones (acalculous cholecystitis is without). If there are no stones present the medical treatment used is often antispasmodics and/or laxatives. Cholangitis;Inflammation of the bile duct itself. Chole = bile and angi = duct. Acute cholangitis is usually caused by a bacterial infection resulting from stagnation of the bile in the duct. Choledocholithiasis, a gallstone that gets stuck or lodged in the bile duct can create an obstruction that results in an infection. Primary Sclerosing Cholangitis;PSC is a disease where the bile ducts of the liver harden, obstructing the flow of bile. It is characterized by inflammation, breaking down of and eventual hardening or fibrosis of the bile ducts within the liver and outside the liver both (intrahepatic and extrahepatic bile ducts.) It is most likely an autoimmune liver disease. Gallbladder Polyps;Gallbladder polyps are growths that protrude from the lining of the gallbladder. They're usually innocuous and rarely cancerous (malignant). 95% are non-cancerous. 10% are the result of inflammation.2. Most polyps are the result of cholesterol deposits. Cholesterol gallstones develop when bile contains too much cholesterol and not enough bile salts. Besides a high concentration of cholesterol, two other factors are important in causing gallstones. 162

The first is how often and how well the gallbladder contracts; incomplete and infrequent emptying of the gallbladder may cause the bile to become overconcentrated and contribute to gallstone formation. The second factor is the presence of proteins in the liver and bile that either promote or inhibit cholesterol crystallization into gallstones. In addition, increased levels of the hormone estrogen as a result of pregnancy, hormone therapy, or the use of combined (estrogen-containing) forms of hormonal contraception, may increase cholesterol levels in bile and also decrease gallbladder movement, resulting in gallstone formation. A gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components. These calculi are formed in the gallbladder, but may pass distally into other parts of the biliary tract such as the cystic duct, common bile duct, pancreatic duct, or theampulla of Vater.Reduced bile salt secretion. This isdue to either a decrease in the bile salt pool, as in Crohns disease or after gut resection, or a prolonged sequestration of bile salts in the gallbladder, as in fasting (possibly even if only overnight) or parenteral nutrition. The latter decreases the enterohepatic circulation of bile salts so that their secretion into the bile is reduced. The causes of an increased concentration of unconjugated bilirubin are :Increased liberation of hemoglobin, for example, in hemolytic anaemia, in which there is so much bilirubin that the glucuronidase- mediated process of conjugation in the liver does not meet demand.

119-Disorders of Small Intestine,Diarrhea.

Problems with the small intestine can include:Bleeding,Celiac disease,Crohn's disease,Infections,Intestinal cancer,Intestinal obstruction,Irritable bowel syndrome,Ulcers, such as peptic ulcer. Coeliac disease ( /sili.k/; spelled celiac disease in North America[1] and often celiac sprue) is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward. Symptoms include chronic diarrhoea, failure to thrive (in children), and fatigue, but these may be absent, and symptoms in other organ systems have been described. The diarrhoea that is characteristic of coeliac disease is (chronic) pale, voluminous and malodorous. Abdominal pain and cramping, bloatedness with abdominal distension (thought to be due to fermentative production of bowel gas) and mouth ulcers[7] may be present. As the bowel becomes more damaged, a degree of lactose intolerance may develop.The changes in the bowel make it less able to absorb nutrients, minerals and the fat-soluble vitamins A, D, E, and K.[4][10] The inability to absorb carbohydrates and fats may cause weight loss (or failure to thrive/stunted growth in children) and fatigue or lack of energy. Anaemia may develop in several ways: iron malabsorption may cause iron deficiency anaemia, and folic acid and vitamin B12 malabsorption may give rise to megaloblastic anaemia. Calcium and vitamin D malabsorption. Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms. It primarily causes abdominal pain, diarrhea. During a colonoscopy, biopsies of the colon are often taken to confirm the diagnosis. Certain characteristic features of the pathology seen point toward Crohn's disease; it shows a transmural 163

pattern of inflammation, meaning the inflammation may span the entire depth of the intestinal wall. Ulceration is an outcome seen in highly active disease. There is usually an abrupt transition between unaffected tissue and the ulcer - a characteristic sign known as skip lesions. A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm. As many as 7090% of such ulcers are associated with Helicobacter pylori. Four times as many peptic ulcers arise in the duodenumthe first part of the small intestine, just after the stomachas in the stomach itself. About 4% of gastric ulcers are caused by a malignant tumor, so multiple biopsies are needed to exclude cancer. Osmotic diarrhea results from the intake of a large number of substances that are poorly absorbable even normally, or in malabsorption . Among the first group are sorbitol (in sugar-free medications and sweets or certain fruits), fructose (in lemonades, diverse fruits, honey), magnesium salts (antacids, laxatives) as well as poorly absorbed anions such as sulfate, phosphate, or citrate. Secretory diarrhea (in the narrow sense)occurs when Cl secretion of the small intestinal mucosa is activated . Within the mucosal cells Cl is secondarily actively enriched by a basolateral Na+-K+-2 Cl symport carrier and is secreted via luminal Cl channels. These open more frequently when the intracellular concentration of cAMP rises. cAMP is formed in greater amounts in the presence of, for example, certain laxatives and bacterial toxins.

120-Inflammatory Bowel Disease. Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small
intestine. The major types of IBD are Crohn's disease and ulcerative colitis. The main forms of IBD are Crohn's disease and ulcerative colitis (UC). The main difference between Crohn's disease and UC is the location and nature of the inflammatory changes. Crohn's can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (epithelial lining of the gut), while Crohn's disease affects the whole bowel wall ("transmural lesions"). Finally, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions. Syptoms; Although very different diseases, both may present with any of the following symptoms: abdominal pain, vomiting, diarrhea, rectal bleeding, severe internal cramps/muscle spasms in the region of the pelvis, weight loss and various associated complaints or diseases like arthritis, pyoderma gangrenosum. Optimal treatment of inflammatory bowel disease depends on what form it consists of. For example, mesalazine is more useful in ulcerative colitis than in Crohn's disease.Generally, depending on the level of severity, IBD may require immunosuppression to control the symptom.Often, antiinflammatory steroids are used to control disease flares and were once acceptable as a maintenance 164

drug. In use for several years in Crohn's disease patients and recently in patients with ulcerative colitis, biologicals have been used such as TNF inhibitors. Severe cases may require surgery, such as bowel resection, strictureplasty or a temporary or permanent colostomy or ileostomy. Numerous environmental factors have been studied that inuence inammatory bowel disease, including smoke exposure, diet, oral contraceptives, and nonsteroidal anti-inammatory agents. In addition, there is evidence that genetic factors also play a role. Finally, the combination and interaction of genetics, environmental inuences, and immunologic abnormalities may play the most important role.

121-Diverticular Disease.Constipation.
Diverticulosis, also known as "diverticular disease", is the condition of having diverticula in the colon, which are outpocketings of the colonic mucosa and submucosa through weaknesses of muscle layers in the colon wall. These are more common in the sigmoid colon, which is a common place for increased pressure. This is uncommon before the age of 40, and increases in incidence after that age. Cramps and tenderness in the affected areas. Uncomplicated diverticulosis Some patients with diverticulosis complain of symptoms such as cramping, bloating, flatulence, and irregular defecation. However, it is unclear if these symptoms are attributable to the underlying diverticulosis or to coexistent irritable bowel syndrome. Complicated colonic diverticulosis This is very uncommon but highly dangerous. The diverticula may bleed, either rapidly (causing bleeding through the rectum) or slowly (causing anaemia). Constipation: The symptom of constipation may signify different things in individual cases, depending on what is considered to be normal: too little, too hard or rare a stool, difficult defecation, or the sensation of incomplete emptying. Constipation is often harmless, but it can be a sign of numerous diseases. The causes of constipation are: ! Low-fiber diet, as intestinal motility depends on the volume of intestinal contents. The larger the volume the greater the motility. ! Reflex and/or psychogenic disorders. These include: 1) anal fissure that is painful and reflexly raises the tone of the anal sphincter, thus increasing the pain, and so on; 2) so-called anismus (outlet obstruction), i.e., contraction (rather than the normal relaxation) of the pelvic floor when the rectum is stretched. Such a false reflex is commonly found in women who were abused as children, but also in patients with Parkinsons disease; 3) paralytic ileus (acute pseudo-obstruction) that may be caused reflexly by operations (particularly in the abdomen), trauma, or peritonitis, and may persist in the colon for several days. Functional disorders of transport, whether of neurogenic, myogenic, reflex (see above), medicinal (e.g., opiates), or ischemic cause (e.g., trauma or arteriosclerosis of the mesenteric arteries). Functional intestinal obstruction is called pseudo-obstruction. ! Neurogenic causes. Congenital absence of ganglion cells near the anus (aganglionosis in Hirschsprungs disease), resulting in persisting spasm of the affected segment due to failure of receptive relaxation (!A, bottom right) and absence of anorectal inhibitory reflexes.Myogenic causes. Muscular dystrophies, scleroderma, dermatomyositis, and systemic lupus erythematosus.

165

122-Etiology and pathogenesis of the liver dysfuntion

Liver dysfunction and subsequent damage can be caused by:Metabolic disorders such as obesity, diabetes, and high triglycerides When the bodys metabolism is not running properly, fat can accumulate around the liver, causing what is known as fatty liver.Alcoholism Excessive and chronic alcohol consumption is the leading cause of cirrhosis. Alcohol converts to acetaldehyde, a carcinogenic toxin. Illness Certain illnesses, such as tuberculosis and malabsorption syndrome, can cause liver damage. Pharmaceuticals Certain prescription medications and over-the-counter drugs list liver damage as a side effect and a risk. Some of these include psychotropic medications (such as antidepressants, antipsychotics, and mood stabilizers), corticosteroids, non-steroidal anti-inflammatory medications (NSAIDs), and others. Its always important to review side effects and risks of pharmaceuticals with your healthcare professional and pharmacist. Chemotherapy Chemotherapy drugs can damage the liver as a side effect. Pregnancy In rare cases, fatty liver can be a complication of pregnancy. Poor diet A diet high in trans fats and heavily refined simple carbohydrates can cause metabolic disturbances that lead to fatty liver. Pesticides and heavy metals These can be stored in body fat over a lifetime and have the potential to produce liver damage. Viral infections Hepatitis A E can lead to liver damage. Excess vitamin A Megadosing of vitamin A can damage the liver. Candida Candida yeast ferments sugars into acetaldehyde, which is the same carcinogen that causes alcohol hangovers. Candida also appears to increase gut and urinary levels of ammonia, which is another liver toxin. The basic pathophysiology of all forms of liver disease represents failures of the numerous and complex hepatic metabolic functions. Although there is some variability in basic pathophysiology from one type of liver disease to another, all forms of liver disease can reasonably be called hepatic failure.It should be made clear at the outset that jaundice, an obvious physical sign, sometimes represents problems other than liver disease and is by no means synonymous with it. There are other, far more important and more complex metabolic problems associated with liver disease so that the problem of jaundice will be dealt with only briefly in this minicourse. The liver plays several complex roles in amino acid metabolism, protein synthesis, carbohydrate metabolism and lipid metabolism. It is also the site of manufacture of a number of blood coagulation proteins. The basic derangements of hepatic failure will be discussed first. These will then be applied to the most common forms of liver disease, acute hepatitis and cirrhosis. In the diseased liver, there are two prime manifestations of liver failure with regard to lipid metabolism. The first of these is the deposition of triglycerides within the organ itself. This is the basic mechanism of socalled "fatty liver," which develops most often as a result of chronic alcoholism. The second prime feature of disordered hepatic lipid metabolism is a diminution in the rate of synthesis of cholesterol The liver is responsible for detoxifying, by chemical modification, many substances that enter it. This includes substances drained from the gut, many kinds of drugs, and circulating hormones. Some 166

substances are converted to water soluble salts or esters and are excreted in the bile. Others are chemically modified and released into the general circulation for renal excretion. Portal Hypertension; Since the liver receives twothirds of its blood supply from the hepatic portal vein and onethird from the hepatic artery, circulatory impairment through the liver results primarily in an increase in venous pressure in the portal drainage system. This direct increase in hydrostatic pressure in the portal system, which drains the entire G.I. tract, results in an increase in hydrostatic pressure in all of the G.I. tract's venous drainage system. This increase in pressure is called portal hypertension.

123-Types of Liver Dysfunction

Acute Liver Failure:Causes of acute liver failure are poisoning and inflammation, for example, fulminant cholangitis or viral hepatitis (especially in hepatitis B and E). The causes of chronic liver failure that is accompanied by fibrosis (cirrhosis) of the liver are: inflammation, for example, chronic persistent viral hepatitis; alcohol abuse, the most common cause; in susceptible patients, side effects of drugs, for example, folic acid antagonists, phenylbutazone; Cardiovascular causes of impairment of venous return, for example, in right heart failure a number of inherited diseases for example, glycogen storage diseases,Wilsons disease, galactosemia, hemochromatosis,"1-antitrypsin deficiency; intrahepatic or posthepatic cholestasisProtein synthesis in the liver is reduced.This can lead to hypoalbuminemia that may result in ascites. Cholestasis occurs , producing not only liver damage but also aggravating any bleeding tendency, because the lack of bile salts decreases micellar formation and with it the absorption of vitamin K from the intestine. Portal hypertension develops and may make the ascites worse because oflymphatic flow impairment. It may causethrombocytopenia resulting from splenomegaly. Chronic liver disease : in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. Causes; Hepatitis B,Hepatitis C,Cytomegalovirus (CMV),Epstein Barr Virus (EBV),Toxic and drugs,Alcoholic liver disease,Amiodarone,Methotrexate,Nitrofurantoin,Non-alcoholic fatty liver disease,Haemochromatosis,Wilson's Disease, Autoimmune Chronic Hepatitis,Primary Biliary Cirrhosis,Primary Sclerosing Cholangitis. Sign of Chronic Liver Dysfunction: Clubbing,Palmar erythema,Spider nevi (angiomata),Scratch marks,Gynaecomastia,Feminising hair distribution,Testicular atrophy. The treatment of chronic liver disease depends on the cause. While some conditions may be treated with medications, others may require surgery or a transplant. Transplant is required when the liver fails and there is no other alternative.

124-Manifestation of Liver dysfunction

The symptoms related to liver dysfunction include both physical signs and a variety of symptoms related to digestive problems, blood sugar problems, immune disorders, abnormal absorption of fats, and metabolism problems. The malabsorption of fats may lead to symptoms that include indigestion, reflux, deficit of fatsoluble vitamins, hemorrhoids, gall stones, intolerance to fatty foods, intolerance to alcohol, nausea and vomiting attacks, abdominal bloating, and constipation.Nervous system disorders include depression, 167

mood changes, especially anger and irritability, poor concentration and "foggy brain", overheating of the body, especially the face and torso, and recurrent headaches (including migraine) associated with nausea. The blood sugar problems include hypoglycaemia.Abnormalities in the level of fats in the blood stream, whether too high or too low levels of lipids in the organism. Hypercholesterolemia: elevated LDL cholesterol, reduced HDL cholesterol, elevated triglycerides, clogged arteries leading to high blood pressure, heart attacks and strokes, build up of fat in other body organs (fatty degeneration of organs), lumps of fat in the skin (lipomas and other fatty tumors), excessive weight gain (which may lead to obesity), inability to lose weight even while dieting, sluggish metabolism, protuberant abdomen (pot belly), cellulite, fatty liver, and a roll of fat around the upper abdomen (liver roll) etc.[citation needed] Or too low levels of lipids: hypocholesterolemia: low total cholesterol, low LDL and VLDL cholesterol, low triglyderides Hepatitis, inflammation of the liver, is caused mainly by various viruses (viral hepatitis) but also by some liver toxins (e.g. alcoholic hepatitis), autoimmunity (autoimmune hepatitis) or hereditary conditions. Alcoholic liver disease is a term used to describe any hepatic manifestation of alcohol overconsumption, including fatty liver disease, alcoholic hepatitis, and cirrhosis. Fatty liver disease (hepatic steatosis) is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells. Cirrhosis is the formation of fibrous tissue (fibrosis) in the place of liver cells that have died due to a variety of causes, including viral hepatitis, alcohol overconsumption, and other forms of liver toxicity. Cirrhosis causes chronic liver failure. Primary biliary cirrhosis is a serious autoimmune disease of the bile capillaries. Primary sclerosing cholangitis is a serious chronic inflammatory disease of the bile duct, which is believed to be autoimmune in origin. Gilbert's syndrome, a genetic disorder of bilirubin metabolism found in about 5% of the population, can cause mild jaundice. A number of liver function tests are available to test the proper function of the liver. These test for the presence of enzymes in blood that are normally most abundant in liver tissue, metabolites or products. LFT's, serum proteins, serum albumin, serum globulin, A/G Ratio, alanine transaminase, aspartate transaminase.

125-Acute Hepatitis
Initial features are of nonspecific flu-like symptoms, common to almost all acute viral infections and may include malaise, muscle and joint aches, fever, nausea or vomiting,diarrhea, and headache. More specific symptoms, which can be present in acute hepatitis from any cause, are: profound loss of appetite, aversion to smoking among smokers, dark urine, yellowing of the eyes and skin (i.e., jaundice) and abdominal discomfort. Physical findings are usually minimal, apart from jaundice in a third and tender hepatomegaly(swelling of the liver) in about 10%. Some exhibit lymphadenopathy (enlarged lymph nodes, in 5%) or splenomegaly (enlargement of the spleen, in 5%).[2] Acute viral hepatitis is more likely to be asymptomatic in younger people.In acute hepatitis the lesions (areas of abnormal tissue) predominantly contain diffuse sinusoidal and portal mononuclear infiltrates (lymphocytes, plasma cells, Kupffer cells) and swollen hepatocytes. Acidophilic cells (Councilman bodies) are common. Hepatocyte regeneration and cholestasis (canalicular bile plugs) 168

typically are present. Bridging hepaticnecrosis (areas of necrosis connecting two or more portal tracts) may also occur. There may be some lobular disarray. Although aggregates of lymphocytes in portal zones may occur these are usually neither common nor prominent. The normal architecture is preserved. There is no evidence of fibrosis or cirrhosis (fibrosis plus regenerative nodules). In severe cases prominent hepatocellular necrosis around the central vein (zone 3) may be seen. In submassive necrosis a rare presentation of acute hepatitis there is widespread hepatocellular necrosis beginning in the centrizonal distribution and progressing towards portal tracts. The degree of parenchymal inflammation is variable and is proportional to duration of disease.[5][6] Two distinct patterns of necrosis have been recognised: (1) zonal coagulative necrosis or (2) panlobular (nonzonal) necrosis.[7] Numerous macrophages and lymphocytes are present. Necrosis and inflammation of the biliary tree occurs.Hyperplasia of the surviving biliary tract cells may be present. Stromal haemorrhage is common. Causes of Acute hepatitis Viral hepatitis :Adenoviridae: Adenoviruses Arenaviruses: Guanarito virus, Bacterial:Anaplasma,Babesia,Bartonella,Chlamydia trachomatis,Coxiella Parasitic;Ascaris lumbricoides,Ancylostoma,Baylisascaris,Capillaria hepatica,Clonorchis sinensis Fungal;Aspergillus[72]Candida[73]Cryptococcus[

126-Chronic Hepatitis
Hepatitis ; is a medical condition defined by the inflammation of the liver and characterized by the presence ofinflammatory cells in the tissue of the organ. Chronic hepatitis often leads to nonspecific symptoms such as malaise, tiredness and weakness, and often leads to no symptoms at all. It is commonly identified on blood testsperformed either for screening or to evaluate nonspecific symptoms. The occurrence of jaundice indicates advanced liver damage. On physical examination there may be enlargement of the liver. Extensive damage and scarring of liver (i.e. cirrhosis) leads to weight loss, easy bruising and bleeding tendencies, peripheral edema (swelling of the legs) and accumulation ofascites (fluid in the abdominal cavity). Eventually, cirrhosis may lead to various complications: esophageal varices (enlarged veins in the wall of the esophagus that can cause life-threatening bleeding) hepatic encephalopathy (confusion and coma) and hepatorenal syndrome (kidney dysfunction). Chronic lobular hepatitis was the term used to describe chronic hepatitis with persistent parenchymal focal hepatocyte necrosis (apoptosis) with mononuclear sinusoidal infiltrates. This is now referred to as 'chronic hepatitis without piecemeal necrosis (or interface hepatitis).' Cirrhosis is a diffuse process characterized by regenerative nodules that are separated from one another by bands of fibrosis. It is the end stage for many chronic liver diseases. The pathophysiological process that results in cirrhosis is as follows: hepatocytes are lost through a gradual process of hepatocellular injury and inflammation. This injury stimulates a regenerative response in the remaining hepatocytes. The fibrotic scars limit the extent to which the normal architecture can be reestablished as the scars isolate groups of hepatocytes. This results in nodules formation. Angiogenisis (new vessel formation) accompanies scar production which results in the formation of abnormal channels between the central hepatic veins and the portal vessels. This in turn causes shunting of blood around the regenerating parenchyma. Normal vascular structures

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including the sinusoidal channels may be obliterated by fibrotic tissue leading to portal hypertension. The overall reduction in hepatocyte mass, in conjunction with the portal blood shunting, prevents the liver from accomplishing its usual functions the filtering of blood from the gastrointestinal tract and serum protein production. These changes give rise to the clinical manifestations of cirrhosis. Acne, abnormal menstruation, lung scarring, inflammation of the thyroid gland and kidneys may be present in women with autoimmune hepatitis Chronic active hepatitis was the term used to described cases of hepatitis for more than 6 months with portal based inflammation, fibrosis, disruption of the terminal plate and piecemeal necrosis. This term has now been replaced by the diagnosis of 'chronic hepatitis with piecemeal (periportal) necrosis (or interface hepatitis) with or without fibrosis. Causes of chronic hepatitis:Alcohol,Autoimmune,Autoimmune hepatitis,Drugs;Isoniazid,Ketoconazole,Methyldopa,Nitrofurantoin .Wilson's disease

127-Circhosis.Etilogy and Pathogenesis.

Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules (lumps that occur as a result of a process in which damaged tissue is regenerated),[1][2][3] leading to loss of liver function. Cirrhosis is most commonly caused by alcoholism, hepatitis B and C, and fatty liver disease, but has many other possible causes. Some cases are idiopathic, i.e., of unknown cause.Ascites (fluid retention in the abdominal cavity) is the most common complication of cirrhosis, and is associated with a poor quality of life, increased risk of infection, and a poor long-term outcome. Other potentially life-threatening complications are hepatic encephalopathy (confusion and coma) and bleeding from esophageal varices. Cirrhosis is generally irreversible, and treatment usually focuses on preventing progression and complications. In advanced stages of cirrhosis the only option is a liver transplant. Pathogenesis; The liver plays a vital role in synthesis of proteins e.g., albumin, clotting factors and complement), detoxification and storage (e.g., vitamin A). In addition, it participates in the metabolism of lipids and carbohydrates.Cirrhosis is often preceded by hepatitis and fatty liver (steatosis), independent of the cause. If the cause is removed at this stage, the changes are still fully reversible. The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, blocking the portal flow of blood through the organ and disturbing normal function. Recent research shows the pivotal role of the stellate cell, a cell type that normally stores vitamin A, in the development of cirrhosis. Damage to the hepatic parenchyma leads to activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation. In addition, it secretes TGF-1, which leads to a fibrotic response and proliferation of connective tissue. Etiology of cirrhosis Alcoholic liver disease (ALD). Alcoholic cirrhosis develops for between 10% and 20% of individuals who drink heavily for a decade or more.[8] Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. Chronic hepatitis B. The hepatitis B virus causes liver inflammation and injury that over several decades can lead to cirrhosis. Hepatitis D is dependent on the presence of hepatitis B and accelerates cirrhosis in co-infection. Primary biliary cirrhosis. May be asymptomatic or complain of fatigue, pruritus, and non-jaundice

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skin hyperpigmentation with hepatomegaly. Autoimmune hepatitis. This disease is caused by the immunologic damage to the liver causing inflammation and eventually scarring and cirrhosis. Findings include elevations in serum globulins, especially gamma globulins. Wilson's disease. Autosomal recessive disorder characterized by low serum ceruloplasmin and increased hepatic copper content on liver biopsy. Cardiac cirrhosis. Due to chronic right sided heart failure which leads to liver congestion. Galactosemia.

128-Circhosis Clinical Manifestation;portal hypertension,ascites and hepatic encephalopaty.

Liver cirrhosis is a disease in which necrosis, inflammation, fibrosis, nodular regeneration,and formation of vascular anastomoses develop more or less simultaneously. It is usually caused by the long-term action of noxious factors, especially alcohol abuse,which is the cause in 50% of cases worldwide.While the probability of cirrhosis developing after a cumulative uptake of 13 kg ethanol/kg body weight is only about 20%, it rises to over 90% after 40 kg. The substance that is most responsible for the development of fibrosis, and thus cirrhosis, is the ethanol metabolite acetaldehyde. Cirrhosis can also be the final stage of viral hepatitis (2040% of cirrhosis cases in Europe). In acute fulminant disease it may develop in a matter of weeks; in chronic recurrent disease after months or years. It can also occur after an obstruction to blood outflow (congestive liver; !p.170) or after other liver damage, for example, as final stage of a storage disease (hemochromatosis, Wilsons disease) or genetically determined enzyme deficiency. Factors involved in liver-cell damage are: ATP deficiency due to abnormal cellular energy metabolism; increased formation of highly reactive oxygen metabolites (O2 , HO2, H2O2) with concomitant deficiency of antioxidants (e.g., glutathione) and/or damage of protective enzymes (glutathione peroxidase, superoxide dismutase). The O2 metabolites react with, for example,unsaturated fatty acids in phospholipids (lipidperoxidation). This contributes to damage of plasma membranes and cell organelles (lysosomes, endoplasmic reticulum). As a result, cytosolic Ca2+ concentration rises, activating proteases and other enzymes so that the cells are ultimately irreversibly damaged. 171

Portal Hypertension: Venous blood from stomach, intestines, spleen, pancreas, and gallbladder passes via the portal vein to the liver where, in the sinusoids after mixture with oxygen-rich blood of the hepatic artery, it comes into close contact with the hepatocytes. Consequences of portal hypertension. Wherever the site of obstruction, an increased portal vein pressure will lead to disorders in the preceding organs (malabsorption, splenomegaly with anemia and thrombocytopenia)as well as to blood flowing from abdominal organs via vascular channels that bypass the liver. These portal bypass circuits use collateral vessels that are normally thin-walled but are now greatly dilated (formation of varices; haemorrhoids of the rectal venous plexus; caput medusae at the paraumbilical veins). The enlarged esophageal veins are particularly in danger of rupturing. Ascites ; is a gastroenterological term for an accumulation of fluid in the peritoneal cavity. The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver disease, its presence can portend other significant medical problems. Diagnosis of the cause is usually with blood tests, an ultrasound scan of the abdomen, and direct removal of the fluid by needle or paracentesis (which may also be therapeutic). Treatment may be with medication (diuretics), paracentesis, or other treatments directed at the cause. Hepatic encephalopathy (also known as portosystemic encephalopathy) is the occurrence of confusion, altered level of consciousness, and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum. It may ultimately lead to death. It is caused by accumulation in the bloodstream of toxic substances that are normally removed by the liver. The diagnosis of hepatic encephalopathy requires the presence of impaired liver function and the exclusion of an alternative explanation for the symptoms. Blood tests (ammonia levels) may assist in the diagnosis. Attacks are often precipitated by an intercurrent problem, such as infection orconstipation.

129-Jaundice
Bilirubin, largely originating from hemoglobin breakdown (ca. 230 mg/d), is taken up by the liver cells and coupled by glucuronyl transferase to form bilirubin-monoglucuronide and bilirubindiglucuronide. This water- soluble conjugated (direct reacting) bilirubin is secreted into the bile canaliculi and 85% is excreted in the stool. The remaining 15% is deglucuronated and absorbed in the intestine for enterohepatic recirculation. The normal plasma concentration of bilirubin is maximally 17 mol/L (1 mg/dL). If it rises to more than 30 mol/L, the sclera become yellow; if the concentration rises further,the skin turns yellow as well (jaundice [icterus]). Several forms can be distinguished: ! Prehepatic jaundice is the result of increased bilirubin production, for example, in hemolysis (hemolytic anemia, toxins), inadequate erythropoiesis (e.g., megaloblastic anemia), massive transfusion (transfused erythrocytes are short-lived), or absorption of large hematomas. In all these conditions unconjugated (indirect reacting) bilirubin in plasma is increased. Intrahepatic jaundice is caused by a specific defect of bilirubin uptake in the liver cells (Gilbert syndrome Meulengracht), conjugation (neonatal jaundice, CriglerNajjar syndrome), or secretion of bilirubin in the bile canaliculi (DubinJohnson syndrome,Rotor syndrome) In the first two defects it is mainly the unconjugatedplasma bilirubin that is increased;

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in the secretion type it is the conjugated bilirubin that is increased. All three steps may be affected in liver diseases and disorders, for example, in viral hepatitis, alcohol abuse, drug side effects (e.g., isoniazid, phenytoin, halothane), liver congestion (e.g., right heart failure), sepsis (endotoxins), or poisoning. When red blood cells have completed their life span of approximately 120 days, or when they are damaged, their membranes become fragile and prone to rupture. As each red blood cell traverses through the reticuloendothelial system, its cell membrane ruptures when its membrane is fragile enough to allow this. Cellular contents, including hemoglobin, are subsequently released into the blood. The hemoglobin is phagocytosed by macrophages, and split into its heme and globin portions. The globin portion, a protein, is degraded into amino acids and plays no role in jaundice. Two reactions then take place with the heme molecule. The first oxidation reaction is catalyzed by the microsomal enzyme heme oxygenase and results in biliverdin (green color pigment), iron and carbon monoxide. The next step is the reduction of biliverdin to a yellow color tetrapyrol pigment called bilirubin by cytosolic enzyme biliverdin reductase. This bilirubin is "unconjugated," "free" or "indirect" bilirubin. Approximately 4 mg of bilirubin per kg of blood is produced each day.The majority of this bilirubin comes from the breakdown of heme from expired red blood cells in the process just described. However approximately 20 percent comes from other heme sources, including ineffective erythropoiesis, and the breakdown of other heme-containing proteins, such as muscle myoglobin and cytochromes.

130-Disorders of The Exocrine Pancreas.Pancreatitis

Acute Pancreatitis Most pancreatic enzymes are activated by enteropeptidase only when they reach the intestinal lumen. The activation of trypsinogen to trypsin is a key feature in this, because trypsin activates other enzymes. If it is activated in the acinar cells, the pancreatic trypsin inhibitorprotein is responsible for trypsin not being effective there. However, if this protective mechanism does not keep up with the trypsin activation, or trypsin becomes active in the lumen of the pancreatic duct, self-digestion of the pancreas occurs, i.e., acute pancreatitis. Even though there is a history of high alcohol consumption and gallstones in 80% of cases, the pathogenetic mechanism is not quite clear. The following possibilities are being discussed as playing a part,either in combination or separately depending on the case: Increased pressure in the pancreatic duct(flow resistance and/or flow too high) can play a part in the development of acute pancreatitis. Alcohol, acetylsalicylic acid, histamine, etc. increase the permeability of the pancreatic duct epithelium, so that larger molecules can pass through it. Enzymes secreted by the acinar cells thus diffuse into periductal interstitial tissue and damage it (!A4). In addition,alcohol in the duct system seems to precipitate proteins, causing a rise in upstream pressure. Trypsin activates other enzymes (phospholipase A2, elastase, etc.), clotting factors (prothrombin to thrombin), tissue hormones (bradykinin and kallidin are activated via kallikrein), and cytotoxic proteins (complement system). In the pancreas (!A6; P in the computed tomogram) there is at first generalized cell swelling (pancreatic edema; Activated elastase, in particular,causes vessel arrosion with bleeding (hemorrhagic pancreatitis) 173

As the activated enzymes appear in plasma,where their presence is of diagnostic significance,hypoalbuminemia develops with resulting hypocalcemia, as well as systemic vasodilation and plasma exudation (triggered by bradykinin and kallidin), ultimately ending in circulatory shock. Phospholipase A2 and free fatty acids (due to increased lipolysis) in plasma destroy the surfactant on the alveolar epithelium, causing arterial hypoxia. Finally, the kidneys will also be damaged(danger of anuria.) Chronic Pancreatitis Chronic pancreatitis is an inflammatory process that destroys the exocrine and endocrine tissues and leads to fibrosis of the organ.Chronic calcifying pancreatitis (!A, left) is the most common form (70 80% of cases),caused by chronic alcohol abuse (> 80 g/d over many years) and is characterized by irregularly distributed tissue lesions with intraductal protein plugs and stones as well as atrophy and stenosis of the ductal system. Three mechanisms play a role in its pathogenesis: 1-While normally, in parallel with the stimulation of the acini (enzyme-rich secretion), there is greater secretion in the ducts (HCO3, water), it is reduced in chronic pancreatitis.As a result, protein concentration in the pancreatic juice is increased. 2. Calcium salts are deposited on the precipitated protein, resulting in the formation of stones in the lumen of small ducts, and concentric calcium deposits on the walls of the larger ducts. The cause of all this may be that two components of pancreatic juice are diminished in chronic pancreatitis, namely those that normally prevent the precipitation of calcium salts from pancreatic juice. One of these components is citrate, which binds calcium complexly, the other is the14 kDa protein, lithostatin (= pancreatic stone protein [PSP]), which holds calcium salts in solution during. 3-Similar to acute pancreatitis (!p.158), intraductal activation of trypsin occurs. This not only contributes to the autodigestion of pancreatic tissue, but also activates other aggressive enzymes, such as elastase and phospholipase. The rarer chronicobstructive pancreatitis (!A, right) is caused by occlusion of the main excretory duct(s) by tumors, scar stricture, or stenosis of the papilla, among others. There is no calcification, but the ductal system is markedly dilated upstream of the stenosis. The results of chronic pancreatitis are tissue atrophy, ductal stenosis, and periductal fibrosis with scarring.

131-Disorders of The Exocrine Pancreas.Pancreatic Insufficiency

Exocrine pancreatic insufficiency (EPI) is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. This disease is found frequently in dogs. EPI is also found in humans afflicted with cystic fibrosis and Shwachman-Diamond Syndrome. EPI is caused by a progressive loss of the pancreatic cells that make digestive enzymes. Most commonly in dogs, this is caused by pancreatic acinar atrophy. The atrophy in turn can be caused by previous infections, a blocked pancreatic duct, or genetics. Chronic pancreatitis is the most common cause of EPI in humans and cats, but it is an uncommon cause in dogs. Loss of digestive enzymes leads to maldigestion and malabsorption of nutrients. In humans, the common causes of EPI are Cystic Fibrosis, which is a hereditary recessive disease of 174

Europeans and Ashkenazi Jews involving a chloride channel called CFTR, and chronic pancreatitis. Shwachman-Diamond Syndrome is the second most common cause of pancreatic insufficiency in humans. EPI is also fairly common in diabetes - both type 1 and type 2. Studies have shown that about 35% of type 2 diabetics and 50% of type 1 diabetics exhibit symptoms and characteristics of EPI. However, treatment is normally only initiated once the patient complains of problems with steatorrhea, bulky stools, abdominal pain, and/or flatulence. Some clinicians refer to this phenomenon as "diabetic diarrhea", however this term is rarely explained as a symptom of EPI possibly because it could also be linked to GI motility problems. Limited and preliminary studies have indicated that treatment of EPI with products such as Pancrelipase have an effect on glucose control. Also, there have been only small differences in the fat soluble vitamin status of diabetics treated with products such as Pancrelipase, as steatorrhea can lead to a decrease in the absorption of fat soluble vitamins. In animals, signs of EPI are not present until 85 to 90 percent of the pancreas is unable to secrete its enzymes. Treatment Often this is treated with Pancreatic Enzyme Products (PEPs), such as pancrelipase, that are used to break down fats (lipases), proteins (proteases) and carbohydrates (amylases) into units that can be digested by those with EPI.

132-Alteration of kidney structure and function in disease.Manifestation of altered kidney function.

Renal damage can impair renal perfusion as well as glomerular and/or tubular functions (!A). In addition, abnormal urine composition can lead to precipitations (urolithiasis) that inhibit the free flow of urine. Abnormal renal function can be caused by reduced renal excretion of useless or harmful substances (e.g., uric acid, urea, creatinine, vanadate, foreign substances [xenobiotics], and so-called uremic toxins) whose plasma concentration then rises correspondingly.Reduced renal excretory function affects the kidneys decisive contribution to the regulation of the metabolism of water, electrolytes, minerals, and acidbase balance.The capacity of the kidney to regulate the composition of extracellular fluid is a function of volume, which, per unit time, is under the control of its epithelia. For substances that are not secreted by tubular cells, the controlled volume corresponds to the glomerular filtration rate. An abnormality of prerenal factors can, despite unimpaired tubular transport, raise the excretion of the affected substance via an increase in its plasma concentration and the amount filtered. Thus, glycosuria may occur even when renal transport of glucose is normal,if the plasma concentration of glucose is higher than its renal threshold, as is the case in diabetes mellitus. Similarly, impaired breakdown of amino acids leads to overflow aminoaciduria. Abnormalities of Urinary Concentration:Depending on requirements, the kidney can normally excrete hypotonic (< 100mosm/L) or hypertonic (> 1200 mosmol/L) urine. Concentration and dilution of urine are in the first instance the result of processes in the thick ascending loop of Henle (pars ascendens) which transports NaCl (, red arrow) to the interstitial space of the renal medulla without water (blue arrow) being able to follow. The tubular fluid becomes hypotonic (50100 mosmol/L) by the time it passes the ascending part, while the interstitial space becomes hypertonic.A protein-low 175

diet impairs the concentrating ability of the kidney because of reduced contribution of urea to the concentrating mechanism. Abnormalities of Glomerular Function: Reduced hydraulic conductivity or areduced filtration surface decreases the GFR.No filtration equilibrium can be achieved; as aresult of the reduced increase in, Peff ultimately rises. But this does not compensate for the reduced conductivity. Constriction of the vas afferens when systemic blood pressure remains constant reduces the filtration pressure and thus the proportion of filtered plasma water (filtration fraction = GFR/RPF). At the same time the renal blood flow and the GFR fall because of the increased resistance. Constriction of the vas efferens (!A4) raises the effective filtration pressure and thus also GFR/RPF. Simultaneously it reduces glomerular perfusion and thus GFR at any given filtration fraction. The constriction of the vas efferens (e.g., on infusion of angiotensin II) orobstruction of venous flow (e.g., by renalvein thrombosis) can thus ultimately reduce GFR. The function of the glomeruli is to produce an adequate GFR, i.e., the volume of plasma water that is controlled by the renal epithelium. The selective permeability of this filter ensures the formation of a nearly protein-free filtrate. As all of the blood flowing through the kidney must pass through the glomerular vessels, the resistance of these vessels also determines RPF. The GFR is determined by the effective filtration pressure (Peff), the hydraulic conductivity (Kf), and the filtering surface (F): GFR =Kf F Peff Masugis nephritis, caused by autoantibodies against the basement membrane, is much less common than immune complex nephritis. The local inflammation initially results in hyperemia, accumulation of neutrophils (exudative phase), and damage to the often markedly thickened basement membrane. It is common for endothelial, mesangial, or capsular epithelial cells to proliferate and ultimately for excess mesangial matrix to form (sclerosing). The glomeruli may also be damaged without any local inflammation, for example, by deposition of amyloid in amyloidosis, by a high concentration of filtrable proteins in plasma (e.g., in multiple myeloma), by high pressure in the glomerular capillaries (e.g., in arterial hypertension, renal vein thrombosis, venous back pressure in right heart failure, or hyperfiltration in diabetic nephropathy) as well as by reduced perfusion (e.g., in atherosclerosis, arteriosclerosis).n glomerulonephritis, resistance in thevasa afferentia and efferentia is increased and the RPF is reduced despite filtration pressure usually being high. The reduced hydraulic conductivity prevents filtration equilibrium being achieved and lowers GFR. The reduced renal perfusion stimulates the release of renin which, via angiotensin and aldosterone, raises blood pressure. In addition, the development of hypertension is aided by reduced excretion of NaCl and H2O, brought about by the decrease in GFR. Selective permeability is lost by damage to the glomerular filter, thus leading to proteinuria and edema .Damage to the kidney can, for example, destroy erythropoietin-producing cells and thus result in the development of anemia. Interstitial Nephritis: The term interstitial nephritis is applied to inflammatory changes in the kidney if the inflammation does not originate in the glomeruli.Renal tissue is infiltrated by inflammatory cells (especially granulocytes) and the inflammation can lead to local destruction of renal tissue. Nephrotic syndrome : If proteinuria, hypoproteinemia, and peripheral edema occur together, this is termed nephrotic syndrome. As the lipoproteins are not filtered even if the filter is damaged, but hypoproteinemia stimulates the formation of lipoproteins in the liver, hyperlipidemia results and thus also hypercholesterolemia. It remains debatable whether a loss of glomerular lipoprotein lipase contributes to the effect.

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133-Acute Renal Failure

Obstruction of the urinary tract, for example,by urinary stones can stop urinary excretion, even though the kidney remainsintactat least at first.In hemolysis and in the destruction of muscle cells (myolysis) hemoglobin or myoglobin, respectively, is filtered through the glomeruli and precipitated in the acidic tubular lumen, especially because their tubular concentration is increased by fluid absorption. The resulting leads to urine formation being interrupted. Renal function can also cease as a result of rapidly progressing renal diseases (e.g., glomerulonephritis) or toxic damage tothe kidney.Loss of blood and fluid impairs renal perfusion and glomerular filtration because in centralization of the circulation. the kidney is treated like a peripheral organ, i.e.,sympathetic activation produces renal vascular constriction via "-adrenoceptors. The result is acute ischemic renal failure. Energy deficiency impairs Na+/K+-ATPase;the resulting increase in intracellular concentration of Na+ also causes, via the 3Na+/ Ca2+ exchanger, a rise in intracellular Ca2+ concentration (!p.10,12) and thus vasoconstriction. The ischemia promotes the release of renin both primarily and via an increased NaCl supply in the macula densa (reduced Na+ absorption in the ascending tubules) and thus the intrarenal formation of angiotensin II, which has a vasoconstrictor action. If there is a lack of energy supply, adenosine is freed from ATP. It acts on the kidneyin contrast to the other organsas a marked vasoconstrictor.Intravascular stasis (sludge) that cannot be flushed out of the network between renal medulla and cortex, even if the perfusion pressure rises. In the first three days of acute renal failure no urine (anuria) or only a little volume of poorly concentrated urine (oliguria) is excreted as a rule (oliguric phase). However, urinary volume alone is a very poor indicator of the functional capacity of the kidney in acute renal failure, because the tubular transport processes are severely restricted and the reabsorption of filtered fluid is thus reduced.Despite normal-looking urine volume, renal excretion of all those substances that must normally be excreted in the urine may be markedly impaired. In this case determination of the plasma and urine creatinine concentration provides information on the true functional state of the kidneys.Recovery after the oliguric phase will lead to a polyuric phase characterized by the gradual increase of the GFR while the reabsorption function of the epithelial nephron is still impaired (salt-losing kidney). If the renal tubules are damaged (e.g., by heavy metals), polyuric renal failure occurs as a primary response, i.e., large volumes of urine are excreted despite a markedly decreased GFR.The dangers of acute renal failure lie in the inability of the kidney to regulate the water and electrolyte balance. The main threat in the oliguric phase is hyperhydration (especially with infusion of large volumes of fluid) and hyperkalemia (especially with the simultaneous release of intracellular K+, as in burns, contusions, hemolysis, etc.). In the polyuric phase the loss of Na+, water, HCO3 and especially of K+ may be so large as to be life-threatening.

134-Chronic Renal Failure.Uremia

A number of renal diseases can ultimately lead to the destruction of renal tissue.If the residual renal tissue is not in a position to adequately fulfill its tasks, the picture of renal failure evolves.Reduced renal excretion is particularly significant.The decreased GFR leads to an inversely proportional rise in the plasma level of creatinine. The plasma concentration of reabsorbed substances also rises, but less markedly, because renal tubular reabsorption is impaired in renal failure. The reabsorption of Na+ 177

and water is inhibited in renal failure by a variety of factors,such as natriuretic hormone, PTH, and vanadate. The reduced reabsorption of Na+ in the proximal tubules also directly or indirectly decreases the reabsorption of othersubstances, such as phosphate, uricacid,HCO3, Ca2+, urea, glucose, and amino acids.The reabsorption of phosphate is also inhibited by PTH. It is probably the disruption in renal water and electrolyte excretion that is responsible, at least partially, for the development of most of symptoms of chronic renal failure. Excess volume and the changed electrolyte concentrations lead to edemas, hypertension, osteomalacia, acidosis, pruritus, and arthritis, either directly or via the activation of hormones. Also, abnormalities of the excitatory cells (polyneuropathy, confusion, coma, seizures,cerebral edemas), of gastrointestinal function (nausea, peptic ulcer, diarrhea), and of blood cells (hemolysis, abnormal leukocyte function, abnormal blood clotting) are due to this.The reduced consumption of fatty acids by the kidney contributes to hyperlipidemia,while reduced gluconeogenesis favors the development of hypoglycemia..While uric acid can be precipitated at high concentrations, especially in the joints, and thus cause gout , sufficiently high concentrations of uric acid are only rarely achieved in renal failure. The role of reduced elimination of so-called uremia toxins (e.g.,acetone, 2,3-butyleneglycol, guanidinosuccinic acid, methylguanidine, indoles, phenols,aliphatic and aromatic amines, etc.) as well as of so-called middle molecules (lipids or peptides with a molecular weight of 300 2000 Da) in producing the symptoms of renal failure remains the subject of considerable debate. High concentrations of urea can destabilize proteins and bring about cell shrinkage. But its effect is partly canceled by the cellular uptake of stabilizing osmolytes. Uremia is a clinical syndrome associated with fluid, electrolyte, and hormone imbalances and metabolic abnormalities, which develop in parallel with deterioration of renal function. The term uremia, which literally means urine in the blood, was first used by Piorry to describe the clinical condition associated with renal failure. Uremia more commonly develops with chronic renal failure (CRF) or the later stages of chronic kidney disease (CKD), but it also may occur with acute renal failure (ARF) if loss of renal function is rapid. As yet, no single uremic toxin has been identified that accounts for all of the clinical manifestations of uremia. Toxins, such as parathyroid hormone (PTH), beta2-microglobulin, polyamines, advanced glycosylation end products, and other middle molecules, are thought to contribute to the clinical syndrome. Causes : Anemia Anemia-induced fatigue is thought to be one of the major contributors to the uremic syndrome. Erythropoietin (EPO), a hormone necessary for red blood cell production in bone marrow, is produced by peritubular cells in the kidney in response to hypoxia. Coagulopathy Acidosis Hyperkalemia Calcium, parathyroid, and vitamin D abnormalities Endocrine abnormalities Cardiovascular abnormalities Cardiovascular abnormalities, including uremic pericarditis, pericardial effusions, calcium and phosphate depositionassociated worsening of underlying valvular disorders, and uremic suppression of myocardial contractility, are common in patients with CRF.[11] Left ventricular 178

hypertrophy is a common disorder found in approximately 75% of patients who have not yet undergone dialysis. Malnutrition

135-Glomerulonephritis
Glomerulonephritis is a type of kidney disease in which the part of your kidneys that helps filter waste and fluids from the blood is damaged. Types : 1-Non Proliferative This is characterised by absence of increase in the number of cells (lack of hypercellularity) in the glomeruli. They usually cause nephrotic syndrome. This includes the following types: Minimal change GN (also known as Minimal Change Disease) This form of GN causes 78.4% of nephrotic syndrome in children, but only 20% in adults. As the name indicates, there are no changes visible on simple light microscopy, but on electron microscopy there is fusion of podocytes (supportive cells in the glomerulus). Immunohistochemistry staining is negative. Focal Segmental Glomerulosclerosis (FSGS) FSGS may be primary or secondary to reflux nephropathy, Alport syndrome, heroin abuse or HIV. FSGS presents as a nephrotic syndrome with varying degrees of impaired renal function (seen as a rising serum creatinine, hypertension). As the name suggests, only certain foci of glomeruli within the kidney are affected, and then only a segment of an individual glomerulus. Membranous glomerulonephritis Membranous glomerulonephritis (MGN), a relatively common type of glomerulonephritis in adults, frequently produces a mixed nephrotic and nephritic picture. Its cause is usually unknown, but may be associated with cancers of the lung and bowel, infection such as hepatitis and malaria, drugs including penicillamine, and connective tissue diseases such as systemic lupus erythematosus. Individuals with cerebral shunts are at risk of developing shunt nephritis, which frequently produces MGN. 2- Proliferative This type is characterised by increased number of cells in the glomerulus (hypercellular). Usually present as a nephritic syndrome and usually progress to end-stage renal failure (ESRF) over weeks to years (depending on type). IgA nephropathy (Berger's disease)
IgA nephropathy is the most common type of glomerulonephritis in adults worldwide. It usually presents as macroscopic haematuria (visibly bloody urine). It occasionally presents as a nephrotic syndrome. It often affects young males within days (24-48hrs) after an upper respiratory tract or gastrointestinal infection. Microscopic examination of biopsy specimens shows increased number of mesangial cells with increased matrix (the 'cement' that holds everything together). Immuno-staining is positive for immunoglobulin A deposits within the matrix.

Post-infectious Post-infectious glomerulonephritis can occur after essentially any infection, but classically occurs after infection with Streptococcus pyogenes. It typically occurs 1014 days after a skin or pharyngeal infection with this bacterium. 179

Membranoproliferative/mesangiocapillary GN:This may be primary, or secondary to SLE, viral hepatitis, or hypocomplementemia. One sees 'hypercellular and hyperlobular' glomeruli due to proliferation of both cells and the matrix within the mesangium. Usually presents with a combined nephritic-nephrotic picture, with inevitable progression to end stage renal failure. The primary form consists of two types: Type 1 (Classical and Alternative Complement activation) Type 2 (also known as Dense Deposit Disease) Alternative Complement activation only. C3 Nephritic Factor stabilizes C3 convertase, leading to Hypocomplementemia. Unlike Type 1, no IgG is detected. Rapidly progressive Glomerolonephritis(Crescentic GN) has a poor prognosis, with rapid progression to kidney failure over weeks. Steroid therapy is sometimes used.[5] Any of the above types of GN can be rapidly progressive. Additionally two further causes present as solely RPGN. One is Goodpasture syndrome, an autoimmune disease whereby antibodies are directed against basal membrane antigens found in the kidney and lungs. As well as kidney failure, patients have hemoptysis (cough up blood). The second cause is vasculitic disorders such as Wegener granulomatosis and polyarteritis. There is a lack of immune deposits on staining, but blood tests are positive for ANCA antibody. Causes, incidence, and risk factors Glomerulonephritis may be caused by specific problems with the body's immune system. Often, the precise cause of glomerulonephritis is unknown.Damage to the glomeruli causes blood and protein to be lost in the urine.The condition may develop quickly, with loss of kidney function occurring over weeks and months (called rapidly progressive glomerulonephritis).In about a quarter of people with chronic glomerulonephritis there is no history of kidney disease and the disorder first appears as chronic renal failure. The following increase your risk of developing this condition: History of cancer Blood or lymphatic system disorders Exposure to hydrocarbon solvents Infections such as strep infections, viruses, heart infections,or abscesses Diabetes Many conditions are known to cause or increase the risk for glomerulonephritis, including: Focal segmental glomerulosclerosis Goodpasture syndrome Membranoproliferative GN IgA nephropathy Lupus nephritis or Henoch-Schonlein purpura Anti-glomerular basement membrane antibody disease Blood vessel diseases such as vasculitis or polyarteritis Common symptoms of glomerulonephritis are: Blood in the urine (dark, rust-colored, or brown urine) Foamy urine Swelling (edema) of the face, eyes, ankles, feet, legs, or abdomen Symptoms that may also appear include the following:Abdominal pain Cough.

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136-Nephrotic Syndrome
Certain glomerular diseases virtually always produce the nephrotic syndrome. In addition, many other forms of primary and secondary. Pathophysiology. The manifestations of the nephroticsyndrome include: 1. Massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children) 2. Hypoalbuminemia, with plasma albumin levels less than 3 gm/dL 3. Generalized edema 4. Hyperlipidemia and lipiduria The various components of nephrotic syndrome bear a logical relationship to one another. The initial event is a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins. It will be remembered that the glomerular capillary wall, with its endothelium, GBM, and visceral epithelial cells, acts as a size and charge barrier through which the glomerular filtrate must pass. Increased permeability resulting from either structural or physicochemical alterations allows protein to escape from the plasma into the glomerular filtrate. Massive proteinuria results. The heavy proteinuria leads to depletion of serum albumin levels below the compensatory synthetic abilities of the liver,with consequent hypoalbuminemia and a reversed albuminglobulin ratio. Increased renal catabolism of filtered albumin also contributes to the hypoalbuminemia. The generalized edema is, in turn, the consequence of the loss of colloid osmotic pressure of the blood with subsequent accumulation of fluid in the interstitial tissues. There is also sodium and water retention, which aggravates the edema. This appears to be due to several factors, including compensatory secretion of aldosterone, mediated by the hypovolemiaenhanced antidiuretic hormone secretion; stimulation of the sympathetic system; and a reduction in the secretion of natriuretic factors such as atrial peptides.The largest proportion of protein lost in the urine is albumin, but globulins are also excreted in some diseases. The ratio of low- to high-molecular-weight proteins in the urine in various cases of nephrotic syndrome is a manifestation of the selectivity of proteinuria. The genesis of the hyperlipidemia is complex. Most patients have increased blood levels of cholesterol, triglyceride, very-low-density lipoprotein, low-density lipoprotein, Lp(a) lipoprotein, and apoprotein, and there is a decrease in highdensity lipoprotein concentration in some patients. These defects seem to be due in part to increased synthesis of lipoproteins in the liver, abnormal transport of circulating lipid particles, and decreased catabolism. Lipiduria follows the hyperlipidemia because not only albumin molecules but also lipoproteins leak across the glomerular capillary wall. The lipid appears in the urine either as free fat or as oval fat bodies, representing lipoprotein resorbed by tubular epithelial cellsand then shed along with the degenerated cells.These patients are particularly vulnerable to infection, especially with staphylococci and pneumococci. This vulnerability could be related to loss of immunoglobulins or lowmolecular- weight complement components in the urine. Thrombotic and thromboerrtbolic complications are also common in nephrotic syndrome, owing in part to loss of anticoagulant factors (e.g., antithrombin III) and antiplasmin activity through the leaky glomerulus. Renal vein thrombosis, once thought to be a cause of nephrotic syndrome, is most often 181

a consequence of this hypercoagulable state. Causes. The relative frequencies of the several causes of the nephrotic syndrome vary according to age and geography. In children younger than 17 years the nephrotic syndrome is almost always caused by a lesion primary to the kidney; whereas among adults, it may often be associated with a systemic diseaseThe most frequent systemic causes of the nephrotic syndrome are diabetes, amyloidosis, and SLE. The most important of the primary glomerular lesions are minimal change disease, membranous glomerulopathy, and focal segmental glomerulosclerosis. The first is most common in children in North America, the second is most common in older adults, but focal segmental glomerulosclerosis occurs at all ages." These three lesions, as well as a fourth, less common disorder, membranoproliferative glomerulonephritis, are discussed individually in the following sections. Other primary causes, the various proliferative glomerulonephritides, frequently present as a mixed syndrome with nephrotic and nephritic features.

137-Renal Stones
Stones may form at any level in the urinary tract, but most arise in the kidney. Urolithiasis is a frequent clinical problem, affecting 5% to 10% of Americans in their lifetime.?' Men are affected more often than women are, and the peak age at onset is between 20 and 30 years. Familial and hereditary predisposition to stone formation has long been known. Many of the inborn errors of metabolism, such as gout, cystinuria, and primary hyperoxaluria, provide good examples of hereditary disease characterized by excessive production and excretion of stone-forming substances. Cause and Pathogenesis. There are four main types of calculi 11 '' 1 ' (1) most stones (about 70%) are calcium containing, composed largely of calcium oxalate or calcium oxalate mixed with calcium phosphate; (2) another 15% are so-called triple stones or struvite stones, composed of magnesium ammonium phosphate; (3) 5% to 10% are uric acid stones; and (4) 1 % to 2% are made up of cystine. An organic matrix of mucoprotein, making up 1% to 5% of the stone by weight, is present in all calculi. Although there aremany causes for the initiation and propagation of stones, the most important determinant is an increased urinary concentration of the stones' constituents, such that it exceeds their solubility in urine (supersaturation). A low urine volume in some metabolically normal patients may also favor supersaturation. Calcium oxalate stones are associated in about 5% of patients with both hypercalcemia and hypercalciuria, caused by hyperparathyroidism, diffuse bone disease, sarcoidosis, and other hypercalcemic states. About 55% have hypercalciuria without hypercalcemia. This is caused by several factors, including hyperabsorption of calcium from the intestine (absorptive hypercalciuria), an intrinsic impairment in renal tubular reabsorption of calcium (renal hypercalciuria), or idiopathic fasting hypercalciuria with normal parathyroid function. Magnesium ammonium phosphate stones are formed largely after infections by urea-splitting bacteria (e.g., Proteus and some staphylococci), which convert urea to ammonia. The resultant alkaline urine causes the precipitation of magnesium ammonium phosphate salts. Uric acid stones are common in patients with hyperuricemia, such as gout, and diseases involving rapid cell turnover, such as the leukemias. However, more than half of all patients with orate calculi have neither hyperuricemia nor increased urinary excretion of uric acid. 182

Cystine stones are caused by genetic defects in the renal reabsorption of amino acids, including cystine, leading to cystinuria. Stones form at low urinary pH. It can therefore be appreciated that increased concentration of stone constituents, changes in urinary pH, decreased urine volume, and the presence of bacteria influence the formation of calculi. Morphology: Stones are unilateral in about 80% of patients. The favored sites for their formation are within the renal calyces and pelves (Fig. 20-57) and in the bladder. Clinical Course. Stones are of importance when they obstruct urinary flow or produce ulceration and bleeding. They may be present without producing any symptoms or significant renal damage. In general, smaller stones are most hazardous, because they may pass into the ureters, producing pain referred to as colic (one of the most intense forms of pain) as well as ureteral obstruction. Larger stones cannot enter the ureters and are more likely to remain silent within the renal pelvis.

138-Primary And Secondary Hyperparathyroidism.Familial hypocalciuric hypercalcemia.

Primary hyperparathyroidism is one of the most common endocrine disorders, and it is an important cause of hypercalcemia. The frequency of the various parathyroid lesions underlying the hyperfunction is as follows: Adenoma: 75% to 80% Primary hyperplasia (diffuse or nodular): 10% to 15% Parathyroid carcinoma: less than 5% Primary hyperparathyroidism is usually a disease of adults and is more common in women than in men by a ratio of nearly 3:1. Studies have begun to provide a molecular understanding of the pathogenesis of primary hyperparathyroidism. In more than 95% of cases, the disorder is caused by sporadic parathyroid adenomas or sporadic hyperplasia . Although familial syndromes are a distant second, they have provided a unique insight into the pathogenesis of primary hyperparathyroidism. The genetic syndromes associated with familial primary hyperparathyroidism include the following: Multiple endocrine neoplasia-1 (MEN-1): The MEN1 gene on chromosome 1 ig13 is a tumor suppressor gene inactivated in a variety of MEN-1-related parathyroid lesions, including parathyroid adenomas and hyperplasia. Multiple endocrine neoplasia-2 (MEN-2): The MEN-2 syndrome is caused by activating mutations in the tyrosine kinase receptor, RET, on chromosome IOq. Morphology. The morphologic changes seen in primary hyperparathyroidism include those in the parathyroid glands as well as those in other organs affected by elevated levels of calcium. Parathyroid adenomas are almost always solitary and, similar to the normal parathyroid glands, may lie in close proximity to the thyroid gland or in an ectopic site (e.g., the mediastinum). Clinical Cases: Primary hyperparathyroidism presents in one of two general ways: (1) It may be asymptomatic and be identified after a routine chemistry profile, or (2) patients may have the classic

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clinical manifestations of primary hyperparathyroidism." Asymptomatic Hyperparathyroidism. Because serum calcium levels are routinely assessed in the work-up of most patients who need blood tests for unrelated conditions, clinically silent hyperparathyroidism is often detected early. SECONDARY HYPERPARATHYROIDISM Secondary hyperparathyroidism is caused by any condition associated with a chronic depression in the serum calcium level because low serum calcium leads to compensatory overactivity of the parathyroid glands. ; ' Renal failure is by far the most common cause of secondary hyperparathyroidism, although a number of other diseases, including inadequate dietary intake of calcium, steatorrhea, and vitamin ll deficiency, may also cause this disorder. The mechanisms by which chronic renal failure induces secondary hyperparathyroidism are complex and not fully understood. Chronic renal insufficiency is associated with decreased phosphate excretion, which in turn results in hyperphosphatemia. The elevated serum phosphate levels directly depress serum calcium levels and thereby stimulate parathyroid gland activity. In addition, loss of renal substance reduces the availability of a-1-hydroxylase necessary for the synthesis of the active form of vitamin D, which in turn reduces intestinal absorption of calcium. Morphology.The parathyroid glands in secondary hyperparathyroidism are hyperplastic.As in the case of primary hyperplasia,the degree of glandular enlargement is not neccessarily symetric. Clinical Course. The clinical features of secondary hyperparathyroidism are usually dominated by those associated with chronic renal failure. Bone abnormalities (renal osteodystrophy) and other changes associated with PTH excess are, in general, less severe than are those seen in primary hyperparathyroidism. Familial hypocalciuric hypercalcemia (FHH) is an autosomal- dominant disorder characterized by enhanced parathyroid function due to decreased sensitivity to extracellular calcium. Mutations in the parathyroid calciumsensing receptor gene (CASK) on chromosome 3q are a primary cause for this disorder.'' Patients with homozygous CASR mutations present in the neonatal period with severe hyperparathyroidism. CASR mutations have not been described in sporadic parathyroid tumors.

139-Hyperparathyroidism & Pseudohypoparathyroidism.

Hypoparathyroidism Hypoparathyroidism is far less common than is hyperparathyroidism. There are many possible causes of deficient PTH secretion resulting in hypoparathyroidism: Surgically induced hypoparathyroidism occurs with inadvertent removal of all the parathyroid glands during thyroidectomy, excision of the parathyroid glands in the mistaken belief that they are lymph nodes during radical neck dissection for some form of malignant disease, or removal of too large a proportion of parathyroid tissue in the treatment of primary hyperparathyroidism. Congenital absence of all glands, as in certain developmental abnormalities, such as thymic aplasia and cardiac defects Familial hypoparathyroidism is often associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency; this syndrome is known as autoimmune polyendocrine syndrome type 1 (APS1) and is caused by mutations

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The syndrome typically presents in childhood with the onset of candidiasis, followed several years later by hypoparathyroidism and then adrenal insufficiency during adolescence. APS1 is discussed further in the section on adrenal glands. Idiopathic hypoparathyroidism most likely represents an autoimmune disease with isolated atrophy of the glands. Sixty per cent of the patients with this disorder have autoantibodies directed against the calcium-sensing receptor (CASK) in the parathyroid gland The major clinical manifestations of hypoparathyroidism are referable to hypocalcemia and are related to the severity and chronicity of the hypocalcemia. The hallmark of hypocalcemia is tetany, which is characterized by neuromuscular irritability, resulting from decreased serum ionized calcium concentration. Mental status changes Intracranial manifestations Ocular disease results in calcification of the lens leading to cataract formation. Cardiovascular manifestations Dental abnormalities Pseudohypoparathyroidism In this condition, hypoparathyroidism occurs because of end-organ resistance to the actions of PTH. Indeed, serum PTH levels are normal or elevated. Central to the understanding of PTH resistance are two key concepts: (1) Gproteins,principally G mediate the cellular actions of PTH on hone and kidney, and (2) GNASI is a selectively imprinted gene, with tissue-specific patterns of imprinting." 1. Pseudohypoparathyroidism type IA is associated with multihormone resistance and Albright hereditary osteodystrophy (AHO), a syndrome characterized by skeletal and developmental defects. Patients with AHO often have short stature, obesity, short metacarpal and metatarsal bones, and variable mental deficits. The multihormone resistance involves three hormones (PTH, TSH, and LH/FSH), all of which activate Got-mediated pathways in target tissues. The PTH resistance is the most obvious clinical manifestation, presenting as hypocalcemia, hyperphosphatemia, and elevated circulating PTH. TSH resistance is generally mild, while LH/FSH resistance manifests as hypergonadotropic hypogonadism in females. The mutation in this disorder is inherited on the maternal allele, severely impeding the actions of PTH on the kidney in maintaining calcium homeostasis. 2. Pseudopseudohypoparathyroidism: In this disorder, the mutation is inherited on the paternal allele, and it is characterized by AHO without accompanying multihormonal resistance. As a result, serum calcium, phosphate and PTH levels are normal.

140-Osteoporosis & Osteomalacia

Osteoporosis Osteoporosis is a disease characterized by increased porosity of the skeleton resulting from reduced bone mass. The associated structural changes predispose the bone to fracture. Thedisorder may be localized to a certain bone or region, as in disuse osteoporosis of a limb, or may involve the entire skeleton, as a manifestation of a metabolic bone disease. Generalized osteoporosis may be primary, or secondary to a large variety of conditions . The most common forms of osteoporosis are senile and postmenopausal osteoporosis. In these disorders, the critical loss of bone mass makes the skeleton 185

vulnerable to fractures. Pathogenesis. Peak bone mass is achieved during young adulthood. Its magnitude is determined largely by hereditary factors, especially the vitamin D receptor allele that is expressed, as well as the genes for collagen 1 A I, estrogen receptor, and insulin-like growth factor 1 and its binding protein.'Physical activity, muscle strength, diet, and hormonal state,however, all contribute. Age-related changes in bone cells and matrix have a strong impact on bone metabolism. Osteoblasts from elderly individuals have reduced replicative and biosynthetic potential when compared with osteoblasts from younger individuals." Also, proteins bound to the extracellular matrix (such as growth factors, which are mitogenic to osteoprogenitor cells and stimulate osteoblastic synthetic activity) lose their biologic potency over time. Reduced physical activity increases the rate of bone loss in experimental animals and humans because mechanical forces are important stimuli for normal bone remodeling. Genetic factors are also important, as noted previously.The type of vitamin D receptor molecule that is inherited accounts for approximately 75% of the maximal peak mass achieved. The body 's calcium nutritional state is important. It has been shown that adolescent girls (but not boys) have insufficient calcium intake in the diet. Hormonal influences. In the decade after menopause, yearly reductions in bone mass may reach up to 2% of cortical bone and 9% of cancellous bone. Morphology. The entire skeleton is affected in postmenopausal and senile osteoporosis , but certain regions tend to be more severely involved than others. In postmenopausal osteoporosis, the Osteoporotic vertebral body (right) shortened by compression fractures, compared with a normal vertebral body.The osteoporotic vertebra has a characteristic loss of horizontal trabeculae and thickened vertical trabeculae. increase in osteoclast activity affects mainly bones or portions of bones that have increased surface area, such as the cancellous compartment of vertebral bodies. Osteomalacia results from defective bone mineralisation. This is a result of a lack of one or more of the factors necessary for osteogenesis: namely, a normal extracellular concentration of calcium and phosphate and a normal pH at the site of calcification. Normal mineralisation depends on interdependent factors that supply adequate calcium and phosphate to the bones. Vitamin D maintains calcium and phosphate homeostasis through its actions on the GI tract, the kidneys, bone, and the parathyroid glands. Vitamin D is obtained from the diet, or it can be produced from a sterol precursor (7-dehydrocholesterol) in the skin following exposure to UV-B light. Sequential hydroxylation of vitamin D is required to produce the metabolically active form of vitamin D. Hydroxylation occurs first in the liver and then in the kidneys and produces vitamin D 1,25(OH). Dysfunction in any of these metabolic steps results in osteomalacia and secondary hyperparathyroidism in adults.

141- 142 Diabetis Mellitus.Pathology & Pathogenesis

Diabetes mellitus (DM) is not a single disease entity, but rather agroup of metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia and attendant

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metabolic dysregulation may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels.

CLASSIFICATION Although all forms of diabetes mellitus share hyperglycemia as a common feature, the pathogenic processes involved in the development of hyperglycemia vary widely. The previous classification schemes of diabetes mellitus were based on the age at onset of the disease or on the mode of therapy; in contrast, the recently revised classification reflects our greater understanding of the pathogenesis of each variant."The vast majority of cases of diabetes fall into one of two broad classes: Type 1 diabetes is characterized by an absolute deficiency of insulin caused by pancreatic B-cell destruction. It accounts for approximately 10% of all cases. Type 2 diabetes is caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic B-cells("relative insulin deficiency" ). Approximately 80% to 90% of patients have type 2 diabetes. NORMAL INSULIN PHYSIOLOGY Normal glucose homeostasis is tightly regulated by three interrelated processes: glucose production in the liver; glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle; and actions of insulin and counter-regulatory hormones, including glucagon, on glucose. Insulin and glucagon have opposing regulatory effects on glucose homeostasis. During fasting states, low insulin and high glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, thereby preventing hypoglycemia. Thus, fasting plasma glucose levels are determined primarily by hepatic glucose output. Following a meal, insulin levels rise and glucagon levels fall in response to the large glucose load. Insulin promotes glucose uptake and utilization in tissues (discussed later). The skeletal muscle is the major insulinresponsive site for postprandial glucose utilization, and is critical for preventing hyperglycemia and maintaining glucose homeostasis. Regulation of Insulin Release The insulin gene is expressed in the B cells of the pancreatic islets (Fig. 2427). Preproinsulin is synthesized in the rough endoplasmic reticulum from insulin mRNA and delivered to the Golgi apparatus. There, a series of proteolytic cleavage steps generate the mature insulin and a cleavage peptide, C-peptide.Both insulin and C-peptide are then stored in secretory granules and secreted in equimolar quantities after physiologic stimulation; increasingly, C-peptide levels are being used as a clinical assay to measure endogenous insulin secretion. The most important stimulus that triggers insulin synthesis and release is glucose itself. Insulin Action and Insulin Signaling Pathways Insulin is the most potent anabolic hormone known, with multiple synthetic and growth-promoting effects. Its principal metabolic function is to increase the rate of glucose transport into certain cells in the body. PATHOGENESIS OF TYPE 1 DIABETES MELLITUS This form of diabetes results from a severe lack of insulin caused by an immunologically mediated destruction of [3 cells. Type I diabetes most commonly develops in childhood, becomes manifest at 187

puberty, and progresses with age. Since the disease can develop at any age, including late adulthood, the appellation "juvenile diabetes " is now considered obsolete.Type 1 diabetes is an autoimmune disease in which islet destruction is caused primarily by T lymphocytes reacting against as yet poorly defined 13-cell antigens. PATHOGENESIS OF TYPE 2 DIABETES MELLITUS Environmental factors, such as a sedentary life style and dietary habits, clearly play a role, as will become evident when obesity is considered. Nevertheless, genetic factors are even more important than intype 1 diabetes. PATHOGENESIS OF THE COMPLICATIONS OF DIABETES The morbidity associated with long-standing diabetes of either type results from a number of serious complications, involving both large- and medium-sized muscular arteries (macrovascular disease), as well as capillary dysfunction in target organs ( microvascular disease). Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting in increased risk of myocardial infarction, stroke, and lowerextremity gangrene. The effects of microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively.

143. COMPLICATIONS IN DIABETES MELLITUS

The morbidity associated with long-standing diabetes of either type results from a number of serious complications, involving both large- and medium-sized muscular arteries (macrovascular disease), as well as capillary dysfunction in target organs ( microvascular disease). Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting in increased risk of myocardial infarction, stroke, and lowerextremity gangrene. The effects of microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively. Diabetes is the leading cause of blindness and end-stage renal disease in the Western hemisphere, besides contributing substantially to the incidence of cardiovascular events each year. Hence, the basis of long-term complications of diabetes is the subject of a great deal of research. Most of the available experimental and clinical evidence suggests that the complications of diabetes are a consequence of the metabolic derangements, mainly hyperglycemia. Formation of Advanced Glycation End Products. Advanced glycation end products (AGEs) are formed as a result of nonenzymatic reactions between intracellular glucose-derived dicarbonyl precursors (glyoxal, methylglyoxal, and 3-deoxyglucosone) with the amino group of both intracellular and extracellular proteins. On extracellular matrix components, such as collagen or laminin, the formation of AGEs causes cross-linking between polypeptides, resulting in abnormal matrix matrix and matrixcell interactions. For example, crosslinking between collagen type I molecules in large vessels decreases their elasticity, which may predispose these vessels to shear stress and endothelial injury Circulating plasma proteins are modified by addition of AGE residues; these proteins, in turn, bind to AGE receptors on several cell types (endothelial cells, mesangial cells,macrophages). 188

AGE residues; these proteins, in turn, bind to AGE receptors on several cell types (endothelial cells, mesangial cells, macrophages). The AGE-receptor ligation results in activation and nuclear translocation of the pleotropic transcription factor NF-KB, generating a variety of cytokines, growth factors and other pro-inflammatory molecules. AGEs also contribute to microvascular injury in diabetes.The AGE inhibitor aminoguanidine has recently been shown to retard the progression of nephropathy in type 1 diabetics. Activation of Protein Kinase C. Activation of intracellular protein kinase C (PKC) by calcium ions and the second messenger diacylglycerol (DAG) is an important signal transduction pathway in many cellular systems. Intracellular hyperglycemia can stimulate the de novo synthesis of DAG from glycolytic intermediates and hence cause activation of PKC. The downstream effects of PKC activation are numerous and include the following:" Production of the proangiogenic molecule vascular endothelial growth factor Increased activity of the vasoconstrictor endothelin-1 and decreased activity of the vasodilator endothelial nitric oxide synthase. Production of profibrogenic molecules like transforming growth factor-B (TGF-B), leading to increased deposition of extracellular matrix and basement membrane material Production of the procoagulant molecule plasminogen activator inhibitor-1 (PAI-1), leading to reduced fibrinolysis and possible vascular occlusive episodes Production of pro-inflammatory cytokines by the vascular endothelium. Intracellular Hyperglycemia with Disturbances inPolyol Pathways. In some tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys, blood vessels), hyperglycemia leads to an increase in intracellular glucose that is then metabolized by the enzyme aldose reductase to sorbitol, a polyol, and eventually to fructose. In this process, intracellular NADPH is used as a cofactor. NADPH is also required as a cofactor by the enzyme glutathione reductase for regenerating reduced glutathione (GSH). GSH is one of the important antioxidant mechanisms in the cell (Chapter 1), and a reduction in GSH levels increases cellular susceptibility to oxidative stress."

144-Body Weight Control By The Hypothalamus .Obesity.

Several regulatory circuits are considered to be responsible for regulating body weight, each governed by the hypothalamus, for example, by its ventromedial nucleus as the satiety center and by the lateral hypothalamus as theeating center. The regulatory cycle that is probably decisive in the long term is the lipostatic mechanism: the bodys fat mass is recognized on the basis of a substance that is secreted by the fat cells (probably leptin), and a feedback loop keeps this fat mass constant during changes in appetite and physical activity (!A). Thus fat, even if surgically removed, is rapidly replaced. Obesity (adiposity, excess weight) is a risk factor for hypertension, type 2 diabetes mellitus, hyperlipidemia, atherosclerosis as well as renal stones and gallstones. More than 40% excessweight is associated with a twofold risk of premature death. Obesity is partly of (poly)genetic, partly of environmental origin. Its causes are little known. Two defective genes have been discovered, one in two male mouse strains with extreme obesity and one in type 2 diabetes. If the ob[esity]-gene is 189

defective, the 16-kDa protein leptin, coded by the obgene, is absent from plasma. Injection of leptin into mice with homozygotic ob mutation counteracts the symptoms of the gene defect. Its administration to normal mice leads to weight loss. But if the db-gene has mutated, the leptin receptor in the hypothalamus (in the arcuate nucleus, among other sites) is defective. While high concentrations of leptin circulate in plasma, the hypothalamus does not respond to them. Some obese persons also have a defective leptin gene, but in most others the plasma leptin concentration is high. In this case the feedback chain after leptin must have been interrupted somewhere (!A, red X). Various possible defects have been postulated: ! Leptin can no longer overcome the blood brain barrier (? defective transcytosis). The inhibitory effect of leptin on the secretion of neuropeptide Y (NPY) in the hypothalamus, which stimulates food intake and reduces energy consumption, is abnormal. ! Leptin does not cause the release in the hypothalamus of "-melanocortin (melanocytestimulating hormone ["-MSH]), which acts there via MCR-4 receptors and has the opposite effect of NPY.Quite recently a homozygotic leptin receptor defect was found in three very obese sisters. As they had never gone through puberty and the secretion of both somatotropin hormone and thyrotropinreleasing hormone had been reduced,it seems that leptin also plays a part in other endocrine regulatory cycles.

145- Pituitary Adenoma

The most common cause of hyperpituitarism is an adenoma arising in the anterior lobe. Other, less common, causes include hyperplasia and carcinomas of the anterior pituitary, secretion of hormones by some extrapituitary tumors, and certain hypothalamic disorders. Pituitary adenomas can be functional (i.e., associated with hormone excess and clinical manifestations thereof) or silent (i.e., immunohistochemical and/or ultrastructural demonstration of hormone production at the tissue level only, without clinical symptoms of hormone excess). Both functional and silent pituitary adenomas are usually composed of a single cell type and produce a single predominant hormone, although exceptions are known to occur. Pituitary adenomas are classified on the basis of hormone(s) produced by the neoplastic cells detected by immunohistochemical stains performed on tissue sections (Table 24-1). Some pituitary adenomas can secrete two hormones (GH and prolactin being the most common combination), and rarely, pituitary adenomas are plurihormonal. Finally, pituitary adenomas may be hormone-negative, based on absence of immunohistochemical reactivity and ultra- structural demonstration of lineage-specific differentiation. Both silent and hormone-negative pituitary adenomas may cause hypopituitarism as they encroach on and destroy adjacent anterior pituitary parenchyma. Clinically diagnosed pituitary adenomas are responsible for about 10% of intracranial neoplasms; they are discovered incidentally in up to 25% of routine autopsies. In fact, using highresolution computed tomography or magnetic resonance imaging suggest that approximately 20% of "normal" adult pituitary glands harbor an incidental lesion measuring 3 mm or more in diameter, usually a silent adenoma.' Pituitary adenomas are usually found in adults, with a peak incidence from the thirties to the fifties. Most pituitary adenomas occur as isolated lesions. In about 3% of cases, however, adenomas are associated with multiple endocrine neoplasia (MEN) type 1. 190

 The great majority of pituitary adenomas are monoclonal in origin, even those that are plurihormonal, suggesting that most arise from a single somatic cell. G-protein mutations are possibly the best-characterized molecular abnormalities in pituitary adenomas. Multiple endocrine neoplasia (MEN) syndrome (discussed in detail below) is a familial disorder associated with tumors and hyperplasias of multiple endocrine organs, including the pituitary. Additional molecular abnormalities present in aggressive or advanced pituitary adenomas include activating mutations of the RAS oncogene and overexpression of the c-MYC oncogene, suggesting that these genetic events arelinked to disease progression.' PROLACTINOMAS Prolactinomas (lactotroph adenomas) are the most frequent type of hyperfunctioning pituitary adenoma, accounting for about 30% of all clinically recognized pituitary adenomas. These lesions range from small microadenomas to large, expansile tumors associated with substantial mass effect. GROWTH HORMONE (SOMATOTROPH CELL) ADENOMAS GH-secreting tumors are the second most common type of functioning pituitary adenoma. As we have mentioned, 40% of somatotroph cell adenomas express a mutant GTPasedeficient a-subunit of the G-protein, G,. Somatotroph cell adenomas may be quite large by the time they come to clinical attention because the manifestations of excessive GH may be subtle. CORTICOTROPH CELL ADENOMAS Corticotroph adenomas are usually small microadenomas at the time of diagnosis. These tumors are most often basophilic (densely granulated) and occasionally chromophobic (sparsely granulated). Both variants stain positively with periodic acidSchiff (PAS) because of the presence of carbohydrate in pre-opiomelanocorticotropin (POMC), the ACTH precursor molecule; in addition, they demonstrate variable immunoreactivity for POMC and its derivatives, including ACTH and [3endorphin. OTHER ANTERIOR PITUITARY ADENOMAS Gonadotroph((LH-producing and FSH-producing) Thyrotroph (TSH-producing) Nonfunctioning pituitary adenomas

146- Hypopituitarism
Hypopituitarism refers to decreased secretion of pituitary hormones, which can result from diseases of the hypothalamus or of the pituitary. Hypofunction of the anterior pituitary occurs when approximately 75% of the parenchyma is lost or absent. This may be congenital or the result of a variety of acquired abnormalities that are intrinsic to the pituitary. Most cases of hypofunction arise from destructive processes directly involving the anterior pituitary, although other mechanisms have been identified: Tumors and other mass lesions: Pituitary adenomas, other benign tumors arising within the sella, primary and metastatic malignancies, and cysts can cause hypopituitarism. Any mass lesion in the sella can cause damage by exerting pressure on adjacent pituitary cells. 191

 Pituitary surgery or radiation: Surgical excision of a pituitary adenoma may inadvertently extend to the nonadenomatous pituitary. Radiation of the pituitary, used to prevent regrowth of residual tumor after surgery, can damage the nonadenomatous pituitary. Pituitary apoplexy: As has been mentioned, this is a sudden hemorrhage into the pituitary gland, often occurring into a pituitary adenoma.; Ischemic necrosis of the pituitary and Sheehan syndrome:Ischemic necrosis of the anterior pituitary is an important cause of pituitary nsufficiency. Sheehan syndrome, or postpartum necrosis of the anterior pituitary, is the most common form of clinically significant ischemic necrosis of the anterior pituitary. ` During pregnancy, the anterior pituitary enlarges to almost twice its normal size. This physiologic expansion of the gland is not accompanied by an increase in blood supply from the low-pressure venous system; hence, there is relative anoxia of the pituitary. Ratlike cleft cyst: These cysts, lined by ciliated cuboidal epithelium with occasional goblet cells and anterior pituitary cells, can accumulate proteinaceous fluid and expand, compromising the normal gland. Empty sella syndrome: Any condition that destroys part or all of the pituitary gland, such as ablation of the pituitary by surgery or radiation, can result in an empty sella. Genetic defects: Rare congenital deficiencies of one or more pituitary hormones have been recognized in children. Less frequently, disorders that interfere with the delivery of pituitary hormonereleasing factors from the hypothalamus, such as hypothalamic tumors, may also cause hypofunction of the anterior pituitary. Any disease involving the hypothalamus can alter secretion of one or more of the hypothalamic hormones that influence secretion of the corresponding pituitary hormones. Hypothalamic lesions that cause hypopituitarism include: Tumors, including benign lesions that arise in the hypothalamus, such as craniopharyngiomas, and malignant tumors that metastasize to that site, such as breast and lung carcinomas. Inflammatory disorders and infections, such as sarcoidosis or tuberculous meningitis, can cause deficiencies of anterior pituitary hormones and diabetes insipidus.

147-Diabetes Insipidus
The clinically relevant posterior pituitary syndromes involve ADH and include diabetes insipidus and secretion of inappropriately high levels of ADH. Diabetes insipidus. ADH deficiency causes diabetes insipidus, a condition characterized by excessive urination (polyuria) owing to an inability of the kidney to resorb water properly from the urine. It can result from a variety of processes, including head trauma, tumors, and inflammatory disorders of the hypothalamus and pituitary as well as surgical procedures involving these organs. The condition can also arise spontaneously, in the absence of an underlying disorder. Diabetes insipidus from ADH deficiency is designated as central to differentiate it from nephrogenic diabetes insipidus, which is a result of renal tubular unresponsiveness to circulating ADH. The clinical manifestations of the two diseases are similar and include the excretion of large volumes of dilute urine with an inappropriately low specific gravity. Serum sodium and osmolality are increased owing to excessive renal loss of free water, resulting in thirst and polydipsia. Patients who can drink water can generally compensate for urinary losses; patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may develop life-threatening dehydration.

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148- Syndrome of inappropriate ADH (SIADH) secretion.

ADH excess causes resorption of excessive amounts of free water, resulting in hyponatremia. The most frequent causes of SIADH include the secretion of ectopic ADH by malignant neoplasms (particularly small cell carcinomas of the lung), non-neoplastic diseases of the lung, and local injury to the hypothalamus or posterior pituitary (or both). The clinical manifestations of SIADH are dominated by hyponatremia, cerebral edema, and resultant neurologic dysfunction. Although total body water is increased, blood volume remains normal, and peripheral edema does not develop. Irreversible neurologic damage and death may occur when the rate of correction of Na+ exceeds 0.5 mEq/L/h for patients with severe hyponatremia. At this rate of correction, osmolytes that have been lost in defense against brain edema during the development of hyponatremia cannot be restored as rapidly when hyponatremia is rapidly corrected. The brain cells are thus subject to osmotic injury, a condition termed osmotic demyelination. Certain factors such as hypokalemia, severe malnutrition, and advanced liver disease predispose patients to this devastating complication.

149-Hyperthyroidism
Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T, and T 4 . Because it is caused most commonly by hyperfunction of the thyroid gland, it is often referred to as hyperthyroidism. However, in certain conditions the oversupply is related to either excessive release of preformed thyroid hormone (e.g., in thyroiditis) or to an extrathyroidal source, rather than hyperfunction of the gland ( Table 24-2). Thus, strictly speaking, hyperthyroidism is only Not Associated with HyperthyroidismSubacute granulomatous thyroiditis (painful)Subacute lymphocytic thyroiditis (painless) Struma ovarii (ovarian teratoma with ectopic thyroid) Factitious thyrotoxicosis (exogenous thyroxine intake) "'Associated with increased TSH; all other causes of thyrotoxicosisassociated with decreased TSH.one (albeit the most common) cause of thyrotoxicosis. The terms primary and secondary hyperthyroidism are sometimes used to designate hyperthyroidism arising from an intrinsic thyroid abnormality and that arising from processes outside of the thyroid, such as a TSH-secreting pituitary tumor. With this disclaimer, we will follow the common practice of using the terms thyrotoxicosis and hyperthyroidism interchangeably. The three most common causes of thyrotoxicosis are also associated with hyperfunction of the gland and include the following: Diffuse hyperplasia of the thyroid associated with Graves disease (accounts for 85% of cases) Hyperfunctional multinodular goiter Hyperfunctional adenoma of the thyroid Clinical Course. The clinical manifestations of hyperthyroidism are protean and include changes referable to the hypermetabolic state induced by excess thyroid hormone as well as those related to overactivity of the sympathetic nervous system (i.e., an increase in the 13-adrenergic "tone"). Excessive levels of thyroid hormone result in an increase in the basal metabolic rate. The skin of thyrotoxic patients tends to be soft, warm, and flushed because of increased blood flow and peripheral vasodilation to increase heat loss. Heat intolerance is common. Sweating is increased because of higher levels of calorigenesis. Increased basal metabolic rate also results in characteristic weight loss despite increased appetite. Cardiac manifestations are among the earliest and most consistent features of hyperthyroidism. 193

Myocardial changes, such as foci of lymphocytic and eosinophilic infiltration, mild fibrosis in the interstitium, fatty changes in myofibers, and an increase in size and number of mitochondria, have been described. In the neuromuscular system, overactivity of the sympathetic nervous system produces tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, and insomnia. Ocular changes often call attention to hyperthyroidism. A wide, staring gaze and lid lag are present because of sympathetic overstimulation of the levator palpebrae superioris. However, true thyroid ophthalmopathy associated with proptosis is a feature seen only in Graves disease. In the gastrointestinal system, sympathetic hyperstimulation of the gut results in hypermotility, malabsorption, and diarrhea. The skeletal system is also affected in hyperthyroidism.Thyroid hormone stimulates bone resorption, resulting in increased porosity of cortical bone and reduced volume of trabecular bone. A diagnosis of hyperthyroidism is made using both clinical and laboratory findings. The measurement of serum TSH concentration using sensitive TSH (sTSH) assays provides the most useful single screening test for hyperthyroidism, as its levels are decreased even at the earliest stages, when the disease may still be subclinical.

150-Hypothyroidism
Hypothyroidism is caused by any structural or functional derangement that interferes with the production of adequate levels of thyroid hormone. It can result from a defect anywhere in the hypothalamic-pituitary-thyroid axis. As in the case of hyperthyroidism, this disorder is divided into primary and secondary categories, depending on whether the hypothyroidism arises from an intrinsic abnormality in the thyroid or occurs as a result of pituitary disease; rarely, hypothalamic failure is a cause of tertiary hypothyroidism. Primary hypothyroidism accounts for the vast majority of cases of hypothyroidism. Primary hypothyroidism can be thyroprivic (due to absence or loss of thyroid parenchyma) or goitrous (due to enlargement of the thyroid gland under the influence of TSH). The causes of primary hypothyroidism include the following. Surgical or radiation-induced ablation of thyroid parenchyma can cause hypothyroidism. A large resection of the gland (total thyroidectomy) for the treatment of hyperthyroidism of a primary neoplasm can lead to hypothyroidism. The gland may also be ablated by radiation, whether in the form of radioiodine administered for the treatment of hyperthyroidism, or exogenous irradiation, such as external radiation therapy to the neck. Autoimmune hypothyroidism is the most common cause of goitrous hypothyroidism in iodinesufficient areas of the world. The vast majority of cases of autoimmune hypothyroidism are due to Hashimoto thyroiditis. Circulating autoantibodies, including antiTSH receptor autoantibodies, are commonly found in Hashimoto thyroiditis.

Causes Of Hypothyroidism Primary: 194

Developmental (thyroid dysgenesis : PAX-8,TTF-2,TSH-receptor Mutations) Thyroid hormone resistance syndrome (TRb Mutations) Postablative Surgery,radioiodine therapy, or external radiation Autoimmune hypothyroidism Hashimoto thyroiditis* Iodine deficiency* Drugs(lithium,iodidesip-aminosaliycylic acid)* Congenital biosynthetic defect (dyshormonogenetic goiter) Secondary: Pituitary failure Tertiary Hypothalamic failure(rare) Associated with enlargement of thyroid ("goitrous hypothyroidism").Hashimoto thyroiditis and postablative hypothroidism account for the majority of cases.

151-Goiter
Diffuse and Multinodular Goiters Enlargement of the thyroid, or goiter, is the most common manifestation of thyroid disease. Diffuse and multinodular goiters reflect impaired synthesis of thyroid hormone, most often caused by dietary iodine deficiency. Impairment of thyroid hormone synthesis leads to a compensatory rise in the serum TSH level, which, in turn, causes hypertrophy and hyperplasia of thyroid follicular cells and, ultimately, gross enlargement of the thyroid gland. The compensatory increase in functional mass of the gland is able to overcome the hormone deficiency, ensuring an euthyroid metabolic state in the vast majority of individuals. If the underlying disorder is sufficiently severe (e.g., a congenital biosynthetic defect or endemic iodine deficiency, see below), the compensatory responses may be inadequate to overcome the impairment in hormone synthesis, resulting in goitrous hypothyroidism. The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency. DIFFUSE NONTOXIC (SIMPLE) GOITER Diffuse nontoxic (simple) goiter specifies a form of goiter that diffusely involves the entire gland without producing nodularity. Because the enlarged follicles are filled with colloid, the term colloid goiter has been applied to this condition.This disorder occurs in both an endemic and a sporadic distribution. Endemic goiter occurs in geographic areas where the soil, water, and food supply contain only low levels of iodine. The term endemic is used when goiters are present in more than10% of the population in a given region. Variations in the prevalence of endemic goiter in regions with similar levels of iodine deficiency point to the existence of other causative influences, particularly dietary substances,eferred to as goitrogens. Sporadic goiter occurs less frequently than does endemic goiter. There is a striking female preponderance and a peak incidence at puberty or in young adult life. Sporadic goiter can be caused by a number of conditions, including the ingestion of substances that interfere with thyroid hormone synthesis.

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Clinical Course. The vast majority of patients with simple goiters are clinically euthyroid. Therefore, the clinical manifestations are primarily related to mass effects from the enlarged thyroid gland. MULTINODULAR GOITER With time, recurrent episodes of hyperplasia and involution combine to produce a more irregular enlargement of the thyroid, termed multinodular goiter. Virtually all longstanding simple goiters convert into multinodular goiters. They may be nontoxic or may induce thyrotoxicosis (toxic multinodular goiter). Multinodular goiters produce the most extreme thyroid enlargements and are more frequently mistaken for neoplastic involvement than any other form of thyroid disease. Because they derive from simple goiter, they occur in both sporadic and endemic forms, having the same female-tomale distribution and presumably the sane origins but affecting older individuals because they are late complications.

152- ADRENOCORTICAL HYPERFUNCTION (HYPERADRENALISM) - Cushing Syndrome

Just as there are three basic types of corticosteroids elaborated by the adrenal cortex (glucocorticoids, mineralocorticoids, and sex steroids), so there are three distinctive hyperadrenal clinical syndromes: (1) Cushing syndrome, characterized by an excess of cortisol; (2) hyperaldosteronism; and (3) adrenogenital or virilizing syndromes caused by an excess of androgens. The clinical features of these syndromes overlapsomewhat because of the overlapping functions of some of the adrenal steroids. Hypercortisolism (Cushing Syndrome) Pathogenesis. This disorder is caused by any condition that produces an elevation in glucocorticoid levels."' There are four possible sources of excess cortisol .In clinical practice, most causes of Cushing syndrome are the result of the administration of exogenous glucocorticoids. The other three sources of the hypercortisolism call be categorized as endogenous Cushing syndrome: Primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH Hypersecretion of cortisol by an adrenal adenoma, carcinoma, or nodular hyperplasia The secretion of ectopic ACTH by a nonendocrine neoplasm Primary hypersecretion of ACTH accounts for 70% to 80% of cases of endogenous hypercortisolism. In recognition of the neurosurgeon who first published the full description of this syndrome and related it to a pituitary lesion,"' this pituitary form of Cushing syndrome is referred to as Cushing disease. The disorder affects women about five times more frequently than men, and it occurs most frequently during the twenties and thirties. In the vast majority of cases, the pituitary gland contains an ACTH-producing microadenoma that does not produce mass effects in the brain; some corticotroph tumors qualify as macroadenomas (>10 mm). In most of the remaining cases, the anterior pituitary contains areas of corticotroph cell hyperplasia without a discrete adenoma. Corticotroph cell hyperplasia may be primary or may arise secondarily from excessive stimulation of ACTH release by a hypothalamic corticotropin releasing hormone (CRH)-producing tumor. Morphology. The main lesions of Cushing syndrome are found in the pituitary and adrenal glands. The pituitary in Cushing syndrome shows changes regardless of the cause. The most common alteration, resulting from high levels of endogenous or exogenous glucocorticoids, is termed Crooke 196

hyaline change. In this condition, the normal granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary is replaced by homogeneous, lightly basophilic material. This alteration is the result of the accumulation of intermediate keratin filaments in the cytoplasm. The morphology of the adrenal glands depends on the cause of the hypercortisolism. The adrenals have one of the following abnormalities: (1) cortical atrophy; (2) diffuse hyperplasia; (3) nodular hyperplasia; and (4) an adenoma, rarely a carcinoma. Diffuse hyperplasia is found in 60% to 70% of cases of Cushing syndrome. Both glands are enlarged, either subtly or markedly, weighing up to 25 to 40 gm.The adrenal cortex is diffusely thickened and yellow, owing to an increase in the size and number of lipidrich cells in the zonae fasciculata and reticularis. Some degree of nodularity is common but is pronounced in nodular hyperplasia. Primary adrenocortical neoplasms causing Cushing syndrome may be malignant orbenign. Adenomas or carcinomas of the adrenal cortex as the source of cortisol secretion are not macroscopically distinctive from nonfunctioning adrenal neoplasms to be described later.

153-Adrenocortical Insufficiancy.Addison's Diseases.

ADRENAL INSUFFICIENCY Adrenocortical insufficiency, or hypofunction, may be caused by either primary adrenal disease (primary hypoadrenalism) or decreased stimulation of the adrenals owing to a deficiency of ACTH (secondary hypoadrenalism). The patterns of adrenocortical insufficiency can be considered under the following headings: (1) primary acute adrenocortical insufficiency (adrenal crisis), (2) primary chronic adrenocortical insufficiency (Addison disease), and (3) secondary adrenocortical insufficiency. Primary Acute Adrenocortical Insufficiency Acute adrenal cortical insufficiency occurs in a variety of clinical settings: As a crisis in patients with chronic adrenocortical insufficiency precipitated by any form of stress that requires an immediate increase in steroid output from glands incapable of responding In patients maintained on exogenous corticosteroids, in whom rapid withdrawal of steroids or failure to increase steroid doses in response to an acute stress may precipitate an adrenal crisis, owing to the inability of the atrophic adrenals to produce glucocorticoid hormones As a result of massive adrenal hemorrhage, which destroys the adrenal cortex sufficiently to cause acute adrenocortical insufficiency. This occurs in newborns following prolonged and difficult delivery with considerable trauma and hypoxia, leading to extensive adrenal hemorrhages beginning in the medulla and extending into the cortex. Secondary Insufficiency Hypothalamic pituitary disease Neoplasm, inflammation (sarcoidosis, tuberculosis, pyogens, fungi) Hypothalamic pituitary suppression Long-term steroid administration Steroid-producing neoplasms

Primary Chronic Adrenocortical Insufficiency (Addison Disease) In a paper published in 1855, Thomas Addison described a group of patients suffering from a constellation of symptoms, including "general languor and debility, remarkable feebleness of the heart 's action, and a peculiar change in the color of the skin" associated with disease of the 197

"suprarenal capsules" or,in more current terminology, the adrenal glands. Addison disease, or chronic adrenocortical insufficiency, is an uncommon disorder resulting from progressive destruction of the adrenal cortex. Pathogenesis. A large number of diseases may attack the adrenal cortex, including lymphomas, amyloidosis, sarcoidosis, hemochromatosis, fungal infections, and adrenal hemorrhage, but more than 90% of all cases are attributable to one of four disorders: autoimmune adrenalitis, tuberculosis, the acquired immune deficiency syndrome (AIDS), or metastatic cancers. Autoinmrune polyendocrine syndrome type 1 (APSI) is also known as autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED). Autoimmune polyendocrine syndrome type 2 (APS2) usually starts in early adulthood and presents as a combination of adrenal insufficiency with autoimmune thyroiditis or type I diabetes. Isolated autoimmune A ddison disease presents with autoimmune destruction restricted to the adrenal glands.However, in terms of age at presentation and linkage to HLA and other susceptibility loci, isolated autoimmune adrenalitis overlaps with APS2, suggesting that the former may be a variant of the latter. Infections, particularly tuberculosis and those produced by fungi, may also cause primary chronic adrenocortical insufficiency.Tuberculous adrenalitis, which once accounted for as much as 90% of Addison disease, has become less common with the development of antituberculous agents.Histoplasma capsulatum and Coccidioides immitis may also result in chronic adrenocortical insufficiency. Patients with AIDS are at risk for developing adrenal insufficiency from several infectious (cytomegalovirus, Mycobacterium aviuinintercellulare)and noninfectious complications (Kaposi sarcoma).Metastatic neoplasms involving the adrenals are another potential cause of adrenal insufficiency. Genetic disorders of adrenal insufficiency include adrenal hypoplasia congenital (AHC) and adrenoleukodystrophy. Morphology. The anatomic changes in the adrenal glands depend on the underlying disease. Primary autoimmune adrenalitis is characterized by irregularly shrunken glands, which may be difficult to identify within the suprarenal adipose tissue. Clinical Course. Addison disease begins insidiously and does not come to attention until at least 90% of the cortex of both glands is destroyed and the levels of circulating glucocorticoids and mineralocorticoids are significantly decreased.The initial manifestations include progressive weakness and easy fatigability, which may be dismissed as nonspecific complaints. Gastrointestinal disturbances are common and include anorexia, nausea, vomiting, weight loss, and diarrhea. Secondary Adrenocortical Insufficiency Any disorder of the hypothalamus and pituitary, such as metastatic cancer, infection, infarction, or irradiation, that reduces the output of ACTH leads to a syndrome of hypoadrenalism that has many similarities to Addison disease. Analogously, prolonged administration of exogenous glucocorticoids suppresses the output of ACTH and adrenal function. With secondary disease, the hyperpigmentation of primary Addison disease is lacking because melanotropic hormone levels are low.ACTH deficiency can occur alone, but in some instances, it is only one part of panhypopituitarism, associated with multiple primary trophic hormone deficiencies. The differentiation of secondary disease from Addison disease can be confirmed with demonstration of low levels of plasma ACTH in the former. Morphology. In cases of hypoadrenalism secondary to hypothalamic or pituitary disease (secondary 198

hypoadrenalism), depending on the extent of ACTH lack, the adrenals may be moderately to markedly reduced in size. They are reduced to small, flattened structures that usually retain their yellow color owing to a small amount of residual lipid. The cortex may be reduced to a thin ribbon composed largely of zona glomerulosa. The medulla is unaffected.

154-Hyperaldosteronism.Conn's Syndrome
Hyperaldosteronism is the generic term for a small group of closely related, uncommon syndromes, all characterized by chronic excess aldosterone secretion. Excessive levels of aldosterone cause sodium retention and potassium excretion, with resultant hypertension and hypokalemia. Hyperaldosteronism may be primary, or it may be a secondary event resulting from an extra-adrenal cause. Primary hyperaldosteronism indicates an autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity. Primary hyperaldosteronism is caused by one of three mechanisms; Adrenocortical neoplasm, either an aldosteroneproducing adrenocortical adenoma (the most common cause) or, rarely, an adrenocortical carcinoma. In approximately 80% of cases, primary hyperaldosteronism is caused by a solitary aldosterone-secreting adenoma, a condition referred to as Corm syndrome. This syndrome occurs most frequently in adult middle life and is more common in women than in men (2:1). Multiple adenomas may be present in an occasional patient. Primary adrenocortical hyperplasia (idiopathic hyperaldosteronism), characterized by bilateral nodular hyperplasia of the adrenal glands, highly reminiscent of those found in the nodular hyperplasia of Cushing syndrome. The genetic basis of idiopathic hyperaldosteronism is not clear, although it is possibly caused by an overactivity of the aldosterone synthase gene, CY P11 NI Glucocorticoid-remediable hyperaldosteronism is an uncommon cause of primary hyperaldosteronism that is familial and genetic. In some families, it is caused by a chimeric gene resulting from fusion between CY P11BI (the 11B-hydroxylase gene) and CY P11 B2 (the aldosterone synthase gene)."_ This leads to a sustained production of hybrid steroids in addition to both cortisol and aldosterone. The activation of aldosterone secretion is under the influence of ACTH and hence is suppressible by exogenous administration of dexamethasone. In secondary hyperaldosteronism, in contrast, aldosterone release occurs in response to activation of the reninangiotensin system. It is characterized by increased levels of plasma renin and is encountered in conditions such as the following: Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis) Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome) Pregnancy (due to estrogen-induced increases in plasma renin substrate). Morphology. Aldosterone-producing adenomas are almost always solitary, small (<2 cm in diameter), well-circumscribed lesions, more often found on the left than on the right. They tend to occur in the thirties and forties, and in women more often than in men.These lesions are often buried within the gland and do not produce visible enlargement, a point to be remembered in interpreting sonographic or scanning images. Conn's syndrome is an aldosterone-producing adenoma. Primary hyperaldosteronism has many causes, including adrenal hyperplasia and adrenal carcinoma. The syndrome is due to: 199

bilateral idiopathic adrenal hyperplasia 70 % unilateral idiopathic adrenal hyperplasia 20 % aldosterone-secreting adrenal adenoma (benign tumor, < 5%) rare forms, including disorders of the renin-angiotensin system Pathogenesis.Aldosterone enhances exchange of sodium for potassium in the kidney, so increased aldosteronism will lead to hypernatremia (elevated sodium level) and low blood potassium known as hypokalemia. Once the potassium has been significantly reduced by aldosterone, a sodium/hydrogen pump in the nephron becomes more active, leading to increased excretion of hydrogen ions and further exacerbating the elevated sodium level resulting in a further increase in hypernatremia. The hydrogen ions exchanged for sodium are generated by carbonic anhydrase in the renal tubule epithelium, causing increased production of bicarbonate. The increased bicarbonate and the excreted hydrogen combine to generate a metabolic alkalosis.The high pH of the blood makes calcium less available to the tissues and causes symptoms of hypocalcemia.

155-Disorders of adrenal androgen production

Adrenogenital Syndromes Disorders of sexual differentiation, such as virilization or feminization, can be caused by primary gonadal disorders and several primary adrenal disorders. The adrenal cortex secretes two compoundsdehydroepiandrosterone and androstenedionethat require conversion to testosterone in peripheral tissues for their androgenic effects. Unlike gonadal androgens, ACTH regulates adrenal androgen formation; thus, excess secretion can occur either as a "pure" syndrome or as a component of Cushing disease. The adrenal causes of androgen excess include adrenocortical neoplasms and a group of disorders that have been designated congenital adrenal hyperplasia. Adrenocortical neoplasms associated with virilization are more likely to be androgen-secreting adrenal carcinomas than adenomas. Conversely, functioning adrenal cortical carcinomas are most often associated with a virilization syndrome, usually in combination with hypercortisolism ("mixed syndrome").These tumors are morphologically identical to other cortical neoplasms and will be discussed later. Congenital adrenal hyperplasia ( CAH) represents a group of autosomal-recessive, inherited metabolic errors, each characterized by a deficiency or total lack of a particular enzyme involved in the biosynthesis of cortical steroids, particularly cortisol."" Steroidogenesis is then channeled into other pathways, leading to increased production of androgens, which accounts for virilization. 21-Hydroxylase Deficiency. Defective conversion of progesterone to 1 1 -deoxycorticosterone by 21hydroxylase ( CY P2IB) accounts for over 90% of cases of congenital adrenal hyperplasia.'' Figure 24 48 illustrates normal adrenal steroidogenesis and the consequences of 21-hydroxylase deficiency. 21-Hydroxylase deficiency may range from a total lack to a mild loss, depending on the nature of the CY P21 B mutation. Three distinctive syndromes have been described:(1) salt-wasting (classic) adrenogenitalism, (2) simple virilizing adrenogenitalism, and (3) nonclassic adrenogenitalism, which implies mild disease that may be entirely asymptomatic or associated only with symptoms of androgen excess during childhood or puberty. The salt-wasting syndrome results from an inability to convert progesterone into 200

deoxycorticosterone because of a total lack of the hydroxylase. Thus, there is virtually no synthesis of mineralocorticoids, and concomitantly, there is a block in the conversion of hydroxyprogesterone into deoxycortisol with deficient cortisol synthesis. There is salt wasting, hyponatremia, and hyperkalemia, which induce acidosis, hypotension, cardiovascular collapse, and possibly death. Simple virilizing adrenogenital syndrome without salt wasting (presenting as genital ambiguity) may occur in individuals with a less than total 21-hydroxylase defect because with less severe deficiencies the level of mineralocorticoid, although reduced, is sufficient for salt reabsorption, but the lowered glucocorticoid level fails to cause feedback inhibition of ACTH secretion. Nonclassic or late-onset adrenal virilism is much more common than the classic patterns already described. Patients with this syndrome may be virtually asymptomatic or have mild manifestations, such as hirsutism. Morphology. In all cases of CAH, the adrenals are bilaterally hyperplastic, sometimes expanding to 10 to15 times their normal weights because of the sustained elevation in ACTH. The adrenal cortex is thickened and nodular, and on cut section, the widened cortex appears brown, owing to total depletion of all lipid.

156-DISORDERS OF THE FEMALE REPRODUCTIVE SYSTEM.MENSTRUAL DISORDERS.

Endometriosis - a condition involving colonization of the abdominal/pelvic cavity with islands of endometrial tissue. Endometrium is the lining layer of the uterus which sloughs off with each menstruation. If endometrial tissue flushes up the uterine tube and spills into the abdomen (peritoneal cavity), the clots of endometrial tissue can attach to abdominal organs such as the bladder, rectum, intestinal loops and then cycle along with the uterus in response to monthly changes in ovarian hormones. Bleeding into the abdomen irritates the lining membrane, the peritoneum, and causes abdominal pain. Pelvic inflammatory disease (PID) although males have a closed abdominal cavity, the female abdominal cavity has a direct anatomical path from the outside world via the female reproductive tract. Bacteria can make their way up the vagina, through the uterus, and traverse the uterine tubes which open into the abdominal cavity. Inflammation of the lining of the abdominal cavity, the peritoneum, causes abdominal pain. Although there are many potential causes of PID, gonorrheal infection is one of them. Chronic Inflammation of the uterine tubes can occlude them resulting in infertility. Prolapsed uterus the uterus is almost directly above the vagina. In fact, the cervix, the neck region, of the uterus extends into the upper vagina. Ligaments hold the uterus in proper position so that it does not prolapse or herniate into the vagina. Severe prolapse can result in the uterine cervix protruding from the vaginal opening. Surgical repair is typically required to restore the uterus to its proper anatomical position.

Hormonal changes in the normal menstrual cycle In the ovulatory cycle, the hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the pituitary to release follicle-stimulating hormone (FSH). This, in turn, causes an ovarian

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follicle to grow and mature. In mid cycle, a surge of luteinizing hormone (LH) occurs with an FSH surge, resulting in ovulation. The developing follicle produces estrogen, which stimulates the endometrium to proliferate. After the ovum is released, FSH and LH levels fall, corpus luteum develops at the site of the ruptured follicle, and progesterone is secreted from the ovary. Progesterone causes the proliferating endometrium to differentiate and stabilize. Fourteen days after ovulation, menstruation results from endometrial shedding secondary to the rapid decline in the levels of estrogen and progesterone from the involuting corpus luteum. Hormonal changes during anovulatory cycles Anovulatory cycles are common in the first 2 years after menarche because of the immaturity of the HPO axis. They can also occur in various pathological conditions.In anovulatory cycles, the follicular growth occurs with the stimulation from FSH; however, due to lack of LH surge, ovulation fails to occur. Consequently, no corpus luteum is formed and no progesterone is secreted. The endometrium continues its proliferative phase excessively.

157-DISORDERS OF THE FEMALE REPRODUCTIVE SYSTEM.Infertilty

Ovulatory dysfunction Hypo-gonadotrophic anovulation occurs as a result of hypothalamic or pituitary abnormalities. Hyper-gonadotrophic anovulation occurs as a result of ovarian failure.Polycystic ovarian syndrome is the most common cause of eugonadotrophic anovulation. Tubal disease Most often caused by gonorrhoea and chlamydia infection. Chlamydia trachomatis is obligate intracellular parasite that invades the cervix, uterus, and fallopian tubes. This organism is the leading cause for acute salpingitis worldwide. The manifestation of this disease is varied, ranging from sub-clinical to an acute tubo-ovarian abscess that can include peritonitis and peri-hepatitis. [19] High anti-chlamydial antibody titres highly correlate to abnormal tubal pathology. The risk of tubal occlusion has been approximated as 10% for an initial episode of salpingitis, and then doubled with every subsequent infection. Any pelvic infection, including appendicitis and diverticulitis, can damage the fallopian tubes. Endometriosis Endometriosis can cause intra-abdominal inflammation and scar tissue. This growth of hormonally responsive endometrial tissue outside the uterus may cause anatomical obstruction of the fallopian tubes. It may also lead to infertility by producing cytokines that may be toxic to sperm or embryos. Age-related Age-related decreases in fecundity are caused by declining oocyte numbers and poorer oocyte quality. Oogenesis begins in utero. By month 7 of gestation, mitosis completes and the peak number of oocytes (approximately 7 million) is achieved. Hormone-independent apoptosis begins at this time and continues until menopause, regardless of factors such as contraceptive use and pregnancy. Although the number of oocytes remaining in the ovary (ovarian reserve) impact on pregnancy rates, age also leads to a higher rate of oocyte aneuploidy due to decreased chromosomal crossover, [23] meiotic spindle fragility, [24] and telomeric shortening. This leads to a high likelihood of implantation failure, miscarriage, and chromosomally abnormal offspring (e.g., trisomy 21).

Unexplained Unexplained infertility or subfertility is defined as the failure to conceive after 2 years of regular unprotected sexual intercourse in the face of normal investigations (namely normal ovulation, normal

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semen analysis, patent fallopian tubes). As couples go through the diagnostic and treatment pathways, an increasing number will acquire some form of diagnosis so that the proportion of couples with so-called unexplained subfertility will decline.The label of unexplained subfertility recognises that there are numerous candidate sites for abnormalities causing reduced fertility that cannot be recognised by standard diagnostic tests, but that, ultimately, treatment may improve the chance of a pregnancy. Uterine abnormalities Uterine abnormalities can be congenital or acquired. Failure of Mllerian duct fusion results in uterine malformations including uterine didelphys, bi-cornuate or uni-cornuate uterus, and uterine septum. [27] Submucosal or large intramural leiomyomata may have an impact on implantation or cause tubal obstruction. Endometritis, particularly when associated with a dilation and curettage procedure, can destroy the endometrial lining and cause Asherman's syndrome (intrauterine adhesions). Cervical abnormalities Cervical mucus is critical to facilitate sperm entry into the uterus and to initiate sperm capacitation, the final step in sperm maturation. During the peri-ovulatory period the mucus becomes abundant, thin, and stretchable. Cervical maladies such as surgery or infection can disrupt the cervical glands and/or mucus production.

158- DISORDERS OF THE MALE REPRODUCTIVE SYSTEM.MALE INFERTILITY.

Hypospadias - literally below the fleshy spike. A condition in which the external urinary meatus (opening) opens anywhere below the tip of the penis rather than at the tip. Hydrocele - a fluid filled sac partially surrounding the testis. Manifests itself as a swelling on the side of the scrotum. May cause discomfort. Can be surgically corrected. And, who would most likely be doing the surgery? A urologist! Varicocele - dilated and twisted veins of the testis, sort of hemorrhoids of the scrotum! Manifests itself as a swelling on the side of the scrotum which may look and feel like a bag of worms. May be surgically corrected if causing discomfort. This condition may also cause reduced sperm count and male sterility due to sluggish blood flow elevating testicular temperature. Cryptorchidism - literally hidden testicle. A condition of lack of descent of one or both testes into the scrotum. If not corrected, usually by surgery, before puberty, can lead to sterility and increased risk of testicular cancer. Benign prostatic hypertrophy (BPH) - swelling of the prostate gland which surrounds the base of the male bladder and urethra causing difficulty urinating, dribbling, and nocturia (remember that word? See urinary system). The bane of old men! BPH becomes more common as men age. Transurethral resection of the prostate (TURP) - the surgical cure for BPH. An instrument inserted through the penile urethra is used to partially cut away the prostate to relieve obstruction of the urinary tract. Prostate Specific Antigen (PSA) PSA is a marker protein for prostate cell secretions which can be detected with a lab test. A rising PSA may be an early sign of prostate cancer, although there may be other causes including false positive tests. How often should men get a PSA test? Check in with The Prostate Cancer Foundation. Male fertility requires normal sperm production and sperm transport, and adequate sexual performance.These functions require normal levels of testosterone. Testosterone is produced by the 203

testicular Leydig cells under the influence of LH. Spermatogenesis is controlled directly by testosterone and FSH. FSH is believed to act on the Sertoli cells, which support spermatogenesis in the seminiferous tubules. The pituitary production of FSH and LH is controlled by the hypothalamic gonadotrophin releasing hormone (GnRH). GnRH and FSH production by the hypothalamus and pituitary is negatively controlled directly by testosterone levels and through its aromatisation to oestradiol at the central or peripheral levels. Inhibin is produced by Sertoli cells and has a negative effect on FSH secretion. Circulating testosterone is bound mainly to the sex hormone-binding globulin (SHBG) and albumin. Levels of SHBG affect the active portion of circulating testosterone or free testosterone. Hyperprolactinaemia has a negative affect on GnRH secretion.The presence of an intact Y and 1 copy of the X chromosome is essential for the differentiation of the embryonic gonads into testicles and for the later development of adequate spermatogenesis. Normal fertilisation of the oocyte requires many motile sperm with intact acrosomal reaction.Sperm production is negatively affected by endocrine effects of obesity, increased local testicular heat, and exposure to environmental toxins or endocrine disruptors. Smoking and alcohol also have a toxic effect on sperm production. A variety of medications can alter testosterone production or have an antitestosterone effect at the receptor level. Other medications or environmental exposures can directly alter spermatogenesis or sperm motility.

159- DISORDERS OF THE MALE REPRODUCTIVE SYSTEM.BENIGN PROSTATIC HYPERPLASIA.

Hypospadias - literally below the fleshy spike. A condition in which the external urinary meatus (opening) opens anywhere below the tip of the penis rather than at the tip. Hydrocele - a fluid filled sac partially surrounding the testis. Manifests itself as a swelling on the side of the scrotum. May cause discomfort. Can be surgically corrected. And, who would most likely be doing the surgery? A urologist! Varicocele - dilated and twisted veins of the testis, sort of hemorrhoids of the scrotum! Manifests itself as a swelling on the side of the scrotum which may look and feel like a bag of worms. May be surgically corrected if causing discomfort. This condition may also cause reduced sperm count and male sterility due to sluggish blood flow elevating testicular temperature. Cryptorchidism - literally hidden testicle. A condition of lack of descent of one or both testes into the scrotum. If not corrected, usually by surgery, before puberty, can lead to sterility and increased risk of testicular cancer. Benign prostatic hypertrophy (BPH) - swelling of the prostate gland which surrounds the base of the male bladder and urethra causing difficulty urinating, dribbling, and nocturia (remember that word? See urinary system). The bane of old men! BPH becomes more common as men age. Transurethral resection of the prostate (TURP) - the surgical cure for BPH. An instrument inserted through the penile urethra is used to partially cut away the prostate to relieve obstruction of the urinary tract. Benignprostatic hyperplasia is another common example of pathologic hyperplasia induced by responses to hormones, in this case, androgens. Although these forms of hyperplasia are abnormal, the process remains controlled, because the hyperplasia regresses if the hormonal stimulation is eliminated. As is discussed in Chapter 7, it is this response to normal regulatory control mechanisms 204

that distinguishes benign pathologic hyperplasias from cancer, in which the growth control mechanisms become defective. Pathologic hyperplasia, however, constitutes a fertile soil in which cancerous proliferation may eventually arise. Thus, patients with hyperplasia of the endometrium are at increased risk for developing endometrial cancer (Chapter 22). Hyperplasia is also an important response of connective tissue cells in wound healing, in which proliferating fibroblasts and blood vessels aid in repair (Chapter 3). Under these circumstances, growth factors are responsible for the hyperplasia. Stimulation by growth factors is also involved in the hyperplasia that is associated with certain viral infections, such as papillomaviruses, which cause skin warts and a number of mucosal lesions composed of masses of hyperplastic epithelium.

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