Chapter One Introduction to Pathology

DEFINITION OF PATHOLOGY

Definition of pathology
Pathology is to study diseases by scientific methods. Disease may be defined as an abnormal alteration of structure or function in any part of the body.

Pathology focuses on 4 aspects of disease

ETIOLOGY: Cause of disease. PATHOGENESIS: Mechanisms of development of disease. MORPHOLOGY: The structural alterations induced in cell and tissues. FUNCTIONAL CONSEQUENCES: Functional consequences of the morphologic changes, as observed clinically. Knowledge of etiology remains the backbone: Disease diagnoses Understanding the nature of diseases Treatment of diseases.

While much still needs to be uncovered to link abnormal genes and the expression of disease, gone are the time when the mechanisms of most diseases were unknown? or obscure? or mysterious?

One etiologic agentone disease. Several etiologic agentsone disease. One etiologic agentseveral diseases.

Causes of cell injury and disease

Oxygen deprivation ( hypoxia, ischemia) Nutritional imbalances Physical agents Chemical agents and drugs Infectious agents Immunologic reactions Genetic derangements

HYPOXIA
Ischemia ( loss of blood supply ). Inadequate oxygenation ( cardiorespiratory failure ). Loss of oxygen-carrying capacity of the blood ( anemia or CO poisoning ).

HYPOXIC INJURY
Loss of oxidative phosphorylation and ATP generation by mitochondria. Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation, resulting in aerobic glycolysis. Depleted glycogen. Reduced intracellular pH: Lactic acid and inorganic phosphate. Clumping of nuclear chromatin.

Four biochemical themes

Oxygen-derived free radicals. Loss of calcium homeostasis and increased intracellular calcium. ATP depletion. Defects in membrane permeability.

PHYSICAL AGENTS
Trauma Heat Cold Radiation Electric shock

CHEMICAL AGENTS AND DRUGS Endogenous products: urea Exogenous agents: Therapeutic drugs: hormones Nontherapeutic agents: lead or alcohol

MECHANISMS OF CHEMICAL INJURY

Directly: Mercury of mercuric chloride binds to SH groups of cell membrane proteins, causing increased permeability and inhibition of ATPase-dependent transport.

MECHANISMS OF CHEMICAL INJURY

By conversion to reactive toxic metabolites which in turn cause cell injury either by direct covalent binding to membrane protein and lipid, or more commonly by the formation of free radicals.

CCl4 in SER of liver cell (P-450) CCl3. lipid peroxidation and autocatalytic reactions swelling and breakdown of ER, dissociation of ribosome, and decreased hepatic protein synthesis ( loss of lipid acceptor protein fatty change of liver cell) progressive cellular swelling, plasma membrane damage, and cell death.

FREE RADICAL INITIATION

Absorption of energy (UV light and x-rays) Oxidative metabolic reactions Enzymatic conversion of exogenous chemicals or drugs (CCl4>CCl3.) Oxygen-derived radicals Superoxide

Cell injury caused by free radicals through Peroxidation of lipids. Cross linking proteins by the formation of disulfide bonds. Induction of DNA damage that has been implicated both in cell killing and malignant transformation.

INFECTIOUS AGENTS
Viruses Rickettsiae Bacteria Fungi Parasites

Marfan syndrome Fibrillin, a scaffolding on which tropoelastin is deposited to form elastic fibers. FBN1, 15q21, mutations in Marfan syndrome. FBN2, 5q3, mutations in congenital contractual arachnodactyly.

Adenomatous polyposis coli APC loci, 5q21 Adenomatous polyposis in colons (in teens). 100% malignant transformation ( 40ys ). APC protein in the cytoplasm. Several partners, including -catenin. -catenin entering the nucleusactivating transcription of growth-promoting genes. Causing degradation of -cateninmaintaining low level of -catenin in the cytoplasm.

CELLS REACT TO ADVERSE INFLUENCES

ADAPTING SUSTAINING REVERSIBLE INJURY SUFFERING IRREVERSIBLE INJURY AND DYING

CELL INJURY AND NECROSIS

General mechanisms: Maintenance of the integrity of cell membranes. Aerobic respiration and production of ATP. Synthesis of enzymes and structure proteins. Preservation of the integrity of the genetic apparatus.

The core of the science of pathology the study the pathogenesis of the disease.

Pathogenesis
The sequence events in the response of the cells or tissues to the etiologic agent, from the initial stimulus to the ultimate expression of the disease.

Pathogenesis
Immunologic, cytogenetic and molecular analyses of tissues and cells are increasingly becoming guides to render diagnoses, to assess prognosis, and to suggest therapy.

MORPHOLOGY
Morphology remains at the heart of diagnostic pathology. Morphologic change
Characteristic of the disease Diagnostic of the etiologic proceess

Functional derangements Clinical significance

Development of Pathology
Organ pathology Cell pathology Molecular pathology