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Cell Injury 1

Terms
- Hypoxia – inadequate oxygenation of tissue (same definition as shock).
o Oxygen is needed for the oxidative phosphorylation pathway.
 Oxidative Phosphorylation Pathway
• It’s where we get ATP from; it’s specifically in the inner mitochondrial membrane.
• The last reaction is oxygen (to receive the electrons). Protons are kicked out the electron
transport system and they end up going back into the membrane forming ATP.
- Oxygen content
o Hemoglobin (Hb) x oxygen saturation (the oxygen attached to the heme group) + partial pressure of
arterial oxygen (PaO2) (the amount of oxygen dissolved in plasma)
o Oxygen saturation
 There’s 4 heme groups on hemoglobin and iron has to be +2.
 If all 4 heme groups on hemoglobin are occupied by oxygen in everyone of the RBCs, the
oxygen saturation is 100%.
 This is measured with a pulse oximeter.
o Partial Pressure
 The amount of oxygen dissolved in plasma.
 Flow of oxygen
• The oxygen flows from the alveoli to the interface.
• It dissolves in the plasma and increases the partial pressure of oxygen.
• It then diffuses through the RBC membrane and attaches to the heme group on the RBC
(oxygen saturation).
 If the partial pressure of oxygen is decreased, the oxygen saturation also has to be decreased.

Tissue Hypoxia
- Ischemia
o The most common cause of tissue hypoxia.
o It is a decrease in arterial blood flow.
o The most common cause of ischemia is a thrombus in a muscular artery. It’s also the most common
cause of death in the U.S. (myocardial infarction).
o A decrease in cardiac output (hypovolemia, cardiogenic shock, …) could also cause ischemia b/c you
have a decrease in arterial blood flow.
- Hypoxemia
o The second most common cause of tissue hypoxia.
o It’s not the same as hypoxia (the big term). Hypoxemia is a cause of hypoxia. Hypoxemia deals with
the partial pressure of arterial oxygen (the oxygen dissolved in plasma); hypoxemia is when the
partial pressure of oxygen is decreased.
o Respiratory Acidosis
 Dalton’s law = the sum of the partial pressures must equal 760 mmHg at atmospheric pressure.
 When you retain CO2, that’s respiratory acidosis. What has to happen to the PO2 when the CO2
goes up is it has to go down (b/c you still have to maintain 760).
 Everytime you have respiratory acidosis from any cause, you have hypoxemia (low PO2).
• If CO2 goes down (respiratory alkalosis), PO2 goes up.
 You have normal hemoglobin, oxygen saturation is decreased, and PO2 is decreased. Oxygen
saturation is decreased b/c PO2 is decreased.
o Ventilation Defect
 Best example is respiratory distress syndrome (aka hyaline membrane disease); the adult
counterpart is called adult respiratory distress syndrome.
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 You have lost ventilation to the alveoli, but you still have perfusion (you’ve created an
intrapulmonary shunt).
 Scenario
• Patient has hypoxemia. They gave him 100% oxygen for 20 minutes. The PO2
didn’t increase. What does it mean?
• It means you have a shunt (intrapulmonary shunt).
• This is how you tell whether you have a shunt or not.
o Perfusion Defect
 This means you knock off blood flow.
 The most common perfusion defect is pulmonary embolus.
 We have ventilation, but no perfusion. This causes an increase in dead space.
 If you give 100% oxygen to someone with a perfusion defect, you will get the PO2 up; b/c
every vessel in the lung is not perfused so other areas of the lung can make up for the difference.
o Diffusion Defect
 You have something in the interface that oxygen can’t get through. An example is fibrosis; the
best example is sarcoidosis. Another example is pulmonary edema or fluid from heart failure.
 In heart failure you activate the J reflex. It’s integrated by the tenth nerve. Fluid or anything
innervates the J receptor, then you get dyspnea.
- Hemoglobin related problems can cause hypoxia.
o Anemia
 Anemia would obviously be a cause.
 In anemia, there is not a decrease in PO2. You don’t have hypoxemia when you have
anemia.
 You have normal gas exchange in a patient with anemia so the PO2 should be normal. The
oxygen saturation should be normal, but the hemoglobin is decreased.
 Because of the tissue hypoxia, they have exercise intolerance.
o Carbon monoxide and methemoglobinemia
 Carbon Monoxide
• Scenario
o A heater in the winter time. You’re in a closed space in a room heater.
o These heaters often have combustible material in them and you can get carbon
monoxide from that.
o Other situations are automobile exhaust and house fires. In a house fire two
things produce tissue hypoxia: carbon monoxide poisoning and cyanide
poisoning (upholsteries made of polyurethane products).
• It’s very diffusible and has a high affinity for hemoglobin. The problem is going to be a
decrease in oxygen saturation.
• Hemoglobin is normal, and so is the PO2 (oxygen in plasma) is normal. The problem is
when it diffuses into the RBC, carbon monoxide is in its place.
• Treatment is 100% oxygen.
• When you have a decrease in oxygen saturation, you have clinical evidence of
cyanosis. However, in carbon monoxide poisoning you don’t see this b/c you have a
cherry red pigment masks it.
• The most common and first symptom of carbon monoxide poisoning is headache.
 Methemoglobin
• It’s iron (+3). If iron is +3 on the heme group, then oxygen can’t bind to it.
• Oxygen saturation is decreased again b/c iron is +3 instead of +2.
• Scenario
o Patient with history of methemoglobinemia. They draw blood and it’s chocolate
colored.
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o It’s chocolate colored b/c there’s no oxygen on the heme groups.

• PO2 is normal and hemoglobin concentration is normal. The oxygen saturation is what’s
decreased.
• RBCs have a methemoglobin reductase (change +3 to +2).
• Scenario
o A person comes out of the rocky mountains and he was cyanotic. They gave
him oxygen and he was still cyanotic.
o He was probably drinking water up there (the water up in the mountains may
have nitrites and nitrates; oxidizing agents). Hemoglobin is oxidized and the
iron becomes +3.
o Oxygen wouldn’t correct the cyanosis b/c.
• Treatment is intravenous methylene blue. An ancillary, but not the primary
treatment is Vitamin C (it’s a reducing agent).
• Scenario
o Dapsone (used in treating leprosy) is a sulfa drug. Sulfa and nitro drugs
produce methemoglobin and have the potential for producing hemolytic
anemia in G6PD deficiency.
o Hemolysis in G6PD deficiency indicates oxidizing agents causing an increase in
peroxide (destroys the RBC). Drugs that can produce this are nitro and sulfa
drugs; they also produce methemoglobin.
o Drug candidates include dapsone, primaquine, trimethoprim-sulfamethoxazole,
nitro…
o These drugs can cause both hemolytic anemia and methemoglobinemia b/c
they’re oxidizing agents.
• Methemoglobinemia is common in HIV b/c they’re on trimethoprim-sulfamethoxazole
for treatment of pneumocystis carinii.
o Shift of curves
 Right-shifts have decreased affinity for oxygen. It will release oxygen to tissues.
• 2,3-BPG, fever, acidosis (low pH), and high altitude shift it this way.
• In high altitude you have respiratory alkalosis and you have to hyperventilate. The
right shift comes from the synthesis of 2,3-BPG.
 Left-shifts
• Carbon monoxide, methemoglobin, HbF, decrease in 2,3-BPG, and alkalosis.
• This is bad b/c it produces tissue hypoxia.
• Carbon monoxide decreases oxygen saturation and also causes a left-shift on oxygen
dissociation.
- Problems related to the oxidative pathway
o Cytochrome oxidase is the last enzyme before it transfers the electron to oxygen (acts as an electron
acceptor).
o 3C’s: cyanide, and carbon monoxide inhibit cytochrome oxidase
o Carbon monoxide now has three ways to produce hypoxia: it increases O2 saturation (can’t carry a
lot of oxygen), left-shifts curve, and inhibits cytochrome oxidase.
- Uncoupling
o Normal “Coupling”
 The mitochondria and the inner mitochondrial membrane have the ability to synthesize ATP.
 The inner mitochondrial membrane is permeable to protons.
 Protons should only go through ATP synthase; protons can’t randomly go into the mitochondrial
matrix (this is what uncoupling agents do).
o Examples of uncoupling agents are: dinitrophenol (a chemical used for preserving wood), alcohol, and
salicylates.
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o Pathogenesis
 Protons end up going through the membrane and little ATP is retrieved from it.
 The reactions that were generating the protons to begin with (reactions making NADH and
FADH) are going to be revved up.
 When you increase the rate of a chemical reaction, the temperature goes up, so you have a risk of
hyperthermia (in salicylate toxicity, one of the complications is hyperthermia).
• If you’re an alcoholic on a hot day, you have a good chance of developing a heat stroke
(you already have uncoupling).

Decrease in ATP (in hypoxia)

- Anaerobic glycolysis
o If you have a decrease in ATP, you have to go to anaerobic glycolysis.
o The end product is lactic acid (pyruvate is converted into lactate b/c of an increase in NADH).
o Anaerobic glycolysis is used when you have hypoxia b/c it can provide energy without involving the
mitochondria.
o Anaerobic glycolysis only provides 2 ATP/glucose; unfortunately you get a build up of lactic acid inside
and outside the cell.
- A buildup of acid (lactic acid) in a cell produces coagulation necrosis.
o An increase in acid in a cell will denature proteins and enzymes (can’t even autodigest itself). This is
called coagulation necrosis. This can occur when you have tissue hypoxia w/in a cell.
o From a gross point of view, coagulation necrosis is termed infarction.
- ATP pump dysfunction
o All ATPase pumps do not function due to the decrease in ATP.
 Sidenote: Digitalis
• Digitalis can block an ATPase pump to allow sodium to go into the cardiac muscle to
open up calcium channels so you can get an increase in force of contraction.
o Since there’s no ATP, sodium can get into the cell and bring water with it (you get cellular swelling); due
to the dysfunction of the sodium potassium pump. Swelling is reversible (get oxygen again and you can
pump it out).
- Calcium influx
o There’s a calcium ATPase pump that pumps calcium out of the cell. If ATP is decreased, calcium can
then enter the cell.
o When calcium is in the cell, it activates numerous enzymes (phospholipases in the membrane – causes
damage to the cell membrane; enzymes in the nucleus – you get nuclear pyknosis and nuclear chromatin
disappears).
o Sidenote: Hypercalcemia produces pancreatitis (the enzymes in the pancreas are activated).
- When the cell membrane is destroyed, you have irreversible damage.
- Cell enzymes can be released:
o CK and CK-MB (in myocardial infarction)
o Transaminases (GOT, AST, ALT)
o Amylase (pancreatitis)

Free Radicals
- A free radical is a compound with an unpaired electron in its outer orbit. This makes it very unstable and it can
damage things.
- Brownish pigment
o Lipofuscin is commonly seen in older people. It requires a history.
o Could be hemosiderin, hemochromatosis, and hemosiderosis. Could also be billirubin.
o When you have free radical damage, one of the end products is lipofuscin. Certain things in the cell
aren’t digestible; this includes lipids (lipofuscin is lipids that you can’t break down all the way).
- Oxygen can produce free radicals
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o Excess oxygen (> 50%) for any period of time can cause them to get superoxide free radicals.
o Reperfusion injury
 This is what’s behind reperfusion injury.
 When you give a tissue plasminogen activator to someone who has a coronary thrombus to try
and dissolve it, most of the time, oxygenated blood goes into the damaged heart muscle and
damages it even further.
o Pulmonary damage
 Kids with respiratory distress can end up with oxygen related free radical injury.
• They can go blind (free radicals and free oxygen can destroy the retina: called
retinopathy of prematurity).
 Free radicals can also produce damage to the lungs (called bronchopulmonary dysplasia) and
you get fibrosis in your lungs.
- Water can produce free radicals
o Water in our tissues can be converted into hydroxyl free radicals. This is what ionizing radiation does
(not UVB light); it occurs in cancer for example.
o These OH- radicals can produce mutations in tissues.
 The most common complication of radiation therapy is cancer: the most common cancer in
radiation is leukemia.

- Iron can produce free radicals

o Iron also can make free radicals (fentin reaction). This is why iron overload disease is so dangerous.
o Wherever tissue iron is located, you’re going to get hydroxyl free radicals and they’ll damage that tissue
 Cirrhosis in the liver
 Restrictive cardiomyopathy in the heart
 Dysfunction in the pancreas

Cell Injury 2

Free Radicals (cont.)

- Tylenol (Acetominophen)
o Tylenol is the number one cause of fulminant hepatitis due to a drug b/c of free radicals.
o Scenario
 Where in the liver does acetominophen toxicity manifest itself?
 Around the central vein.
o Treatment = N-acetylcysteine
 Sidenote: Superoxide free radicals are neutralized by superoxide dismutase (SOD).
o Glutathione (comes from the hexose [or pentose] phosphate shunt; NADPH is also generated from this
shunt). NADPH is the main substance used for all anabolic biochemical reactions (synthesizing steroids,
cholesterol, etc.).
 Mechanism (glutathione)
• Glutathione’s main function is to neutralize free radicals (any free radical derived from
peroxide).
• Glutathione gets used up in the acetaminophen free radicals. When you give it N-
acetylcysteine (aka mucames), you replenish glutathione (it’s made out of N-
acetylcysteine). You basically give the substrate to make more glutathione to keep up
with neutralizing the acetaminophen free radicals.
• Methotrexate-Leucovorin analogy
o It’s like methotrexate and leucovorin rescue so you don’t get folate deficiency.
The leucovorin makes a substrate that you can still make your DNA even with a
block of dihydrofolate reductase.
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- Carbon tetrachloride
o Is seen in the dry cleaning industry.
o It can also be converted into a free radical in the liver. It forms CCl3 and you get fulminant liver
failure.
- Acetominophen and Aspirin effect on the kidneys
o This combination if prolonged is destructive to the kidneys.
o Free radicals from acetaminophen annihilate the renal medulla (it only gets 10% of the blood supply).
Aspirin inhibits the vasodilator of the kidneys (PGE2) in the afferent arteriole; this leaves
angiotensin II (a vasoconstrictor in charge of the renal blood flow). Your ability to concentrate urine in
the loop is decreased (analgesic nephropathy).

Apoptosis
- It’s programmed cell death.
- We have apoptosis genes involved in cell death.
- It has normal functions.
o Embryology
 Organs initially used to be solid. They got to have lumens because of apoptosis.
 Y chromosome
• Mullerian inhibitory factor in the germinal ridges of the testicles.
• All the mullerian structures (uterus, cervix, and upper 1/3 of vagina) are gone b/c of
apoptosis working through mullerian inhibitory factor (it signaled apopotsis through
caspases).
 X chromosome
• The absence of a Y chromosome causes germinal ridge to go the ovarian route. They
have a factor that knocks off Wolfian duct structures.
 Thymus
• It’s atrophied in older people and active in children.
• If it was absent, they’d have DiGeorge’s syndrome and tetany with it as well.
• It involuted b/c of apoptosis.
o Mechanism
• A signal (hormone or a chemical) activates the caspases (enzymes).
• Caspases destroy everything (membrane damage and DNA fragmentation) and results in
membrane-bound cell cleavage products called apoptotic bodies, which are easily
phagocytosed by surrounding macrophages with no tissue necrosis.
• It ends up destroying the cell w/o any inflammatory infiltrate. What is left over that
can’t be digested is lipofuscin.
o It’s also a major mechanism in killing cancer cells and atrophy of cell mass or tissue mass. It is also
involved in hepatitis.
o Hepatitis:
 A virally infected cell is destroyed by cytotoxic T-cells by apoptosis.
o Apoptosis could be related to ischemia as well.

Necrosis
- When we damage tissue and it dies.
- Coagulation Necrosis
o When we have ischemia or tissue hypoxia and we have no oxygen, lactic acid builds up in a cell and it
denatures everything in it and we end up with coagulation necrosis.
o The gross manifestation is called infarction.
o Infarctions
 The consistency of the tissue determines whether the tissue will be pale or hemorrhagic in
appearance after infarction (via coagulation necrosis).
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 Hemorrhagic (Red)
• Bowel, which has a loose texture consistency.
• A testicle, if it underwent torsion.
• The lungs will also be red, b/c it has a loose consistency. When the blood vessels
rupture, the RBCs can easily trickle out into the damaged tissue and produce a
hemorrhagic appearance.
• Bowel infarction
o The second most common cause of bowel infarction is getting a piece of small
bowel trapped in an indirect inguinal hernia sac.
o The most common causeis adhesions from previous surgery.
• In lungs, you would have a wedge-shape infarction near the pleural surface. You
would have an effusion (it’s an exudate). It would be hemorrhagic with neutrophils in it.
If you inflame the pleura, you have pleuritic chest pain (a knife-like pain on
inspiration).
 Pale
• If it’s good consistency and when the tissue dies including the blood vessels, then when
the blood vessels die and the RBCs are released, they can’t diffuse out into the tissue (b/c
the tissue has good consistency). It will grossly look pale.
• Organs expected to be pale are heart, kidney, spleen, and liver (rarest to infarct b/c of a
double blood supply).
• Most are due to embolization.
o Most emboli in the systemic circulation arise from the left side of the heart.
o A spleen could produce a pale infarct from an embolus from a vegetation.
 Vegetations
• Rheumatic fever wouldn’t produce an embolism, the vegetations
in acute rheumatic fever rarely embolize (they’re too small)
• Infective endocarditis can produce embolisms large enough to
produce an infarction.
o Mitral stenosis can predispose to clots and thrombi in the left atrium and then
get atrial fibrillation (the worst arrhythmia). The arrhythmia most associated
with embolisation in the systemic circulation is atrial fibrillation b/c it produces
stasis in the atria, clot formation, and when the atria vibrates, bits and pieces can
come off and embolize.
o Gangrene
 Dry
• You don’t have pus.
• Dry gangrene of the foot is common in diabetics
o The problem is in the popliteal artery (it can have atherosclerosis in it and
possibly even be thrombosed).
o The most common cause of non-traumatic amputation in the U.S. is diabetes (b/c
it enhances atherosclerosis).
o The popliteal artery has a small lumen and if it has atherosclerosis in it, it can
pose a serious problem.
• It is related to coagulation necrosis related to ischemia (decrease in arterial blood flow).
o Brain Infarction
 It is the one exception to the rule that coagulation necrosis is the underlying type of necrosis in
infarctions. Brain infarctions have liquefaction necrosis instead of coagulative necrosis.
 The most common infarction occurs in the internal carotid; you listen with the stethoscope
for a bruit (a noise you hear when you have a vessel with a narrow lumen).
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• This is the place where a platelet thrombus develops over an atherosclerotic plaque,
blocks it, and you end up with a stroke.
• It is also the place where bits and pieces of atherosclerotic plaque chip off and produce
transient ischemic attacks (produces motor or sensory abnormalities that go away w/in
24 hours).
 The brain has little meshwork.
• The astrocyte is analogous to the fibroblast in the brain b/c of its protoplasmic processes.
• When we infarct the brain, it doesn’t have any structure and liquefies.
• You don’t see vague outlines of what used to be there (coagulation necrosis); it forms a
cystic space (liquefactive necrosis).
o Liquefactive nerosis
 It liquefies tissue.
 Neutrophils play a dominant role. Neutrophils main purpose is to phagocytose and destroy
things with its enzymes (liquefy them).
 Liquefactive necrosis in most cases refers to an infection when neutrophils are involved (usually
an acute inflammation) producing an abscess or some type of inflammatory condition.
 The one exception to the rule of is an infarction of the brain (not an inflammatory condition).
 Staph. aureus vs. Streptococcus
• In abscesses with Staph. aureus, you would see gram positive cocci in clusters (b/c of
coagulase). Coagulase is why you see abscesses; it converts fibrinogen into fibrin, so
itlocalizes the infection (neutrophils can’t get out b/c of the fibrin).
• Streptococcus releases hyaluronidase; this breaks down the glycosaminoglycans in
tissues (this is why the infection spreads through tissues; this is called cellulitis).
o Granulomatous necrosis (aka Casseous necrosis)
 Tuberculosis
• Scenario
o Patient presents with fever, night sweats, and weight loss.
 Casseous means you have a cheesy consistency.
 It means you either have a mycobacterium infection (any, including atypical) or systemic
fungal infection.
 The lipid in the cell wall is what gives the granuloma its cheesy appearance.
 Sarcoidosis has granulomas, but it’s not casseous (b/c it’s not related to mycobacteria or systemic
fungi).
 In Crohn’s you also get granulomas, but they’re not casseous (not related to mycobacteria or
systemic fungi).
o Fat necrosis
 Pancreas (enzymatic fat necrosis)
• Scenario
o Person has epigastric distress with pain radiating to the back. What is it?
o Pancreatitis
• The pancreas is retroperitoneal and when it gets inflamed, the pain is referred to the back.
• It has an enzymatic fat necrosis. It’s fat necrosis due to enzymes.
• The enzymes are breaking down fat into fatty acids. The fatty acids then combine with
calcium salts to produce chalky areas of enzymatic fat necrosis (called
suponification; forming a soap-like salt). These can be seen on x-ray b/c they have
calcium in them.
• It tends to occur in a patient who is an alcoholic.
• Wherever you see blue on a histologic section (ex. a coronary vessel and you know it’s
atherosclerotic) it’s always calcium.
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• In hemorrhagic pancreatitis, amylase is elevated as well as lipase (lipase is more specific

b/c it’s only found in the pancrease; amylase is found in the parotids, small bowel, and
fallopian tubes).
 Breasts (traumatic fat necrosis)
• Scenario
o A woman with pendulous breasts damages them from running without support
and she gets fat necrosis.
o This is not enzymatic, but traumatic fat necrosis.
• It can calcify and look like cancer on a mammogram. The difference between this
and calcification in a cancer is it’s painful vs. painless (the cancer).
o Fibrinoid necrosis
 It looks like fibrin, but it isn’t.
 It’s a necrosis of immunologic disease.
• Some examples are palpable purpura (small vessel vasculitis; immune complex type III),
henoch-schonlein purpura (which has palpable purpura).
• Rheumatic fever also has type III hypersensitivity. If it had vegetations on the mitral
valve, they would be found to be sterile and to be composed of fibrin-like material in
them.
 It’s the necrosis of immunologic diseases; immune complexes can be found in them.
 Pathogenesis of immune complexes
• Damage is from type III hypersensitivity.
• It’s an antigen-antibody complex that travels in the circulation. It deposits in places
available to the circulation (glomerulus, small vessel, etc.).
• It works by activating the alternative complement system which produces C5a. C5a
is chemotactic to neutrophils.
• Neutrophils are the one that do the damage in type III hypersensitivity.
o Liver
o Sidenote: Triad
 Triad = portal vein, hepatic artery, and bile duct
 The hepatic vein, hepatic artery, and portal vein will dump their blood into sinusoids.
 The liver is an example of a sinusoid organ; other examples of sinusoid organs are bone marrow
and spleen.
• Gaps are characteristic of sinusoids; gaps are between the endothelial cells so that things
like RBCs, inflammatory cells, etc. can fit through them (this is unlike the glomerulus
basememnt membrane that is fenestrated).
 Congestion
• If you have right heart failure and blood builds up behind the failed heart, the liver is
going to get congested with blood and you get the “nut-meg” liver (congestive
hepatomegaly).
• If you block the portal vein, nothing happens to the liver because it’s before the liver.
• If you block the hepatic vein (Budd-Chiari syndrome; involves blockage by
thrombosis), your liver gets congested.
 The central vein is the part of the liver normally susceptible to injury. It’s susceptible to
injury because it is furthest away from the sinusoids (zone 3).
• Zone 2 is where “midzone necrosis” occurs due to yellow fever (transmitted by the
Aedes aegyptii mosquito).
• Scenario
o In acetaminophen toxicity, which part of the liver is most affected?
o The part around the central vein b/c it gets the least amount of oxygen.
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Fatty change
- The most common cause is alcohol.
- Alcohol Metabolism
o In alcohol metabolism, NADH and acetyl coA is all over the place.
o Acetyl coA can be converted into acetate (a fatty acid) in the cytosol and also to ketone bodies
(acetoacetate, beta-hydroxybutyrate, and acetone).
o NADH causes pyruvate to form lactate in anaerobic glycolysis.
 Lactic acidosis is the metabolic acidosis always seen in alcoholics because the increase in
NADH drives it in that direction.
o Alcoholics have fasting hypoglycemia
 If pyruvate is forced to become lactate, an alcoholic in a fasting state is going to have trouble
making glucose by gluconeogenesis (you need pyruvate to start it off).
 In a fasting situation, liver glycogen stores are depleted and maintenance of blood glucose
depends entirely on gluconeogenesis.
o In alcoholics, of the two ketoacids (acetoacetic and beta-hydroxybutyrate) beta-hydroxybutyrate is what
you will see because it’s an NADH driven reaction.
- Two types of metabolic acidosis
o You see lactic acidosis (b/c you’re driving pyruvate into lactate).
o You get ketoacidosis because of the excess of acetyl coA (shunted to produce ketone bodies . The main
ketoacid is beta-hydroxybutyrate (b/c of the excess of NADH).
- Increased VLDL and fatty liver
o In glycolysis, around reaction four, you get dihydroxyacetone phosphate gets driven by NADH (b/c of
the increase of NADH in alcoholics) to form glycerol-3-phosphate.
 Glycerol-3-phosphate is also the carbohydrate backbone for making triglyceride (just have to add
3 fatty acids to it).
o The abundance of glycerol and free fatty acids (reduction in the citric acid cycle leads to shunting of
acetyl coA and to increased fatty acid synthesis) results in an increased production of triacyl-glycerol,
with increased export from the liver as very-low-density-lipoprotein (VLDL), and a fatty liver.
o The fatty liver comes from impaired protein synthesis preventing assembly and secretion of VLDL,
causing triacylglycerols to accumulate in the liver).
- How diet affects synthesis of VLDL
o Restricting fat wouldn’t decrease the synthesis of VLDL.
o Restricting carbohydrates would reduce the synthesis of VLDL (it’s a glucose intermediate that it’s
madefrom – glycerol-3-phosphate [a product of glycolysis]).
Inflammation 1

Liver and Fatty Change

- Kwashiorkor
o Mechanism
 When you make VLDL, and you want to get it out of the liver, you need a protein (apoproteins)
o In Kwashiorkor, the problem is a decrease in protein intake. They have an adequate amount of calories,
but it’s all carbs; they can’t get the VLDL out b/c they have no apolipoprotein to cover it and put it out
into the blood stream and solubilize it in water.
o The reason for the protuberant abdomen is because:
 They have decreased protein, which decreases oncotic pressure and you get ascites.
 The main reason is they have huge livers b/c of fatty change (the mechanism is different than
an alcoholic [they have increased in synthesis of VLDL]). In Kwashiorkor, it’s due to lack of
protein to put around the VLDL to get out of the liver so it accumulates; this is the reason for the
fatty change.
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Ferritin – is a soluble form of circulating iron; it’s a good marker for the amount of iron you have in your bone marrow.
It’s also the test of choice for diagnosing any iron-related problem like iron deficiency, anemia of chronic disease, or iron
overload diseases (hemochromatosis or hemosiderosis).

Types of Calcification
- Dystrophic
o Abnormal calcification
o It means you’ve had damaged tissue and it gets calficified.
o Enzymatic fat necrosis is an example.
o Serum calcium is totally normal except that you have damaged tissue and it may be calcified.
o It can happen in an atheromatous plaque. This makes it hard to dissolve the plaques.
 The only way to get rid of dystrophically calficied blood vessels is to be on a diet called the
Ornish diet (pure vegan diet).
o It’s the most common cause of aortic stenosis.
o It’s the most common cause of a certain hemolytic anemia.
- Metastatic
o Sometimes if you have hypercalcemia or hyperphosphatemia, calcium could be made to deposit in
normal tissue that hasn’t been damaged.
o If someone had hypercalcemia, the most common cause would be primary hyperparathyroidism.
o If it was in a hospital, the most common cause would be malignancy-induced calcemia.
o Because you have hypercalcemia, you can put calcium in normal tissue (metastatic calcification).
o When you deposit calcium in bone, it’s the phosphorous part of the solubility product that drives
calcium into bone.
 If you have high phosphate levels, it’s dangerous b/c it’ll take calcium and drive it into
normal tissue.
 This is why when they have renal failure and they have high phosphate levels, they have to
dialyze the phosphate because it’s going to be driving calcium into normal tissue like the heart,
renal tubules, and the basement membrane (called nephrocalcinosis).

Aortic Stenosis
- The most common cause is a congenital bicuspid valve (it should be tricuspid).

Spherocytosis
- If you can’t see a central area of pallor, then it’s a spherocyte.

Cell Membrane Defects

- Absence of spectrin
o It causes the RBC not to be able to form a biconcave disc. If spectrin is defective, then it forms a sphere.
- Ubuquitin
o It’s a stress protein; it helps to destroy misfolded proteins.
o In some of the intermediate filaments (like keratin, desmin, vimentin,…) are part of the superstructure of
our cells. They keep our cells from collapsing on themselves and being a big protoplasmic mass.
o When intermediate filaments get damaged, then ubiquitin tags them for destruction.
o Examples of ubiquinated products
 Mallory bodies are found in liver and are an example of ubiquinated keratin; they’re used to say
that a patient has alcoholic hepatitis.
 Neurofibrillary tangles are also an example of an ubiquinated neurofilament.
• Neurofibrillary tangles (in a silver stain) are not just found in Alzheimer’s disease, but in
Huntington’s chorea and Jakob-Creutzfeldt disease.
• Remember the Tau protein is associated with neurofibrillary tangles.
 Lewy bodies are an example of ubiquination.
 13

• Seen in Parkinson’s Disease

• The neurotransmitter deficient is dopamine.
• It’s also a damaged neurofilament.
- Cell Cycle
o Three types of cells
 Labile cells
• A cell whose division is via a stem cell.
• Three tissues that have stem cell are bone marrow, basement membrane of skin, and the
base of the crypts in the intestine.
• These cells are in the cell cycle the most.
• These cells are most likely affected by pharmacology that affects the cell cycle.
• There are different drugs that affect the cell cycle and cause bone marrow suppression,
diarrhea, excess mucous, and rashes on the skin. These occur because these tissues have
labile cells.
 Stable Cells
• Are in the Go (resting) phase.
• Most are in parenchymal organs such as the liver, spleen, kidney, andonly smooth
muscle.
• They’ll undergo division, but most of the time they’re resting in the Go phase;
something (a hormone for example) has to stimulate them to get into the cell cycle
and divide.
o Example is a estrogen and a woman.
 If a woman is in the proliferative phase of her menstrual cycle, then her
endometrial cells would have been initially in the Go phase; when
estrogen came up, it stimulated the Go cells to go into the cell cycle.
• Most of the time, the stimulus is a growth factor or a hormone.
 Permanent Cells
• Can’t get into the cell cycle.
• They’ve been permanently differentiated.
• Muscles other than smooth muscle (striated and cardiac) fit into this category.
• Neurons are also permanent cells.
 Hypertrophy and Hyperplasia
• The only muscle that is not a permanent tissue is smooth muscle.
• Hypertrophy involves an increase in size, whereas hyperplasia has an increase in number.
• A permanent cell could not undergo hyperplasia, but could undergo hypertrophy.
Smooth muscle can undergo both hyperplasia and hypertrophy.
 G1 phase
• The most variable phase of a cell cycle is the G1 phase.
o In women, the most variable phase of the menstrual cycle is the proliferative.
o It’s analogous to the G1 phase of the cell cycle; it can be shortened or lengthened
(none of the other phases like S, G2, or M can vary in the cell).
o Most cancer cells have a longer cell cycle (takes them longer to get through a
cell cycle). What’s responsible for this is a longer G1 phase. The inverse is true;
if you had a cancer cell that had a shorter cell cycle than normal it’s because it
had a shorter G1 phase.
 Kinase – always means phosphorylation. Phosphorylation usually involves sending a message to
something. Usually when you phosphorylate something, you activate it; when you
dephosphorylate, you deactivate.
 Glucagon is a phosphorylater and insulin is a dephosphorylater.
 14

• Glucagon is more likely to activate protein kinase whereas insulin would

dephosphorylate and deactivate it.
 Cyclin-D dependent kinase
• Cyclin D activates it.
• G1 makes Cyclin D
• Once Cyclin D is made in the G1 phase, then it activates the Cyclin-D dependent kinase.
• The key area in the cell cycle to control is going from G1 to S phase.
o If you had a mutation and you went into the S phase and you duplicated it, then
you have the potential for cancer.
o There are two suppressor genes that control this:
 Rb suppressor gene (on chromosome 13); it makes a protein called Rb
protein. It prevents the cell from going from the G1 to the S phase.
• The active cyclin-D dependent kinase phosphorylates the Rb protein (and
inactivates it); when it phosphorylates it, it can go from the G1 phase into the S phase.
• This enzyme is checked by p53 suppressor gene (on chromosome 17).
o It makes a protein product that inhibits the cyclin-D dependent kinase; this
would prevent phosphorylation of the Rb protein and it’s going to remain in the
G1 phase.
o The p53 suppressor gene is the most important gene for cancer.
o Sidenote: Human Papilloma Virus
 The human papilloma virus inactivates the Rb suppressor gene and
the p53 suppressor gene; it makes two gene products E6 and E7.
 E6 knocks off the p53 and E7 knocks off the Rb suppressor gene.
• If an Rb suppressor gene is knocked off by a point mutation, nothing is there to stop
the cell from going into the S phase.
o You run the risk of cancer: retinoblastoma (what Rb stands for), osteogenic
sarcoma (Codman’s triangle, a sunburst appearance on X-ray). If you’re a
woman and you had a breast cancer, Rb suppressor gene can be involved in that
too.
• By knocking off the p53 suppressor gene, the kinase would always be active and it would
always be phosphorylating the Rb protein and you’d always be going into the S phase.
• If you knock off either one of the genes, then the G1 phase goes into the S phase.
• The p53 is actually called the “guardian of the cell”.
o It inhibits the cell from going into the S phase and gives the cell time to detect if
there’s any abnormalities in DNA (splicing defects, codon,…).
o There are DNA enzymes that can splice out the abnormality and the cell is then
ready to go into the S phase.
o If the cell has been damaged too much in its DNA, then it is removed by
apoptosis.
 S phase
• The S phase means the synthesis phase.
• This is where everything is doubled (includes DNA, chromosomes [you’re 4n at this
point; you were 2n in G1]).
 G2 phase
• G2 phase is where you make tubulin (the protein from which you make the
microtubules for the mitotic spindle); it’s blocked by etoposide and bleomycin.
 M phase
• M for mitosis; it’s where the cell divides into 2n cells.
• The cell can either go into a Go resting phase or continue going on in the cycle and
divide again or it can be permanently differentiated.
 15

 Drugs and where they work in the cell cycle

• Vinca alkaloids work at the mitotic spindle – M phase.
• Paclitaxel affects the M phase.
• Colchicine – M phase.
• Etoposide – G2 or S.
• Bleomycin – G2
• Methotrexate – S phase.
• Grieseofulvin – M phase.
• Scenario
o A patient has rheumatoid arthritis has macrocytic anemia. The drug responsible
does what and is located where?
o Methotrexate – it blocks dihydrofolate reductase and it works at the S phase.
• Scenario
o You have an HIV positive person that has dyspnea, tachypnea, and something
out of the lung. He’s put on a drug and ends up with cyanosis. Where would the
drug have worked?
o Dapsone (has nothing to do with the cell cycle).
• Scenario
o This drug used to be used in the treatment of acute gouty arthritis, but because
of side effects is no longer used. Where would it work?
o M phase; it’scolchicine.
• Scenario
o This drug is a chemotherapy agent made from a yew tree. What drug is it and
where?
o Paclitaxel in the M phase.
• Vinca alkaloids are made from periwinkle plants

Growth Alterations
- Atrophy
o The diagnosis is a decrease in tissue mass; the cell actually decreases in size. It has enough organelles to
survive; it has less mitochondria than normal. It’s waiting for whatever it needs to stimulate it so it can
come back.
o Hydronephrosis
 The thinning of the cortex of the medulla is due to compression atrophy.
 The most common cause of hydronephrosis is a stone in the ureter.
 Scenario
• What’s the growth alteration?
• Atrophy; because of the increased pressure on the cortex and medulla, this will produce
ischemia. Blood flow will decrease and it will produce atrophy of the renal tubules.
o Brain atrophy
 Could be because of atherosclerosis (the most common cause) or because you have knocked
off the neurons (in layers 3, 5, and 6).
• An example is Alzheimer’s disease (you have degeneration of neurons).
o The cerebral cortex has its neurons in layers 3, 5, and 6; if they get destroyed, it
would reduce the overall mass of the brain.
• Atherosclerosis could be a cause or Alzheimer’s disease (related to the beta amyloid
protein – toxic to neurons).
o Muscle atrophy
 Could be due to Lou Gehrig’s disease (amytrophic lateral sclerosis).
 If you knock off the nerve to the muscle, you would get atrophy.
 16

 A leg in a cast could lead to muscle atrophy.

 Endocrine could also be related.
• In hypopituitarism, the adrenal gland would be atrophied (in particularly the fasiculata
and reticularis; not the zona glomerulosa).
o ACTH has nothing to do with stimulating aldosterone release (fasiculata is
where you make cortisol and glucocorticoids; reticularis is where you make sex
hormones [17-keto steroids]).
• If someone’s taking thyroid hormone, the thyroid atrophies b/c the thyroid hormone
decreases the thyroid stimulating hormone (TSH).
o Nothing is stimulating the gland and therefore it undergoes atrophy.
o Pancreas
 Scenario
• Biopsy of a pancreas from a child with cystic fibrosis. What’s the growth alteration
present?
• Atrophy; The biopsy shows tubules filled with a reddish stuff like concrete.
 Cystic Fibrosis
• In cystic fibrosis the transmembrane regulator on chromosome 7 is defective, then you
have problems with secretions; they become thicker. It blocks the ducts and then the
glands which are making the fluids in the pancreas (exocrine part).
• If you block the lumen, there’s a backpressure on them. Just like there was atrophy
of the renal cortex and medulla from a backpressure related to urine, the same thing
happens if you block the lumen of the duct; you get atrophy of the glands. This is
why you get malabsorption in all children with cystic fibrosis.
o Kidney
 Renal vasculature hypertension causes renal atrophy.
• The renin level is high in the atrophied kidney. The other kidney would have a
hypertrophy alteration.
 Scenario
• The growth alteration noted in this patient (renal atrophy) is similar to a growth alteration
in…
o Cardiac hypertrophy
 In hypertrophy of a cardiac muscle, the muscle is permanent.
 The supposed block is before the G2 phase (after the S phase and everything is doubled); the
number of chromosomes would be 4n.
• 1n is something like a sperm, 2n is a normal diploid cell, 3n means you probably have
cancer or a trisomy disease, and 4n is this situation.
 Hypertrophy is an increase in size of a cell, not number.
- Hyperplasia
o It has increased mitosis.
o In the proliferative phase, you have increased mitosis. You end up getting endometrial mucosa with
increased mitosis. The number of endometrial glands is increased by increasing cell division.
o If you had unopposed estrogen, you could end up with cancer because if you didn’t have progesterone
to undo what estrogen did, you would get cancer (you would go from hyperplasia to atypical hyperplasia
to endometrial cancer).
o In hyperplasia left unchecked, you run the risk for cancer with one exception; the prostate. Prostate
hyperplasia does not predispose to prostate cancer; you will have an increase in micturation
frequency.
o Gravid uterus – a woman’s uterus after delivery. This is an example of 50% hypertrophy of the
smooth muscle cells in the wall of the uterus and 50% related to hyperplasia.
o Bone Marrow
 17

 Normally, you should have 3x as many white blood cells as red blood cells.
 A bone marrow aspirate from a bone marrow with RBC hyperplasia would not be expected in
iron deficiency (you lack iron to make RBCs), nor thalassemia (you have a defect in making
globin chains).
• You would expect it in someone with chronic obstructive pulmonary disease (COPD)
because they have hypoxemia releasing erythropoietin (it’s made in the endothelial cell
of the peritubular capillary).
• A bone marrow showing RBC hyperplasia is an erythropoietin stimulated marrow;
erythropoietin is made in the endothelial cell of the peritubular capillary.
o Psoriasis
 It’s an example of hyperplasia.
 It’s an unregulated proliferation of squamous cells in the skin; you get a raised red plaque with
silvery scales on it (corresponding to the excess in stratum cornea; hyperplasia).
 Methotrexate can work for psoriasis b/c it’s cell cycle specific to the S phase and prevents
the basal cells from proliferating.
o Prostate and Bladder
 Prostate only demonstrates hyperplasia of glands and smooth muscle, not hypertrophy. It’s
due to hormones; all hormone-stimulated glands undergo hyperplasia, not hypertrophy.
 Since you have a decreased caliber of the urethra (due to prostate hyperplasia), the bladder has
to work more and its muscle hypertrophies.
• The bladder wall thickens b/c of hypertrophy of smooth muscle cells related to an
increase in afterload.
- Metaplasia (Barrett’s)
o The replacement of one adult cell type by another.
o In the lower esophagus, Barrett’s esophagus can present with mucous secreting cells and goblet cells
(this is not what should be present there; it should be squamous).
o Barrett’s esophagus is a precursor to adenocarcinoma; in adenocarcinoma, the distal esophagus has
surpassed squamous cell carcinoma of the mid-esophagus; it’s the most common esophageal cancer in the
U.S.
o GERD is the number one precursor for esophageal cancer (instead of squamous, it’s
adenocarcinoma).

Inflammation 2

Metaplasia and Hyperplasia in the lungs

- The main stem bronchus is lined by ciliated columnar-pseudostratified columnar. If you were smoking, you would
undergo squamous metaplasia.
- If you had increased goblet cells in the mainstem bronchus (seen in all smokers).
o This is an example of hyperplasia b/c you normally have goblet cells in the mainstem bronchus.
- Smokers also have goblet cells in the terminal bronchioles; this is an example of metaplasia.

Metaplasia in the stomach

- Goblet cells in the stomach would be abnormal; they should be present in the intestine, not in the stomach (called
glandular metaplasia).
o It is a precursor for adenocarcinoma of the stomach.
o The most common cause of adenocarcinoma of the stomach is H. pylori.
 Because H. pylori produces damage to the pylorus and antral mucosa, it produces a chronic atrophic
gastritis with intestinal glandular metaplasia and it’s the precursor lesion for adenocarcinoma.

Metaplasia can predispose cancer.

 18

- Lungs
o In the lungs, ciliated columnar epithelium becomes squamous metaplasia. You then get squamous
dysplasia. From dysplasia, you can get into squamous carcinoma.
- Esophagus
o In the distal esophagus it went from squamous to a glandular epithelium (b/c squamous epithelium can’t
handle acid; it needs mucous secreting epithelium as a defense against the acid injury).
o The glandular metaplasia can go on into an atypical metaplasia and go on to adenocarcinoma of the distal
esophagus.
- Parasites
o In parasitology, there’s only two parasites that produce cancer.
o Clonorchis sinensis (Asian liver fluke) and it produces cholangial carcinoma.
o Schistosoma haematobium causes the transitional epithelium to undergo squamous metaplasia. From
squamous metaplasia, squamous dysplasia, and from squamous dysplasia, squamous cancer.

Hyperplasia predisposing Cancer

- Hyperplasia left unchecked could potentially produce cancer; for example endometrial hyperplasia is the most
common precursor lesion for endometrial adenocarcinoma (it’s usually due to unopposed estrogen).

Dysplasia
- Is an atypical hyperplasia. Dysplasia is a precursor for cancer; either glandular or squamous dysplasia.
- The precursor for squamous carcinoma of the skin is Actinic keratosis.
o Scenario: Actinic keratosis
 A farmer had a lesion on the back of his neck (A SUN EXPOSED AREA). He scraped it off and
then three months later it grew back. What is it?
 Actinic keratosis (aka Solar keratosis). It’s a precursor for squamous cell carcinoma. It’s due to
UVB damaged skin.
- Basal cells carcinomas are more common than squamous cell carcinoma.

Inflammation
- Acute Inflammation
o Redness (Rubor)
 Histamine is the most important vasodilator in acute inflammation. It vasodilates arterioles. It’s
responsible for the redness of acute inflammation.
o Hot (Calor)
 Due to histamine. When you vasodilate, it gives off heat; this is why when you go in shock
(endotoxic shock or septic shock), you get warm skin opposed to cold skin (due to vasodilating the
arterioles).
o Tumor
 It becomes a raised structure. It’s due to increased vasopermeability by histamine of the venules.
Venules are thin and are endothelial cell basement membrane. Histamine contracts the endothelial
cells and leaves the basement membrane bare; you get increased vessel permeability producing an
exudate and swelling of tissue.
o Dolor (pain)
 This is due to bradykinin (part of the kininogen system; between Hageman’s factor XII and XI).
• When you activate the intrinsic pathway, you automatically activate the kinonogen
system.
• When you activate factor XII (Hageman’s factor) it activates factor XI and the kininogen
system (the end product being bradykinin).
• Bradykinin is degraded by angiotensin converting enzyme.
o You get angioedema as a complication of an angiotensin converting enzyme
inhibitor.
 19

o By using an angiotensin converting enzyme inhibitor, you also inhibit the

metabolism of bradykinin which increases vessel permeability producing the
angioedema (swelling of tissue).
• Bradykinin can also produce cough.
 Bradykinin and PGE2are the two things producing pain.
o Pathogenesis of acute inflammation
 Pavementing (or Margination)
• Neutrophils in the small vessels will begin getting sticky b/c of adhesion molecules
synthesis.
• The endothelial cells will also begin synthesizing adhesion molecules. Eventually the
neutrophils will stick to the endothelial cells (called pavementing or margination).
 Passing through the Basement Membrane
• The neutrophils will then go and look for bare basement membrane on the venules.
• The neutrophils have type IV collagenase (b/c collagen type IV is what makes up the
basement membrane).
o Sidenote: Cancer cells
 To stick to endothelial cells, they have adhesion molecules (usually against
laminin in the basement membrane).
 Cancer cells also have type IV collagenase; this is how they get through and
metastasize.
 Chemotaxis
• When the neutrophils get out of the small vessels (usually the venules) they emigrate.
• They have directed chemotaxis. Some of the chemotactic molecules are C5a and LTB4
(they’re also involved in making adhesion molecules in neutrophils).
 Opsonization
• If we have an infection (i.e Staph. aureus), we know that the bacteria are being prepared
before they get destroyed (opsonization).
• Two opsonizers are IgG and C3b.
• Sidenote: Bruton’s agammaglobulinemia
o It’s a sex-linked recessive disease where you are missing all the immunoglobulins
including IgG.
o The most common cause of death is infection; you can’t opsonize.
o The mechanism of the infection is they have no IgG to opsonize bacteria; therefore,
you can’t phagocytose it.
- Chronic Inflammation
o For chronic inflammation instead of neutrophils, you have either macrophages or monocyte (monocytes
become macrophages). T

Phagocytosis and killing bacteria

- The macrophages, monocytes, and the neutrophils would obviously have to have receptors for the opsonins (IgG and
C3b).
- When you phagocytose the bacteria, the lysosomes will go down the microtubules and empty their enzymes into the
bacteria.
- Sidenote: I-cell Disease
o It’s characterized by an inability to phosphorylate the mannose residues of the lysosomal enzymes in the
Golgi apparatus.
o The lysosomes therefore lack lysosomal enzymes and are unable to degrade complex substrates, which
accumulate in the lysosomes as inclusion bodies.
o The acid hydrolases lacking the recognition marker cannot be targeted to the lysosomes but are secreted
extracellularly.
 20

o Patients have psychomotor retardation and an early death.

Oxygen-dependent Myeloperoxidase system

- NADPH oxidase oxidizes NADPH and in the process, reduces oxygen to superoxide anion.
o NADPH oxidase isin the cell membrane of neutrophils and monocytes, butnot macrophages (they lose
the system).
o NADPH, the cofactor, is mainly synthesized in the pentose phosphate shunt; the enzyme responsible for
that particular part of the reaction is glucose-6-phosphate dehydrogenase (glucose-6-phosphate is converted
to 6-phosphogluconate). You get NADPH and a neutralizing factor for free radicals (glutathione).
o NADPH oxidase responds to activating stimuli by producing reactive oxygen intermediates (such as
superoxide) within the lysosome where the ingested substances are segregated, and the cell’s own organelles
are protected.
o Superoxide
 Superoxide has an unpaired electron in its outer orbit that gives off energy (called a respiratory
burst) whichcan be measured by radiation detectors or nitroblue tetrazolium (NBT dye test).
 Nitroblue Tetrazolium (NBT dye test)
• They get a test tube and they add in a colorless dye (NBT).
• If neutrophils and monocytes are working okay, they will phagocytose it, they’ll have a
respiratory burst and the free radical oxygen (superoxide) will cause a color change to
occur and make it colored (bluish).
• The neutrophils (or monocytes) are removed and smeared on a slide and looked at for color
in the dye.
• If there’s color, you know that the respiratory burst is working; if there isn’t any color in
the dye, it means they don’t have a respiratory burst system. This is used to find out if you
have chronic granulomatous disease from childhood.
 The free radical oxygen (superoxide) is neutralized by superoxide dismutaseinto peroxide.
- Peroxide itself could kill bugs, but myeloperoxidase is even better.
o The red granules (eosinophilic granules) you see in monocytes and neutrophils are in lysosomes.
Myeloperoxidase is one of many enzymes in these granules and it catalyzes the reaction joining peroxide
together with chloride to form bleach (which kills bugs); this is why myeloperoxidase is the most potent
bactericidal mechanism.
- The myeloperoxidase system is oxygen dependent and found in neutrophils and monocytes; not macrophages.
- Sidenote: Macrophages as a reservoir for AIDS
o The macrophage in the central nervous system is a microglial cell; it serves as the reservoir cell for CNS
AIDS. Outside the CNS, the reservoir is the dendritic cell (a macrophage) located in the lymph nodes.
- Glucose-6-phosphate dehydrogenase deficiency
o If you have glucose-6-phosphate dehydrogenase deficiency, infection is the most common thing that
precipitates hemolysis.
o This is because you don’t have NADPH, which means you have no functioning oxygen-dependent
myeloperoxidase system. You would be susceptible to infection which would set off the hemolysis of the
RBC.

Chronic granulomatous disease of childhood & Myeloperoxidase Deficiency

- Chronic Granulomatous Disease of Childhood
o It’s sex-linked recessive. The mother (an asymptomatic carrier) is the one who gives it to the boy. All of the
females of a male with the disease are asymptomatic carriers; they transmit the disease to 50% of their sons.
o They’re missing an enzyme – NADPH oxidase.
o The NBT dye test is abnormal; it doesn’t show the color of the dye.
o They’re missing the respiratory burst.They don’t have superoxide, peroxide, but they do have
myeloperoxidase and chloride.
 21

 We have myeloperoxidase and chloride, but these kids are missing peroxide (have no NADPH
oxidase).
 If a bacteria was phagocytosed in a neutrophil or monocyte and it could make peroxide and add it
inside the phagolysosome, this would be enough to kill the bacteria.
 All living organisms make peroxide; this includes bacteria. However, not all bacteria contain
catalase (an enzyme that breaks down peroxide).
o These kids can’t kill Staph., but they can kill Strep.
 The reason is Staphylococcus is not only coagulase positive, butcatalase positive (have the ability
to breakdown peroxide).
 Staph. aureus can make its peroxide and release catalase and neutralize it. The myeloperoxidase
system is rendered useless in the child because it too depends on peroxide (to combine with chloride
to make bleach).
 If it was a Streptococcus (catalase negative), when it makes its peroxide (like any normal bacteria) it
doesn’t have catalase, so it’s adding what the child was missing to make bleach. The kid can then
kill Strep.
- Myeloperoxidase Deficiency
o In someone with myeloperoxidase deficiency, they still have a respiratory burst (b/c they have NADPH
oxidase).
o They have peroxide, superoxide free radicals, and chloride.
o They have a normal NBT dye test (it depends on the presence of superoxide), but they can’t kill the
bacteria b/c they can’t make bleach.
o This type of defect would be called a microbiocidal defect.
o Myeloperoxidase deficiency is not sex-linked recessive; it’s autosomal recessive.
- Chronic granulomatous disease of childhood and myeloperoxidase deficiency are both microbiocidal defects (can’t
kill bacteria).

Adhesion Molecule Defect

- Scenario
o A child has to have his umbilical chord removed surgically. Histologically it doesn’t show neutrophils w/in
the tissue or lining the small vessels.
o This is an adhesion molecule defect; could be a beta2 integrin defect (integrins are adhesion molecules). The
umbilical chord needs to have an inflammatory reaction involving neutrophils; they have to stick in order to
get out.

Serotonin
- It’s made from the tryptophan amino acid.
- It’s a neurotransmitter.

Anaphylatoxins
- C3a and C5a.
- They stimulate mast cells to release histamine (which causes vasodilatation and increase in vessel permeability).
- They also play a role in shock (if you activate the complement system, they will also be activated).

Nitric oxide
- It’s made in endothelial cells.
- It’s a potent vasodilator.
- It’s used in treating pulmonary hypertension.
- It plays a big role in septic shock.

Il-1
- It’s associated with fever.
 22

- It’s a pyrogen; it stimulates the hypothalamus to make prostaglandins; the prostaglandins stimulate your
thermoregulatory center to produce fever.

Corticosteroids
- Inhibits phospholipase A2; you don’t release arachidonic acid from phospholipids (you don’t make prostaglandins
or leukotrienes).
- Linoleic acid (omega 6 fatty acid) can make arachidonic acid. It’s found in walnuts and fish oils. They act like
aspirin.
- Linolenic acid (omega 3 fatty acid) blocks platelet aggregation.

Zileuton
- It’s used as to block 5-lipoxygenase. Other drugs block the receptors.

LTC4, LTD4, LTE4

- They are potent bronchoconstrictors. These are important in causing asthma.

LTB4
- It’s increases neutrophil adhesion and neutrophil chemotaxis.

Aspirin
- Blocks cyclooxygenase; it blocks it irreversibly (it preferentially affects platelets more than endothelial cells).

PGI2 (prostacyclin)
- It’s made in the endothelial cell and is why it’s called prostacyclin synthase.
- It’s a vasodilator and it inhibits platelet aggregation.

Thromboxane A2 (TXA2)
- It’s produced in platelets. It causes vasoconstriction, bronchoconstriction, and platelet aggregation.

Dipyramidole
- It blocks thromboxane synthase.
- It’s also used in doing stress testing for coronary artery disease.

PGE2
- It’s a vasodilator in the kidney.
- It maintains the patent ductus open.
- It makes your mucous barrier in the stomach.

PGF2
- It causes dysmenorrhia (primary dysmenorrhia).
- It increases uterine contractility.
- It’s made as an abortifactant.

Corticosteroids
- It blocks phospholipase A2.
- Effects on cells
o Increases Neutrophil Count
 It increases adhesion molecule synthesis along with other steroids (like epinephrine and
norepinephrine).
 If you decrease adhesion molecule synthesis, it would increase the neutrophil count in the CBC (in
a white person, 50% of neutrophils are already stuck to the endothelium of small vessels and 50%
circulate).
 23

 The white blood cell count would be doubled.

o Corticosteroids destroy both T and B cells; they’re lymphocytotoxic.
 They do it by apoptosis. Corticosteroids are the signal for caspases to kill the cells.
o It decreases eosinophil counts as well (this is why they’re used in type I hypersensitivity reactions).
o When you’re on corticosteroids, the only thing increased is neutrophils (this is b/c it decreases adhesion
molecule synthesis). Lymphocytes and eosinophils are decreased.
- If you had Addison’s disease, you don’t have cortisol and you have the opposite effect mentioned above.
- Sidenote:
o Person who has a myocardial infarction has a high CBC count (most of which are neutrophils)
o The mechanism is epinephrine.
 It decreases adhesion molecule synthesis and the neutrophil count goes up.

Electron Microscopy of Inflammatory Cells

- To identify the alveolar macrophage, you see black dots all over the place (lysosomes).
- Lamellar bodies are the structures within type II pneumocytes.
o Inside lamellar bodies, you can find lecithin and phosphatidylcholine.
o They are involved in the production of surfactant.

Monocyte
- It has a grayish cytoplasm. It usually has a single nucleus and has a lot of garbage in the cytoplasm (it scavenges
around).
- It can form a foam cell in an atherosclerotic plaque b/c it can phagocytose and oxidize LDL. Oxidized LDL is a free
radical. Vitamin E neutralizes oxidized LDL.

Lymphocyte
- On the electron microscope, it looks like all nucleus with very little cytoplasm.
- The odds are T cells (60% of the peripheral blood lymphocytes are T). Since helper T-cells (CD4) outnumber
suppressor (CD8) 2:1, the odds are that a lymphocyte would be a helper T cell.

Rough Endoplasmic Reticulum

- It has ribosomes on it that makes protein (like immunoglobulins).
- If it has a rough endoplasmic reticulum with many ribosomes, odds are it’s a plasma cell.
o The nucleus is eccentrically located. The cytoplasm is always sky blue.
o The plasma cell derived from a B cell.
 They would be located in the germinal follicle.

Eosinophil
- It has granules that are the red.
- It’s the only inflammatory cell that has crystals in the granules.
o In an asthmatic, the crystals are Charcot-Leyden crystals; they’re degenerated eosinophil in the sputum of
an asthmatic.
- Killing invasive helminths involves type II hypersensitivity.
o Eosinophils have IgE receptors; they hook into the IgE antibodies (that bind to helminths) and release their
chemicals (the major one is major basic protein) that destroys the helminth.
o It’s type II hypersensitivity b/c it’s a cell hooking into an antibody on a target cell.
- Sidenote: type I hypersensitivity
o In type I hypersensitivity, eosinophils aren’t the effector cells; mast cells are.
o Mast cells release histamine and eosinophil chemoctactic factor.
o Eosinophils’ purpose in a type I hypersensitivity reaction is neutralize leukotrienes (they have
histaminase and aryl sulfatase).
 24

Basophil
- It has purplish granules.

Cluster Designations
- CD4 – helper T-cell
- CD8 – cytotoxic T-cell
- CD3 – the recognition site for all T-cells
- CD1 – the antigenic marker for histiocytes (include Langerhan’s cells)
- CD10 – The marker for themost common leukemia in children; it’s also called CALLA (common ALL antigen;
positive B cell leukemias).
- CD15 and CD30 – are the Reed-Sternberg
- CD21 – is only on B cells
o Epstein-Barr virus hooks onto this receptor.
 The atypical lymphocytes, however, aren’t the B cells, but the T cells (reacting against the infected
B cells).
o Burkitt’s lymphoma is a B cell lymphoma.
- CD45 – it’s on all leukocytes

Fever
- Most of the time, Il-1 is responsible for fever. It stimulates the hypothalamus to makePGE2; that stimulates the
thermoregulatory center.
- Fever is good b/c it right-shifts the oxygen-saturation curve.
o We want lots of oxygen in our tissue when we have inflammation b/c of oxygen-dependent
myeloperoxidase system.
o When we give antipyretics, we are diminishing the myeloperoxidase system.
o Also, hot temperatures aren’t good for reproduction of bacteria and viruses.

Types of inflammation
- Suppurative Inflammation
o Pus in the lacteriferous duct
 Scenario
• Post-partum woman has pus coming out of her lactiferous duct. What is the organism?
• Staph. aureus. This is an example of suppurative inflammation.
o Osteomyelitis
 Scenario
• A child with sepsis shows in the metaphysis of bone a yellowish area which turns out to be
an abscess. What is it?
• Osteomyelitisdue to Staph. aureus
 If the kid had sickle cell, it would be Salmonella.
 It’s the metaphysis of bone b/c that’s where all the blood supply to the bone goes. The
mechanism of osteomyelitis is hematogenous (it comes from another source).
o Cellulitis on the face
 Odds are it’s Strep. pyogenes.
o Diptheria and a pseudomembrane.
 Scenario
• The type of necrosis in a person with diphtheria and a pseudomembrane would be analogous
to what other type of necrosis?
• Clostridium difficile.
o Corynebacterium diphtheriae is a gram positive rod; it makes an exotoxin which
ADP-ribosylates elongation factor 2 (EF-2). The toxin damages the mucosa and
 25

submucosa producing a pseudomembrane. The bacteria doesn’t invade, but produces

a toxin that invades.
o Clostridium difficile is similar b/c it also produces a pseudomembrane and a toxin.
The toxin is what is measured in stool to make the diagnosis.
- Fibrinous inflammation
o “Bread and butter” pericarditis
o It’s usually due to increased vessel permeability.
o It’s usually seen in lupus; it would be the most common heart lesion in lupus (you’d have a friction rub).
o You see it in the first week of a myocardial infarction. Then six weeks later (Dressler’s syndrome: a
postmyocardial syndrome characterized by pleuritic chest pain, pericarditis, fever, and leukocytosis) we see it
there.
o It’s seen in coxackie infections.

Pseudomonas
- The most common organism that produces infection inthird degree burns is Pseudomonas.
- It’s color is green due to pyocyanin.

Wound Healing
- The basal cell layer on both sides of the cut proliferate and they go underneath the clot and seal it; they don’t go
over the clot.
- The key for healing of a wound is the presence of granulation tissue.
- Fibronectin
o It’s a proteoglycan involved in the healing of a wound.
o Fibronectin is an adhesion agent and a chemotactic agent that invites all the people around it (i.e. fibroblasts)
to help in the healing process.
- Granulation tissue
o Granulation tissue stops on day 3 and is in its prime on day 5.
o The scab on a wound is granulation tissue.
o Women who are pregnant can get them on the gums, called pyogenic granulomas (basically granulation
tissue).
o If you don’t have granuation tissue, you can’t heal your wound.
- Collagen
o The type of collagen responsibleinitially inwound healing is type III (located in the initial stages of wound
repair).
o Type I collagen has the highest tensile strength and is found in bone, skin, tendons, and ligaments.
o Over weeks and months, the type III collagen gets broken down by collagenases (type III) and replaced by
type I collagen.
 Zinc (a metalloenzyme and a trace element) is associated with the collagenase that helps
convert type III to type I collagen.
• Zinc deficiency commonly produces problems with wound healing; it screws up the
collagenase.
o The maximum tensile strength that you can get in a wound after three months is 80%. The most common
cause of poor wound healing is infection.
o Ehlers-Danlos Syndrome
 Has a defect in collagen (synthesis or breaking down).
 You have poor wound healing (Marfan’s also has poor wound healing).
o Scurvy
 Patient has a defect in hydroxylation of two amino acids (lysine and proline).
• Hydroxylation of these acids is important because itpromotes cross-bridges in collagen to
increase strength.
 26

 Lysyl oxygenase is the enzyme and copper is the cofactor responsible for forming the cross-
bridges. Lysyl oxidase oxidizes the lysine side chain to reactive aldehydes that spontaneously form
cross-links.
 The cross-bridges hook into the places where there’s hydroxylated proline and lysine.
 In Scurvy, you have weak, abnormal collagen b/c there’s no cross-bridges (they can’t attach to
anything).
 You can’t heal wounds and end up with hemorrhages and hemarthrosis.

Inflammation3

Granulation Tissue
- It has a lot of blood vessels b/c of fibroblast growth factor.
- Inflammatory cells can be found in the granulation tissue such as plasma cells and lymphocytes.
- The rich vascular tissue is essential for normal wound healing.

Keloid (or a hypertrophic scar)

- Is an excess in type III collagen deposition. It causes tumor-looking type of lesions on the skin.
- There is a genetic predisposition. It’s seen commonly in the black population.
- Burns can cause keloids.

Draining Sinus Tracts and Squamous Cell Carcinoma

- Scenario
o A chronically draining sinus tract in the skin; they tried putting antibiotics on it and it didn’t work. There
was an ulcered lesion on the orifice of the chronically draining sinus tract. What is it?
o Squamous Cell Carcinoma
- There’s a lot of turnover that goes on in a scar tissue. Fibroblasts are involved and there’s cell divisions going on.
Whenever you have cell divisions going on, there’s always a chance for mutation and cancer (it’s usually
squamous).
- Squamous cancer is very common in the setting of scars related to third degree burns and also from
chronically draining sinus tracts (such as chronic osteomyelitis).
- At the orifice of the draining sinus tract is a lot of hyperplasia (epithelium) and it predisposes squamous cell
carcinoma.

Acute vs Chronic Inflammation

- Acute
o The main immunoglobulin of acute inflammation is IgM.
 It’s IgM b/c you need a lot of complement components (C3a, C5a, C3b, ….) involved in the
healing process.
 The most potent activator of the complement system is IgM b/c it’s got 10 antigen recognition
sites (it’s the pentamer).
• All you need is one IgM and you have the classical pathway and it will go from 1 to 9
(in terms of the complement cascade). IgG, on the other hand, requires two to activate
the classical pathway and it doesn’t go beyond C3.
- IgM switch to IgG
o After 10 days to 2 weeks, there’s an isotype switching where the same plasma cell that was making IgM
gets the heavy chain spliced out (it’s the heavy chain that defines the specificity of the immunoglobulin)
and it splices in a gamma heavy chain. The same plasma cell then makes IgG.
- Chronic Inflammation
o Chronic inflammation has a brief phase of IgM before it goes to IgG. The main immunoglobulin of
chronic inflammation is IgG and not IgM.
 27

- The cells are different

o Acute Inflammation
 In acute inflammation, the key cells are neutrophils.
 If you have an allergic acute reaction, one of the key cells you see are eosinophils; you won’t see
mast cells b/c they’re in tissues.
 If we’re talking about viral infections, the main acute inflammatory cells are lymphocytes.
 When we have an increased vessel permeability and we have emigration of neutrophils into
interstitial tissue, the protein rich fluid (> 3.0 grams of protein/dL) and the cell rich fluid is
called an exudate(basically pus). It produces the tumor of acute inflammation.
o Chronic Inflammation
 In chronic inflammation, we start talking about monocytes and macrophages being the key.
 We see more plasma cells and more lymphocytes in tissue. We don’t see pus (or exudate); it’s
not a characteristic of chronic inflammation.
- Granuloma
o If it’s roundish and pink and you see multi-nucleated giant cells, it’s a granuloma.
o Type IV hypersensitivity
 The pathogenesis of this is type IV hypersensitivity (delayed reaction hypersensitivity).
 Cytotoxic T cells are involved in type IV hypersensitivity. When they kill neoplastic cells or
virally infected cells, that’s also a type IV hypersensitivity (no antibody is involved in this).
 Poison ivy also is a type IV hypersensitivity reaction, not type I; it’s an example of delayed
reaction hypersensitivity.
o Tuberculosis
 Alveolar macrophages
• In tuberculosis, the alveolar macrophages phagocytose it but nothing happens. The
alveolar macrophages take it all around the body (the lympho-hematogenous spread) and
there’s still no problem.
• The macrophage is processing the antigen and after some weeks it presents it to a helper
T cell.
 Mechanism
• The key actors in delayed reaction hypersensitivity are macrophages (process antigen)
and then they present the antigen (via class II antigen sites) to helper T cells.
• Helper T cells are the ones that release the cytokines. The cytokines involved in
forming the granuloma are gamma-interferon and the macrophage inhibitory
factor.
• Gamma-interferon is going to activate the macrophage to kill the TB, the
Cryptococcus, the histoplasmosis, … Gamma-interferon is the trigger for the
macrophage to kill those organisms; macrophages by itself can’t kill it (when it gets
activated by gamm-interferon it does).
 Since systemic fungi and mycobacterium have a lot of lipid in the cell wall, you get casseous
necrosis.
 All the pink staining cells are epitheloid (they’re activated macrophages; activated by gamma-
interferon). When the macrophages die, they fuse together and form multi-nucleated giant cells.
o Pathogenesis of a Granuloma
 The two main actors in a granuloma are helper T-cells (CD4) and macrophages.
 There’s two subsets of helper T-cells.
• One subset is involved in type IV hypersensitivity reactions.
o Macrophages have Il-12; when a macrophage secretes Il-12, it presents the
antigen to the subset one T-cells.
 28

o These subset one T-cells become the memory T-cells of the event. Il-12was
what made the connection with the memory of the antigen experience with the
subset one of the helper T-cells.
o Most people after their first primary diseases usually recover with no problem and they get the
granulomas (may become dystrophically calcified).
o Even though the granuloma may be calcified, everything is not dead. Most second cases of TB tend to be
reactivation of a previous TB.
o PPD (Purified Protein Derivitive)
 It’s injected into the skin.
 The macrophage of the skin (Langerhan’s cell or a histiocyte) has a CD1 designation.
Langerhan’s cells have Birbeck granules (they look like tennis rackets on EM).
 Langerhan’s phagocytose the PPD and they process it.
 The Langerhan’s cell then presents the PPD to the helper cell subset one (that has memory of
previous exposure to the protein in the wall of the mycobacterium).
• It hooks in by class II antigen site (as all immune cells do) and once it gets presented
with the PPD that has been processed by the Langerhan’s cell, the helper T cell releases
cytokines producing the inflammatory reaction with an induration (what we call a
positive PPD).
o Effects of age and immunodeficiency on response
 Older people usually don’t have good type IV hypersensitivity (less of an immune response).
 AIDS patient
• A patient with AIDS (has a decreased helper T cell count) may not get any reaction. A
person with AIDS wouldn’t have a granuloma in the tissue b/c there’s not enough
helper T cells to be able to form the granuloma.
o The macrophage inhibitory factor keeps the macrophages in the area; this is how
you get a localized granuloma. You get TB organisms with no granulomas.
• When you do PPDs on them, you accept five millimeters as a positive PPD; they are
considered immunocompromised. Normal (non-immunocompromised) people in an area
of low incidence have >15 mm as a positive PPD; non-immunocompromised people in
an area of high incidence have >10 mm as a positive PPD.

Reactions to Injury
- Heart
o Reaction is scar tissue.
o Scar tissue doesn’t contract, so the more damage you have to your free wall of your left ventricle, the
more your ejection fraction (Stroke volume / end diastolic volume) decreases.
- Kidney
o It also forms a scar tissue.
o Susceptible Areas in the Kidney
 The renal medulla is more susceptible to injury.
 The straight portion of the proximal tubule is most susceptible to injury b/c most of the
oxidative metabolism is located in that. That’s where the reabsorption of sodium and reclaiming
of bicarbonate, and more occurs.
 A close second is the medullary segment of the ascending limb (where the Na+-K+-2Cl-
cotransport pump is). This area is a close second for getting destroyed in tissue hypoxia.
• The pump generates free water.
o Water is obligated to out with every sodium, chloride, potassium, etc in your
urine. To generate free water (water that isn’t obligated), you take sodium,
potassium, and chloride away from its obligated water (the pump does that).
 29

o Antidiuretic hormone can reabsorb or get rid of free water, not obligated
water; ADH doesn’t work at the Na+-K+-2Cl- cotransport pump.
• In obligated water, you need 20 mL of water for every sodium, every potassium, and
every chloride.
o If you reabsorb 1 Na+, you leave 20 mL of free water in the urine.
o If you reabsorb 1 K+, you leave another 20 mL.
o If you reabsorb 2 Cl-, you have leave 40 mL.
o By reabsorbing Na+, K+, and 2Cl-, you generated 80 mL of free water.
• This is the pump that lasix blocks (in the thick ascending limb of the medullary
segment).
- Lung
o The repair cell of the lung is the type II pneumocyte (it can even repair and replace type I). Type II
also synthesizes surfactant.
- CNS
o The astrocyte is the repair cell of the CNS.
 It proliferates b/c it’s a stable cell; it’s not a neuron.
 It can proliferate and produce an increase in protoplasmic processes (called gliosis).
 An astrocyte proliferation is the reaction to injury in the brain; it’s analogous to the
fibroblast laying down type III collagen in a wound.
- Peripheral Nervous System
o In the peripheral nervous system, you have Wallerian degeneration.
 If you cut a nerve in half, the distal portion of the fiber undergoes wallerian degeneration.
 Within a day, the axon begins to break down, and the affected Schwann cells begin to catabolize
myelin and later engulf axon fragments, forming small oval compartments (myelin ovoids).
 Macrophages are recruited into the area and participate in the phagocytosis of axonal and myelin-
derived debris.
o The analogous cell in the CNS to the Schwann cell is the oligodendrocyte; both make myelin.
 A tumor of the Schwann cell is called a Schwanoma.
• If it involves the eighth nerve, it’s called an acoustic neuroma. Neurofibromatosis (an
autosomal dominant) has an association with acoustic neuromas.
- Sedimentation Rate (erythrocyte sedimentation rate) an IgM
o When the cells are stuck together like coins or aggregated, the cause is an increase in IgM.
o There’s a negative charge that normally keeps RBCs from sticking to each other; IgM is big enough that
it can offset the negative charge.
o IgM is a cold reacting antibody (cold agglutinins); they commonly produce agglutination; this is why in
cold weather you can get Raynaud’s phenomenon.
 IgM in cold weather causes RBCs to agglutinate in your digital vessels, nose, and ears and you
get ischemia to those areas (why you turn blue).
 Cryoglobulins (have nothing to do with IgM) congeal in cold weather; they can also produce a
similar symptoms as Raynaud’s.
 HCV has a high association withcryoglobulins.
 Both IgM and Cryoglobulins increase sedimentation rate.
- Multiple Myeloma
o Tends to involve IgG most of the time.
o Increases sed rate.
- Waldenstrostrom’s macroglobulinemia
o It’s a disease of plasma cells in which there’s macroglobulinemia marked by an excess in IgM (IgM is a
macroglobulin).
o It also increases the sed rate.
- Acute appendicitis
 30

o A CBC would be expected to show an absolute neutrophilic leukocytosis, it means you really have an
increase of neutrophils in you peripheral blood.
o You’re also looking for toxic granulation.
o The granules in the neutrophils has more granules (azurophilic) than normal.
o You also see a left-shift.
 Assuming you start from a myeloblast on the left and then through a series of divisions forms a
segmented neutrophil on your right, we normally go from left to right in maturation.
 When we do left-shift, it means that we go back to immature neutrophils; the definition is
>10% band neutrophils (aka stabs).
 If you had even one metamyelocyte or one myelocyte, that’s automatically left-shifted, you
don’t have to count bands.
o Myeloperoxidase is located in the azurophilic granules which are lysosomes. Toxic granulation ensures
that we have enough myeloperoxidase around to combat the bacteria.
 31

Fluid and Hemodynamics1

Begins at 31:14

Edema
- Edema vs. Pus
o Is excess space in the interstitial space; it’s the extracellular compartment and outside the vessel.
o Pus (an exudate) in the interstitial space is edema, but it doesn’t pit.
- Pitting Edema
o Someone with right heart failure (and transudate) and swelling of the lower extremities (there’s fluid in the
interstitial fluid) would have pitting edema.
o Exudates don’t pit, transudates do pit.
- Lymphatics
o If you block the lymphatics, it causes an increase in lymphatic fluid in the interstitial space; early on it does
pit, but for the most part it doesn’t pit.
- The three things that produce edema are transudates, exudates, and lymphedema; these are fluids in the
interstitial space. Only transudates can form pitting edemas.

Starling’s forces
- Albumin
o Albumin is responsible for keeping fluids in the blood vessels; this is called oncotic pressure. 80% of our
oncotic pressure is related to our serum albumin concentration.
o Anytime we have hypoalbuminemia, then we would have leaking of a transudate (a protein poor < 3.0
gm/dL cell poor fluid) through capillaries and venules (causing pitting edema).
- Hydrostatic Pressure
o Hydrostatic pressure is normally trying to push fluid out in our vessels.
- Hydrostatic Pressure and Oncotic Pressure
o In a normal person, oncotic pressure is greater than hydrostatic pressure, otherwise we would have
dependent pitting edema.
o Transudate could be produced in our interstitial space by a decrease in oncotic pressure and an increase in
hydrostatic pressure.
- Albumin Pathologies
o Albumin is made in the liver. If you had chronic liver disease, you’d have low albumin.
o Albumin can’t be vomited out in significant amounts. It can be eliminated in feces; it’s called
malabsorption.
o You can urinate it out; it’s called nephrotic syndrome. You can lose it from the skin in third degree
burns; you basically lose plasma.
o Another possibility for a low protein count is Kwashiorkor (decrease protein intake).

Alkalinity and Tiredness

- When you’re tired, it’s because you’re alkaline inside.
- Mechanism
o For every hydrogen that went into your stomach to make hydrochloric acid when you were thinking about
food (the cephalic phase of digestion).
 The cephalic phase is mediated by the vagus nerve and it stimulates parietal cells (to secrete acid)
and G-cells to release gastrin.
o Every hydrogen proton that went into the stomach combined with chloride but also had bicarbonate
simultaneously formed.
 The proton and bicarbonate were generated from carbon dioxide combining with water in the
parietal cell. Bicarbonate formed went into the bloodstream.
o Because of the increased bicarbonate, you develop metabolic acidosis.
 32

o In the gastric phase you’re in the process of reabsorbing the food that you ate. The hydrogen ions in the food
will be reabsorbed and reunite with the bicarbonate and you’ll no longer be in metabolic alkalosis.
o The compensation for metabolic alkalosis is respiratory acidosis; during respiratory acidosis the PO2
goes down.
o You have tissue hypoxia from a left-shift of the oxygen dissociation and this is why you get tired.

Left Heart Failure and Transudate in the Lungs

- Mechanism
o Increased hydrostatic failure from left heart failure.
o Things are backed up and since the lungs are behind the left heart and the cardiac output decreased, the end
diastolic volume and pressure in the left ventricle increase.
o The pressure is transmitted back into the left atrium.
 Since the pulmonary vein empties into the left atrium; it normally has an 8 mm Hg pressure and an
oncotic pressure of 25 mmHg (the oncotic pressure is up by 17 mmHg).
 As the hydrostatic pressure rises, it backs up blood into the lung and it approaches the oncotic
pressure and you start leaking transudate into the interstitial space which activates J receptors
and you get dyspnea.
o You get Kerney’s B lines on x-ray from the fluid in the interstitium.
o The fluid then goes into the alveoli and you get pulmonary edema.

Bee Sting on the arm and the face swells up

- It causes an exudate b/c it’s an anaphylactic reaction.
- The main operator is histamine and it’s a type I hypersensitivity. You have increased vessel permeability and you
have an exudate formed.
- First step in management is airway, next step is a 1/1000 aqueous epinephrine applied subcutaneously.

Cirrhosis
- Transudate is formed and pitting edema and ascites are present.
o Mechanism (2)
 Decreased oncotic pressure b/c you can’t synthesize albumin.
 Another cause is increased hydrostatic pressure b/c of portal hypertension.
• Because you have cirrhosis of the liver, the portal vein can’t empty into the liver so the
hydrostatic pressure increases and it pushes the fluid out into the peritoneal cavity.
o Another cause (unrelated to cirrhosis) is an increase in aldosterone which causes an increase in reabsorption
of salt and water.

Pitting Edema in the Legs

- Right Heart Failure and Increased Hydrostatic Pressure
o Scenario
 Patient had right heart failure and later started developing dependent pitting edema. What is the
mechanism?
 An increase in hydrostatic pressure.
 When you have right heart failure, then blood behind the failed right heart enters the venous system.
- If it’s cirrhosis of the liver, then it’s due to a decrease in oncotic pressure.

Lymphedema
- Modified Radical Mastectomy
o Scenario
 Patient had a modified radical mastectomy. The patient then developed a non-pitting type of edema.
What is the diagnosis?
 33

 Lymphedema. Modified radical mastectomy is the most common cause of lymphedema in this
country; in third world countries it can be due to parasitic worms.
- Lymphogranuloma venereum
o It also produces lymphedema. It’s a subtype of Chlamydia trachomatis.
o It has a tendency of scarring tissues and lymphatics.
o You can get lymphedema of the scrotum or the vulva.
- Peau D’orange
o Inflammatory carcinoma of the breast (peau d’orange of the breast) is also an example of lymphedema as
well.
o If you do a section through the breast, you’ll see dermal lymphatics plugged with tumor (the lymphatic
fluid leaks out into the interstitium).
o The ligaments that hold the skin down tether the skin down and the excess fluid produces dimpling effect
(peau d’orange).
- When you have chronic lymphedema you can run the risk of a sarcoma.

ECF and ICF

- ECF is extracellular fluid (1/3 of Total Body Weight)
o It has two compartments – vascular and interstitial. Interstitial is 2/3s larger than the vascular.
- ICF is intracellular fluid compartment (2/3 of Total Body Weight)
o It’s 2/3s larger than the ECF.
- Scenario
o How many liters of isotonic saline (only expands ECF) would you have to infuse in a patient to get 1 liter
into the plasma?
o 3 liters b/c of the 2/3 and 1/3 relationship. [Note: BRS of physio says plasma is ¼ of the ECF and not 1/3;
the rest is the interstitial space]
o You have to give 3 liters of isotonic saline; two of those liters would end up in the interstitial space, only one
would end up in the vascular compartment.
- In order to keep a patient’s blood pressure up when you’re hypovolemic, you have to really infuse the isotonic saline
b/c it’s not just staying in the vascular compartment (it equilibrates with the interstitial fluid compartment).

Osmolality
- It’s a measure of solutes in a fluid.
- Osmolality is mainly due to sodium, glucose, and blood urea nitrogen (BUN).
- Na is usually multiplied times 2 b/c it has chloride.

Fluid and Hemodynamics 2

Osmolality
- It’s a measure of solutes in a fluid. You can do an osmolality for urine, spinal fluid, sweat, …
- Calculating Osmolality
o It’s two times the sodium;(2x Na+).
o The glucose is divided by 18; (Glucose/18)
o Blood Urea Nitrogen (BUN)
 Urea Cycle
• The urea cycle is located in the liver (part is in the cytosol and part is in the
mitochondria; urea came from ammonia).
• The end product of the urea cycle is urea, but ammonia is what is fed into the system.
 The normal amount of ammonia is about 12 and you divide it by 3 so you get about 4;
(Ammonia/3)
- Quick Estimate
 34

o In a normal person, sodium is responsible for plasma osmolality. You double the serum sodium and
add ten; this will be roughly what the measured osmolality would be.
- Compartmentalization
o Sodium and glucose are limited to the ECF compartment.
o Urea if increased can equilibrate between the ECF and ICF across the cell membrane.
o Because sodium and glucose are limited to the ECF compartment, then changes in its concentration can
result in the movement of water from low to high (against the gradient and against diffusion); this is
called osmosis.
- Mental Status Abnormalities and Changes in Sodium Concentration
o If you have hyponatremia, water is going to go from ECF (the lower part is in the ECF) to ICF (it gets
expanded by the law of osmosis).
 If the brain were a single cell, we’d see cerebral edema.
 We will have mental status abnormalities.
• Signs and symptoms of hyponatremia would include mental status abnormalities (by the
law of osmosis). The intracellular fluid compartment of all the cells in the brain would
be expanded.
o If you had hypernatremia, you would have water going from ICF to ECF.
 The ICF gets contracted.
 In the brain, the intracellular compartments of the cells get contracted; this produces mental
status abnormalities.
o Whether you get hypo- or hypernatremia, you’re going to get mental status abnormalities.
- Glucose Affecting Osmosis
o If you have diabetic ketoacidosis and you have 1000 mg % blood sugar. Glucose now is the major factor
in osmosis (both sodium and glucose are limited to the ECF compartment).
o Sugars are only in sufficient quantity in the ECF
 Glycolysis doesn’t lead to glucose in the intracellular fluid compartment; all sugars are
phosphorylated to trap them.
 Glucose always goes in with phosphorous. Glucose immediately becomes glucose-6-phosphate
and is immediately metabolized.
 Fructose and galactose also get phosphorylated and metabolized immediately; fructose into
fructose-1-phosphate and galactose into galactose-1-phosphate.
o Water moves in the direction of the hyperglycemia, from ICF to ECF. ECF normally has 140 mEq of
sodium in it. The addition of water from ICF to ECF causes the serum sodium concentration goes down;
it’s called dilutional hyponatremia.
- The two things that control water movement in the ECF compartment are sodium and glucose; in a normal
situation, sodium is the major factor.

Tonicity
- Salines
o Normal saline is 0.9%.
o Hypotonic salines are ½ normal, ¼ normal, and 5% dextrose in water.
o Hypertonic sallies are 3% and 5%.
- Tonicity
o The tonicity of plasma is controlled by serum sodium.
- Types of tonicity
o Isotonic State
o Hypotonic State
o Hypertonic State
- When we do the serum sodium concentration in a laboratory, it is a reflection of your total body sodium
divided by your total body water.
o You can have hypernatremia and have a normal total body sodium by losing total body water.
 35

o Hyper- and hypornatremia is really a ratio of total body sodium to total body water.
- Total body sodium is not measured; clinical exam determines your total body sodium (edema). Serum sodium
can be measured in plasma (serum).
- There are different kinds of fluid abnormalities; we can lose or gain a certain tonicity of fluid.
o Isotonic loss of fluid (an example is diarrhea)
 It means you’re losing equal amounts of salt and water.
 The fluid would be lost from the ECF compartment.
 Your serum sodium concentration would be normal.
 Your ECF compartment would be contracted.
 You wouldn’t have an osmotic gradient for water movement into or out of the ICF.
 Examples are hemorrhage and diarrhea.
o Isotonic gain of fluid
 We gain an equal amount of salt and water.
 An example is a person getting too much isotonic saline.
 Serum sodium would be normal b/c it has equal amount of salt and water.
 The excess isotonic saline would be in the ECF compartment.
 There wouldn’t be any osmotic gradient for water movement.
o Hypotonic solutions
 The most common cause is hyponatremia. Hypoglycemia can’t produce a hypotonic condition
(b/c it is divided by 18).
 An example is if we lost more salt than water, then the serum sodium would be decreased.
 A diuretic would cause the loss of a hypertonic urine and you end up with hyponatremia and
hyponatremia.
 ICF has water move into it.
o Gaining pure water
 An example is inappropriate ADH syndrome (SIADH).
 Small cell carcinoma of the lung causes secretion of aldosterone.
 ADH renders the distal collecting and collecting tubule permeable to water (free water).
 You absorb water into the ECF compartment, diluting the serum sodium, and the ECF would be
expanded. The ICF would be expanded as well b/c of osmosis.
 Small cell carcinoma would lead to mental status changes b/c of the reabsorption of water.
 The treatment of choice for inappropriate ADH is to restrict water (not salt; the total body
sodium is normal). When ADH is present, you’re going to be concentrating the urine.
 The lowest serum sodiums are in inappropriate ADH. Serum sodium < 120; SIADH is
always the answer.
 Oralsulfonureas (especially the first generation ones) produce ADH 30% of the time.
 We would have a hypotonic gain of fluid and have a hypertonic loss of salt producing
hyponatremia.
 Edema
• You get water and salt (a little more water than salt). You still end up with
hyponatremia.
• Right heart failure, cirrhosis of the liver, …
• Your kidneys reabsorb a little more water than salt. You end up with hyponatremia and
pitting edema.
• The total body sodium (not the same as serum sodium; takes into account total body
water), when it’s increased, always produces pitting edema.
o The total body sodium is in the ECF compartment; the biggest compartment of
that is the interstitial. Whenever you have an increase in total body sodium,
 36

most of it is in the interstitial space; it expands with a transudate and you end up
with pitting edema.
o Hypertonic state
 It means you have hypernatremia or hyperglycemia (any patient who is in diabetic
ketoacidosis is by definition in a hypertonic condition; it’s more common than hypernatremia).
 When you have hypernatremia, the ICF compartment is contracted. You can gain more salt
than water.
 It can be seen in primary aldosteronism.
 When we lose pure water it’s called diabetes insipidus.
 We can lose a little more water than salt in the urine; this is called osmotic diuresis.
• When you have glucose or mannitol in your urine, you’re losing hypotonic salt
solution in your urine.
 Baby Diarrhea
• Baby diarrhea is a hypotonic salt solution; adult is isotonic.
o If a baby had no access to water, and a baby had a rotavirus infection, their
serum sodium would be high.
o They lose more water than salt and have hypernatremia.
o Treatment for the baby is pedialyte (a hypotonic salt solution); it replaces what
you lost.
 Pedialyte and Gatorade have to have glucose to reabsorb sodium in the GI tract. Sodium
has to be reabsorbed with glucose or galactose (fructose doesn’t facilitate it).
• Scenario
o In the oral replacement of patients with cholera, what has to be in that in order
for sodium to be reabsorbed?
o Glucose (b/c of the cotransport trump).
 Sweat is also a hypotonic salt solution. If you were sweating on a hot day, you should have
hypernatremia.

Arterial Blood Volume

- Effective Arterial Blood Volume (EABV) is the same thing as stroke volume and cardiac output.
- Baroreceptors
o The low pressure ones are on the venous side.
o The high pressure ones are on the arterial side (like carotids and arch of the aorta). The high pressure
ones are usually innervated by the ninth and tenth nerve.
- Physiology of a Decrease in Arterial Blood Volume
o When you have a decrease in arterial blood volume (aka a decrease in stroke volume or cardiac output)
you underfill the arch vessels and the carotid.
o Instead of having a ninth and tenth nerve response, you have a sympathetic nervous tissue response;
catecholamines are released.
 The catecholamines constrict the venous system; it increases blood returning to the right side of
the heart.
 It will also increase the force of contraction and increase the stroke volume a little.
 The systolic pressure will increase a little and the rate will also increase. The arterioles on the
systemic side will stimulate the beta receptors in the smooth muscle.
 Your diastolic pressure is really due to the amount of blood in your arteriole system while your
heart is filling up in diastole.
• The amount of blood in the arteriole system when your heart is filling up in diastole is
controlled by the peripheral resistance arterioles (this maintains the diastolic blood
pressure).
 37

• When the arterioles constrict, there’s little blood going to tissues; the bad news is the
tissues won’t get a lot of blood, but the good news is you keep your diastolic pressure
up (this is good b/c your coronary arteries fill up in diastole).
• This is all done by catecholamines.
 Catecholamines also stimulates the renin-angiotensin aldosterone system.
o Renin-Angiotensin II
 Renin is released and angiotensin II is going to be present; angiotensin II is a vasoconstrictor of
the arterioles (thereby increasing total peripheral resistance).
 Angiotensin II stimulates18-hydroxylase, converts corticosterone into aldosterone.
Aldosterone will reabsorb salt and water (get cardiac output up).
 If the stroke volume is decreased, then the renal blood flow to the kidneys is also decreased. This
is also a stimulus for the renin-angiotensin aldosterone system.
• The receptors for juxtaglomerular apparatus are in the afferent arteriole. ADH will
be released; it just contributes pure water (no salt).
- Normal saline can keep your blood pressure up; normal saline is plasma w/o the protein. Normal saline stays
in the ECF.
- Peritubular capillary pressures.
o Most sodium is reabsorbed in the proximal tubule (60-80%) into the peritubular capillaries. In
order for them to reabsorb, the starling forces in the peritubular capillaries have to be amenable to it (have
an increased oncotic pressure).
 If renal blood flow is decreased (when your stroke volume and cardiac output is decreased), the
hydrostatic pressure in the peritubular capillary is also decreased (and the oncotic pressure is
increased).
 The increase in oncotic pressure during a decrease in renal blood flow is what’s responsible
for reabsorbing anything into the blood stream from the kidney.
 In any patient with a decrease in cardiac output, this will happen automatically.
o When we have a decrease in ECF or a decrease in cardiac output, thekidney normally reabsorbs a
hypotonic solution.
 The tonicity of the fluid that you reabsorb out of the proximal tubule is isotonic.
 Aldosterone (from the renin-angiotensin system) reabsorbs a roughlyisotonic solutionfrom the
distal tubule, but not as much as the proximal tubule.
 ADH contributes pure water; this is what causes the overall fluid being reabsorbed to be
hypotonic.
- If the stroke volume and arterial blood volume were increased, then the reverse would happen.
o The baroreceptors are going to be stretched; they’re innervated by the 9th and 10th nerve.
o We don’t get a sympathetic nervous system response, but a parasympathetic response.
o We have no aldosterone or ADH activation.
o The peritubular hydrostatic pressure now is higher than oncotic pressure; even if salt was reabsorbed, you
wouldn’t be able to reabsorb it into your blood stream.
 You would lose a hypotonic fluid in your urine when you have an increase in arterial blood
volume.
- Atrial Natriuretic Peptide is a hormone made in the left and right atrium released if you have dilatation in
either atrium.
o It will cut off ADH and also cause a dumping of salt (acts like a diuretic).
o ANP is only released in volume overloaded states.
- Scenario
o Patient is given 3% hypertonic saline.
o You’re adding a hypertonic salt solution, the osmolality increases.
o If you have an increase in osmolality, it would increase the ADH; an increase in osmolality of plama or
serum causes the release of ADH.
 38

- Determining the total body sodium in a patient clinically

o If it’s high, they would have indentations in the skin
o If it’slow, their tongue would be dry.
o When you pinch someone’s skin and it goes down (testing turgor) you test if the total body sodium is
normal.
o If you have dependent pitting edema, total body sodium is increased.
o If you had inappropriate ADH and you’re gaining pure water, the total body sodium is normal, but the
sodium serum concentration is low. Water would have to be restricted.
- If you have right heart failure and dependent pitting edema your serum sodium is going to be low (b/c you
absorb a hypotonic solution; a little more water than salt).
- Treatment for Edemas
o A non-pharmacologic treatment of any edema states (heart failure and cirrhosis for example) is salt
restriction and water restriction.
o Treatment for inappropriate ADH is restrict water.
o Treatment for any pitting edema state is restrict salt and water.
o Pharmacologic treatment of pitting edema is diuretics.

Shock
- Causes of hypovolemic shock
o Diarrhea (cholera)
o Blood loss
o Sweating
o Diabetes Insipidus does not cause hypovolemic shock (you lose pure water and your total sodium is
normal). Most of the pure water would be lost from the ICF compartment.
o The salt is what’s important in hypovolemic shock.
- Scenario
o A woman when lying down had normal blood pressure and pulse. When she sat up, her blood pressure
went down but the pulse went up. What does it mean?
o It means they’re volume depleted. This is called the tilt test.
o The patient’s blood pressure and pulse was normal because no effect of gravity. When you sit the patient
up, you decrease (by gravity) the venous return to the right side of the heart. If you’re hypovolemic, it
will show up by a decrease in blood pressure and an increase in pulse. All these things occur when your
cardiac output is decreased; it’s due to catecholamines.
o Treatment would be normal saline.

Fluid and Hemodynamics3

- Sweat is a hypotonic salt solution.

- Scenario
o Patient ran a marathon and had profuse sweating. The pt. collapsed. Upon examination, the pt. has a
blood pressure of 100/80 and a pulse of 120 lying down. When sat up, the pt., has a 70/50 blood pressure
and a pulse of 150. What’s the first step in management?
o You infuse normal saline to increase the blood pressure. The blood pressure returns to normal, but the
patient still has signs of volume depletion. You have to give the patient a hypotonic salt solution. You
can’t give 5% dextrose b/c there’s no salt in it. A good choice for a hypotonic salt solution is ½ normal
saline.
- In fluid therapy, you give the patient what they lost. If the patient is hypovolemic, you first start with
normal saline.
- Scenario
o In diabetic ketoacidosis, you have osmotic diuresis. You have the have the loss of a hypotonic fluid in
urine when you have excess glucose in it. They have severe hypovolemia and that is what kills them.
 39

o First step in management is volume repletion. The first step is normal saline to make them normotensive.
Since you’re losing more water than salt, you use a hypotonic saline (1/2 normal saline) with insulin.
- Scenario
o You have a patient with diabetes insipidus. They go through surgery and afterwards they have a serum
sodium of 165. The patient’s blood pressure is stable and the patient is lucid. How would you treat this?
o You give them water.
o If it was dangerous to give them water (they could aspirate it), then you give them water intravenously
(5% dextrose in water is close enough to water).

Shock
- There’s 4 kinds of shock
o Skip neurogenic (for part 2); it deals with spinal cord injuries.
- Hypovolemic shock
o Blood loss, diarrhea, salt loss.
- Cardiogenic shock
o Most commonly due to a myocardial infarction
- Septic shock
o Most commonly due to E. coli (not Staph aureus). E. coli is the most common cause of sepsis in a
hospital; it probably comes from an indwelling urinary catheter.
o Gram negative organisms are gram negative b/c of endotoxins in the cell wall (lipopolysaccharides).
Gram negatives have lipid (endotoxins) in their cell wall; gram positives don’t. If you have E. coli sepsis,
you are going to be in septic shock. You can get septic shock from Gram positive organisms, but it’s
more common with gram negative organisms.
- Hypovolemic and Cardiogenic shock
o Skin feels cold and clammyb/c of vasoconstriction of the peripheral vessels by a decreased EABV
(Effective Arterial Blood Volume), stroke volume, and cardiac output. The main vasoconstrictors are
catecholamines and angiotensin II; they constrict the vessels in the skin and redirect the blood flow to
more important organs in the body (brain and kidney).
o Blood pressure is decreased and pulse is increased. In septic shock you have a decrease in both.
o Sidenote: Poiseuille’s law (R (total peripheral resistance) = 8ηl/[πr4])
 It’s a concept that teaches you about your peripheral resistance arterioles which control your
diastolic blood pressure.
 Resistance is directly proportional to the viscosity of the blood.
 Resistance is directly proportional to the length of the vessel
 Resistance is inversely proportional to the fourth power of the vessel radius.
 Scenario
• What is the main factor controlling TPR?
• The radius (it’s to the fourth power).
• The viscosity of the blood is controlled by hemoglobin. If you’re anemic, the viscosity
of your blood is decreased; if you have polycythemia it’s increased.
- Pathogenesis in Septic Shock
o In septic shock, you release endotoxins.
o The endotoxins activate the alternative complement system and cause the release of C3a and C5a
(they’re anaphylotoxins).
 C3a and C5a stimulate the mast cells to release histamine.
 Histamine vasodilates of arteries (the peripheral resistance arterioles).
• If the blood flow is increased in peripheral resistance arterioles, your skin feels warm
(like in acute inflammation).
 Endotoxins also damage your endothelial cells and cause the release of more vasodilators.
• Nitric oxide and prostacyclin (PGI2) are potent vasodilators; they further add to the
vasodilation of peripheral resistance arterioles.
 40

o Effects of Vasodilation
 TPR is decreased if you have vasodilation of arterioles (in endotoxin shock).
 TPR arterioles control your diastolic blood pressure b/c when they’re constricted, they can
control the amount of blood that remains in your arterial system while your heart is filling up in
diastole.
 If your arterioles are dilated, your diastolic blood pressure is going to decrease.
 When your peripheral resistance arterioles are vasodilated, blood comes gushing and it goes into
the capillary system (supposedly feeding tissues with oxygen).
• The blood is going too fast for the tissues to be able to get oxygen from it.
• The blood is going through fast and coming back faster than usual to the right side of the
heart.
• If blood is returning back faster than normal, then the cardiac output in septic shock is
increased.
o The cardiac output in hypovolemic and cardiogenic shock is decreased and the skin feels cold and
clammy; the opposite of septic shock. In septic shock, a high output failure occurs.
- Swan Ganz catheters can be used to see the parameters of the heart.
o Cardiac output can be measured.
o Systemic vascular resistance can be calculated based on things in the right heart; this is the TPR (tells you
what your arterioles are doing).
o Venous oxygen content
 Oxygen content = 1.34 x hemoglobin x oxygen saturation + PO2
 This can be measured in the right atrium with a Swan Ganz catheter
• It’s the best test for tissue hypoxia.
• Lactic acid is not a good test; there’s many things that can increase it.
o Mixed Venous Oxygen Content in different shocks
 Hypovolemic and Cardiogenic Shock
• Cardiac output in hypovolemic and cardiogenic shock is low.
o There’s not a lot of blood and it’s not being pushed out with a great amount of
force.
o The tissue will have time to extract the oxygen from the blood.
o The mixed venous oxygen content in hypovolemic-cardiogenic shock is
decreased (it’s very low).
 Septic Shock
• In septic shock, the mixed venous oxygen content is increased b/c it’s passing at a fast
rate.
o Pulmonary capillary wedge pressure
 It’s a measure of the left ventricular end diastolic volumeand pressure.
o Hypovolemic shock and Cardiogenic shock vs. Septic Shock
 Cardicac Output
• In hypovolemic shock and cardiogenic shock, cardiac output is decreased.
• It’s increased in septic shock.
 Systemic vascular resistence (aka total peripheral resistance) is the measure of what the arterioles
are doing.
• In hypovolemic and cardiogenic shock, it’s increased. It’s correlated with
vasoconstriction.
• The TPR in septic shock is decreased.
 Mixed venous oxygen content
• In hypovolemic and cardiogenic shock it’s low
• In septic shock it’s high.
 Pulmonary Capillary Wedge Pressure
 41

• It’s a measure of left ventricular end diastolic pressure.

• In hypovolemic shock, it would be low. In cardiogenic shock it would be high.
- Affect Of Shock on The Kidneys
o The kidneys suffer greatest from a decrease in blood pressure; in particular the medulla.
o The brain doesn’t suffer b/c of the circle of willis; if there’s a decrease in cardiac output, the circle of
willis will distribute blood flow to those areas of the brain with neurons.
o Acute Tubular Necrosis
 Someone with shock will present with oliguria, an increase in BUN, and creatinine which cause
shivers in your body.
 You can increase renal blood flow with dobutamine; this prevents the patient from going into
acute tubular necrosis.
 Your kidney can undergo coagulation necrosis; your dead renal tubules will slough off and
produce renal tubular casts (the pathognomonic cast in the urine for acute tubular necrosis) and
block urine flow (producing oliguria).
 In addition, other things will happen causing a decrease in glomerular filtration rate and you are
in acute tubular necrosis.

Sickle Cell Trait and Renal Medulla Sickling

- A person with sickle cell trait can get kidney disease b/c of the renal medulla’s oxygen tension is low enough to
induce sickling.
o Scenario
 Young black woman has normal physical exam except laboratory study revealed microscopic
hematuria. Everything else was normal. What’s the first step in the workup of the patient?
 Sickle cell screen
 The low oxygen tension in the renal medulla is low enough to induce sickling in the peritubular
capillaries; this produces microinfarctions in the kidney.

Acid-Base (includes Blood Gases)

- Henderson-Hasselbach
o If you have an acidosis (an increase in hydrogen ions), you have a decrease in pH.
o If you have an alkalosis (a decrease in hydrogen ions), you have an increase in pH.
- If we increased PCO2, it would increase hydrogen ions and you’d have respiratory acidosis.
- pH = bicarb/PCO2
o If we increase bicarbonate, it should increase the pH; metabolic alkalosis.
o If we decrease bicarbonate, it should decrease pH; metabolic acidosis.
o If we increase the PCO2, it would decrease the pH; respiratory acidosis.
o If we decreased the PCO2, it would increase the pH; respiratory alkalosis.
- Compensation
o The body’s attempt to try and maintain a normal pH.
o If you want to make the pH roughly stay at normal and you had metabolic alkalosis (an increase in
bicarbonate), you would have to increase the denominator (PCO2), this is respiratory acidosis, to try to
keep it normal.
o If we had metabolic acidosis (pH is decreased), we would try to get rid of PCO2 to increase the pH; the
compensation is respiratory alkalosis.
o Hyper- and hypo- ventilation refers to PCO2. Hyperventilation gets rid of CO2 and hypoventilation
refers to retaining CO2.
o Full compensation doesn’t exist; you never bring the pH back into the normal range. The one
exception is chronic respiratory alkalosis in high altitude people (in other countries).
- Controlling Breathing
o Respiratory center is in the medulla oblongata. This is what controls our breathing rate.
 42

o We have the upper airways and we have the chest bellows (diaphragm, intercostals, and
sternocleidomastoid).
 The most important muscle of respiration is the diaphragm.
• When the diaphragm goes down, your negative intrathoracic pressures increase; it sucks
air into your lungs and blood into the right side of your heart (this is your neck veins
collapse on inspiration).
o On expiration you have a positive intrathoracic pressure; it helps the left heart push blood out and helps
your lungs get rid of air.
o Respiratory Acidosis (due to decrease in breathing rate)
 If you take a barbiturate that depresses your respiratory center you’re going to get respiratory
acidosis. If you had CNS injury to the medulla, you would also get respiratory acidosis.
- Respiratory alkalosis (due to increased breathing rate)
o The most common cause is anxiety.
o As you get alkalotic, you’re ionizing calcium gets lower (the alkalotic state increases the number of
negative charges on albumin; more calcium is bound to albumin at the expense of the ionized calcium
level) and you get tetany (you twitch and feel numbness and tingling).
- Pregnancy
o All pregnant women have respiratory alkalosis.
o Estrogen and progesterone overstimulate the respiratory center.
o Women have spider angiomas (arteriovenous fistulas; related to high estrogen).
 In the lungs, there are many spider angiomas (A-V fistulas) so they clear more CO2 per breath
than a non-pregnant woman.
 The a-v fistulas (spider angiomas) go away after pregnancy.
- Septic Shock’s effect on the Respiratory System
o Endotoxins overstimulate the respiratory system.
o All patients in endotoxic shock have respiratory alkalosis.
o You have two Blood Gas Disorders at Once
 Since they’re in shock, they’re in anaerobic metabolism (so they have metabolic acidosis due to
lactic acid).
 They have respiratory alkalosis b/c of endotoxins overstimulating the system.
 The two states compensate each other somewhat. The pH is normal; this doesn’t mean you’re
fully compensated.
- Salicylates effect on the Respiratory Center
o Salicylates also overstimulate your respiratory center. It causes respiratory alkalosis.
o Salycylic acid (aspirin) is an acid so it causes metabolic acidosis. Your pH should be normal.
Salycylate intoxication usually have the mixed disorder.
- Inspiratory Stridor
o Scenario
 There’s a kid 6/o with inspiratory stridor. What’s the first step in management?
 Do a lateral x-ray and look for thumb print sign; this means you have a swollen epiglottis.
The diagnosis is acute epiglottitis due to H. influenza. The vaccination is decreased immensely.
H. influenza isn’t the most common meningitis in kids due to the vaccination.
o The most common depends on age.
 From 1 month (y/o???) to 18 y/o the most common is N. meningitis.
 If it’s a three month old kid with inspiratory stridor. It’s croup and due to
laryngotracheobronchitis.
• This is due to parainfluenza.
• On a lateral x-ray you see a steeple sign.
• The obstruction in croup is in the trachea (not at the level of the larynx, but below it).
- Café coronary (choking on food)
 43

o Chest pain, cyanosis, and collapse (or sudden death) during a meal, caused by aspiration of a bolus of
food into the trachea.
o If it’s a complete obstruction (they can’t talk) you do the Heimlich maneuver.
o If they can talk (it’s a partial obstruction) you do nothing and let them cough it out.
- Chest Bellows
o It’s innervated by the phrenic nerve.
o Erb-Duchenne Palsy
 Kids with Erb-Duchenne palsy are usually delivered by a breach and there’s a brachial plexus
injury.
 The kid has respiratory difficulty. The chest x-ray reveals the diaphragm on the right side was
elevated. If you paralyze the diaphragm, you’re going to retain CO2.
o ALS (amyotrophic lateral sclerosis) can die by from a paralyzed diaphragm.
o Scenario: Guillain-Barre
 You have an ascending paralysis in someone one week ago that had an upper respiratory
infection. Now they get a paralysis. Spinal fluid shows increased spinal fluid protein, a slight
increase in lymphocytes, and a negative gram stain. What is it?
 Guillain-Barre
o Polio virus can also lead to dysfunction of the diaphragm.
o Obstructive lung disease and restrictive lung disease.
 Obstructive lung disease has a problem in getting air out. Compliance is increased and elasticity
is increased.
 You retain CO2 so you usually have respiratory acidosis.

Nutrition

Nutritional Screening
- > 10% in 6 months
- > 5% in 1 month
- > 3% in 1 week
- Inadequate oral ingestion

Nutritional Norms
- Body Mass Index: 20-25 Kg/m2
Energetic Metabolism Norms and Nutritional Requirements
 44

i. Nutrients
a. Proteins = 4 kcal/g, Carbs = 4 kcal/g, Lipids = 9 kcal/g
b. NOTE: Carbs given intravenously give 3.4 kcal/g
c. Water, vitamins, minerals
ii. Nitrogen Balance
a. Balance = Nitrogen ingested – (nitrogen in urine in 24 hours + 4)
iii. Respiratory coefficient (RQ)
a. RQ = VCO2 (CO2 prod.)/VO2 (oxygen consumed)
b. Values according to which energy source is oxidated
i. Glucose = 1.0
ii. Lipids = 0.8 (in marasmus: marked depletion of subcutaneous fat)
iii. Protein = 0.7 (in kwashiorkor: lack of proteins in diet)
iv. Harris-Benedict (to calculate basal energy use)
a. Men: 66.47 + (13.75)wt.(kg) + (5)ht.(cm) + (6.76)age(yrs.)
b. Women: 655.1 + (9.56)wt. + (1.87)ht. + (4.67)age
v. Caloric Calculation (preferred to Harris-Benedict)
a. 20-30 Kcal/Kg/day
vi. Daily Protein requirements (affected by wt. and age)
a. Healthy: 0.8-1.0g/Kg/day
b. Diseased: 1.0-2.0 g/Kg/day
c. Pre-dialysis pts.: 0.55-0.6 g/Kg/day
d. Dialysis pts.: 1.0-1.4 g/Kg/day
vii. Carbohydrate requirements
a. 50-60% of total calories
b. Shouldn’t be greater than 5mg/Kg/min if infused
c. Shouldn’t be greater than 25Kcal/Kg/day
viii. Lipid recommendations
a. Linoleic Acid: 2-7 g/day
b. 20-30% total calories
c. No more than 1 g/Kg/day
ix. Water Requirements
a. ~ 1 ml/Kcal or ~ 25-30 ml/Kg
b. If there is a water deficit:
i. Water deficit (L) = wt. (kg) x 0.6[1-(140/Na)]
ii. Water deficit (L) = wt. (kg) x 0.6[1-(280/Osm)]
iii. Water deficit calculation does not include normal daily requirements
x. Vitamins (alimentation should be given < 24 hrs in order to obtain the best prognosis).

Nutrition1

Caisson’s Disease (aka Decompression Sickness)

- Occurs in people who go underwater.
- For every 30-33 ft. you increase 1 atmospheric pressure.
- The reverse is true when you go in high altitude.
o For example on the top of Mount Everest, the atmospheric pressure is 200; you still breathe 21% oxygen.
o The formula for calculating alveolar oxygen is 0.21(atmospheric pressure-partial pressure of
water[normally 47]) – PCO2/0.8.
o You have to hyperventilate at high altitude b/c as you lower the PCO2, you automatically increase the
PO2 in your blood.
- When you go under the atmospheric pressure increases.
o The nitrogen gases get dissolved in your tissue; that increases pressure.
 45

o If you suddenly come up after being deep underwater, nitrogen bubbles can develop in the body
fluids either intracellularly or extracellularly.
 The bubbles get in your tissue and also in your blood vessels; they block the blood flow (called
the bends).
 You end up with pain and could end up with quadriplegia b/c the little vessels that supply your
spinal cord are very susceptible to that. You could get loss of bladder control.
 The treatment for it is to put you in a hyperbaric oxygen chamber.

Nutrition
Eating Disorders
- Anorexia Nervosa vs. Bulimia Nervosa
o Biggest difference is distorted body image.
o Anorexia
 Woman with anorexia nervosa can be 60 lbs. but they think they’re fat.
• As you lose weight, your gonadotropin releasing hormone decreases (FSH and LH
decrease). You end up with low estrogen levels and you have no periods. It also means
you are going to develop osteoporosis as if you were post menopausal.
 Usually they die of cardiac disease and heart failure.
o Bulimia Nervosa
 They don’t have to be thin; they can be obese, thin, or normal weight.
 They don’t have a distorted body image.
 They binge; they eat a lot and then force vomit.
 Because of the vomiting, the acids will wear down enamel in the teeth. You’ll end up with just
dentin showing (it looks brown).
 They have a metabolic alkalosis because of the forced vomiting.
• This is a bad acid-base disorder b/c it left-shifts your curve and the compensation is
respiratory acidosis (it drops your PO2).
• You really develop hypoxia when you have metabolic alkalosis.
o It’s bad to your heart and your heart develops premature ventricular
contractures that can lead to v-fib and death.
 They can vomit up blood and get a Mallory-Weiss (have a tear in the distal esophagus-
proximal stomach).
• They may get Boerhaave syndrome where they have a rupture; air and secretions from
the esophagus get into the pleural cavity.
o The air can dissect through the subcutaneous tissue, come around to the anterior
mediastinum, and you get Hamman’s crunch.
o Scenario
 You have a young lady and when you put the stethoscope on the chest,
there’s a crunching sound there.
 It’s due to air that has dissected up into the interstitial tissue and into
your mediastinum. It means you have ruptured your esophagus.
Boerhaave’s syndrome is very common in bulimics.
 In Bulimia, the key things you want to remember are the vomiting, metabolic alkalosis
(which can induce arrhythmias), and Boerhaave’s syndrome.

Obesity
- In obesity, body mass index is used. It’s determined by kg of body weight/meter of height squared.
o If your BMI is 30 or greater, you’re obese.
o If it’s 40 or greater, you’re morbidly obese.
- The main complication of obesity is hypertension.
 46

o The mechanism isn’t fully understood, but it commonly occurs in obese individuals.
o If you have hypertension, you can get left ventricular hypertrophy and eventually you run the risk of heart
failure if you have left ventricular hypertrophy.
o Cardiac disease is the most common cause of death in hypertension.
- Gallbladder disease and cancers are associated with obesity.
- If you have a lot of adipose, then it means that you aromatize (from aromatase) a lot of 17-ketosteroids
(like androstenedione) into estrogens.
o If you have hyperestrinism (all women who are obese have hyperestrinism), you have an increased risk
of estrogen related cancers (breast cancer, endometrial adenocarcinoma).

Marasmus
- Is total calorie depravation. They have wasting away of their muscle.
- They have a good chance of survival b/c they get food.

Kwashiorkor
- They have calories, but it’s all carbs (they’re missing proteins).
- They have anemias, cellular immunity problems (when you skin test them for ability to react to Candida or
Mumps, they show no reaction). They have low albumin levels, ascites, fatty livers.
- They are more likely to die than those with marasmus.
- They’re apathetic and you have to force feed them.

Vitamins
- Fat Soluble Vitamins
o They dissolve in fat.
o It’s taken up by chylomicrons.
o It’s more likely to be stored in fat; toxicities are much greater than in water soluble.
- Water soluble Vitamins
o Are all cofactors for biochemical reactions.
- Vitamin A
o Vitamin A deficiency
 You look at the eye and would see an area of squamous metaplasia and see white spots.
Goosebumps (follicular hyperkeratosis) can be present on the skin.
o Functions
 It’s important in the growth of children (bone and muscle). You can have failure to thrive in
Vitamin A deficiency.
 It has a purpose in the eye (rhodopsin). The first sign of vitamin A deficiency is night
blindness.
 It prevents squamous metaplasia.
o Vitamin A deficiency can lead to squamous metaplasia in the eye; if it gets to be extensive, it could grow
over the eye and you could get softening of the cornea (keratomalacia) and you go blind.
o Vitamin A deficiency is number two cause of global blindness; number one being trachoma (Chlamydia
trachomatis). In the United States the leading cause is diabetes mellitus.
o Hypervitaminosis of Vitamin A
 The big game hunter who eats bear liver. He can get a headache because of cerebral edema.
Also papilledema; it can produce a headache.
o Retinoic acid is used for treating acne and acute promyelocytic leukemia.
o Vitamin A toxicity not only can produce intracerebal edema but also severe liver toxicity.
 If you have someone taking isotretinoic acid for cystic acne, you have to check her liver enzymes
and check for a headache (papilledema or cerebral edema).
- Vitamin D
o The most common source of vitamin D is when you go outside (sunlight).
 47

 7-dehydrocholesterol in your skin is what gets photoconverted to Vitamin D.

o It gets reabsorbed in your jejunum.
o It has to undergo two hydroxylation steps.
 First one is in the liver; it’s 25-hydroxylated.
 Second one is in the kidney; it’s 1-alpha hydroxylase in the proximal tubule.
• Parathyroid hormone is responsible for 1-alpha hydroxylase.
o Now you have active vitamin D
o Active vitamin D reabsorbs calcium and phosphorous from your jejunum.
 It has to absorb the two b/c its main job is mineralizing bone and cartilage; you have to have
an appropriate solubility product to be able to do this.
 Calcium and phosphorous are necessary to mineralize cartilage and bone.
o Parathyroid Hormone
 You get reabsorption of calcium where the thiazides block (early part of the distal tubule).
• There is a calcium channel that parathyroid hormone helps in the reabsorption of
calcium.
• Calcium has to take turns with sodium so most of the time, a sodium is being reabsorbed
out.
o When you’re on thiazides and you block sodium reabsorption, the channel
is open completely for calcium; this is why hypercalcemia is a potential
complication of thiazides.
 You could use it in therapy for calcium stone formers (the majority have
hypercalciuria). They have hypercalciuria b/c they reabsorb too much
calcium from their gut.
• It decreases reabsorption of phosphorous in the proximal tubule and bicarbonate.
• It also makes 1-alpha hydroxylase in the proximal tubules. It also helps Vitamin D get
that second hydroxylation.
o Vitamin D and Parathyroid Hormone
 Vitamin D’s main function is mineralizing bone.
• Osteoblasts are involved in this function.
• The receptor for Vitamin D is located on the osteoblast.
o When vitamin D hooks with the receptor, it causes the release of alkaline
phosphatase.
 Whenever you’re growing bone or making bone from a fracture, you
expect to see an increase in alkaline phosphatase.
 Parathyroid hormone breaks down bone and helps maintain calcium levels in the bloodstream.
• You’d think that it’s receptor would be on the osteoclast (the cell that usually breaks
bone down), but it isn’t.
o Calcitonin is the only hormone that has a receptor on an osteoclast.
 When calcitonin hooks into an osteoclast receptor, it inhibits the
osteoclast and this is why it’s used in treating hypercalcemia and
osteoporosis.
o The receptor for Parathyroid hormone is actually on the osteblast.
 When it hooks to its receptor on the osteoblast, it releases IL-1 (aka
osteoclast activating factor).
• The IL-1 released from the osteoblast is what stimulates the
osteoclast to break down bone and maintain our calcium levels
in our blood stream.
• IL-1 is checked by estrogen in women and testosterone in
men to prevent too much osteclastic activity.
 48

o This is the mechanism behind osteoporosis in women

after menopause; estrogen can’t check IL-1.
• Both work with calcium metabolism.
o Parathyroid hormone has a little bit more relationship with maintaining the
calcium levels in our blood; vitamin D is concentrated on mineralizing bone and
cartilage.
o When you have vitamin D deficiency, there could be a lot of reasons.
 Lack of sunshine, poor diet, liver disease.
 Inducing the P-450 System
• Scenario
o A patient was on phenytoin and the patient had hypocalcemia. Why?
o The phenytoin (along with barbiturates, alcohol, and rifampin) induces the
cytochrome P450 system (located in the smooth endoplasmic reticulum).
 You get smooth endoplasmic reticulum hyperplasia; this means you
metabolize drugs and other things made in the liver faster (which
includes 25-hydroxy vitamin D).
 Alcohol, phenytoin, rifampin, barbiturates, … anything that revs up the
cytochrome P-450 will cause a decrease in vitamin D as well as drugs
that you give the patients.
• Scenario
o You have a woman on phenytoin and birth control pills got pregnant. What
happened?
o Phenytoin revved up the system and increased the metabolism of the estrogen
and metabolism in the birth control pills so she didn’t have significant enough
levels to prevent her from getting pregnant.
• The smooth endoplasmic reticulum has gamma glutamyl transferase is the enzyme
of the smooth endoplasmic reticulum; when it’s revved up by drugs, you have an
increase in gamma glutamyl transferase (one of the key tests for picking up an
alcoholic).
 Liver Disease
• Liver disease can also do it; you can’t hydroxylase vitamin D.
 You can have a drug that revs up the system and it increases the removal and metabolism of it.
The most common, however, is renal disease.
• The most common cause of chronic renal disease in the U.S. is diabetes mellitus.
• You have tubular damage, no 1-alpha hydroxylase and then you have inactive
vitamin D.
o This is why all people that have chronic renal failure are put on 1-25
dihydroxycholecalciferol (vitamin D); this isn’t what you get in the store.
 If someone gets over the counter vitamin D it would have to get 25
hydroxylated in the liver and 1-hydroxylated in your kidney.
o Vitamin D deficiency in kids vs. adults
 It’s called rickets in kids; in adults its called osteomalacia (soft bones). Pathologic fractures are
very common.
 Kids
• In kids (rickets), they have craniotabes (soft skull); you can press in on their skulls and
it will recoil.
• They can get “rachitic rosary” (palpable areas at the juncture of the ribs with their
cartilage).
o Because that’s where osteoid is located in the costochondral junctions and b/c
they’re vitamin D deficient, there’s lots of normal osteoid waiting to be
 49

mineralized, but there’s not an appropriate calcium-phosphorous solubility

product.
o You get an excess of osteoid there that looks like little bumps (“rachitic rosary”).
• The rest is the same (pathologic fractures are the main one).
• Type I Vitamin-D dependent Rickets
o You’re missing the 1-alpha hydroxylase.
• Type II Vitamin-D dependent Rickets
o You’re missing the receptor for vitamin D.
o Hypervitaminosis of Vitamin D
 You run the risk for having hypercalcemia and then you run the risk of hypercalciuria.
Hypercalciuria can predispose renal calculi.
- Vitamin E
o Its main function is to maintain cell membranes; prevent lipid peroxidation of your cell membranes
(prevent it from getting broken down by phospholipase A).
o Its other function is it can neutralize oxidized LDL (more atherogenic than regular LDL). It therefore is
cardioprotective.
 Oxidized LDL is the LDL that macrophages will phagocytose and then become foam cells (part
of the atherosclerotic process).
o Deficiency is very uncommon
 If we see it, it would be in kids with cystic fibrosis. It’s because from birth, kids with cystic
fibrosis have not only respiratory problems, but also have malabsorption problems (b/c of
problems in the pancreas).
 One of the features is hemolytic anemia. If it’s susceptible to free radical damage and you
damage the membrane of the RBC, you’re gonna get a hemolytic anemia.
 Another feature is related to myelin.
• They can get posterior column disease and spinal cerebellar types of disease.
 You can get neurological problems and hemolytic anemia.
 Vitamin E toxicity
• It prevents the synthesis of the Vitamin-K dependent coagulation factors (II, VII, IX,
X, protein C, and protein S). In other words, you’re anticoagulated.
o If you have an anterior myocardial infarction, they frequently anticoagulate you
(you go home on 3 months of warfarin).
o If you take a lot of vitamin E with warfarin (blocks gamma carboxylation of the
vitamin K dependent factors), you overcoagulate yourself.
- Vitamin K
o Most of it is synthesized from colonic bacteria (anaerobes).
o Babies and Vitamin K deficiency
 When babies are born, they only have about 3 days worth of vitamin K (it’s not in breast milk
and they don’t have the bacteria in their gut to make the vitamin K).
• This is why you can get a hemorrhagic disease of the newborn during this time; they can
bleed in the brain and die.
 After five days, their gut is colonized and then there’s no problem.
o Activating Vitamin K (K2 to K1)
 The bacteria make a vitamin K inactive form (K2).
 K2 has to be converted into K1 (the active form); this is accomplished by epoxide reductase.
o Function of Vitamin K
 Activation of Vitamin-K dependent clotting factors
• K1 gamma carboxylates the vitamin K dependent factors (II, VII, IX, X, protein C and
S).
 50

o Gamma carboxylation of the vitamin K factors activates them so that they’re

functional.
• The vitamin K-dependent factors all have something in common; they have to be
activated by vitamin K1 and they’re the only coagulation factors that are bound to a clot
by calcium.
• If you can’t bind them, then you’re anticoagualted.
• Mechanism
o Vitamin K gamma carboxylates the glutamic acid residues on the vitamin-K
dependent factors; it allows calcium to bind those factors.
• You’re now able to form a clot.
o Warfarin inhibits the epoxide reductase; this means that all the vitamin K we have is K2 and we
can’t gamma carboxylate anything.
o Vitamin K deficiency
 The most common cause is broad spectrum antibiotics.
 Poor diets, being a newborn, a malabsorption syndromes.
 If you’re deficient in it, you have a hemorrhagic diathesis (into brain, skin, …).
 Scenario
• A 6 day old child was being breast fed and had a bleeding diathesis. Why is that?
• There wasn’t enough vitamin K in breast milk and the kid was vitamin K deficient.
 Scenario
• A kid ate rat poison.
• Rat poison is warfarin.
• Treatment is intramuscular vitamin K.
 Scenario
• A kid lived with his grandparents (you have to assume they have warfarin) who are
elderly and the kid developed a hemorrhagic diathesis. Why?
• The kid got a hold of some of the warfarin from the grandparents, ate it, and then became
anticoagulated.
Nutrition2
Water Soluble Vitamins

Vitamin C
- Vitamin C hydroxylates proline and lysine. It does this in the golgi apparatus; it’s a post-translational modification.
- Vitamin C is a cofactor in the production of catecholamines; convert norepinephrine to epinephrine.
- Vitamin C Deficiency
o Scenario: Scurvy
 Elderly person on a tea and toast diet (tells you they’re malnourished). The patient gets bleeding
of the gums when they’re brushing their teeth.
 Give away for scurvy.
o Vitamin C deficiency results in weak collagen b/c you can’t cross-bridge it.
o Your blood vessels are unstable and they rupture.
o Your gums bleed b/c the gums have type I collagen and it’s weak. You get inflammation, bleeding from the
gums, you can lose your teeth, and you frequently get hemarthrosis.
o Scenario
 What vitamin deficiency is associated with a complication commonly associated with severe
hemophilia A (hemarthrosis)?
 Vitamin C
o Perifollicular hemorrhage
 The hair follicles will have hemorrhage all around them b/c of the blood vessels around the follicles.
You can also get corkscrew hair.
 51

o Glossitis and angular cheilosis.

- Excess Vitamin C
o Increase in uric acid stones and other stones.
- Therapy
o It can be used as ancillary treatment of methemoglobinemia.
o It’s a reducing agent and is a great scavenger hunter for free radicals.
Thiamine
- Cofactor
o Thiamine is a cofactor for transketolase reactions and dehydrogenases in oxidative decarboxylation of alpha
keto acids.
 Transketolase reactions are involved in the pentose phosphate shunt.
 Pyruvate dehydrogenase is an example of a dehydrogenase involved in oxidative decarboxylation of
alpha keto acids.
• Pyruvate dehydrogenase is the main reaction that converts pyruvate into acetyl coA;
pyruvate can also be converted to oxaloacetic acid with a carboxylase enzyme.
• When you combine acetyl coA with oxaloacetate, you make citrate and you are in the TCA
cycle with the potential for making many ATP.
- Thiamine Deficiency
o If you were thiamine deficient, you’re going to decrease acetyl coA, which decreases citrate, which decreases
ATP. The problem with thiamine deficiency is ATP depletion.
 Just going from pyruvate to acetyl coA generates 2 NADH; since it’s in the mitochondria, it can
generate 3 ATP and you can have a net gain of 6 ATP. The citric acid cycle can generate 24 ATP.
o The most common cause of thiamine in this country is alcohol.
o Dry Beriberi
 In dry beriberi, you have peripheral neuropathies (also refers to Wernicke-Korsakoff).
• You need a lot of ATP to make myelin.
o If you’re ATP depleted, you can’t make myelin.
• You get peripheral neuropathies like foot drop (due to common peroneal palsy), wrist drop
(radial nerve), claw hand (ulnar nerve), …
 In Wernicke’s encephalopathy (you get confusion, ataxia, and nystagmus); Korsakoff’s psychosis
(you can’t remember old things and new things).
o Wet Beriberi
 Wet beriberi refers to cardiomyopathy.
 The heart needs ATP, so thiamine deficiency will cause congestive cardiomyopathy.
 Their heart is going to have biventricular enlargement and they have both left and right heart
failure.
• They get pitting edema, which is a sign of right heart failure related to increased hydrostatic
pressure behind the failed heart.
• You also get pulmonary edema b/c of left heart failure. If you give intravenous thiamine to
alcoholics that have this, in some cases you can reverse this entirely.
o Scenario
 A person comes into the emergency room with something that requires an IV. They’ll say what was
put in intravenously was 5% dextrose and normal saline. They’ll say that all of a sudden the patient
developed confusion and the patient has nystagmus. They may talk about opthalmoplegia and eye
weakness. What happened?
 They were in subclinical thiamine deficiency. As soon as you hung up the glucose on him, the
glucose went to pyruvate, and the pyruvate went to his acetyl coA and used up the rest of his
thiamine (and you went into acute Wernicke’s encephalopathy).
 The moral of the story is you give IV thiamine before you hang up any IV with glucose in it
(usually in the setting of an emergency room).
 52

• When people come into the emergency room comatose or semicomatose, a couple things you
do are 50% glucose (incase it’s due to hypoglycemia), nalaxone (incase it’s an overdose), and
IV thiamine.
Niacin
- Niacin Deficiency (Pellagra)
o Has a rash in a sun exposed area (dermatitis is a rash).
- NAD+ and NADP+ are derived from niacin.
- Tryptophan can be used in synthesizing niacin; tryptophan can also be used to synthesize serotonin.
- Nicotinic Acid
o The least expensive lipid lowering drug is nicotinic acid; it has flushing associated with it (you’re
supposed to take an aspirin before it).
o It’s used in treating familial combined hyperlipidemia.
o When you have elevated cholesterol and triglyceride, it’s the drug of choice.

Riboflavin
- FAD and FMN reactions are riboflavin cofactor reactions.
- In the first reaction that converts oxidized glutathione to glutathione, glutathione reductase is the enzyme and
riboflavin is the cofactor for it.

Pyridoxine
- The first reaction in the synthesis of heme involves succinyl CoA + glycine (the enzyme is ALA synthase and the
cofactor is B6).
o It’s important in the synthesis of hemoglobin and heme proteins. The cytochrome system is the heme system
also.
o Myoglobin has heme, except myoglobin differs from heme in that hemoglobin has 4 heme groups where
myoglobin has 1.
o There’s heme in the liver (cytochome system) and B6 is important in that.
- Pyridoxines are involved in the transaminase reactions.
o An amino acid can be used to make glucose b/c of transamination; transaminases can take amino groups, and
put amino groups into things.
 The most abundant substrate for making glucose in the fasting state is alanine (an amino acid
from muscle).
• Transamination of alanine produces pyruvate (an alpha-keto acid); the vice versa is true.
 If you take aspartate (an amino acid) and take its amino group, you have oxaloacetate (a substrate
for gluconeogenesis); the vice versa is true.
- B6 is also involved in the synthesis of neurotransmitters.
o This is why if a child is B6 defiicent, they end up with severe neurologic problems and convulsions.
- The most common cause of deficiency is isoniazid; this is why isoniazid should be given along with vitamin B6,
otherwise they can develop neurologic problems or sideroblastic anemias (related to the heme problem).

Panthothenic acid
- Is involved with fatty acid synthase (not the rate limiting acid in fatty acid synthesis, but is important in making
palmetic acid [a 16 carbon fatty acid]).
- It also helps in making coenzyme A reactions (acetyl CoA, HMG-coA).

Biotin
- It’s a cofactor in another reaction with pyruvate (pyruvate is converted to oxaloacetate by pyruvate carboxylase; it
involves biotin). Remember thiamine is involved in converting pyruvate to acetyl CoA.
- Biotin Deficiency
o If you’re deficient in it, you’d have to eat 20 raw eggs a day (they have avidin in them).
o You go bald and have a rash.
 53

o If you’re biotin deficient, you can’t form oxaloacetate, then it means you can’t form citrate either.
 This is the first step in gluconeogenesis and you end up with fasting hypoglycemia.
 Second, you get a buildup of pyruvate; it’s going to be forced to go into lactic acid.

Trace Elements
- Chromium
o It’s used for the glucose tolerance factor; it helps insulin do its job.
o If you’re a type II diabetic, it would help b/c it enhances what little insulin you have.
- Copper
o Lysyl oxidase requires it. It’s the enzyme that puts the cross-bridges between collagen fibrils and elastic
tissue as well.
o If you’re copper deficient, then you have weak collagen and weak elastic tissue. This is why you can get a
dissecting aortic aneurysm.
o Red hair in a person with Kwashiorkor is due to copper deficiency.
- Fluorine
o You need it to prevent dental caries.
o If you have too much fluorine, you’re going to get mottled teeth (white chalky teeth). If you’re from
Colorado, you got it, b/c the water from there has too much fluorine.
o Too much can cause calcification of the ligaments where the ligaments go into bone.
- Selenium
o It’s a component of glutathione peroxidase (converts hydrogen peroxide to water in the pentose phosphate
pathway).
 Riboflavin helps this enzyme (it helps convert oxidized glutathione to glutathione via glutathione
reductase).
 Glutathione can neutralize peroxide; this requires glutathione peroxidase (selenium is the cofactor for
it).
o Selenium is an antioxidant b/c if you’re deficient in it, then glutathione can’t break down peroxide.
- Zinc
o Scenario
 An older person that has dysgeucia (means abnormal taste). They also have anosmia (can’t smell).
o Smell and taste are both deficient in zinc deficiency.
o Zinc is a metalloenzyme (an enzyme that has a trace metal as a cofactor).
 An example is collagenase (it has zinc in it); it breaks down the type III collagen so that you can
form type I collagen.
• This is why if you are deficient in zinc, you have poor wound healing. You can get a rash
on your face.
o Diabetics are all zinc deficient unless they’re taking zinc supplements.

Dietary fiber
- Soluble vs. Insoluble
o Soluble is the fiber that can lower cholesterol.
o Insoluble Fiber
 Oatmeal has insoluble fiber in it.
- When its in your gut, it sucks up water into it (from the colon) and damaging things (like lithocholic acid).
o 95% percent of bile acids and bile salts are reabsorbed in the terminal ileum; the 5% is lithocolic acid (it’s
carcinogenic and produces colon cancer).
o If you’re on fiber (insoluble or soluble), it sucks the lithocolic acid out into the interior of the stool (it has no
contact with your bowel mucosa).
- It also causes you to defecate more often; this causes even less contact with the stool.
- Fiber also increases estrogen excretion
 54

o Women recycle estrogen.

o The main way of excreting estrogen is in bile and out of stool, but a small percentage of the estrogen is
recycled back into the system.
o When you’re on fiber, it takes the estrogen that would be recycled back, and it’s eliminated; you decrease
risks of breast cancer, ovarian cancer, and uterine cancer.

Special Diet
- Protein restriction
o Renal Failure
 Renal failure would require protein restriction, b/c if you have excess protein, it’s going to be broken
down into ammonia and other things.
 Ammonia will have to be metabolized in the urea cycle, you’ll have increased urea, and this means
that the kidney is going to have to get rid of more urea.
o Cirrhosis
 Cirrhosis of the liver also requires protein restriction.
 You have a defective urea cycle and therefore you can’t metabolize ammonia.
 Most of the ammonia we have in our bodies comes from bacteria in our colon that have urease in
them (Helicobacter pylori and anaerobes).
• Urea is broken down into ammonia in our colon. Ammonia is then reabsorbed. It’s
supposed to go back to our liver and go into the urea cycle and become urea and we get rid of
it.
 If we have cirrhosis, we have no urea cycle so the ammonia levels increase in our blood and
they result in the different changes associated with hepatopathic encephalopathy(mental status
abnormalities, asterixis,…).

Neoplasia1
Starts at 31:24

Nomenclature
- Benign vs. Malignant
o Benign usually doesn’t metastasize and malignancy has the capacity to do so.
o There are exceptions (an invasive mole is a benign tumor that can metastasize to your lungs but will go
away).
o Basal cell carcinoma is the most common skin cancer; it invades but doesn’t metastasize.
- Leiomyoma
o Scenario
 The most common benign tumor in a woman is most commonly located in which of the
following organs?
 Uterus b/c the most common tumor is a leiomyoma. Leiomyoma is a tumor of smooth muscle.
o Fibroids is often used for leiomyomas, but it isn’t.
o They look like scar tissue.
o They don’t become leiomyosarcomas.
- Lipoma
o This is the most common benign tumor in a man.
o It’s yellow.
- Adenoma
o A benign tumor of glands.
o It can be found in the adrenal glands.
 55

 It could be making cortisol (would suppress ACTH and produce Cushings). Zona reticularis
and zona vesiculata would undergo atrophy.
 It could make mineralcorticoids (Conn’s syndrome). It would cause atrophy of the zona
glomerulosa (normally produces mineraalcorticoids.
 The three layers are GFR (glomerulosa, fasiculata, and reticularis). Glomerulosa affects salt,
fasiculata affects glucocorticoids, and reticularis sex hormones.
o Tubular Adenoma is the most common precursor lesion for colon cancer (looks like a strawberry on
a stick).

Carcinoma and Sarcoma

- Carcinoma is a malignancy of epithelial tissue (there’s three: squamous, glandular, and transitional).
o Squamous carcinoma
 Recognized by swirls of increased redness (squamous pearls).
o Adenomocarcinoma
 You would see glands inside.
o Transitional Cell Carcinoma
 They would come from the genital urinary tract (bladder, ureter, and renal pelvis; all have
transitional epithelium).
- Malignant Melanoma

o First step in management is excision.

o It’s a malignancy of melanocytes. The benign lesion is called a nevus.
o It’s the most rapidly increasing cancer in the U.S.
o They’re S-100 antigen positive and they’re APUD tumors (amine precursor uptake decarboxylation).
 S-100 antigen is an antigen used for staining things of APUD origin (neural origin); most
will take up the stain.
 APUD tumors are of neurosecretory or of neural crest origin. When you do an electron
microscopy, they have neurosecretory granules.
• APUD tumors are melanomas, small cell carcinoma (of the lung), and bronchial
carcinoid tumors.
o Bronchial carcinoid is also an APUD tumor and is less malignant than small
cell carcinoma. It’s a carcinoid tumor of the tip of the appendix.
• Neuroblastomas are also APUD neurosecretory tumors. They can be found in the
medulla of the kidney in a child.
 Scenario
• 2 y/o had nodules all over the skin. They did a biopsy and found small hyperchromatic
cells that were S-100 antigen positive. Where is the tumor coming from?
• Adrenal Medulla; it was a neuroblastoma that metastasized from the skin.
- Sarcoma
o They’re a malignancy of mesenchymal tissue, not epithelial.
o Osteogenic sarcoma
 This tumor makes bone. You see it on the metaphysis of a bone; it can split up the periosteum
and show “Codman’s triangle”.
 On an x-ray you can a “sun-burst” pattern.
o Embryonal rhabdomyosarcoma (aka Sarcoma botryoides)
 Scenario
• A little girl had a biopsy. She had a necrotic mass coming out of her vagina. It was
vimentin negative, keratin negative, and desmin positive.
 It has striations in it.
 56

 Is the most common sarcoma in children. It comes out of the vagina in little girls and out of
the penis of little boys.
o Leiomyosarcoma – sarcoma of smooth muscle.
o Rhabdomyosarcoma – sarcoma of striated muscle.
o Liposarcoma – sarcoma of fat.

Mixed tumor (aka Pleomorphic Adenoma)

- Can be encountered as a movable mass at the angle of the jaw in the parotid gland.
- It’s your most common overall salivary gland tumor. It’s usually benign and occasionally malignant.
- It’s mixed b/c it has two histologic different types of tissue, but they derive from the same cell layers (it’s not
a teratoma; they’re derived from all 3 cell layers [endoderm, ectoderm, and mesoderm]).
o Scenario: Cystic teratomas of the ovary
 16 y/o girl with a sudden onset of right lower quadrant pain (to confuse with appendicitis,
Crohn’s disease, ectopic pregnancy, follicular cyst,…). An x-ray shows calcifications in the
pelvic area.
 Cystic teratoma. The calcifications could be bone or teeth.
 Also known as germ cell tumors (b/c they’re totipotential). They have a tendency of staying in
the midline.

Leukemia vs. Lymphoma

- Auer rod in a myeloblast. (Due to leukemia)
-
- Hypersegmented neutrophil. Due to B12 folate deficiency.
-
- Leukemia
o Is a malignancy of stem cells arising from the bone marrow.
o Like all cancers, they can metastasize out of it and always do.
 Lymph nodes – you have generalized lymphadenopathy.
 Hepatosplenomegaly
- Malignant lymphoma
o Arise from lymph nodes.
o Because they’re malignant, they can metastasize wherever they want (including bone marrow).
o The most common site for a lymphoma not developing in a lymph node is the stomach.
 Most extranodal (outside lymph node) primary lymphomas occur in the stomach. Helicobacter
pylori can produce them.
o The second most common location is in Peyer’s patches (a lymphoid organ in the GI tract). Peyer’s
patches are located in the terminal ileum.
o Follicular B-cell lymphoma

 It’s an example of inactivation of an apoptosis gene. It’s a 14-18 translocation of a heavy
chain. When you get the translocation, the B cells make a BCL-2 product which inactivates
the apoptosis gene in the B cell. BCL-2 is involved in programmed cell death.
 B cell lymphoma is the most common of all the lymphomas.

Trophoblastic Tumors
- These are tumors we see in pregnancy.
- Males can get them too (non-gestational).
- Hydatidiform mole
-
o It looks like a bunch of grapes.
 57

o They present in the first trimester with signs of pre-eclampsia.

 Any patient that presents with hypertension, proteinuria, and edema in the first trimester, you
have to do an ultrasound and you’ll see that you have a uterus too large for gestational age
with snowstorm effect from the ultrasound.
o The hyadatidiform mole is a benign tumor of the whole chorionic villus. It looks like grapes b/c
they’re all dilated up.
- Mole
o Is a uterine mass arising from a poorly developed or degenerating ovum.
o A complete mole has the highest tendency for going into choriocarcinoma.
o A mole is a benign tumor of the chorionic villus.
 Chorionic villi.
• Chorionic villi are lined by trophoblastic cells.
o They include syncytiotrophoblast on the outside; this is the part that has
contact with the blood and where oxygenis extracted.
• Under the trophoblasts are the cytotrophoblasts, then the Warton’s jelly in the chorionic
villus.
• In the middle of the chorionic villus is the vessel that then becomes the umbilical vein.
o The umbilical vein is the one vessel thathas the most oxygen of all the vessels
in the fetus.
- Choriocarcinoma
o It’s not a malignancy of the chorionic villus (hydatidiform mole).
o It’s a malignancy of the lining of the chorionic villus (syncytiotrophoblast and the cytotrophoblast).
 Syncytiotrophoblast is the one that makes hormones.
• Beta-hCG
• Human placental lactogen (growth hormone of pregnancy) gives the amino acids and
glucose from the mother to the baby.
o When they’re gestationally derived, even though the metastatic to lung (their favorite site), they respond
very well to chemotherapy (methotrexate, chlorambucil,…).
 It’s an example of a highly malignant tumor, but you can get near entire remission with
chemotherapy.
Neoplasia 2

All that ends in –oma is not necessarily benign

- Melanoma for example is not benign; it’s a malignant melanoma. Lymphoma too; it’s a malignant tumor of the
lymph nodes.
- All that ends in –oma isn’t necessarily a neoplasm.
- Hamartoma
o It’s an overgrowth of tissue that’s normally present in that area.
o Bronchial Hamartoma
 It’s benign cartilage.
 It presents as a solitary coin lesion in the lung.

o Peutz-Jegher’s
 The polyp of Peutz-Jegher’s syndrome is a hamartoma; it isn’t a neoplasm. This is why
there’s no increase risk for colon cancer in Peutz-Jegher’s syndrome; the polyps aren’t
neoplasms.
 The hyperplastic polyp – the most common polyp in the entire GI tract is the hamartoma
(not a neoplasm).

- Choristoma (Heterotopic Rest)
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o A section of stomach shows in the muscle wall a benign pancreatic tissue. It doesn’t belong there.
o When you have benign tissue in a place that shouldn’t be is called a choristoma or heterotopic rest.
o Meckel’s Diverticulus
 Meckel’s diverticulus is a classic example.
 The most common complication is bleeding from usually either gastric mucosa that’s ulcerated
or something pancreatic tissue causing the ulceration.
 Gastric mucosa shouldn’t be in a Meckel’s diverticulum (it’s a small bowel, roughly 2 feet from
the ileal cecal valve); it’s an example of a heterotopic rest (pancreatic tissue shouldn’t be in it).
o Hamartoma’s are non-neoplastic lesions and therefore have no potential for producing cancer.

Cancer
- A misconception is that increased mitotic rate means cancer.
- What makes a mitosis malignant is more chromosomes than normal.
- When you have an atypical mitotic spindle (it relates to the fact that it’s aneuploid – have more than the normal
46 chromosomes), that’s cancer.
- The key thing that determines if something’s malignant is the ability for something to metastasize.
- Malignant cells usually have a longer cell cycle from the one they derived from.
- 30 doubling times is the number of doubling times it takes before you can get a tumor you can detect
clinically.
- Malignant cells are immortal.
o Burkitt’s lymphoma cells are used for tests in immune complexes.
- The cells lack adhesion and it’s important b/c if they were stuck to each other, they wouldn’t be able to infiltrate
tissues.
- They have simple biochemical systems, usually anaerobic metabolism.
- They have lots of enzymes; they have to have proteases (it’s what is used to break through the tissues).
Collagenases are an example (to break through the basement membrane).
- Metastasis
o Three modes of metastasis
 Lymphatic
 Hematogenous
 Seeding
o Carcinomas usually initially metastasize by lymph nodes.
 They drain to their regional lymph nodes (i.e for breast cancer, they go to the axillary or
internal mammary nodes; for colon cancer, the nodes around it; for esophageal cancer, the local
lymph nodes).
 They go to the subcapsular sinus part of the lymph node.
 If they can get through that lymph node, then they go into the efferent lymphatics; that drains into
the thoracic duct which goes into the subclavian and then they’re hematogenous (this is how they
can spread hematogenously).
 When they’re hematogenous (it means they got through the lymph node), they can go to bone and
liver, and other places.
o Carcinomas vs. Sarcomas
 Because carcinomas go to the lymph nodes first, we can feel the lymph node (by physical
exam) and probably pick it up at an early stage; unlike sarcomas (they go right through
blood vessels and they usually characteristically metastasize hematogenously).
• This is why the lungs and the bone are such common sites for sarcomas.
• If you have an angiosarcoma of the breast, you wouldn’t have to do a radical dissection
of the axilla (b/c angiosarcomas don’t go to lymph nodes).
 59

o If it was a breast cancer (carcinoma), you would take the breast or you’d do a
lumpectomy and you’d sample a couple of lymph nodes or do a complete
dissection (b/c carcinomas go there).
 Sarcomas like to go in the blood vessel. Some carcinomas like to go into the blood vessel (ex.
follicular cancer of the thyroid and renal adenocarcinoma [it likes to invade the renal vein]).
 Hepatocellular carcinomas always invade vessels.
o Seeding
 Cancers that are in cavities (ex. ovarian) have a tendency of seeding malignant implants.
 Most ovarian cancers are surface derived; they’re derived from the lining around an ovary.
• It’s easy for them to seed and through out malignant implants of small pieces of cancer;
they go over the omentum and into the Douglas pouch [poster to the uterus and anterior
to the rectum; felt by rectal exam]).
• The pouch of Douglas is to a woman as the prostate gland is to a man; when you do a
rectal on a man and press forward, you feel the prostate and on a woman you feel the
rectal pouch of Douglas.
o It’s the most dependent part of a woman’s pelvis; where things like unclotted
blood go and a ruptured ectopic, where endometrial implants go in
endometriosis, where seeding goes in ovarian cancers (the pouch of Douglas).
 Ovarian cancer can seed (invade) the omentum.
 You can also seed in the pleural cavitiy; if you have a peripherally located lung cancer.
 Glial blastoma multiforme – the most common primary malignancy of the brain in adults
can seed into the spinal fluid and implant the entire spinal cord. A medulloblastoma in a child
can do the same thing.
- Most common cancers
o First ask yourself is metastasis more common than the primary cancer? In most cases, metastasis is the
most common cause of cancer in an organ, not a primary cancer.
 Exception: renal adenocarcinoma is the most common cancer (it’s a primary cancer).
o Lung
 Most common cancer is metastasis from the breast. Women are more likely to have metastasis
to lung.
o Bone
 Most common cancer of bone isn’t multiple myeloma or osteogenic carcinoma; it’s metastasis –
breast (b/c of Batson system).
 Batson’s system
• Batson’s system is a venous complex that goes from the base of the skull down to the
sacrum; it has no valves in it and little tributaries communicate with the vena cava and
little tributaries go right into the vertebral bodies.
• They may collect all together on the inside of the spinal cord and go back up.
• Scenario
o A woman with a plug of tumor in the intercostal vein; she picks something off
the ground and she dislodges that piece of cancer from the vein, into the vena
cava, into the Batson plexus in the vertebral body.
o Three months later she’s complaining about lower back pain and suddenly she’s
stage IV cancer.
 The most common bone metastasized to is the vertebral column. The second most common
is the head of the femur.
o Lymph Nodes
 The most common organ metastasized tois the lymph nodes, b/c carcinomas are more common
than sarcomas and carcinomas like to go to lymph nodes.
o Liver
 60

 The most common cancer of liver is metastasis; the most common primary is lung.
 The most common cancer metastasizing to liver is lung, then it’s colon (b/c of portal vein).
o Testicular Cancer
 A testicular cancer would metastasize to the paraortic lymph nodes (not the inguinal lymph
nodes); it derived from the abdomen and then descended into there.
o Left supraclavicular node (Virchow’s node)
 Metastasis is the most common cancer; the most common primary is stomach.
 Scenario
• There’s a mass in the left supraclavicular node. In someone with weight loss and
epigastric distress.
• They won’t say Virchow’s node.
o Radionuclei scan is the best test for looking for bone metastasis.
o Metastasis can be lytic or blastic
 Lytic = they break bone down; multiple myeloma has punched out lesions b/c all malignant
plasma cells haveIL-1 in them, aka osteoclast activating factor.
• We can get pathologic fractures from it.
• We can also get hypercalcemia.
 Blastic
• Some go in the bone and induce an osteoblastic response.
• Alkaline phosphatase would be elevated in the patient. Odds are a male with prostate
cancer (almost always osteoblastic).
• The most common location for metastasis is the lumbar vertebra.
o Scenario
 You have an 80 y/o man with lower lumbar pain with point tenderness.
First step in management?
 Rectal exam b/c that would be stage IV disease (definitely the prostate
would be palpable); it’s also the cheapest.
 In lytic metastasis, you have lucencies (absence of bone); in blast you’ll have densities.
o CT scan of liver

 If you see a gross specimen, an x-ray, CT, MRI, … If it has multiple lesions in it, it’s
mestastasis.
o Review of Most Commons
 The most common cancer of brain is metastasis; the most common primary site for cancer in
the brain is primary lung.
 The most common cancer killer in men and women is lung cancer.
 The most common cancer in thelung is metastasis; the most common primary isbreast.
 The most common tumor metastasis into adrenal is lung.
 Blastic; the most common cause is prostate cancer.

Stains
- Desmin (it’s an intermediate filament)
o It’s a stain for muscle.
- Keratin
o Most carcinomas have keratin in them.

Electron Microscopy
- Used if nothing else works.
- If we had an APUD tumor, we would see neurosecretory granules.
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- If we had a histiocytic tumor (like histiocytosis X, Letterer-Siwe, Hand-Schuller-Christian), we would see

Birbeck granules (look like tennis rackets). The cluster designation (CD) would be CD1.
- If we had muscle, we would see actin and myosin filaments.
- Vascular Malignancy
o If it was a vascular malignancy, we’d see Weibel Palade bodies.
o Weibel Palade bodies are structures that have von Willebrand’s factor in them. You can see them
when we know it’s of endothelial origin.

Oncogenesis
- Think of a fraternity/sorority analogy
o The first step in malignancy is initiation (means mutation).
o The second step is promotion of oncogenesis (you make multiple copies; go into G1 of the S phase).
o The third step is progression (different kinds of cancer cells have different functions). It’s basically a
community of malignant cells that has one purpose – kill you.
- Two sets of genes involved in cancer
o Those involved in the growth process (cell cycle).
o We also have those kinds of genes that monitor things (suppress things).
o Things involved in trying to get a cell to divide.
 Protooncogenes are genes that are cancer genes, but normally, when they haven’t been activated,
they serve a normal function in the normal growth process.
• Certain protooncogenes code forgrowth factors
o SIS is a protooncogene whose only function is to make the growth factors. All
growth factors have to hook into a receptor.
• Certain protooncogenes whose main job is to make receptors
o erbB-2 is the classic one for breast cancer.
o RET – is in MENs syndromes (I, IIa, IIb).
• To send a message to the nucleus we have another set of protooncogenes.
o RAS is an example of a protooncogene found on thecell membrane. It uses
GTP to send a phosphorylated protein message to the nucleus.
o ABL protooncogene – livesin the cytosol close to the membrane; it also is
involved in messages.
 The message is sent to a group of protooncogenes that are in the nucleus;
once the message is sent to them, they stimulate nuclear transcription of
the message (cell divides and makes what it’s supposed to make).
• The classic protooncogenes in the nucleus are the MYC (N-MYC for neuroblastoma
and small cell carcinoma of the lung; C-MYC for Burkitt lymphoma; L-MYC is
specifically for small cell carcinoma.)
o Nuclear transcribers in the nucleus (MYC oncogenes) are controlled by the
suppressor genes (RB and p53). They try to keep the cell in the G1 phase so it
can be cleaned up before going into the S phase (and gets initiated).

Mutations (in Initiation)

- Point mutations are the most common
o The two most important genes involved in cancer both involve point mutations (p53 suppressor and the
RAS oncogene).
o All suppressor genes are point mutations
- Amplification
o It makes multiple copies of something.
o The erbB-2 (makes receptors) in breast cancer is an amplification type of system.
- Translocation
o Taking it from one place and putting it in another; it can’t go back.
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o Classic translocations:
 Chronic Myelogenous Leukemia (CML); t(9,22)
• Chronic myelogenous leukemia is translocation of the ABL (non-receptor tyrosine
kinase activity) from chromosome 9 to 22; there it fuses with the break cluster region to
form a fusion gene.
• Because it has tyrosine kinase activity, it sends a message and those stem cells keep on
dividing. Chromosome 22 with the fusion gene is called the Philadelphia chromosome.
 Burkitt’s Lymphoma; t(8,14)
• It’s a cancer associated with Epstein-Barr virus.
o The virus translocates the MYC nucleus transcriber gene from chromosome 8
and sticks it on to chromosome 14.
o There’s a receptor for Epstein-Barr virus in all of our B-cells called CD21.
 When it hooks into that receptor, it causes B cells to become plasma
cells and produce antibodies (Cytomegalo virus does this as well).
 Because it stimulates B cells to become plasma cells, there’s a lot of
divisions that occur.
o EBV predisposes Burkitt’s lymphoma b/c it stimulates divisions in plasma cells;
if there’s a translocation of MYC oncogene (8 to 14), you continue making
multiple copies of it (progression) and you have Burkitt’s lymphoma.
o Scenario
 A lymphoma composed of small lymphocytes with interspersed
macrophages surrounded by clear spaces = “starry sky appearance”.
o It usually occurs as a jaw lesion in epidemic form in Africa (associated with
Epstein-Barr virus) and in a sporadic form that usually involves the pelvic or
abdominal organs.
 B Cell Lymphoma; t(14,18)
• Translocation of 14 to 18 occurs in the B cell lymphoma and involves the inactivation of
the suppressor genes.
• Along with bcl-2 is associated with follicular lymphoma.
 Acute Progranulocytic Leukemia; t(15-17)
• You can treat it with vitamin A (retinoic acid) and cure the patient; it matures the blast.
- Suppressor genes
o RB, p53, APC (adenomatous polyposis coli) is for familial polyposis, NF (neurofibromatosis), WT
(Wilms tumor), BRCA-1 and BRCA-2 (both are involved in DNA repair. BRCA-2 is totally associated
with breast cancer while BRCA-1 can be associated with breast, ovarian, and others).
- How are these things affected, three main ways:
o Chemicals
o Viruses
o Radiation
o Of the three, chemicals is the most common mechanism for initiating a cell (producing a mutation).
Smoking is the most common cause of death in the US. Polycyclic hydrocarbons are the carcinogen in
smoke.
- Papillary Tumor in the Bladder

o The most common cause of it (transitional cancer) is smoking. If you worked in a dye industry, it
would be aniline dye.
o Scenario
 A patient had Wegener’s granulomatosis and was put on a drug. This patient ended up wit
hematuria. You did a cytology and saw some abnormal cells. What drug was the patient on?
 63

 Cyclophosphamide (associated with hemorrhagic cystitis and transitional cell carcinoma;

it’s prevented with mesna)
- Lung Cancer
o The most common cause is polycyclic hydrocarbons from smoke.
o The cancers most associated with smoking and mainstem cancers are squamous and small cell.
- Kaposi’s sarcoma
o It’s a virus associated cancer;Herpes 8 (6 is Roseola).
o Can produce non-pruritic raised red lesions.
- Burkitt’s lymphoma
o Associated with Epstein-Barr virus (others are nasal pharyngeal carcinoma in Chinese).
o In liver, it’s associated with hepatocellular carcinomaandhepatitis B. In Asia there’s a high incidence
of hepatitis B and there’s a certain mold in the food (aflatoxin E) that is also a risk factor for liver cancer.
- HIV
o Associated with primary CNS lymphoma
 Scenario
• The rapidly increasing incidence of primary CNS lymphoma is the U.S. is directly
attributable to?
• HIV
- EBV is associated with malignant lymphomas other than Burkitt’s.
- Human Papilloma Virus
o It causes squamous cancer; cervix, vagina, vulva, and anus in homosexuals (unprotected intercourse).
o HPV 16, 18, 31 can produce cervical, vaginal, or vulvar cancer; it’s the same one that can produce anal
squamous cell carcinoma in homosexuals.
o HPV worked by E6 E7 protein products; E6 knocks off p53 and E7 knocks off RB.
- Radiation
o Chronic myelogenous leukemia
o The most common cancer associated with radiation is leukemia. The most common leukemia
associated with radiation is chronic myelogenous leukemia; has the 9-22 translocation of ABL
protooncogene.
o Papillary Carcinoma of the Thyroid
 Scenario
• Person with history of radiation in the head and neck area. They had non-tender nodular
masses in the cervical region. What is it?
• Metastatic papillary carcinoma of the thyroid related to ionizing radiation.
o Scenario
 Which medical profession would most likely get leukemia?
 Radiologist. The most common radiation induced cancer is leukemia.
- Basal Cell Carcinoma
o Derives from the basal cell layer.
o It’s multifocal.
o It’s non-ionizing radiation, due to UV-B light (UV-A is fluorescing superficial dermatophytes and
finding chagrine patches in tuberous sclerosis you use Wood’s light [UV-A]).
o UV-B light is the light you try to protect yourself from. Basal Cell cancer is the most common,
squamous cell is the second most common, and then malignant melanoma. UV-D causes thymidine
dimmers.
- Actinic Keratosis (Solar Keratosis)
o Precusor lesion for squamous cancer.
o It’s commonly seen in sun-exposed area. You can scrape it off and it comes back. It can look pearly
grayish white.
 It’s a dysplastic lesion; you get squamous dysplasia and it grows back.
 64

o Only about 3-4% of actinic keratosis becomes squamous cancer.

o Arsenic can predispose this. Arsenic is also involved in lung cancer and angiosarcoma of the liver.
o Retinoblastoma
 It’s on chromosome 13.
 It can be sporadic or familial.
 It takes 2 separate mutations for a sporadic to become retinoblastoma.
• You have to knock one off on chromosome 13 and then on the other chromosome.
 If it’s autosomal dominant inheritance, it only requires one mutation. You’re born with one
chromosome inactivated. All you need is one more on the other chromosome and then you get
retinoblastoma.
 White-eye reflex (leukocoria – a white or abnormal papillary reflex) is not commonly due to
retinoblastoma. Congenital cataract is the most common cause of a white-eye reflex; could
be due to some of the congenital infections like CMV, rubella, … A person with Cushings
syndrome could have cataracts b/c corticosteroids (they predispose to cataracts).
Neoplasia 3

Genetic Disease

Xeroderma pigmentosum
- It can occur in sun-exposed areas and can predispose all skin cancers.
- It’s an autosomal recessive disease.
- The defect is in DNA repair enzymes (other diseases with DNA repair enzyme defects are BRCA-1, BRCA-1
and p53).
o They’re called chromosome instability syndromes and include things like Wiskott-Aldrich syndrome,
Bloom’s syndrome, ataxia telangiectasia, Fancouni syndrome); these all have problems with DNA
repair.

From upper lip up is basal cell country; from lower lip down is squamous cell.

Squamous Cell Carcinoma

- Squamous Cell Carcinoma developed in areas of drainage from a sinus and also from ulcers that don’t heal
with antibiotics.
- Where there’s constant irritation and divisions of cells related to the irritation, there’s always a greater risk for
cancer; the most common cancer is squamous cancer (b/c you’re dealing with squamous epithelium and not
glandular).
- This doesn’t hold for scar cancers by the way of the lung. Most scar cancers that relate to old TB scars or
something like that are adenocarcinomas.

The only bacteria associated with cancer is Helicobacter pylori; the two cancers are adenocarcinoma and low-grade
malignant lymphomas.

Grade of Cancers
- Grade is what it looks like
- Low-grade (aka well differentiated)
o It can be doing something like making keratin or making glands.
o Are identifiable under the microscope.
- High-grade (anaplastic; fully-differentiated)
o You can’t tell what it is by looking at it under the microscope.

Stage
- Remember the TNM System
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o It’s the most common staging system; it goes from least important to most important.
o Ex. Breast Cancer
 The lower axillary nodes are involved; it’s not the worst, but the end part. What’s worst is if it’s
outside the lymph node (bone, lung, or liver). Just b/c it goes to the lymph node, it doesn’t mean
that it’s the most important prognostic factor.
o T stands for the size of the tumor. If a tumor is over 2 cm, it has a chance of metastasizing.
o N stands for nodes.
o M stands for metastasis outside of nodes. It’s Stage IV by definition.
o The most important prognostic factor for cancer isn’t grade, but stage; in staging the most important
factor is metastasis to other areas.

Host Defenses
- The most important defense we have is the cytotoxic CD8 T-cell.
- It puts out porforin (the signal for caspases to apoptotically kill the cell).

Cachexia
- The cause is tumor necrosis factor alpha (TNF-α) output.
- It’s irreversible.

Hematology
- The most common anemia present in malignancy is anemia of chronic disease.
- Colon cancer;left side obstructs and right side bleeds.
o If you have a right-sided colon cancer, iron deficiency would be more common.
- If you metastasize to bone and replace all the bone marrow, that could be a mechanism. If you use chemotherapy
drugs that are cell cycle specific or non-specific and you wipe out the marrow.

Most patients that have disseminated cancer are hypercoagulable (they have a tendency for forming clots).
- Scenario
o A male patient has a painless jaundice. He has a left supraclavicular node. He has light-colored stools
and has peculiar lesions in the vein that jump from one part of his body to the next. What is this?
o Trousseau’s sign (superficial migratory thrombophlebitis in a patient with carcinoma of the head of the
pancreas); it’s an example of a hypercoagualble state.Pancreatic cancers can also go to the left
supraclavicular node.
Thrombocytosis (an elevated platelet count) are also seen in disseminated cancer.

The most common cause of fever in malignancy is a gram negative infection. The gram negatives are usually from the
hospital; E. coli if you have an indwelling catheter, Pseudomonas if you have a respirator, indwelling catheter in a vein or
something like that then it’s Staph. aureus (gram positive).

The most common cause of death in cancer is infection.

Paraneoplastic syndromes
- Signs and symptoms that say that you may have an underlying cancer present.
- Most common paraneoplastic syndrome is hypercalcemia.
o There’s two mechanisms for hypercalcemia in malignancy.
 You metastasize to bone and produce some kind of chemical (IL-1 or prostaglandin E2) that
activates osteoclasts, produces lytic lesions in bone, and then you have hypercalcemia. This is
the most common.
 It could be a cancer that sits there (i.e. renal adenocarcinoma or squamous carcinoma of the
mainstem bronchus) and makes parathyroid hormone peptide and causes hypercalcemia to
occur b/c it acts like parathyroid hormone (in broken bones down). This is paraneoplastic; it’s
not the most common one.
 66

- Gastric Adenocarcinoma
o Acanthosis nigricans and seborrheic keratosis (one lesion doesn’t mean anything). When a lot of
them develop overnight, it’s called the Leser-Trelat sign. This is a phenotypic marker for gastric
adenocarcinoma.
o Acanthosis nigricans is also associated with insulin-receptor deficiency (related to diabetes), MEN
syndromes, and most commonly gastric adenocarcinoma.
- Hypertrophic osteoarthropathy
o It’s an inflammation underneath in the bone (periostitis).
o It’s the inflammation of the underlying bone that stimulates the increase in soft tissue development
around it and produces the clubbing.
o Clubbing isn’t always associated with malignancy; you can see it in bronchiectasis, inflammatory
bowel disease. If it were to be a malignancy, it would most likely be primary lung cancer.
- Dermatomyositis
o This is the least common collagen vascular disease, but the one most commonly associated with an
underlying cancer.
o They also have an elevation in serum CK.
o They have a rash that takes the form of a lilac or heliotrope discoloration of the upper eyelids with
periorbital edema(“raccoon eyes”).
 It’s due to an inflammation of skin and muscle.
o They get myositis (releases serum CK).
o It also has a high association with leukemias, lung cancer, lymphomas, …
o Patches over the knuckles are called Gottron’s patches.

Marantic Endocarditis
- Vegetations on the mitral valve; they’re sterile and they’re associated with mucous producing cancers like colon
cancer.
- It’s a paraneoplastic syndrome.
- They can embolize.
- You would need history to separate it from rheumatic fever.
- Leibman-Sacks endocarditis has vegetations all over the place.

Small Cell Carcinoma

- Has hormones related to it.
- They’re output tumors, are S-100 antigen positive, of neural crest origin, and have neural secretory granules on
electron microscopy.

Renal Adenocarcinoma
- Can make parathyroid hormone-like peptide (hypercalcemia) and also can make erythropoietin
(polycythemia).

Hepatocellular Carcinoma
- Can make erythropoietin (polycythemia), and insulin-like factor (hypoglycemia).

Medullary Carcinoma of the Thyroid

- It can be an autosomal dominant variety of it.
- This tumor is one of the rare tumors where the tumor marker can be converted into amyloid (calcitonin).

Tumor Markers
- When you have a male with a testitcular cancer, the two tumor markers you always get are alpha-fetoprotein
and hCG.
 67

o Alpha-fetoprotein in a testicular cancer is a marker for yolk-sac tumor (aka endodermal sinus tumor).
Alpha-fetoprotein is like the albumin for the fetus.
 Tumors in kids in the reproductive organs are most commonly yolk sac tumors.
 Alpha-fetoprotein is also associated with hepatocellular carcinoma.
 It’s increased in open neural tube defects. You have to be on folate before pregnancy to
prevent open neural tube defects.
 In Down syndrome, alpha-fetoprotein is decreased.
- Multiple Myeloma
o It’s a malignancy of bone associated with a monoclonal spike.
o Bence Jones proteins are the light chain of the immunoglobulin.
- Prostate Cancer
o PSA
 It’s not specific for prostate cancer; it can be increased in hyperplasia.
 It’s sensitive but not specific.
 It’s not increased if you do a rectal examination (it’s not an enzyme; it’s an antigen that’s
inside the cell). If it was prosthetic acid phosphatase, it would.
- Mucins and Other Glycoproteins
o CA-15-3 is associated with breast cancer.
o CA-125 is associated with ovarian cancer.
- Carcinoembryonic antigen (CEA) is for colon cancer; it’s also used in small cell and breast, but mainly colon
cancer.
o It can be part of an immune complex CEA-anti-CEA immune complexes which deposit in the kidney
and produce nephrotic syndrome (diffuse membranous glomerulonephritis).
- If a woman had a trophoblastic tumor or a mole, you would get a beta-hCG marker.
- What’s the most common primary tumor (benign or malignant) of the brain in kids = a cerebellar cystic
astrocytoma (all astrocytomas are benign)
o Medulloblastoma is the most common primary cancer in a kid. It derives from the cerebellum.
- The most common childhood cancer is leukemia (specifically ALL = acute lymphoblastic leukemia). The
second group is central nervous system tumors.
- Ewing’s sarcoma
o Tumor of the bone.
o It has an “onion-skinning” type of calcification.
- In adults
o Incidence
 In woman, the most common cancer is breast, second is lung, third is colon.
 In men, the most common is prostate, second is lung, third is colon.
o Cancer killers
 Lungs for men and women.
 Men
• Second is prostate, third is colon.
 Women
• Second is breast, third is colon.
o The second most common cancer and cancer killer in men and women combined is colon cancer.
o After 50, the most common cause of positive stool guiac is colon cancer.
o GYN cancers
 Incidence
• Most common is (without breast) endometrial. Second is ovarian. Third is cervix (it’s
the least common GYN cancer b/c of PAP smear). The PAP smear is picking up cervical
dysplasia, not cancer.
 Cancer killers
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• Number one is ovarian, second is cervical, three is endometrial.

 Endometrial is the most common but it has the best prognosis.
o Hepatitis B
 Is the only known existing tumor vaccine.
 It is the most common infection transmitted by accidental needle stick in a hospital. The viral
burden of hepatitis B in the blood is greater than any infection.
 If you’ve been vaccinated, the three things you’re not going to get are hepatitis B and D, and
hepatocellular carcinoma related to hepatitis B cirrhosis.

Extra:
Neuroblastoma
- It’s a childhood tumor of the sympathetic nerves, which most commonly arises along the paravertebral chain or
within the adrenal medulla. Neuroblastoma has two characteristic genetic markers: a 1p deletion and an N-myc
translocation. N-myc is an oncogene that resides on chromosome 2p, and is amplified up to 300 times in
neuroblastoma. Amplification of this gene is associated with poorer prognosis.
- Scenario
o A newborn child with a bulky abdominal tumor. CT scan shows mass in right abdomen and
retroperitoneum.
o Tumor is resected and shows ganglion cell and primitive, small, round cells occasionally organized in
rosettes, embedeed in pink matrix.
- Cellular aneuploidy and hyper diploidy reflect a better prognosis for neuroblastoma, whereas diploid and
tetraploid tumors have an intermediate or poor prognosis.
- Tumor presentation at a younger age predicts a better outcome for neuroblastoma. Children under one year of
age have an excellent prognosis, regardless of tumor stage.
- Ganglion cells within the tumors are a reflection of focal differentiation of the neuroblastoma into
ganglioneuroma. Better differentiated tumors have a more favorable outcome.
- In general, tumor stage is not very predictive of neuroblastoma survival. Nonetheless, higher grades of tumor (III
and IV) extend across the vertebral midline and into distal viscera or nodes.
Oral Squamous Cell Carcinoma
- The most common primary site is the floor of the mouth.

Liposarcoma
• Compared to lipoma:
• Liposarcomas are one of the most common soft tissue tumors, affecting middle-aged and elderly persons.
• The thigh and retroperitoneum are the most frequent sites.
• The tumor is composed of pleomorphic lipocytes that resemble embryonal lipoblasts. The cytoplasm of
neoplastic cells is filled with lipid vacuoles (positive for fat stains), which characteristically indent the nuclear
membrane.
• The prognosis of liposarcomas, as of all soft tissue tumors, is dependent predominantly on location and age (deep
tumors in elderly patients behave more aggressively than ones in superficial locations in younger patients).
 69

Cardiovascular 0 (31:41 of Hematology8)

Jugular Venous Pulse

- Usually on the right side is where we examine the patient; the best way to find out which of the waves it is, is to
find out when systole occurs (first heart sound).
- C wave = first heart sound (beginning of systole).
- There’s three positive waves: A, C, and D; X & Y are negative waves
o A wave
 Due to atrial contraction in late diastole (get that last bit of blood out to fill up right ventricle).
o C wave
 Tricuspid valve closes in systole and there’s a contraction (blood goes up pulmonary artery;
some hit against tricuspid valve and bulges it out into right atrium = C wave)
o X wave
 Blood goes up pulmonary artery and creates a negative pressure behind it (sucks the valve down
a little = X wave)
o V wave
 The beginning of the V wave = filling up of right atrium (in systole). Tricuspid valve is still
closed; systole is still occurring; blood is still going out the pulmonary artery, but the right atrium
has to fill up again = V wave.
 Corresponds with actual beginning of diastole (S2 heart sound).
o Y wave
 Diastole begins; tricuspid valve opens and blood goes out into ventricle = Y wave.
- If one had an irregular irregular pulse (atrial fibrillation) the A wave is disappeared b/c it’s atrial contraction.
o If you have an absent A wave (atrial fibrillation), you’ll lose S4 b/c it relates to atrial contraction against
an increased resistance.
- If you had tricuspid stenosis (the atrium had to contract against a valve that didn’t open), then the A wave would
get huge “a giant A wave”.
 70

- If you had tricuspid regurgitation; the valve didn’t close properly so when systole occurred, a lot of the blood
went into the right atrium and some up the pulmonary artery. You get a giant C-V wave.

Triglycerides and Cholesterol

- When you have trepidity of plasma you draw blood out and it’s turbid, it’s due only to triglyceride (NOT
cholesterol).
- There’s two fractions that carry triglyceride: chylomicrons (from triglyceride you eat; saturated fat = long chain
fatty acids). Chylomicrons are exogenous (diet derived triglycerides).
o If you get an accurate triglyceride level, you must fast. You don’t fast for an accurate cholesterol;
there’s less than 3% of cholesterol in chylomicrons.
- The triglycerides one makes are called VLDL (very low density lipoprotein); it’s made in the liver from glycerol
3-phosphate and it comes from glucose.
o VLDL is increased in alcoholics b/c of NADH pushing DHAP to glycerol 3-phosphate.
o VLDL’s are more dense than chylomicrons (they float in a tube [placed in a refrigerator 4 degrees
overnight]); VLDL is the pinkish infranate under the chylomicrons.
 The most common cause of a chylomicron layer found in a test tube is the patient didn’t fast.
 If there’s no supernate, but you had a turbid infranate; it means you have an increase in
VLDL. The lipid abnormality is type IV; the most common hyperliperproteinemia = an
increase in VLDL.
- Xanthelasma (yellow eyelid)
o Yellow plaques on the skin (along the nasal portions of one or both eyelids).
o Cholesterol is the lipid underneath causing it to be yellow.
- Achilles Tendon Xanthoma = Familial Hypercholesterolemia
o Patient can present with family history of death by coronary artery disease by 20 years of age.
o Familial Hypercholesterolemia is autosomal Dominant. It has an absent LDL receptor.
o Familial hypercholesterolemia = type II hyperliperproteinemia.
o The lack of LDL receptor means that LDL can’t go into cells and it builds up. By 18 you get your first
coronary and die shortly after.
- Atherosclerosis
o The reaction to injury is considered to be the current theory for how atherosclerosis develops. It says
something is injuring the endothelial cells lining the elastic arteries and muscular arteries.
o Ammonia in cigarette smoke, carbon monoxide in cigarette smoke, and other things in cigarettes have a
risk for atherosclerosis.
o LDL itself damages it (it’s damage is increased if oxidized).
o Chlamydia pneumonii (the second most common cause of atypical pneumonia) has been associated in
predisposing atherosclerosis.
o Viral infections and homocysteine can also damage endothelial cells.
o Mechanism of injury
 When you damage endothelial cells, platelets stick to it and they release platelet derived growth
factor (PDGF).
 PDGF causes the smooth muscle cells in the media of the vessel to start proliferating; they
undergo hyperplasia and then the smooth muscle cells chemotactically start migrating from the
media to right underneath the endothelial cells (the intima of the vessel).
 Monocytes now have access to the vessel b/c it’s been injured. Monocytes also have growth
factors that do the same thing.
 If you have an increase in LDL, it is phagocytized by monocytes, smooth muscle cells, and
macrophage. This produces the fatty streak.
 Over time, there’s an injury that occurs; fibroblasts develop in there and you end up with a fibro-
fatty plaque = the pathognomonic lesion of atherosclerosis.
 It can become complicated by dystrophic calcification, fissuring, thrombosis, …
Cardiovascular 1
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Atherosclerosis (cont.)
- Many cells are involved: platelets, monocytes, macrophages, and cytotoxic T-cells (cytokines). Neutrophils
aren’t involved.
- Is a primary factor of certain diseases.
o Coronary artery disease b/c atherosclerosis could give you a thrombus that could give you a stroke.
o Abdominal aortic aneurysm is a purely an atherosclerosis problem with weakening of the vessel.
o Non-traumatic amputation of lower extremity. Peripheral vascular disease is predominantly an
atherosclerosis problem. Mesenteric angina, small bowel infarction, renal vascular hypertension, and
more.
- It only involves muscular arteries and elastic arteries.

Hyaline Arteriolosclerosis
- It’s a disease that can harden small vessels like arterioles.
- Hyperplastic arteriolosclerosis looks like the cross-section of an onion.
- Diabetes and hypertension produce hyaline arteriolosclerosis but by different mechanisms.
o In diabetes, it’s caused by non-enzymatic glycosylation (also occurred in HaA1C; glycosylated
hemoglobin).
 Sidenote: Glycosylation is glucose attaching to amino acids in proteins. In terms of HbA, it’s
glucose attaching to amino acids in HbA. HbA1C levels correlate with 6-8 levels of what your
blood glucose levels were; it’s the best way of seeing long-term glucose management. If you’re a
diabetic, you should stay below 6% (normal glucose range)
 Sidenote about diabetes:
• Damage is purely related to glucose. The only two pathologic processes are non-
enzymatic glycosylation of small blood vessels (including capillaries in the kidney) and
osmotic damage.
• Osmotic damage
o Aldose reductase can convert glucose to sorbitol (sorbitol is osmotically active
[sucks water into it] and cells die). The tissues that contain aldose reductase:
lens, pericytes in the retina, Schwann cells.
o You get cataracts, microaneurysms in the eye (b/c periocytes are destroyed and
weakened).
o You get peripheral neuropathies b/c Schwann cells are destroyed.
 Non-enzymatic glycosylation renders basement membrane of small vessels permeable to protein.
The protein in the plasma leaks through the basement membrane, and it goes into the vessel wall
and produces this hyaline change and narrows the lumen.
 Non-enzymatic glycosylation of the basement membrane of the glomerulus would render it
permeable to protein (protein in the urine = microalbuminuria; it’s the first change that one sees
in diabetic nephropathy).
o Hypertension just uses brute force.
 The proteins (b/c of the increase in diastolic pressure) are driven through the basement
membrane to produce hyaline arteriolosclerosis.
 A kidney in hypertension is shrunken with a cobble-stone appearance on the surface because they
have hyaline arteriolosclerosis of the arterioles in the cortex (leads to ischemia and it’s wasting
away with fibrosis and atrophy of tissue).
 Lacunar strokes are the tiny areas of infarction that occur in the internal capsule area. It’s a
hyaline arteriolosclerosis problem related to hypertension.

Hyperplastic arteriolosclerosis
- Seen in malignant hypertension (when you get 240/160 BPs).
- More common in blacks and whites (b/c hypertension is more common in them).
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Aneurysms
- An aneurysm technically is an area of outpouching of the vessel due to weakening of the vessel wall.
- In an abdominal aneurysm the weakening is due to atherosclerosis.
- The analogous lesion in the lungs = bronchiectasis (destruction of the elastic tissue and you get outpouching
dilatation of the bronchi).
- The G.I. “aneurysm” is a diverticular disease; you have a weakening and an outpouching of mucosa and
submucosa through the area of weakening.
- The Law of LaPlace says that wall strength increases as radius increases. This means that once you start dilating
it, it doesn’t stop; in other words, all aneurysms will rupture (the most common complication of aneurysms).
- The abdomen is the most common location for aneurysms b/c there’s no vaso vasorum (blood supply to the
aorta) below the renal arteries.
o The abdominal aorta can only get oxygen and nutrients from the blood that’s in its lumen.
o It would be more susceptible if it had atherosclerosis; leads to weakening of the wall and aneurysm.
o Abdominal aorta rupture triad: sudden onset of left flank pain (aorta is retroperitoneal and so the
bleeding is not into the peritoneal cavity but the peritoneal tissue), hypotension, and pulsatile mass
on physical exam.
- Aneurysm of the arch of the aorta:
o The most common cause is tertiary syphilis.
 The pathology of syphilis is vasculitis of arterioles.
 Vasculitis even occurs in the chance; actually this is why it is painless.
• The chancre is painless because arterioles are surrounded by plasma cells and the lumen
of the vessel is totally shut (it’s ischemic necrosis; ischemia of the overlying tissue and it
undergoes necrosis).
• Because nerves are right next to vessels, it they are destroyed as well and this is why a
chancre is painless.
o In the arch of the aorta, the treponema infects the vaso vasorum; the aorta has the richest supply of
vaso vasorum. The result is endarteritis obliterans; obliterating the lumen which leads to ischemia,
weakening, and an aneurysm. The aortic valve ring is stretched and you get an aortic regurgitation
murmur.
 Sidenote: Murmurs can occur because you can have valvular damage or b/c the valve ring that
they’re on is stretched.
• The aorta should be closing in diastole. Since the aortic valve can’t close properly,
you’re going to have blood leaking back in. You’re going to have more volume of blood
in your left ventricle in someone with aortic regurgitation.
• Normally you have 120 ml of blood in the left ventricle and you get out 80 ml normally;
the ejection fraction is 80/120 = 0.66. If you have 200 ml of blood (b/c blood dripping
back in) you can get out 100 (b/c of Frank-Starling); the ejection fraction, however, is
decreased (100/200 = 0.5). Frank-Starling is not a normal physiologic process; it occurs
in a pathologic condition.
o Because the left recurrent laryngeal nerve goes around the arch, it gets stretched and you get hoarseness.
The most common complication is rupture.
- Dissecting aneurysm
o The key factor for causing a tear in the aorta is hypertension (it imposes stress on the wall of the vessel);
there also has to be weakening going on in the vessel.
o Elastic tissue fragmentation is what is weakening the elastic artery.
o Cystic medial necrosis: the glycosaminoglycans mix together and get a mucinous cystic pocket can also
be a risk factor.
o Wherever the area of weakness is in the elastic artery, the blood will dissect.
o A proximal dissection goes toward the pericardial sac and into the heart. A person dies from a cardiac
tamponade. A proximal dissection is the most common dissection.
 73

 It’s very common to have an absent pulse; when it dissects, it closes off the lumen to the
subclavian artery (usually on the left).
o The chest pain is distinct: you’re going to have a tearing, retrosternal pain into the back.
o Diagnose it with an x-ray: widening of the proximal aortic knob. To confirm it, you do a
transesophageal ultrasound or angiography.
o Some diseases that can predispose to dissections:
 Marfan’s
• They have unicoid proportions: the height from the pelvic brim to the feet is greater than
the pelvic brim to the head. Another definition is the arm span is greater than the height.
• Marfan’s is autosomal dominant; chromosome 15, the defect is fibrillin (component in
elastic tissue).
• Elastic tissue is weak; why they have dislocated lenses and why they have dissecting
aortic aneurysms.
• They all have mitral valve prolapse and even tricuspid valve prolapse.
• They get some conduction defects and go into sudden death; more common than
dissections.
 Ehler-Danlo syndrome can also predispose because of defects of collagen; dissecting aneurysm
is the most common cause of death.
 Pregnancy can also predispose because if you’re pregnant, you have twice the plasma volume as
a pregnant woman than as a non-pregnant woman.
• You increase plasma volume by 2 and RBC mass by 1; it decreases hemoglobin [].
• For all pregnant women, you use 11.5 as the cutoff point for anemia; normal women it’s
12.5.
• In some women, the excess volume can cause weakening and predispose an aneurysm.

Superior Vena Cava syndrome

- Usually due to primary lung cancer.
- Patient may complain of headache and blurry vision. Physical exam may show retinal vein engorgement and
congested from chest up.
- The primary lung cancer knocks off the superior vena cava and so you get the backup of venous blood into the
jugular system and the dural sinuses.
- Treatment is radiation but prognosis is poor.
- Not to be confused with pancoast tumor (associated with Horner’s syndrome).

Sturge-Weber Syndrome
- It’s a vascular malformation(“port wine stain”) in the face. It’s in the trigeminal nerve distribution.
- On the same side of the brain, there’s an A-V malformation which predisposes to bleeding. These patients are
also a little mentally retarded.

Osler-Weber Rendu
- Have small telangiectasia.
Spider angioma (telangiectasia)
- Have small telangiectasia, but if pressed, they go away.
- Spider angiomas are normal in pregnant women due to hyperestrinism.
- If a non-pregnantperson had a spider angioma, they probably have cirrhosis. The most common cause of
cirrhosis is alcohol.
o If you have cirrhosis, you can’t metabolize estrogen.
 Estrogen builds up and you get gynecomastia, warm skin, palmar erythema, and spider angiomas
(related to hyperestrinism).
o Another reason for spider angiomas from cirrhosis is due to inability to metabolize 17-ketosteroids.
They therefore get aromatized in adipose into estrogen and contribute to hyperestrinism.
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- Spider angiomas blanch when pressed because they are arteriole-venule fistulas (they bypass capillaries).

Capillary hemangioma (a vascular tumor)

- If a kid is presented with a red lesion (capillary hemangioma) on the face, you don’t surgically remove it; you
leave it alone because by 8 years old it will be gone.

Kaposi’s sarcoma
- Caused by herpes virus 8.
- In AIDS patients, there’s a lesion only in them that looks like Kaposi’s but is due to a bacteria (bacillary
angiomatosis) = Bartonella henselae (also the cause of cat scratch disease). You see it by silver stain. Treat it
with sulfa drugs.

Angiosarcoma of the liver

- VAT: vinyl chloride is a common cause of this, arsenic, and thoratrat?? (not really asked)
- Vinyl chloride is present in people who work with plastics and rubbers and is a risk factor. Arsenic is a part of
pesticides.

Vasculitis
- Small vessel (palpable purpura)
o When you have small vessel vasculitis, most of the time it’s typeIII hypersensitivity (involves immune
complex deposition that will deposit in the small vessel).
o The deposited immune complexes activate complement C5a, which attract neutrophils, and you get
fibrinoid necrosis to that small vessel. You also get palpable purpura.
- Muscular arteries
o Muscular arteries (PAN, Wegener’s granulomatosis, Kawasaki’s) give you a thrombosis of the vessel
and not a palpable purpura.
o You’re going to have an infarction (for example Kawasaki’s disease in children; they get a coronary
artery vasculitis).
 The most common cause of a coronary of a mild coronary infarction in children is Kawasaki’s
disease (also presents with mucocutaneous inflammation, desquamation of skin, and
lymphadenopathy).
o Infarction is what you see with muscular artery vasculitis.
- Elastic arteries (no pulse and stroke)
o When you attack an elastic artery, you deal with arch vessels and you get pulseless disease (Takayasu’s
arteritis). The vasculitis will block off the lumen of one of the arched vessels.
o You get strokes because it can knock off part of your internal carotid.
- Temporal arteritis
o Patient presents with a headache, can’t see out of an eye, has aches and pains all over the body, and when
he/she chews it hurts.
o It’s a granulomatous (multi-nucleated giant cell) vasculitis of the temporal artery. It can involve other
portions of the artery (including the ophthalmic branch and produce blindness).
o The only indication for a sedimentation rate is to screen for temporal arteritis; you get an increased
SER; you do the SER b/c it takes time to do a biopsy and the patient could go blind. If you suspect it,
you have to give them corticosteroids (because they might go blind).
- Buerger’s Disease (thromboangiitis obliterans)
o Usually in young males who smoke. They get digital vessel thrombosis and autoinfarction of fingers
and toes.
- Henoch-Schonlein Purpura
o The most common vasculitis in children.
o Clinical situation:
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 14 y/o boy with a respiratory infection a week ago presents with polyarthritis, hematuria w/RBC
casts, and palpable purura of the buttocksand lower extremity.
o It’s an immune complex (as are all small vessel vasculitidities). It’s an IgA-anti-IgA immune complex
and the RBC cast is glomerulonephritis. Most people think that IgA glomerlonephritis (Berger’s disease)
and Henoch-Schonlein Purpura are the same thing; Berger’s is typically an isolated renal disease whereas
Henoch-Schonlein Purpura is a systemic disorder.
- Wegener’s Granulomatosis
o Patients present with saddle-nose deformity (the most common cause in the United States), problems
with sinus infections and upper respiratory problems, lung problems (with nodular masses), and even
a glomerular disease.
o It’s a granulomatous inflammation and a vasculitis (involves the upper airways, lungs, and the
kidneys).
o There’s an antibody that’s associated with it that’s c-ANCA. Remember b/c the treatment of choice is
cyclophosphamide (begins w/c).
 Cyclophosphamide can give you hemorrhagic cystitis and bladder cancer. Can prevent
hemorrhagic cystitis by mesna.
- Polyarteritis Nodosum
o Is a male dominant disease and involves muscular arteries (infarction is part of it). It also has an anti-
neutrophil cytoplasmic antibody (P-ANCA = p for polyarteritis).
o It’s associated with Hepatitis B surface antigenimia.
o How asked on Boards:
 You have an IV drug user with chronic Hepatitis B who has a nodular inflamed mass on the
lower extremity and hematuria (kidney infarct). What does the patient have?
 Case presented Hepatitis B and a vascular problem (glomerular problem).

Rocky Mountain Spotted Fever (caused by Rickettsia)

- Rickettsia infects endothelial cells.
- The spots are in fact petechiae and unlike other Rickettsial diseases with rash, this starts on the extremities and
goes to the trunk (other ones go from trunk to extremities).
- Vector = tick (other tick-borne diseases are Lyme disease [Borrelia burgdoferi])
o Sidenote: Borrelia recurrentis/hermsii causes relapsing fever and has antigenic shifts. It’s a spirochete
(other spirochetes are Leptospira and Treponema pallidum [Syphillus])

Mucor mycosis
- A fungus with a wide-angled (branching at 90 degrees) non-septate. The patient is diabetic ketoacidosis and
has cerebal abscess related to the fungus.
- Diabetics commonly have mucor in their frontal sinuses so when they go into ketoacidosis; the mucor starts
proliferating and they go into the cribriform plate and invade the frontal lobes, infarct it and infect it.

Raynaud’s phenomenon
- Can be caused by many diseases. Some involve cold-reacting antibodies and cold-reacting globulins.
- IgM cold agglutinin disease or cryoglobulinemia in an old person with hepatitis C (c’s match).
- Progressive Systemic Sclerosis (aka Scleroderma)
o First manifestation is Raynaud’s; it involves a digital vasculitis and eventually a fibrosis.
- CREST syndrome (diagnosed with anti-centromere analysis)
o First manifestation is Raynaud’s but it’s a different mechanism; it’s an actual vasculitis of the digit and
eventually it will fibrose.
o C = calcinosis (dystrophic calcification) and centromere antibodies
o R = Raynaud’s
o E = Esophageal dysmotility
o S = Sclerodactylia (narrow finger)
 76

o T = telangiectasia
- Other causes are due to vasoconstriction; it’s common in people who have migraine headaches (due to dilatation
of vessels) that take ergot derivatives.
- Buerger’s disease can also be associated.

Hypertension
- The most common cause of death is myocardial infarction, second is stroke, and third is renal failure
- Blacks have the highest incidence of hypertension.
o It’s a multifactorial inheritance (aka polygenic inheritance).
 Gout, coronary artery disease, type II diabetes, affective disorders, congenital pyloric stenosis,
and essential hypertension are multifactorial inheritance.
 You have a genetic tendency for it but not necessarily will get the disease; you can try and
control weight, reduce salt intake, and exercise.
- Essential Hypertension
o The mechanism of essential mechanism is too much salt retention (can’t get rid of salt in urine); also
occurs in adult old people.
 When you retain salt, that salt is going to be retained in ECF; the plasma volume would increase
(the stroke volume would have to be increased = systolic hypertension).
 When you have excess salt, it likes to go into smooth muscle cells (peripheral resistance
arterioles). When sodium enters muscles, it opens up channels for calcium to go in; it contracts
the smooth muscle and the peripheral resistance arterioles are in vasoconstriction and peripheral
resistance is increased.
 More blood is retained in arterial system and it registers as an increase in diastolic
pressure.
o Hydroclothiazide (treatment of choice for essential hypertension in blacks and old people)
 You get rid of salt and water (drop BP) but if you have a hyperlipidemia it’s contraindicated.
o It’s a low renin type of hypertension because you have increased plasma volume (increased blood
flow to renal artery = decreased renin).
- Hypertension in coronary artery disease is a risk factor for myocardial infarction (it’s the most common cause of
death). Next cause of death is stroke
o Globus pallidus and putamen is where almost all hypertensive bleeds occur in the brain. It’s because
the lenticulostriate vessels (branches from the middle cerebral artery) under increased pressure form
aneurysms (Charcot-Bouchard aneurysm) and they rupture. This isn’t an infarct but a hematoma
(blood clot).
o Third cause of death is renal failure; kidney has a cobblestone appearance because of hyaline
arteriolosclerosis (causes ischemia, atrophy of tubules, destruction of glomeruli, and shrinkage).
The most common overall abnormality in hypertension is left ventricular hypertrophy. This is because of an
afterload problem (having to contract against an increased resistance).

Cardiovascular 2

Cardiac Hypertrophy
- Due to increased work load (could be pre-load or after-load)
- Can be concentric or dilated
o Concentric (afterload problem)
 Is due to an afterload problem.
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 For example having to work more due to a stenotic aortic valve or an increased TPR (from
hypertension).
o Dilated (preload problem)
 Due to a volume overload (a preload problem).
 If you had a valvular problem and it led to excess volume in the ventricle (regurgitation).

Heart Sounds
- S1
o S1 is the closing of the mitral and tricuspid valves (mitral before tricuspid); they close because of an
increase in pressure.
o S1 marks the beginning of systole.
- S2 (P2 and A2)
o S2 is the closing of the aortic and pulmonic valves.
o There’s a variation with respiration b/c as the diaphragms go down and increase the intrathoracic
pressure, blood is being sucked into the right side of the heart (pulmonic valve closes later than the aortic
valve).
 P2 (pulmonic component of S2) separates from A2 (aortic component of S2) on inspiration
(diaphragm goes down) and then comes back on expiration.
o Marks the beginning of diastole.
- S3 (early diastole; indicates a ventricular overload)
o Can be normal in someone under 30-35 y/o but if they’re older than that, it could be pathologic.
o Is in early diastole. It’s due to blood (in diastole) going into a chamber that’s overloaded. Could be
from the left ventricle overload (left heart failure) or right ventricle is overload (right heart failure).
o S3 can be either right-sided or left-sided.
- S4 (in late diastole; also indicates ventricular overload; indicates a problem with compliance)
o Occurs when the atrium is contracting and you get that last bit of blood into the ventricles.
o You get an S4 if you have a problem with compliance (a filling term); in trying to get blood into a
ventricle that is non-compliant, you meet resistance and that creates a vibration that produces the S4 heart
sound.
o Could occur because of hypertrophy or because it’s already filled up and it has to put more blood into
an already overfilled chamber.
o If you had hypertension, you would have an S4 abnormal heart sound.
- Volume overload would have S3 and S4; heard in regurgitations.
- Left or Right Side
o To determine whether it’s from the left or right you use breathing. When you breathe in you suck blood
into the right side of the heart.
 All right sided heart murmurs and abnormal heart sounds (i.e. S3 and S4) increase in intensity
on inspiration if they’re on the right side. If left sided, it increases in intensity on expiration.
 On expiration, when you have positive intrathoracic pressures (helping the ventricles push blood
out of the heart), abnormal heart sounds and abnormal murmurs increase in intensity on
expiration.

Murmurs
- Stenosis and Regurgitation
o Stenosis is a problem opening the valve; regurgitation or insufficiency is a problem in closing the
valve.
o For stenosis murmurs, when the valve is opening, that’s when the murmur’s going to occur; for
regurgitation murmurs, when the valve is closing, that’s when you have the murmur.
- Location for hearing valves:
o Aortic valve: right 2nd intercostal space
o Pulmonic valve: left 2nd intercostal space
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o Tricuspid valve: left parsternal border

o Mitral valve: apex
- Systolic Murmurs (Aortic and Pulmonary Stenosis: Diamond)
o In systole, aortic and pulmonic valves are opening; the murmurs of aortic stenosis and pulmonic
stenosis occur in systole.
 Aortic stenosis: left ventricle contracts and encounters resistance. The intensity of the murmur
goes up as it pushes and gets to a peak and decreases (it’s a diamond-shaped configuration) and
this is why it’s called an ejection murmur. An ejection murmur (like aortic stenosis) has
crescendo and decrescendo.
• In aortic stenosis you have an ejection type of murmur in systole heard best in the right
2nd intercostal space.
• It radiates to the carotids. The murmur intensity increases on expiration. You
probably hear an S4 abnormal heart sound.
 Pulmonic stenosis you hear it on the left side. It’d be an ejection type murmur and it would
increase on expiration as well.
o The murmurs are due to a ventricle trying to overcome resistance.
- Diastolic Murmurs (Mitral and Tricuspid stenosis: Snap then Rumble)
o In diastole, stenosis murmurs, mitral and tricuspid valves are opening.
o Mitral stenosis: the problem is with the left atria.
 The left atrium gets dilated and hypertrophied.
• You get predisposed to atrial fibrillation and stasis of blood and thrombus.
 The blood builds up in the atrium and then snaps the valve (opening snap) and then comes
rushing into the ventricle (mid-diastolic rumble).
 Mitral stenosis is a problem in opening the valve so there’s a problem in filling the ventricle.
You have no hypertrophy at all.
 Heard best at the apex and increases in intensity on expiration.
o The murmurs are due to an atrium trying to overcome resistance
- Regurgitation (blowing murmur and has S3 and S4 [present in volume overload])
o Problem in closing the valve.
o In systole, mitral and tricuspid valves close.
 Murmurs will represent blood rushing through the incompetent valve = pansystolic or almost
(no crescendo or decrescendo). Sometimes it obliterates S1 and S2.
 Mitral regurgitation
• Apical murmur, pansystolic, S3 and S4 (b/c of a problem with compliance), and
increases in intensity on expiration (b/c left sided).
 Tricuspid regurgitation
• Pansystolic, S3 and S4, left parasternal border, increases in intensity on inspiration
(b/c right sided).
o In diastole, aortic and pulmonary valves close.
 Aortic regurgitation (like in syphilitic aneurysm). Because blood is dripping in at the beginning
of diastole, you’re going to get a volume overloaded chamber.
• The regurgitation would then be heard right after the second heart sound because the
valve is not closing and blood is dripping back in.
• You get a high-pitched diastolic blowing murmur in the right 2nd intercostal space. It
increases in intensity on expiration. S3 and S4are heard because you have a volume
overloaded chamber.
• The dripping blood hits the anterior valve leaflet.
o Austin-Flint murmur
 The anterior leaflet is one side of the outflow tract down into the aorta;
that creates an Austin-Flint murmur.
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 When you have aortic regurgitation and you hear an Austin-Flint

murmur, you have to remove the valve; it means you are significantly
dripping back in there.
- Review of Murmurs
o Systolic Murmurs
 Stenosis
• Aortic and Pulmonary = diamond shaped (crescendo and decrescendo)
o Aortic
 Radiates to carotids
 Heard best on the right 2nd intercostal and increases on expiration
o Pulmonary
 Heard best on the left 2nd intercostal and increases on inspiration
 Regurgitation (all regurgitations may have S3 and/or S4)
• Mitral and Tricuspid = Pansystolic
o Mitral
 Heard best in apex and increases on expiration
o Tricuspid
 Heard best on left parasternal border and increases on inspiration.
o Diastolic Murmurs (locations and inspiration/expiration differentiation the same as in systolic)
 Stenosis
• Mitral and Tricuspid = Opening Snap and mid-diastolic rumble
 Regurgitation
• Aortic and Pulmonary = High-pitched diastolic blowing sound
• Aortic regurgitation may have an Austin-Flint murmur
Heart Failure
- Left Heart Failure (forward failure and symptoms)
o It’s forward failure; you’re having problems in getting blood outside of the heart.
o Possible causes:
 An increased afterload (hypertension).
 Excess volume.
 Many infarcts of the left ventricle replacing muscle with fibrous tissue leading to a reduction in
contractility.
o Your end diastolic volume is going to increase because you can’t get all the blood out.
o The increased pressure and volume will go back into the left atrium and back into the pulmonary vessels,
increase the hydrostatic pressure and cause pulmonary edema.
o Chronic left heart failure
 You have hemorrhage and alveolar macrophages that phagocytose the RBCs in the lungs. You
end up with this rusty colored sputum and in cytology you see heart failure cells (alveolar
macrophages that have phagocytosed RBCs and it’s broken down into hemosiderin).
 Pulmonary edema is always left heart failure.
o Left heart failure is a diagnosis of symptoms: the main symptom of left heart failure is dyspnea.
- Right Heart Failure (backward failure and signs [found on physical exam])
o Right heart failure is a diagnosis of signs and not so much symptoms.
o The right heart has a problem getting blood through the pulmonary vessels to the left heart.
o If it fails, then blood builds up behind it (it’s a backward failure).
o The hydrostatic pressure will increase in the venous circuit and you get:
 Neck vein distention
 Hepatomegaly (“nut-meg” liver). The increased pressures in the vena cava are transmitted into
the hepatic vein (which empties into it) and back into the liver to the central vein.
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 The most common cause of a congestive hepatomegaly is right heart failure.

o The increase in hydrostatic pressure also produces pitting edema and possibly ascites.
- Paroxysmal nocturnal dyspnea
o When you lie down and go to sleep, you can reabsorb up to a liter of fluid (fluid from the interstitium will
go into the venous side of the circulation).
o You have a bit of extra blood going into the right heart and then the left heart.
o If you have left heart failure, you have excess blood (that wasn’t there when you were standing up) and
the left heart sends the blood back (into the lungs) resulting in paroxysmal nocturnal dyspnea.
o “Pillow orthopnea”, the use of pillows to relieve the dyspnea (decreases venous return to the right side
of your heart) is also a sign of left heart failure.
- Treatment
o The best non-pharmacological treatment is restriction of water and salt.
o The best single drug treatment (decreases afterload and preload at the same time) is an ACE inhibitor;
you increase longevity.
o The combination of an ACE inhibitor and spironolactone has been shown to be the best treatment.

High output failure

- Endotoxic shock
o You have increased venous return to the heart.
 If you vasodilate peripheral resistance arterioles, you decrease TPR and more blood comes back
to the right heart, the left heart has to deal with it and you get high output failure.
- Thiamine deficiency
o Another cause is thiamine deficiency. In thiamine deficiency, you have ATP depletion. The smooth
muscle cells in the periphery are affected and dilate.
- Graves’ disease
o Hyperthyroidism causes an increase of Beta receptors in the heart and you get an increase in force of
contraction (systolic pressures are higher and you go into high output failure).
- Arterio-Venous fistulas
o If you got stabbed in the leg and developed an arterio-venous malformation (arterial blood bypasses
microcirculation going directly into venous circulation) causes blood to be come back faster to the
heart.
o A bruit would form over the mass and it would be pulsatile.
o If you pressed the proximal portion of the mass, your heart rate would slow (Branham’s sign).

Congenital Heart Disease

- Fetal circulation
o The baby is not exchanging blood with oxygen in the lungs (the pulmonary vessels in the fetus look like
they have pulmonary hypertension; they’re so thick that it’s hard to get blood through the pulmonary
artery into the left ventricle; this is why you need a patent ductus to get it out of there).
o The oxygen is coming from the chorionic villus dipping into blood that derives from the mother’s
spiral arterioles. The chorionic villi dip into blood and extract oxygen.
o Since it’s not as efficient as extracting oxygen in the lungs, you need a high affinity hemoglobin to get
what little oxygen is down in the area (HbF). When HbF gets it, it doesn’t want to give it up; tissue
hypoxia causes erythropoietin to be released and causes the fetus to have an 18 hemoglobin
(essentially polycythemia).
- Order of fetal circulation
o Oxygen goes through trophoblasts (of chorionic villus), then the cytotrophoblasts, then myxomatous
stroma (of chorionic villus), and then into the blood vessels (of the chorionic villus).
o The blood vessels of the chorionic villi coalesce to form the umbilical vein (this has the highest oxygen
content).
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o
o From the umbilical vein, the blood proceeds into the liver and it can go either into the hepatic sinusoids
(recollects into the hepatic vein and dumped into the vena cava) or it can go into the ductus venosus and
right into the inferior vena cava.
o Once in the inferior vena cava it goes up to the right side of the heart and through the foramen ovale
(between the atria) and into the left atrium into the left ventricle and out the aorta.
o Superior vena cava blood, however, goes straight down into the tricuspid valve into the right ventricle.
 It can’t go to the lungs because the pulmonary arteries are too thick (the pressure is too much); so
the blood in the pulmonary arteries goes through the patentductus arteriosus (maintained
opened by PGE2 produced by the placenta as a vasodilator).
 This serves as a right-to-left shunt and how the blood can get out of the pulmonary artery and
into the aorta.
o When blood goes out the aorta, it goes into two umbilical arteries (these are the vessels with the least
amount of oxygen). The umblilical arteries are accompanied by the umbilical vein when leaving the
fetus; the umbilical vein has the most amount of oxygen.
- Once the baby takes its first breath, the pulmonary vessels open. Blood is going through the pulmonary arteries
and gas exchange occurs in the lungs. The patent ductus begins functionally closing and it becomes the
ligamentum arteriosum.
- On the boards, they’ll ask you about oxygen saturation in different chambers; this is how they know which
direction the shunts are going.
- Step-up and Step-down
o If you have a left-to-right shunt and you have oxygenated blood going into unoxygenated blood, the
oxygen saturation on the right side is increased (step-up).
o If you have a right-to-left shunt with unoxygenated blood going into oxygenated blood, you get a step-
down.
- Oxygen saturation of the right side of the heart returning from the body is 75%; the oxygen saturation on the left
side is 95%.
- Ventricular Septal Defect (the most common)
o Normally there’s just a membrane (not a muscle) that has no hole in it that’s there.
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o Since the left ventricle is stronger, the shunt is going to go left-to-right.

o Oxygenated blood gets dumped in the right ventricle (step-up) and it goes to the pulmonary artery (also is
stepped up).
o If not corrected, the right side of the heart would be volume overloaded. This would result in
pulmonary hypertension (this puts stress on the right ventricle and it gets hypertrophied).
 You then run the risk of reversing the shunt (the right ventricle can become stronger than the
left); this reversal of the left-to-right shunt is called the Eisenmenger’s syndrome.
 Once you reverse the shunt you get cyanosis.
o Most VSD’s close spontaneously; some need to be patched.
- Atrial Septal Defect
o It’s normal for a fetus, but not for a newborn.
o Blood goes left-to-right b/c left is stronger than the right. In the right atrium, there’s a step up (as well
as in the right ventricle and the pulmonary arteries).
o The main difference between oxygen saturations in a VSD vs. an ASD is there’s a step-up in the right
atrium in an ASD.
o Since you’re volume overloading the right side of the heart, you run the risk of Eisenmenger’s syndrome.
o You also run the risk for paridoxycal embolisation.
 If you have a deep venous thrombosis in your leg and it embolized up while the pressures in the
right side of your heart are increasing (and you have a patent foramen ovale), that embolus could
go into your left atrium and result in a venous clot in your arterial circulation.
o The most common teratogen producing disease that has atrial septal defect associated with it is fetal
alcohol syndrome.
- Patent Ductus Arteriosus
o It’s not normal in a newborn.
o There’s a connection between the aorta and the pulmonary vessels. Since the aorta has a stronger
pressure, oxygenated blood goes from the left ventricle and gets dumped into the pulmonary artery
before it goes into the lungs; in the pulmonary arteries you have a step-up.
o Since there’s an opening between the aorta and the pulmonary artery, you have blood going back and
forth between systole and diastole. This produces a murmur called “machinery” murmur. It’s heard
best between the shoulder blades.
o With this left-to-right shunt you volume overload the right side of the heart and get pulmonary
hypertension. Now the shunt will reverse and go the way it did when it was a fetus: you have
unoxygenated blood dumping into the aorta (the ductus empties distal to the subclavian artery).
 The baby will be pink on top and blue on the bottom b/c you dump unoxygenated blood below
the subclavian artery (differential cyanosis).
o The teratogen associated with patent ductus arteriosus is congenital rubella.
o If you wanted to close the PDA (in a heart that wasn’t dependent on it), you could give indomethacin
(it’s an NSAID that inhibits PGE2).
- Tetralogy of fallot
o It’s the most common cyanotic congenital heart disease.
o The four things you have are:
 An overriding aorta: it straddles the septum
 A membranous septal defect
 Pulmonic stenosis below the valves
 Right ventricular hypertrophy
o Cyanosis is determined by the degree of pulmonary stenosis
 If the degree of pulmonic stenosis wasn’t that bad, when the right ventricle contracts, more
blood would go up the pulmonary artery and get oxygenated instead of going into the left
ventricle (probably would not have cyanosis at birth).
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 If you had very severe pulmonic stenosis, when the right ventricle contracted, most would be
shunted from right to left and then the blood in the left ventricle is stepped down.
o Patent ductus arteriosus and atrial septal defect are cardioprotective in a patient with tetralogy of
fallot.
 An atrial septal defect would cause blood to go left to right; we’d get oxygenated blood emptying
into the right atrium. This would step up oxygen in the right atrium. Now when blood goes from
the right ventricle to the left ventricle there’s at least a little more oxygenated blood in it than
before.
 A patent ductus arteriosus would push blood from the aorta (that is unoxygenated) to the
pulmonary artery to get oxygenated.
o If you have right-to-left shunting, you’re going to get polycythemia and an increased risk for infective
endocarditis b/c of the shunts (from the right cycle going right into the systemic circulation).
Vegetations can spread to your brain and you can get multiple cerebral abscesses.
- All congenital heart diseases have an increased risk for infective endocarditis.

Cardiovascular 3

Transposition of the Great Vessels

- The main question is immotile cilia syndrome (Kartagener’s syndrome).
o The heart is on the right side instead of the left and the liver is on the left instead of the right.
o They imply that in a complete transposition of the great vessels, everything is switched.
o You have a normal heart, but it’s on your right side.
- None of the atria are transposed; the right atrium still gets unoxygenated blood and the left atrium still gets 95%
oxygen saturated blood from the pulmonary vein.
- The problem is in the ventricles: the right ventricle is being emptied by the aorta. The left ventricle is emptied by
the pulmonary artery. The transposition occurs in the ventricles.
- This is incompatible with life unless you have shunts. You usually have 3 shunts: patent foramen ovale,
septal defect, and a patent ductus.
o Starting from the left atrium (where you have 95% oxygen saturation), you have a left-to-right shunt (b/c
of the patent foramen ovale) which goes to the right atrium.
o Because of the left-to-right shunt via the patent foramen ovale, you get a step-up of oxygen in the right
atrium and a step up of oxygen in the right ventricle as well. Some of the oxygenated blood goes out the
aorta and some goes into the left ventricle (which is emptied by the pulmonary artery which leads back to
the lungs to get oxygenated).
o Unless you have shunts, the right ventricle is emptied only by the aorta would just be all unoxygenated
blood and the left ventricle (emptied by the pulmonary artery) would be in trouble.
- Tausing-Bing Malformation
o It is a variant of transposition of the great arteries because the aorta arises from the morphological right
ventricle (on the right side of the heart) and the pulmonary artery arises from both ventricles.
- Sidenote:
o Maternal Diabetes is associated with Transposition of the Great Vessels.
Coarctation of Aorta
- Preductus vs Postductus
o Preductal occurs in Turner’s syndrome (one of their more common congenital heart disease). Unless
they’re corrected, they go right into failure.
o Postductals aren’t present at birth; they can occur at any time in a patient’s life.
 They’re important to recognize b/c they’re a surgically correctable cause of hypertension.
- Proximal
o A murmur would be heard (in systole), probably between the shoulder blades.
o The proximal aorta would get dilated and there would be an increased pressure going up the branched
vessels (subclavian and internal carotids).
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o The blood pressure in the upper extremities is going to be higher than it is in the lower extremities.
o Because there’s an increased blood flow going into the brain, your risk for berry aneurysms is
increased.
 Sidenote of berry aneurysms:
• At the junction where the communicating branches meet the main branch of the cerebral
vessel we have no internal elastic lamina and no smooth muscle (it’s a weak area in
everyone); this means that everyone has the potential for developing berry aneurysms.
• Hypertension (any kind) would exacerbate the risk for berry aneurysms.
o The aortic valve ring may get stretched and get a murmur of aortic regurgitation (like syphilis).
o The increased pressure on the wall of the proximal aorta could predispose it for dissecting aortic
aneurysm.
- Distal
o You see decreased blood flow and claudication (angina of the peripheral vessels); when they walk they
get calf pain or buttock pain.
o Muscle mass will be decreased and the blood pressure will be lower in the lower extremities.
o The blood flow to the renal arteries is decreased; the renin-angiotensin aldosterone system is
activated and you have hypertension (it’s a high-renin hypertension). If coarctation is corrected, the
hypertension should go away.
o To get around the coarctation:
 The rarest is the superficial epigastric artery (the lateral border of the triangle of Hesselbach)
collateralizing with the internal mammary artery.
 The intercostals (in the undersurface of the ribs) get excess blood through them and produce rib
notching.

Risk factors for Coronary Artery Disease

- Age is the most important risk factor; after 45 for men and 55 for women (estrogen causes them to have more
HDL).
o HDL is the risk factor for coronary artery disease, not LDL.
- HDL < 35; if HDL > 60, you can subtract one from major risk factors

Ischemic heart disease

- Four types
o Angina
o Mild Cardiac Infarction
o Sudden Cardiac Death Syndrome
o Chronic Ischemic Heart Disease
- Sudden Cardiac Death Syndrome
o Death w/in one hour.
o In autopsy, you don’t see coronary thrombus (it’s uncommon) but you will see severe coronary artery
atherosclerosis.
o Death is from ventricular arrhythmia.
o Smoking predisposes SCDS.
- Chronic Ischemic Heart Disease
o When you have little infarcts or a small heart attack (endocardial infarctions) causes the muscle to be
replaced by fibrous tissue (has no contractility). Eventually the left ventricle becomes all fibrous tissue;
the ejection is decreased and you die of heart failure.
o It’s the second most common indication for heart transplant.
- Angina (most common)
o Exertional, Printzmetal, and Unstable
 Exertional (classical)
• You get chest pain when you do work. It goes away w/in 5-10 minutes of resting.
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• When you do a treadmill examination (stress test) you get an ST depression; this is
followed up by a coronary angiogram.
o ST depression = subendocardial ischemia; because coronary arteries supply out
to in (occurs when you have atherosclerosis of coronary arteries).
 Prinzmetal
• Usually in women
• Occurs in the morning
• Due to vasospasm of coronary artery. When you have vasospasm of a coronary artery,
you have transmural ischemia (ischemia throughout full thickness of the myocardium);
this produces ST elevation.
o ST elevation = transmural ischemia.
 Unstable (Resting or pre-infarction)
• Angina just resting; history is they had initially classical and now they get it when
resting.
• You put them in the hospital, get angiogramed and usually end up with angioplasty.
- The saphenous vein is used for doing a CABG (coronary artery bypass graft); the tributaries have to be tied
off otherwise it leaks.
o After ten years, the vein becomes arteriolized and they have a high tendency for fibrosing off.
o The internal mammary can also be used since it’s an artery (remain patent) and it’s nearby. The problem
is you can’t do a four vessel bypass with it.

Acute Myocardial Infarction

- Thrombus = a group of platelets held together by fibrin. Tissue Plasminogen Activator only has to break the
fibrin bonds and it falls apart. A venous clot has more fibrin and is harder to eliminate.
- Reperfusion injury
o Oxygenated blood goes into injured tissue, you get superoxide free radicals and calcium and the some
injured cardial cells die.
o Once the cells die, however, there’s no further extension and it improves longevity.
- Vessels
o Left anterior descending artery
 It’s the most common location for thrombosis.
 It supplies the anterior part of your heart and the anterior 2/3 of the interventricular septum.
 Most of the conduction bundles are in the anterior 2/3 of the septum. If you have a complete
heart block that requires a pacemaker, the most likely vessel that was thrombosed is the left
anterior descending.
o Right coronary artery
 The second most common location of thrombosis.
 It supplies the entire posterior part of the heart, the posterior 1/3 of the interventricular septum,
and the entire right ventricle.
 The AV node
• The SA node has an equal distribution between left and right. The AV node, however,
is 95% supplied by branches from the right coronary artery.
• If you knock off the AV node, it would cause sinus bradycardia.
 Mitral regurgitation and Mitral valve
• The mitral valve has two valves and it has papillary muscles (postero-medial papillary
muscle is supplied by the right coronary artery).
• If you got a patient that has a mitral regurgitation type of murmur it could be related to
postero-medial papillary muscle dysfunction (the papillary muscle that usually ruptures).
If the papillary muscle breaks, you know that it was a right coronary artery thrombosis.
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• A murmur of mitral regurgitation that occurs during myocardial infarction would

be due to right coronary artery.
 Atypical chest pain
• Sidenote: LAD
o When you have LAD, you have the substernal classical chest pain radiation to
the left arm and maybe into the arm.
• The right coronary artery can cause epigastric pain (atypical chest pain) and
simulate gastroesophageal reflux disease.
- Timeline
o Between 3-7 days the heart is softest and has the greatest chance for rupturing.
o Pale infarct appears at 24 hours.
o Coagulation necrosis at maybe 4-6 hours.
Mural thrombus
- Aspirin with heparin and warfarin are given to prevent mural thrombus after an anterior myocardial infarction.
- Mural thrombi are mixed clots.
o When you have a transmural infarction, you have injury to the endothelial surface of the heart. Platelets
then stick to the endothelial surface.
o On top of the platelets, a venous-like clot develops (has coagulation factors in it) from stasis.
o By taking aspirin, you prevent a coronary thrombosis (decreasing platelet aggregation) but you also
prevent a mural thrombus from initially developing.
o By putting the patient on warfarin and heparin, you prevent the other part of the clot (venous clot) from
developing.
- They can embolize.

Fibrinous pericarditis (1st week or 6 weeks later)

- Can occur two times in a person with acute myocardial infarction: the first week (get a friction rub and chest pain
relieved by leaning forward) due to a transmural infarction and increased vessel permeability, etc.
- The second is usually a case such as a person with a transmural infarct and six weeks later comes in with fever,
muscle aches, and pain. They also have a three component friction rub in the chest.
o Dressler’s syndrome is an autoimmune pericarditis; it’s characterized by pleuritic chest pain,
fever, pericarditis, and leukocytosis.
o When the patient had the infarct and you damaged the pericardial surface, you developed autoantibodies
against your pericardial tissue.
 It took 6 weeks to get a high enough titer to begin attacking the pericardium and it also caused
systemic symptoms related to the immunologic reaction.
o Treatment is NSAIDS

Ventricular aneurysm
- Patient would present 3 weeks later after a myocardial infarction with a systolic chest bulge of the precordium.
This occurs because blood collects in the aneurysm and bulges it out and makes your chest bulge out.
- The most common complication isn’t rupture.
o Normally all aneurysms rupture, but this aneurysm is lined by scar tissue.
- The most common cause of death in a ventricular aneurysm is heart failure (it occupies a lot of space in the left
ventricle).

Scar tissue
- Is very white and patchy looking vs. a pale infarct.
- It can be anywhere from 3 weeks to 10 years; can’t tell when the infarct occurred.
- It decreases contractility and the ejection fraction (its your best prognostic factor for how you will do
following an infarct).
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Diagnosing Myocardial Infarctions

- The test of choice is Troponin I
o It appears after 2-6 hours and lasts 5-10 days (Cecil’s).
o Tropinin T can also be used but is less specific than Troponin I.
- CK-MB (an isoenzyme of creatine kinase) is the test of choice for recurrent angina (reinfarction) once troponin
elevated.
o It appears after 3-6 hours and lasts 2-4 days.
o The reappearance of CK-MB after 3 days = reinfarction.
- LDH isoenzymes have a lower specificity than the two mentioned above.
o Normally LDH 2 is higher than LDH 1 (in cardiac muscle).
o When you have an infarct, you release LDH 1 and LDH 1 > LDH 2. (The LDH 1-2 flip; happens at
about 18 hours and peaks in 2-3 days and lasts for a week).

Valvular Diseases
- Mitral Valve Prolapse
o Most common mitral valve lesion.
o It’s when you have too much valve and it looks like a parachute.
o Blood underneath the “parachute” will push and prolapse the mitral valve into the atrium; when it stops it
makes a click noise and followed by a short murmur of mitral regurgitation. It’s click then murmur, not
snap murmur (opening snap = mitral/tricuspid stenosis).
o The pathology is myxomatous degeneration.
o Dermatan sulfate (a glycosaminoglycan [GAG]) makes up the valve (also found in skin). You have an
excess of dermatan sulfate in the valve and it becomes redundant (like a “floppy” parachute).
o Blood goes underneath the valve and prolapse it in.

Cardiovascular 4

Mitral Valve Prolapse

- Click and murmur
o Deals with preload.
o If we can increase the volume in the left ventricle, the click and murmur come closer to S2 b/c it takes
longer for all the events to get the blood out.
o If we decrease the amount of blood (decrease preload), the click and murmur come closer to S1.
o If you have mitral valve prolapse and are standing up, you have less preload (vs. lying down). The click
and murmur comes closer to S1. When you lie down the click and murmur comes closer to S2.
o In anxiety (HR increases), the click and murmur comes closer to S1.
- Most common symptom is palpitations.
- Two genetic diseases that always have mitral valve prolapse associated with them are Marfan’s and Ehlers-
Danlosyndrome. Mitral valve prolapse can cause sudden death in someone with Marfan’s; they have a very
serious mitral valve prolapse along with conduction problems.

Aortic Stenosis
- Most common valvular cause of syncope with exercise (start running and you have a decreased cardiac output so
you faint) and angina with exercise.
- Most common cause of microangiopathic hemolytic anemia.
- It’s an ejection type of murmur.
- Increases in intensity on expiration.
- Intensity with different positions
o Decrease amount of blood, that decreases the intensity of the ejection murmur (not that much blood
having to go through the valve).
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o If you increase blood and you have to get the blood out, it increases the intensity. It’s important because
it distinguishes it from hypertropic cariomyopathy.
- They get angina with exercise. The pulse is diminished (stroke volume is decreased).
o Your coronary arteries fill up in diastole; you have less blood available to fill the coronary arteries (you
get angina).

Mitral Stenosis
- Left atrium gets dilated.
- The murmur occurs in diastole; the mitral valve has a problem opening (you get a snap and then rumble).
- Located in apex and increases intensity on expiration.
- The most common cause is rheumatic fever.
o Acute rheumatic fever is due to a Group A Beta Streptococcal infection (Strep pyogenes).
o Usually it’ll occur post pharyngitis as opposed to post-streptococcal glomerular nephritis which will be
either as pharyngitis or skin infection.
o When you culture the blood in patients in rheumatic fever, you’re not going to be able to grow (it’ll be
negative) because it’s not an infective endocarditis (it’s immunologic).
o The M protein in Strep. pyogenes in certain strains have antigens in it that are similar to antigens that are
in our heart, joints, and other areas in our body (mimicry). When we make antibodies against the M
protein, we also make them against our own tissue.
o The most common valve involved is the mitral valve and the vegetations are sterile; they line right along
the line of closure of the line. Embolization is not a big feature.
o The Jones criteria for diagnosing acute rheumatic fever is joint pain (polyarthritis), swelling, erythema
marginatum (skin zit), “rheumatoid” (subcutaneous) nodules, dyspnea, bibasilar rales, pansystolic
murmur (at the apex) that increases in intensity on expiration, S3 and S4 heart sound is present; the most
common symptom is polyarthritis (differential diagnosis is juvenile rheumatoid arthritis, Henoch-
Schonlein purpura, rubella, and acute rheumatic fever). A late manifestation is choreoform
movements (Syndeham’s chorea).
o The most common valvular lesion in acute rheumatic fever isn’t mitral stenosis (takes 10 years of
repeated attacks); the murmur heard in rheumatic fever is mitral regurgitation (all parts of the heart
are inflamed: pericardium [friction rubs], myocardium [you get myocarditis], and the endocardium [the
valves and the vegetations]).
o The ASO titer (anti-streptolysin O for S. pyogenes) is also used sometimes because they can be elevated.
o Aschoff bodies are the reactive histiocytes in the myocardium.
- It sometimes has a “fish mouth” appearance.
- Sidenote: Left Atrium
o The most posterior located chamber is the left atrium; this is why the best way to see it is with a
transesophageal ultrasound.
- Ortner’s Syndrome
o Because the left atrium is posteriorly located and enlarged and dilated in mitral stenosis, it often times
presses on the esophagus (get dysphagia for solids, but not liquids). It can stretch the left recurrent
laryngeal nerve and produce hoarseness (Ortner’s syndrome).
- Thrombi in patients with mitral stenosis
o If they have an irregular irregular pulse = atrial fibrillation.
o Thrombi can form in the left atrium of patients with mitral stenosis because you have a lot of stasis;
patients have to be anticoagulated.

Tricuspid Regurgitation
- IV drug abuse with infective endocarditis.

Carcinoid Heart Disease

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- In order to have carcinoid syndrome, you have to have metastases to the liver of a carcinoid tumor. Then the
serotonin in the tumor nodules gets sent to the hepatic vein tributaries, then into the venous blood. It ends up
bathing the right side of the heart and serotonin produces a fibrous tissue response of the valves.
- You get tricuspid TIPS (tricuspid insufficiency and pulmonic stenosis).

Infective Endocarditis
- The most common organism causing infective endocarditis is Strep Viridans.
- If you have an underlying cardiac disease, you run the risk of getting bacterial endocarditis.
- The second most common organism is Staph aureus; it can infect a normal valve or a damaged valve.
- The most common valve involved in infective endocarditis is the mitral valve; the second most common is the
aortic valve.
- If you are an IV drug abuser, the most common valve involved is the tricuspid valve; the second is the aortic.
They would present with a pansystolic mumur that increases in intensity on inspiration (tricuspid) or you could
get a murmur of aortic regurgitation (high pitched diastolic blowing murmur after the second heart sound).
- If you have colon cancer or ulcerative colitis (something with ulceration of the colonic mucosa) it’s a unique
type of infective endocarditis associated with it: Streptococcus bovis (Group D).
- If you have a ventricular septal defect, you can get vegetations on your aortic valve. Remember if you have a
congenital heart defect or damage to your valves, you have an increased risk for infective endocarditis.
- Signs of infective endocarditis (all type III hypersensitivities) are:
o Splinter hemorrhages - small linear hemorrhages under the fingernails or toenails.
o Osler nodes - small, painful cutaneous nodes usually present in the fingers and toes.
o Janeway lesions - erythematous or hemorrhagic nontender lesions on the palms or soles.
o Roth spots in the eye; you would see retinal hemorrhages that look like Koplik’s spots (present in the
mouth of someone with measles) in that both are red with white spots in the middle.
- Libman-Sach’s endocarditis (= lupus)
o Endocarditis that occurs in patients with lupus (patient can present with a positive ANA).
o It’s not the most common lesion of the heart in people with lupus; pericarditis is the most common
heart lesion.
o Fibrinoid necrosis occurs, just like in rheumatic fever.
- Marantic Endocarditis (aka Nonbacterial Thrombotic Endocarditis)
o Is due to noninfective vegetations; small masses of fibrin, platelets, and other blood components are
deposited on the leaflets of the cardiac valves.
o It is often encountered in debilitated patients, such as those with cancer or sepsis.

Myocarditis and Pericarditis (Coxsackie virus)

- Coxsackie virus is the most common cause for many diseases: myocarditis and pericarditis, viral meningitis,
hand-foot mouth disease, and herpangina.
o Question may present as a person in heart failure. An endocardial biopsy showed lymphocytic infiltrate.
o To diagnose coxsackie myocarditis, you do have to do a biopsy of the subendocardial tissue; you’ll see
a lymphocytic infiltrate (as with any virus).

Cardiomyopathies
- Case:
o A woman six weeks postpartum is having dyspnea. After doing a chest x-ray she has generalized
cardiomegaly. She has effusions at both lung bases.
o She has congestive cardiomyopathy (Dilated cardiomyopathy).
- Congestive Cardiomyopathy (Dilated cardiomyopathy)
o It’s a disease of the muscle
o There’s many causes. One cause is postpartum (6 weeks usually). Other causes are Coxsackie.
o It’s the most common reason for cardiac transplants in an adult.
o Cardiotoxic drugs cause these kinds of cardiomyopathies.
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o Alcohol can also cause this kind of cardiomyopathy; due to thiamine deficiency.
- Hypertrophic Cardiomyopathy (used to be called Idiopathic Hypertrophic Subaortic Stenosis)
o It’s the most common cause of sudden death in an athlete.
o The interventricular septum can be asymmetrically thicker than the outer wall.
o Sidenote:
 If you had aortic regurgitation and blood dripped back, it would hit the anterior leaflet of the
mitral valve and produce Austin Flint murmur.
o The obstruction is not at the level of the aortic valve but below it. When things (blood) go through a
narrow opening, there’s a negative pressure behind it. The negative pressure behind blood after passing
through the aortic valve sucks the anterior leaflet against the septum and it stops blood.
o Treatment is an increased preload. Increased preload would decrease the amount of obstruction.
o Things that increase preload would make the intensity of the murmur less and improve the patient all
together. Digitalis would be contraindicated here because it would increase the force of contraction and
make it go faster and obstruct quicker.
o A beta blocker or a calcium channel blocker would help because it would decrease the force of
contraction and slow down the heart rate and increase preload.
o Mechanism = abnormal conduction
 A biopsy of the septum would show an abnormal configuration of muscles. The conduction
bundles are in disarray and there are conduction defects. This contributes to ventricular
tacchycardias and can lead to sudden death.
- Endocardio fibroelastosis
o An example of restrictive cardiomyopathy; the ventricle is prevented from filling up.
o It is the most common disease producing restrictive cardiomyopathy in children. It’s also the most
common reason for a child needing a heart transplant.
o Other causes are Pompe’s (glycogen storage disease type II: a deficiency of lysosomal alpha-
glucosidase), iron overload, or amyloid in the heart.

Cardiac Myxoma
- Most are in the left atrium (85%); the rest are on the right.
- They’re benign tumors and are movable. Because they’re movable, they can block the orifice of the mitral
valve and produce syncope. They can also embolize. It can leak out a variety of cytokines and result in fever
and malaise.
- A transesophageal ultrasound can diagnose it.
- It’s the most common benign tumor in the heart in adults.
- If they ask for a tumor in the heart of a kid, don’t pick myxoma. Rhabdomyomas are what they’re looking for
and are associated with tuberous sclerosis (an autosomal dominant disease where multiple tumors appear in the
skin, brain, heart, and kidneys of affected children).

Pericardial effusion
- An x-ray would show a “waterbottle” configuration.
- Symptoms include muffled heart sounds, whenever the person breathes in, the neck veins distend (should not
happen b/c when you breathe in and increase intrathoracic pressure, the neck vein should collapse on inspiration).
o The patient’s radial artery pulse decreases upon breathing in (when the neck veins distend). When you
take the pressure, there’s a 10 mmHg drop in blood pressure on inspiration.
o Beck’s triad = hypotension, distended neck veins, and muffled heart sounds
o Kussmaul’s sign = elevation of the neck veins (and of central venous pressure) during inspiration
o Pulsus paradoxus = a decrease in BP > 10 mmHg on inspiration
- Pathogenesis:
o The heart can’t fill up because there’s fluid around it (why you have muffled heart sounds).
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o When you breathe in (blood should be sucked into the right side of your heart), the right side of your
heart can’t expand and your neck veins distend instead of collapse. Since there’s no blood going into the
right or the left side of the heart, on inspiration the pulse drops.
- The question would be what’s the first step in the workup of the patient; this would be doing an
echocardiogram to prove that they have fluid in there.
- It’s most commonly due to pericarditis; the most common cause of pericarditis is Coxsackie.
- If you had a woman with a positive ANA it would be lupus. Any young woman that has an unexplained
pericardial effusion or pleural effusion is lupus until proven otherwise. This is because serositis
(inflammation of serosal membranes) is a feature of lupus.

Constrictive pericarditis
- In third world countries it’s due to TB most commonly; in the U.S. it’s a previous cardiac surgery.
- The pericardium is thick but has no fluid in it. When you breathe in, the blood goes into the right side of the
heart; it fills up some and hits the wall (makes a “pericardial knock” noise).
- One of the things that distinguishes a pericardial effusion from constrictive pericarditis is you have muffled heart
sounds in an effusion with no knock as opposed to constrictive pericarditis.

Hematology1

Big Picture (know the MCV’s because that’s what’s given on the test)
I. Microcytic anemias (MCV< 80)
a. Iron deficiency most common
b. Chronic anemia disease
c. Thalassemias
d. Sideroblastic anemias
II. Macrocytic anemias (MCV >100)
a. Vitamin B12 or Folate deficiency; odds are folate and alcoholic
III. Normocytic anemias
a. Low reticulocyte count corrected
b. Aplastic anemia
c. Renal disease, etc.
d. Corrected reticulocyte count increased
i. Hemolytic anemias (spherocytosis, sickle cell, G6PD deficiency, Autoimmune hemolytic anemia,
...)
- Reticulocyte count, next to a complete blood cell count is the first step in the workup of any anemia.
 92

o A reticulocyte is a young red blood cell; in 24 hrs, a reticulocyte will become a mature blood cell with a
biconcave disc
o If you have an anemia, the reticulocyte count tells you where the problem is (in the bone marrow –
making the red blood cell; or outside the bone marrow).
o If the bone marrow was the problem, then the reticulocyte count would not be an appropriate response
(marrow has RBC hyperplasia to compensate for anemia and some should be premature)
o It takes at least 5-7 days before the reticulocyte count to change; like the kidneys dealing with
bicarbonate in acid-base disorders (3-4 days)
o If there’s a good reticulocyte response, there’s no need for a bone marrow exam because there’s
nothing wrong with it – it’s responding accurately.
o You have to correct the reticulocyte count to the degree of the anemia
 The correctedreticulocyte count is the Hct of the patient divided by 45 (considered the normal)
and multiply it times the reticulocyte count given.
 (Hct/45) x reticulocyte count
 Anything over 3% is considered increased; less than 3% is a bad response.
o A reticulocyte requires a special stain to see the black filaments (RNA filaments [not ribosomes] –
means the reticulocyte is still synthesizing hemoglobin); can’t confuse it with a Heinz body
 Ribosomes don’t look like threads, they look like dots; that’s basophilic stifling. So when we
talk about lead poisoning cause - basophilic stifling, those are persistent ribosomes, not
filaments.
o Wright-Giemsa stain produces a bluish (polychromasia) cell; these are younger RBCs than the 24
hour reticulocyte; these are cells that still have basophilia usually present in the marrow; when we see
them, it means that the bone marrow is really responding (pushing the real younger cells out)
 So when the boards says polychromasia present, these cells are what they’re talking about and
they take 2-3 days before maturing
 When these cells are present, we have to make a correction.
• When we do the reticulocyte stain, these cells are going to have RNA filaments in them
and be counted in the reticulocyte count (falsely elevated). We don’t want them in there
(take 2-3 days to mature).
 To factor them out we divide by two. If the CBC says polychromasia present, we divide by
two. Remember that below 3% is not a good response.
- Rule of 3s: if you multiply the hemoglobin by 3, it should roughly equal the hematocrit. You can also work
backwards too.
o Sidenote: transfusion of packed, not whole blood cells.
 For every unit of packed RBCs you transfuse in a patient, you need to increase the
hemoglobin by one and the hematocrit by 3% (this is what you should expect the next day; it
may not happen if say the patient is having a G.I. bleeding)
• The most common cause of anemia in the world is iron deficiency; the most common
cause of iron deficiency is G.I. bleeding; so the most common reason why Hb and Hct
don’t go up after transfusion of RBCs is you’re losing blood (most common in the G.I.
track)
- Hb electrophoresis is mainly used to detect different kinds of hemoglobinopathies
- MCV (mean corpuscular volume)
o The best way of classifying anemia
 Normal is 80-100
 If < 80, by definition microcytic; odds are iron deficiency
 If between 80 and 100; normocytic anemia
 If > 100, then it’s macrocytic anemia; it’s either B12 or folate deficiency
o Because it’s an average if you had small cells and large cells (dimorphic RBC population) the MCV
would be normal (it’s like blood gases: if you have metabolic acidosis and metabolic alkalosis the pH
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would be normal). So you could have macrocytic anemia and microcytic anemia and the MCV
would be normal.
 How could this happen:
• Say you have an iron deficiency and a folate deficiency. Know where these things are
reabsorbed: iron is absorbed in the duodenum, folate in the jejunum, and B12 in the
terminal ileum.
o You could have both iron deficiency and folate deficiency if you have small
bowel disease like celiac disease.
o When you have malabsorption, it affects different areas of your small bowel, it
will affect those things.
- RDW (Red Blood Cell Distribution Width; not really asked)
o It is the machine looking at the RBCs coming to the aperature and saying are they uniformly small or
uniformly normal or uniformly macrocytic….
o It reports it as a number.
- WBC
- Spherocyte (anorexic cell)
o Has too little membrane, why it can’t hold biconcave disc and form a sphere
- Target cell (obese cell)
o Has too much membrane.
o Because it’s bulged, there’s more hemoglobin that can collect in there and it makes it look like a
bull’s eye.
o They’re markers for alcoholics. It alters the cholesterol concentration in the membrane.
o Secondly hemoglobinopathies: thalassemias, sickle cell, hemoglobin C (always have target cells)
- Mature RBC
o Looks like a biconcave disc. It’s thin in there and there’s less hemoglobin in there. There’s more
hemoglobin at the edges; that’s why you have a central area of power in a normal RBC when it’s lying
flat.
o Microcytic anemias all have a decrease in hemoglobin synthesis.
 The redness of the cells is going to drastically decreased and you see a greater area of pallor.
o Spherocyte (a cell with too little membrane and then it’s a sphere) has no area of pallor.
 It will be little red cells all red with no area of central power.

Hematology 2

- Review of before
o Reticulocyte count (have to correct it for the degree of anemia, hematocrit of the patient, and
polychromasia) is the most important way of separating how the bone marrow is working.
o If the reticulocyte count is 3% or higher, bone marrow is responding appropriately
o If polychromasia is present, divide initial correction for anemia by two. Look at number again for
response.
- Physical signs of anemia
o Spoonnails (aka koilonychia) – a sign of iron deficiency
o Cheilosis – cracking (not specific for anything)
 Can see it in iron deficiency or riboflavin deficiency
o Pylovic conjunctiva??
 If your conjunctiva are pale, you have about 6 gms or less of hemoglobin
o Palmar crease (only for Caucasian)
 If you don’t see red in them, you’re anemic.
o Lead line (on gum line)
 Lead poisoning
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o Neurologic exam is important in B12 deficiencies because you knock off the posterior columns and
lateral cortical spinal tracts (proprioception abnormalities, decreased vibratory sensation)
- 4 iron studies that you get:
o Serum iron (normal is about 100, same as alveolar)
o Serum ferritin (soluble circulating form of iron storage); it represents the amount of iron you also
have stored in your bone marrow.
o TIBC (total iron binding capacity; % saturation)
 Carrying protein for iron is transferrin (carries iron); it’s made in the liver
 Transferrin and TIBC are the SAME!!
 There’s a relationship between iron stores in the bone with the transferrin synthesized in the liver;
when the iron stores in your bone marrow are deficienct (i.e. iron deficiency), that is the
signal for your liver to make more transferrin (it’s increased, therefore the TIBC is
increased)
 So low iron stores increase transferrin synthesis (increase TIBC); think of it like T4 and TSH
o % saturation of iron is the calculation = serum iron (normally 100) / TIBC (normally 300); so normal %
saturation is 33% (the normal binding percent of hormones to their binding proteins)
- Microcytic anemias (all 4 groups have a decrease in hemoglobin)
o The problem is in making hemoglobin (when a RBC is developing in the marrow, it’s the hemoglobin []
in that developing RBC that determines the number of cell divisions).
o If the hemoglobin synthesis is decreased, that’s a signal to the RBC and marrow to increase the number
of mitoses (they go from something that’s originally big to something small).
o Hemoglobin (heme + globin). Heme = iron + protoporphorin; globin = (2 alpha + 2 beta = HbA), (2
alpha + 2 delta = HbA2), (2 alpha + 2 gamma = HbF)
o 2 of the 4 are iron deficiency related (no iron to form heme)
 You have no iron (dietary)
 Anemia of Chronic Disease (have iron but it’s locked in macrophages)
• When we have inflammation, our bodies respond as if it’s an infection. Bugs (esp.
bacteria) increase reproduction w/iron; more iron, the more they reproduce.
• When you have anemia of chronic inflammation, your body assumes that it’s
related to a bacterial infection, the object is to keep iron away from the bacteria.
o It does this like a safety deposit box (iron is normally stored in macrophages in
the bone marrow; where transferring goes to pick up the iron to deliver to the
RBCs).
o Iron is locked away in the macrophages in the bone marrow, but you can’t get it
out.
• Unlike iron deficiency (there’s no iron in the macrophages in the bone marrow), there’s
piles of iron in the macrophages (Serum Ferritin is Increased).
• Serum iron is decreased (b/c it’s all in the macrophages) and you don’t have enough
iron to make heme.
o Sideroblastic anemias (rarest of microcytic anemias)
 3 different biochemical reactions that have a cytosol and mitochondria component; the defect has
to do with mitochondria (iron ends up getting accumulated in it).
• Gluconeogenesis starts in the mitochondria and ends up in the cytosol.
• Urea synthesis starts in the mitochondria and ends up in the cytosol and comes back into
the mitochondria.
• Heme synthesis: part of it in the michondria, part in the cytosol, part in the michondria
o The first part of heme synthesis (or porphorin synthesis) begins in the
mitochondria.
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 1st reaction is succinyl coA (in TCA cycle and substrate for
gluconeogenesis) is put back together with glycine to form delta
aminolevulinic acid (catalyzed by aminolevulinic synthase).
• Glycine sidenote:
o Glycine is an inhibitory neurotransmitter of muscle; it’s
blocked by tetanus toxin (why you get tetanic
contraction – muscles are in constant state of
contraction)
o Every 3rd amino acid in collagen is glycine.
o In heme synthesis
 Rate limiting enzyme sidenote:
• In cholesterol it’s HMG-coA reductase
• In heme synthesis (porphorin synthesis) it’s aminolevulinic acid
(ALA) synthase; the co-factor is pyridoxine (vit. B6).
 ALA synthase and pyrodixine come together and form delta ALA
• Sidenote: delta ALA is increased in lead poisoning.
o Once delta ALA is formed, it exits the mitochondria into the cytosol. It
undergoes a number of reactions in the cytosol and then returns to the
mitochondria to form heme.
o Ferrrochelatasecombines iron together with protoporphyrin to form heme.
o Heme has a feedback mechanism (as do all rate-limiting enzymes) with ALA
synthase.
 Three main causes of sideroblastic anemia (alcohol, Pyridoxine deficiency, or lead
poisoining):
• The most common cause is alcohol (it’s not the most common anemia in alcohol; the
most common anemia is anemia of chronic disease followed by folate disease) b/c it’s a
mitochondrial poisoning (uncouples oxidative phosphorylation and damaged the inner
mitochondrial membrane and allowed protons to go in there and drain them off – forms
megamitochondria). Heme synthesis (a process that occurs in the mitochondria) is
screwed up.
o Iron is delivered to RBC by transferrin and most goes into mitochondria (it
can’t get out). So we have a ringed sideroblast – the marker cell for
sideroblastic anemia; it’s also an iron overload disease.
o Can’t get heme b/c the whole mitochondria is damaged by alcohol.
• B6 (pyridoxine) deficiency
o No B6, no heme; the first reaction isn’t going to happen. Iron accumulates and
forms a ringed sideroblast.
• Lead poisoning
o Lead is a denaturer (all heavy metals denature proteins [enzymes are proteins]).
It denatures ferro-chelatase. So iron comes into the mitochondria and
accumulates.
o Sidenote: if ferrochelatase is inhibited, heme decreases, but protoporphyrin
increases (used to be screening test of lead poisoning).
 If you don’t have iron present, protoporphyrin also increases; now no
longer the test of choice.
 Blood lead level is the screening and confirmatory test for lead
poisoning (no longer RBC protoporphyrin b/c too many false positives).
o Thalassemias (autosomal recessive)
 Alpha – thalassemias
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• Seen in Asians and Blacks; all genetic diseases involving hematology are in Black
population
• Hemoglobin electrophoresis
o It separates things down on size and charge; separate Hb A, HbF, HbA2,….
o Quantity is determined by staining (cellulose acetate) to produce density; it
correlates with []
o % is determined by densitometer (converts density of stain to percentage)
o Normals
 (HbA) Euhemoglobin A (2alphas + 2betas) is the predominant Hb in an
adult, 95-96%
 (HbA2) Euhemoglobin A2 (2alphas + 2deltas) maybe 1-2 %
 (HbF) Euhemoglobin F (2alphas + 2gammas) maybe 1%
• Alpha Thalassemia is a problem in making alpha globin chains.
o Alpha thalassemia won’t show up (be diagnosed) on a Hb electrophoresis b/c all
hemoglobins are equally decreased.
• There are 4 genes that could show alpha chain synthesis
o If you have a deletion of one, you don’t even have anemia.
o 2 gene deletions (is a problem); you’re minimally decreased that gives you a
mild anemia (is microcytic b/c the globin part is decreased). This is called alpha
thalassemia minor
o 3 gene deletions (rarely asked on Boards). Really bad anemia; even has a
hemolytic component. Four beta chains get together and form Hb H. It can be
diagnosed with Hb electrophoresis.
o 4 gene deletions – spontaneous abortion usually (Hydrops fetalis). Hb Barts
(four gammas) form; it would show up on electrophoresis but the baby is dead.
 Sidenote: spontaneous abortion rate in the far east is high b/c that’s
where alpha thalassemias are most commonly located.
• Therefore the cancer most commonly seen in the far east if
the incidence of spontaneous abortions is increased is
choriocarcinoma.
• Treatment (DON’T GIVE THEM IRON)
o Leave them alone
 Beta thalassemia (is autosomal recessive, but has nothing to do with gene deletions)
• Population involves Black, Greek, and Italians
• Beta chain is decreased;
o B (by itself) means you’re making a normal amount of Beta chains
o B(with + on it) means you’re making it but not a lot
o B(with a 0 on it) means you’re not making it at all
• Deals with splicing defects, stop codons (the severest form)
• Mild
o Slightly decreased Beta chains (prob. b/c of splicing); alpha, delta, and gamma
are okay.
o HbA is going to decrease and HbA2 and HbF increase (that will show up on
Hb electrophoresis).
o The only way to diagnose Beta thalassemia is through Hb electrophoresis.
• Cooley’s anemia (severe Beta thalassemia)
o Don’t live past 30; require constant transfusion (most of the times die from iron
overload, Hepatitis C).
• Beta-Delta thalassemia
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o Hb electrophoresis would show increase in HbF (called hemoglobin F disease

or hereditary persistence of HbF)
o People are asymptomatic
o Some causes of iron deficiency
 Prematurity – b/c everyday that a baby’s not in utero, it’s losing iron. All premature babies
have to be given iron supplements.
 Newborns – if they have iron deficiency, check their stool, it probably will be positive for their
blood (HbF).
• To prove that it’s their blood rather than their mom’s blood use an APT test.
o Most of the time the blood is from mother’s.
o When it’s their blood (HbF), most common cause is Meckel’s diverticulus.
 Meckel’s diverticulum is the most common cause of iron deficiency in a
newborn and a child in general. It’s not in adults.
 Women
• A woman under 50, the most common cause is menorrhagia is the most common
cause.
• If under 20, most common cause is anovulatory cycles.
• Between 20 and 50, it’s ovulatory cycles (regular shedding of endometrium; inadequate
luteal phase, or pregnancy related bleeds, endometrial polyp, ….)
 Men
• Men under 50, it’s peptic ulcer disease; odds are duodenal ulcers.
 Over 50, men and women, clear cut unequivocal colon cancer.
o Review of microcytic anemias
 Iron Deficiency
• Serum iron is low; the TIBC is high.
• The % saturation (iron which is low / TIBC which is high) is low.
• Serum ferritin level is low.
 Chronic Disease
• It’s related to inflammation. Plenty of iron, except you can’t get it out.
• Serum iron is low, but TIBC is low (remember it’s inverse relationship to serum ferritin).
• Percent saturation is low. Serum ferritin is high.
 Main difference in laboratory tests that will distinguish chronic disease anemias from iron
deficiencies is ferritin. Other is TIBC, but no one uses that.
 In mild alpha thalassemias and beta thalasemias, the iron studies are normal: they have to do
with globin chains and not iron.
 Looking at a smear
• If there’s not an appropriate amount of Hb, that means that it’s more than likely a
microcytic anemia and it could be either iron deficiency, chronic disease anemia,
thalassemia, or lead poisoning.
 Ring sideroblast
• Only way to see it is to do bone marrow. You also have to stain it with Prussian blue
(stains iron). Mitochondria are usually around the nucleus and they’re all filled up with
iron (ringed sideroblast); it’s pathognomonic of a sideroblastic anemia.
• The only confirmation for sideroblastic anemia is bone marrow study.
• If you have lead poisoining, you can do bone marrow, but you should do a lead blood
level.
 Lead poisoning
• Basophilic stippling; have RBC that have blue dots all over them. It shows up on a
regular Giemsa stain.
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o It occurs b/c lead denatures ribonuclease.

 The purpose of ribonuclease is to break down ribosomes; since it’s
denatured, ribosomes aren’t broken down and they’re a good marker in
the peripheral blood.
• If it’s an RNA filament, that’s a reticulocyte, but if it’s a persistent ribosome, we’re
talking about lead poisoning.
• It’s the only heavy metal that can deposit in the epiphyses of bones; expect an X-ray.
• Clinical scenarios
o A child in a poor area eating paint or plaster. Classic presentation is severe
abdominal colic, problems with cerebral edema, convulsions, and a severe
microcytic anemia. You can do a flat plate and see the lead in the intestines.
A flat plate can show iron (if a kid took the tablets from his mom), lead, and
mercury.
 Cerebral edema is related to increased vessel permeability to the brain
and relates to the buildup of delta aminolevulinic acid (apparently it’s
toxic to neurons).
o Guys working in an automobile factory that have abdominal colic and diarrhea.
Lead poisoning because they have exposure to batteries (used to recycle lead).
o Moonshine is a give away.
o Trickiest is one with a pottery painter:
 Pottery is commonly painted with lead-based paints. Lead ends up on
the tongue of the paint-brush and they get lead poisoning. In country X,
pottery that you could use for dishes often has lead-based paint on it and
you could get lead poisoning for that.
o Adults seem to get the neuropathies: slapping gait, perineal palsy, wrist drop,
radial nerve palsy, claw hand, lead lines in the teeth, other than colic and
diarrhea.
 Iron overload
• Serum iron is high, TIBC is low, % saturation is high, ferritin is high.

Hematology 3

- Macrocytic anemias
o B12 (Cobalamin) and Folate (methyl THF) deficiency
 You’re not going to be able to make DNA: specifically you can’t make dTMP (deoxythymidine
monophosphate).
 You can’t mature that nucleus (remember immature nuclei don’t have a lot of DNA).
• As you make DNA, they become more mature and the nucleus starts getting smaller and
smaller and more condensed.
 Because you can’t make DNA, you have a big nucleus that never matures that makes all the
nucleated cells in your body.
 Any cell that has a nucleus has DNA (any cell with a nucleus is big), so all the nucleated cells
are huge (not just the hematopoietic cells).
 Interaction of B12 and Folate
• B12 has cobalt in it; why it can be called cobalamin. Circulating form of folate is methyl
tetrahydrofolate.
• The purpose of cobalamin is to take the methyl group off of methyl tetrahydrofolate
(circulating form of folate).
o Cobalamin is now called methyl cobalamin, and now methyl tetrahydrofolate is
called tetrahhydrofolate (FH4).
o You need both B12 and folate to make DNA.
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o If we don’t get the methyl group off of folate, we don’t make DNA.
 Cobalamin and methylation of homocysteine
• Cobalamin is involved in transferring a methyl group to homocysteine. When you add a
methyl group to homocysteine it becomes methionine (is the amino acid you want to
have for 1 carbon transfer reactions).
• If you’re B12 or folate deficient, the serum homocysteine levels are going to be high.
o Homocysteine produces thromboses, including myocardial infarctions.
o It damages endothelial cells, predisposing it to thromboses (including MI).
o If you’re deficient in either B12 or folate, you will be predisposed to thromboses.
 Out of B12 and folate, folate deficiency is more common.
 Biochemistry of forming dTMP (used for DNA).
• THF (formed thanks to cobalamin) seems to be the start of the cycle; it goes through
another reaction before it’s ready to be used by thymidilate synthetase.
• Thymidilate synthethase is where the DNA is made; it catalyzes dUMP to dTMP.
o THF (folate) provides a substrate in this reaction used to make dTMP (used to
make DNA).
• Dihydrofolate reductase converts oxidized dihydrofolate back to tetraydrofolate.
o There’s lots of drugs that block DHF reductase: methotrexate, … They decrease
DNA and cause macrocytic anemia
o Vitamin B12 is necessary in prionate metabolism (odd-chain fatty acid metabolism); It’s a co-factor for
methylmalonyl coA mutase
 B12 is necessary for odd chain fatty acids b/c they can only be broken down to propionyl coA.
Lack of B12 leads to dementia and proprioception problems.
 Proprionate (always acetylate them) forms methylmalonyl coA; Vitamin B12 is necessary for
methylmalonyl coA to be converted to succinyl coA that eventually enters the citric acid
cycle.
 If you’re B12 deficient, methylmalonyl coA builds up along with proprionates. Methylmalonyl
coA becomes methylmalonic acidwhich is a very sensitive and specific test for B12
deficiency (it will increase).
 The reason you get neurologic problems in B12 deficiency is b/c of the proprionate metabolism;
you can’t convert odd-chained fatty acids into succinyl coA. They build up and it screws up
myelin. You end up with dementia, with demyelination of the posterior columns, and of the
lateral cortical spinal tract. Myelin stains in the spinal cord won’t show myelin in the
posterior column or the lateral cortical spinal tract. Because posterior column disease, you
have problems with proprioception, vibratory sensation; because you knock off the lateral
cortical tract, you have problems with upper motor neurons – spasticity, Babinsky signs, and
dementia. These are related to B12, not folate (it’s not involved in propionate metabolism.
 On the Boards they will tell you that if you have B12 deficiency and you can correct the
anemia with high doses of folate, but you can’t correct the neurologic disease. Therefore,
you must make a specific diagnosis.
 Anyone who has dementia, you have to get a TSH exam (rule out hypothyroidism) and a B12
exam (methylmalonic acid test to rule out B12 deficiency) because they are reversible causes of
dementia.
 Normal metabolism of B12 (remember it’s an animal product). You cannot be a pure vegan and
get B12. If you’re an oval-lacto vegetarian, you’re taking dairy products (an animal product) and
you wouldn’t have to be on B12 supplements. If you’re a pure vegan, you would require B12
supplements.
 First thing that happens when you chew is it binds to R factor in saliva (its purpose is to bind
B12 to protect it from getting destroyed by acid in the stomach). Intrinsic factor (is made by
parietal cells, located in the body and fundus); it isn’t destroyed by acid.
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• The B12-R factor complex enters the duodenum where there’s intrinsic factor waiting
for it. In order for intrinsic factor to bind to B12, the R factor has to be cleaved off
(requires a functioning pancreas).
• Remember duodenum is iron country. When they hit the ligament of Treitz (fixes the
of ascending fourth part of duodenum) which is the beginning of the jejunum. The
jejunum is folate country. The intrinsic factor complexes have to go all the way to the
terminal ileum before they can be reabsorbed (because that’s where the intrinsic factor
receptors are).
o The terminal ileum is the same place you reabsorb bile salts and the same place
Crohn’s disease hits; so it’s fair to say that if you have Crohn’s disease, you have
bile salt deficiency with concomitant malabsorption and also B12 deficiency.
 Themost common cause of B12 deficiency is pernicious anemia – an autoimmune disease with
destruction of the parietal cells. There’s autoantibodies against parietal cells (it destroys the
parietal cells) and against intrinsic factor. Everything in its vicinity gets destroyed; you end up
with an atrophic gastritis of the body and fundus. No parietal cells and no acid. No intrinsic
factor.
• No acid (achlorhydria) is a predisposing cause of cancer (gastric adenocarcinoma).
 If have chronic pancreatitis (common in alcoholics), you can’t cleave off the R factor, leading to
vitamin B12 deficiency.
 If you have a Diphyllobothrium latum (a tapeworm/cestode acquired from eating raw,
freshwater fish: a lake trout in Chicago) you can have B12 deficiency.
 Bacterial overgrowth can cause B12-intrinsic factor deficiency. It can lead to peristalsis
problems in the small intestine. Diverticular pouches and spaces predispose infection; this is true
in urine too (a bladder that doesn’t peristalse). Bacterial overgrowth also eat bile salts.
 Terminal ileum disease (equates with Crohn’s disease) also can lead to B12 deficiency.
o Folate
 It’s seen in animal and plant products (don’t get def. from being a vegen).
 When you eat it, it’s in a polyglutamate form. This means you can’t reabsorb it in the
jejunum. It has to be converted to a monoglutamate form; an enzyme in the small intestine
called intestinal conjugase that does this.
• Phenytoin is a drug that blocks intestinal conjugase. They ask you about a someone
who ends up with a macrocytic anemia, hypersegmented neutrophils, neurologic exam is
normal (excluded B12); then they ask you what drug is the patient on.
 Once you have monoglutamate in the jejunum, there’stwo things that prevent the absorption
of monoglutamate form: 1) is a birth control pill, 2) is alcohol. The most common cause of
folate deficiency is alcoholism; it blocks the reabsorption of folate. Also, you have a 6-9 supply
of B12 in your liver; why it’s uncommon to get a deficiency from that. However, folate only has
a supply of 3 to 4 months.
 The circulating form of folate is methyl-tetrahydrofolate; B12 takes the methyl group off and
gives it to homocysteine which becomes methionine.
 Folate deficiency presents cells with Auer Rods.
 A cell with more than five lobes is hypersegmented and means you have B12 or folate
deficiency (even if you don’t have anemia; it’s the very first thing that comes up). If neurologic
exam is normal = folate; if abnormal = B12. The test for propioception is the Romberg test. B12
deficiency would also present as absent vibratory sensation; these are all posterior column things.
o Megaloblastic cells
 Are cells that are huge and never matured.
 Hematopoietic cells are made outside the sinusoids in the bone marrow.
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• It’s analogous to the chords of Billroth in the spleen (a place where there are fixed
macrophages, then the RBCs and WBCs have to get back into the sinusoids in the
circulation through these holes to get into sinusoids).
• In the bone marrow, you have a place equivalent to the chords of Billroth (that’s where
they’re made), then to get into the circulation, they have to fit through these narrow holes
to get into the sinusoids of the bone marrow.
• Megaloblastic cells can’t go through the narrow holes and back into the sinusoids
(WBCs, RBCs, and even platelets) and the macrophages kill them.
 In the peripheral blood you don’t see anything (pancytopenia). Severe macrocytic anemia,
neutropenia, thrombocytopenia. These are characteristic findings of B12 and Folate
deficiency. Everything’s too big to get out into circulation.
o Schilling’s Test
 A test for localizing B12 deficiency (to determine the cause).
 You give radioactive B12 by mouth. They swallow it and you collect the urine for 24 hours to
see if any of it comes out in the urine.
• If nothing comes out, you prove they have a problem with reabsorbing B12 and do the
next step.
 You give radioactive B12 w/intrinsic factor together. Collect the urine for 24 hours.
• If B12 comes out in the urine, you have pernicious anemia because you added what
was missing.
• If B12 doesn’t come out in the urine, you excluded pernicious anemia and do the next
step.
 Give 10 days of broad spectrum antibiotic. Come back in 10 days and give radioactive B12.
• If B12 comes out in urine, the diagnosis is bacterial overgrowth.
• If B12 doesn’t come out, move on to the last step.
 Give pancreatic extract. Then you give them radioactive B12.
• If 24 hours later, B12 comes out in urine, you diagnose chronic pancreatitis.
• If that doesn’t work it’s one of the other things: Crohn’s disease, a worm, …

- Normocytic Anemias
o If you do the correction for the anemia and the corrected reticulocyte count is less than 2% (bone
marrow isn’t responding correctly).
 First two things you see here are early iron deficiency and anemia chronic disease. This is true
because you have to have a normocytic anemia before you have microcytic. A normocytic
anemia with a corrective reticulocyte count < 2%, you still have to get ferritin.
• In iron deficiency it goes through different stages. First thing that happens is ferritin
levels go down. Then the next thing is iron decreased, TIBC increased, % sat decreased,
but you still won’t have anemia. All the iron studies are abnormal before any anemia in
iron deficiency, then you get a mild normocytic anemia, and eventually microcytic
anemia.
o Could be caused by blood loss in less than a week.
 You wouldn’t have an increase in reticulocyte response b/c there’s not enough time (you need 5-
7 days to start getting revved up).
o Aplastic anemia (means you have no marrow)
 In the peripheral blood you would have pancytopenia. You have to do bone marrow study.
 Most causes are idiopathic. Have to get a good history: drugs would be the most common
known causes of aplastic anemia. Chloramphenicol (use for something special: Rocky
Mountain Spotted Fever). Think things like indomethacin, phenylbutazone, and thyroid
related drugs. Check out the PDR to see if they can produce marrow depression.
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 Infections can also cause this, esp. Hepatitis C. If you have purely an aplasia of RBC’s and
everything else is okay, you have a parvovirus. When everything is destroyed, Hepatitis C is
usually the cause. Radiation also can do it.
o The mechanism of a normocytic anemia with a reticulocyte count less than 2% corrected and renal
failure is decreased erythropoietin. We have a drug from recombinant DNA that is given to replace
erythropoietin. Cyclists also take it (doping) to increase their amount of RBCs to carry more oxygen.
o Malignancy is another cause.
o Mechanisms of hemolysis
 There’s 2 ways to kill a RBC: 1) intravascularly (within the vessel) or 2) extravascularly (outside
the vessel)
• Extravascular hemolytic anemias (destruction) is caused by macrophages (usually in
chords of Billroth in the spleen). Every RBC has to take a couple of trips a day through
the chords of Billroth and be examined by a macrophage.
o Autoimmune hemolytic anemias
 If the RBC has IgG or C3b macrophages will phagocytose and
destroy the cell.
o If you don’t have IgG or C3b cells can still die if they’re out of shape (they
sphere and can’t get into the sinusoids); so spherocytes are going to be removed
extravascularly.
 Sickle cells can’t get through the 2 um slit and also get destroyed.
o Cells with Howell-Jolly bodies (a piece of nucleus remaining in the RBC).
Macrophages will try to get that out; sometimes they do it without killing the
cell, sometimes not.
o The end product of phagocytosing an RBC is unconjugated billirubin. When
an RBC is broken down and you got hemoglobin, there’s an enzyme that splits
heme from globin and the globin is broken up into amino acids and it goes into
the amino acid pool; the heme is split and the iron is saved, but the
protoporphyrin is broken down into billirubin in the macrophage (in the
spleen). The bilirrubin (lipid-soluble unconjugated) is spit out into the blood by
the macrophage. The unconjugated billirubin binds to albumin, goes to the
liver, and is taken up and conjugated.
o The clinical finding you see in patients with extravascular anemia is jaundice.
The billirubin doesn’t get in the urine because it’s lipid soluble and it’s bound to
albumin (doesn’t get in the urine).
• Intravascular is the less common type of hemolytic anemia.
o You die w/in the vessel if you bang into something that shouldn’t be there
(remember congenital bicuspid aortic valve with calcium there).
o If you had IgM on the surface of the RBC (IgM is the most potent activator of
the complement system). IgG stops at C3; IgM goes from C1 to C9.
o If you kill RBCs intravascularly, you release hemoglobin into the bloodstream.
There’s a specific protein (haptoglobin; aka the suicide protein) made in the
liver. When there’s intravascular hemolysis, it binds to hemoglobin and then
forms a complex that’s phagocytosed by a macrophage (it gives its life to
retrieve the hemoglobin). Haptoglobin levels decrease in patients with
intravascular hemolysis. It’s possible to get jaundice but usually you don’t.
o The key thing for intravascular hemolysis is you get hemogloinuria and you
have low haptoglobin levels.
Hematology 4

- Intrinsic vs. Extrinsic (Hemolytic anemia)

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o Intrinsic has something wrong w/in the RBC that’s causing it to hemolyze like no spectrin in the cell
membrane or no decaying accelerating factor in the cell membrane to neutralize complement, no G6PD
enzyme in the pentose phosphate shunt, or abnormal hemoglobin (like hemoglobin S).
o Extrinsic means there’s nothing wrong with the blood cell but it was in the wrong place at the wrong
time (it smashed into a calcified valve). Or if IgG, IgM, or C3b sat on the cell when there was nothing
wrong with it.
o Intrinsic
 There’s nothing wrong with the bone marrow, but there’s something intrinsically wrong w/the
RBC. So the corrected reticulocyte count is greater than 3% after we correct for everything.
 Mnemonic, MAD: membrane defect (spherocytosis, paroxysmal nocturnal hemoglobinuria),
abnormal hemoglobin (sickle cell trait or disease), deficient enzyme (G6PD deficiency).
 Spherocytosis
• When you don’t see central area pallor; therefore it must be a spherocyte. It will be
removed extravascularly.
• Clinical manifestation is jaundice (unconjugated billirubin is the main type). The defect
is spectrin (autosomal dominant). Since the spleen is the one removing these cells, it
gets a little bit hypertrophied (always seen in these patients after a period of time).
• Gallbladder disease is quite common b/c they do have a lot more unconjugated
billirubin, so there’s a lot more conjugation occurring and there’s a lot more billirubin
in the bile than usual. Supersaturation of anything that’s a liquid, you run the risk of
forming a stone. Supersaturation of bile with billirubin will give you a calcium
billirubinate stone.
o Pts. commonly have gallbladder disease at a very early age related to gallstone
disease. When they do a CBC, you see a normocytic anemia with a corrected
retic. count that’s elevated.
• Osmotic fragility is the diagnostic test; RBCs are put in a test tube with different
tonicities of saline (they blow up right away).
• Treatment: Splenectomy
 Paroxysmal Nocturnal hemoglobinuria
• It’s a defect in decay accelerating factor.
• When we sleep at night we have a little bit of respiratory acidosis (we don’t breathe as
fast). When you have acidosis, thatpredisposes complement coming and sitting on
cells that are circulating in the blood stream. We don’t get complement destruction every
night b/c in our membranes we have a decay accelerating factor which causes an
increase degradation of the complement (it doesn’t have an opportunity of drilling a
hole in the membrane).
• If you’re missing decay accelerating factor then complement is activated and it goes
from 1-9 (intravascular hemolysis).
• When you wake up in the morning, you pee out hemoglobin. When they do a CBC on
you, you not only have a severe anemia (normocytic) but you also have neutropenia and
thrombocytopenia (pancytopenia).
 Sickle Cell (autosomal recessive)
• Sickle cell trait has no anemia and no sickle cells in the peripheral blood. You can have
sickle cells in certain parts of your body (renal medulla and peritubular capillaries).
• The amount of sickle hemoglobin (HbS) in your RBC determines whether it sickles or
not. The magic number is 60%; if you have 60% or more hemoglobin S in your RBC,
then it can spontaneously sickle. Oxygen tension also has an affect: if you lower the
oxygen tension (hypoxemia) can induce sickling.
• Sidenote: autosomal recessive
o Usually both are traits. There’s about a 25% chance of a totally normal child, a
50% chance of a sickle cell trait, and a 25% of a sickle cell disease.
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o Same as cystic fibrosis.

 Key characteristics of sickle cell trait and sickle cell disease
• Sickle cell trait if you have a black individual that’s totally normal CBC but has
microscopic hematuria in their urine (it’s always abnormal), your first step in the work
up is sickle cell screening.
• Sickle disease – you have two things
o Hemolytic anemia (usually extravascular)
o Vasoocclusive crisis – you have occlusion of small blood vessels by these sickle
cells. You have ischemia to whatever tissue it’s supplying and you have pain
(ischemia always produces pain). It can be in any organ in the body (lungs,
liver, spleen, to bone marrow). In little children it begins in hands and feet
(so-called dactylitis).
o Over time it produces damage to individual organs (kidneys get screwed up,
spleen eventually autoinfarcts – shrinks to size of thumb at about 18-20 y/o;
first ten years you have splenomegaly; after two years, it’s totally non-
functional). You can tell that the spleen isn’t working because you see Howell
Jolly bodies (nucleus in RBCs) because if it was working, a fixed macrophage in
the chords of Billroth would have pitted that out and removed it.
 Fortunately, spleen becomes non-functional by 2 y/o so they can
receive pneumovax. When your spleen is non-functional, there’s one
infection you’re gonna get guaranteed; that’s Strep. pneumoniae and
sepsis. It’s the most common cause of death in a child with sickle cell
disease.
 For exam question: Howell Jolly body + sickle cell. They ask what’s
going on in the spleen – it’s non-functional.
o Common question is when do they get their first sickle cell crisis (swollen
painful hands and feet – dactylitis). It doesn’t occur right at birth b/c HbF
inhibits sickling and newborns have about 70-80% of their RBCs normally
having HbF. In a sickle cell disease, 60-70% of RBCs have HbF and the other
ones have HbS (there’s enough HbF to prevent sickling). As RBCs get broken
down and replaced, HbF decreases and HbS increases; by 6-9 months of age,
there’s a high enough [] to induce sickling and their 1st vaso-occlusive crisis
(dactylitis).
• Osteomyelitis
o Pt.s are very susceptible to osteomyelitis (not usual Staph. aureus cause but
Salmonella).
o Salmonella is destroyed by macrophages, it’s not destroyed by other
mechanisms. B/c the spleen is totally dysfunctional, it cannot filter out
Salmonella (why it’s the more common cause of osteomyelitis in sickle cell
disease).
• Hydroxyurea can be used to decrease the incidence of vaso-occlusive crisis. It worked
by increasing HbF synthesis. You have to take chemotherapy agents, however.
 G6PD deficiency (sex-linked recessive)
• Most enzyme deficiency conditions are recessive, but when you’re talking about inborn
errors and metabolism (like PKU, albinism, homocystinuria) the majority of those are
autosomal recessive.
• Sex-linked recessive is recessive too. Two sex-linked recessive enzyme deficiencies.
One is G6PD and the other one is purine metabolism (Lesch-Nyhan syndrome).
Children with Lesch-Nyhan syndrome are mentally retarded, self-mutilation,
increase in uric acid, and HTPRT is deficient.
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• Involved in: make glutathione, ribose 5 carbon sugars for making DNA, glycogen.
Glycogen can be converted to glucose 1 UDP glucose and glycogen or glucose 6
phosphate can be the substrate used for making glutathione and other substrates.
• You’re going to be able to make NADPH (the major factor for anabolic types of
biochemical reactions, i.e. steroid synthesis).
• NADPH will convert oxidized glutathione to its reduced glutathione
form.Riboflavin was the vitamin that catalyzed the reaction. Glutathione’s job is to
neutralize peroxide into water; the enzyme that helped glutathione neutralize peroxide is
glutathione peroxidase; the trace metal that was involved in there was selenium.
• Every living cell makes peroxide as an end product. That’s why every living cell has to
have a way of handling it. Remember catalase is present in all cells except RBCs; it
can neutralize peroxide (stored in peroxisomes). Other way to neutralize peroxide is
with glutathione (the only thing available to RBCs).
• If you were deficient in this enzyme you have a problem b/c as peroxide increases; it
would increase to a point of hemolysis if you had an infection or if you took a certain
drug that was an oxidizing drug (sulfa drug or a nitro drug: primaquine [in a medical
missionary question with malaria] and dapsone [in treating leprosy]). Peroxide is not
going to be able to be neutralized if you’re deficient in G6PD. What happens is
peroxide does a job on your hemoglobin; causes it to clump up and form Heinz
bodiesand on the RBC membrane (the real problem) that the primary mechanism for
destruction is intravascular.
• This disease is seen in pretty much the same people with Beta thalassemia: Black, Greek,
and Italian population
• Heinz bodies; with a special stain, you see blue clumps. When macrophages see this in
the chords of Billroth, it will take a bite to remove the Heinz bodies and result in “bite
cells” (has a piece of it’s membrane missing). “Bite cells” are very characteristic.
• In patients that are Greeks or Italians that have the severe form of G6PD deficiency, they
can just eat fava beans and precipitate it (“favism”).
• Diagnosis
o An acute hemolytic episode, the last thing to do is an enzyme assay b/c the
only cells that are hemolyzed are the ones missing the enzyme; the ones that
have the enzymes are still going to be there, so you have a normal assay.
o Do a special stain to identify the Heinz bodies. When the hemolytic episode is
over, that’s when you confirm the diagnosis with a G6PD assay.
 Autoimmune hemolytic anemias
• Warm reacting antibodies are IgG and cold reacting antibodies are IgM
• The most common autoimmune hemolytic anemia is warm and the most common
cause is Lupus. When you have autoimmune disease in your family, you have certain
HLA types that predispose to that autoimmune disease. Therefore you should not be
surprised that if you have one autoimmune disease, you’re likely to have another. Lupus
patients may also commonly have autoimmune hemolytic anemia, autoimmune
thrombocytopenia, autoimmune neutropenia, autoimmune lymphopenia.
o Patients with Hashimoto’s thyroidism (the most common cause of
hypothyroidism) commonly have pernicious anemia, vitiligo (autoimmune
destruction of melanocytes).
o One board question could be that if you have one family that has an autoimmune
disease, the single best screening test to use would be HLA.
o Lupus would be the most common cause of autoimmune hemolytic anemia
(has IgG and C3b on the surface of the RBC). It’s going to be removed by
macrophages (extravascular hemolytic anemia).
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o We’re going to use the directCoomb’sto tell the presence of IgG and/or C3b
on the surface of RBC. Indirect Coomb’s (aka antibody screen) is what
women get when they have pregnant; they do an ant-D, anti-… basically when
you’re looking for an antibody in serum (not on a RBC). Can’t do a direct
Coomb’s on platelets or neutrophils; can only do it on RBCs.
• Drug-induced hemolytic anemia
o Is the second most common cause (most common is lupus).
o Penicillin;mechanism of penicillin is PBO group (peniciloyl group of
penicillin) attaches to your RBC. If you develop an IgG antibody to that, it
would attach to the PBO group on the surface of your RBC, when it goes to the
spleen, it’s going to get removed extravascularly. This is a type
IIhypersensitivity.
o Methyldopa (aldomet) is used in antihypertensive; it can be given to a pregnant
woman (basically two; other is hydralzine). Methyldopa can produce a
hemolytic anemia; hydralzine can precipitate a drug-induced lupus (second to
procainamide as the cause of drug-induced lupus).
 Methyldopa screws around with Rh antigens on the surface of RBC
and alters them. They’re screwed up so bad that you make antibodies
against your own Rh antigens (IgG antibodies). IgG antibodies also
attach to RBC; macrophages remove it (type II hypersensitivity).
 Sidenote: Type III is immune-complex. Classic drugs are quinidine.
Quinidine acts as hapten and an IgM antibody attaches to the drug
to form an immune complex. The drug and an antibody circulate in the
bloodstream. Because it’s IgM, it activates the classical pathway (stop at
C9) and it has intravascular hemolysis (haptoglobin would be
decreased and hemoglobin would be present in the urine).
 Microangiopathic Hemolytic Anemia
• Schiztocytes (schizto – means split) are fragmented RBCs.
• Schiztocytes hit something; most common cause of this type of hemolytic anemia is
aortic stenosis (intravascular hemolysis: Hb [] goes down, haptoglobin is lost in the
urine).
o Sidenote:
 They don’t say aortic stenosis; they go through murmur characteristics.
Systolic ejection murmur, right 2nd intercostal space, radiating to
carotids, has an S4 heart sound, increases in intensity on expiration, has
a prominent PMI, and they have the following CBC findings…..
• Fragmented RBCs
• This is a chronic intravascular hemolysis. You’re going to be losing a lot of
hemoglobin in you’re urine. Because hemoglobin has a lot of iron in it, another
potential anemia that you can get in these patients is iron deficiency anemia.
• Other causes are DIC (disseminated intravascular coagulation).
• Schiztocytes are also involved in TTP (thrombotic thrombocytopenia purpura) and
hemolytic uremic syndrome. This is because if you have little platelet plugs scattered
throughout all the small blood vessels in your body, you’re going to have a problem
banging into these things and you’re going to have schiztocytes and microangiopathic
hemolytic anemia.
• Also known in “Runner’s Anemia”. If you’re doing long-distance, you smash your
RBCs when you hit the pavement and very commonly you pee after the marathon and
see hemoglobin in it.
 Malaria
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• Falciparum – only has ring form and you have suprainfection (more than one ring form).
Comma-shaped (gametocytes) are also in there.
• Produce a hemolytic anemia; it correlates with the fever when the cell ruptures.
• Fever pattern is quotidian?? (can come up anytime).
 Benign changes in different types of cells
• When you have acute inflammation (i.e. appendicitis) you get neutrophilic leukocytosis
left shift and granulation.
• Leukamoid reaction is something that looks like it’s leukemia but it’s not. It can
involve any of the cell lines (lymphocytes, neutrophils, ….).
o It’s caused usually by serious infection (TB, sepsis, and you get greater than
30,000 or 50,000 cells in the peripheral blood).
o It’s an overexagerated response to an infection.
o Kids are the ones who really get this. When kids get any kind of infection (otitis
media), don’t be surprised if you get a CBC of 30,000. Pertussis (whooping
cough) gives you a high (60,000) lymphocytosis. They’re worried about ALL
(acute lymphoblastic leukemia) except they don’t have anemia and they don’t
have thrombocytopenia. The kids come in pale.
• An atypical lymphocyte (large bluish-staining cells)
o It can be a lymphocyte acting normally when presented with an antigen (it
divides and gets bigger).
o The first thing that goes through your mind is mono (due to Epstein Bar).
 It can be transmitted by kissing because the virus is held up in the
salivary glands. It infects B cells; the receptor is CD21.
 You get viremia, generalized painful lymphadenopathy, exudative
tonsillitis (common), hepatitis (but not jaundice), and transaminases are
off the map, and spleen with a tendency of wanting to rupture(a kid
with mono in high school who doesn’t listen to advice and wrestles or
plays football and they rupture their spleen and they die).
o Other things that can produce this are CMV, toxoplasmosis, any cause of
hepatitis, and phenytoin (produced macrocytic anemia and blocked intestinal
conjugase).

Hematology 5

Atypical lymphocyte (cont.)

- They’re big cells w/lots of cytoplasm.
- Many causes: mono, hepatitis (w/o jaundice).
- Monocytosis
o Classic case (of mono); they ask you for what test do you order (you look for mono spot, but it’s not
there b/c that’s the trade name).
o Mono spot = is really trying to detect heterophile (hetero = different, phile = loving) antibody. The
heterophile antibodies in mono are anti-horse RBC antibodies and of course RBC antibodies.
Specifically anti-horse RBC antibodies is what you’re looking for in a mono spot.
o Once you have mono, you always have it; you have a chance of developing recurrent diseases (3-4
lifetime). You never lose Epstein Barr virus; you always have it. It lives in your B cells. The atypical
lymphocytes are actually T cells reacting against the infected B cells.
- Monocyte
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o It’s the “king” of chronic inflammation; we would expect monocytosis in patients that have chronic
infections: rheumatoid arthritis, Crohn’s disease, Ulcerative colitis, Lupus, and autoimmune diseases.
o Monocytosis is seen in chronic things; i.e. malignancy.

Eosinophilia
- Hay fever, rash in a patient with penicillin. No protozoa produces eosinophilia (rules out amebiasis, malaria,
giardia).
- Only invasive helminths (not a pinworm – the male and female take a trip to anus and sleep while you’re sleeping
and lay eggs in your eggs; they do not invade mucosa and therefore have no eosinophilia). Strongyloides, young
asciariasis (not adult; they just obstruct your bowel). It’s only when young asciariasis obstruct your lungs that
you have eosinophilia.
- Anything with type I hypersensitivity – yes.
- S2AT2
o Strongyloides, Schistosoma, Ascaris (young), Trichinella spiralis, and Taenia solium.
Creatine sidenote:
- Gives you energy b/c it’s what binds phosphate (the one that you get from making ATP).
- Creatinine (the end product of creatine metabolism) are elevated in pts. taking creatine for muscles; BUN level
is normal.

Polycythemia
- It means that you have an increased RBC count (Hb or hematocrit)
- There’s a difference between RBC mass versus count. Sodium sidenote: serum sodium is mEquivalence/L of
plasma; total body sodium is mL/kg body wt. Similarly, RBC mass is the total number of RBCs you have in your
entire body in mL/kg body wt. (all you have can be measured by a radioactive tech man); RBC count is the
number of RBCs you have in a uL of blood.
- If you went out and ran and got volume depleted, your RBC count would be high b/c if you’re volume depleted,
then you’d be hemoconcentrating your RBC (less plasma volume than when you weren’t running). RBC mass,
however, wouldn’t change (it’d be normal).
- Relative and absolute (two types of polycythemia)
o Relative is where you have a decrease in plasma volume causing an increase in RBC count, but the
RBC mass is normal (this is the most common cause of polycythemia).
 If you actually have an increase in RBCs, you have to decide if it’s appropriate or inappropriate.
 Appropriate increase in RBCs would be tissue hypoxia (lung disease; such as COPD, live at
high altitude). If you had normal blood gas and there was no tissue hypoxia, but there was an
increase in RBC mass; this would be inappropriate.
- There’s two things we have to think about when there’s an increase in RBC mass:
o First, Polycythemia rubra vera, an example of a myeloproliferative disease (a stem cell disease in the
bone marrow; they no longer respond to external stimuli; it’s a neoplastic disease).
 There is a propensity for going into leukemias (b/c it’s also a stem cell disease).
 4Hs (hyperviscocity, hypervolemia, histaminemia, and hyperuricemia)
• 1st H = hyperviscosity (TPR = viscosity/radius4); viscosity is increased, decreasing TPR
and sludges blood. If viscosity is increased, thrombosis risk is increased (dural sinuses,
hepatic vein, Budd-Chiari [most common cause is hepatic vein thrombosis], coronary
artery, ….). This is why phlebotomies are done; to reduce viscosity so you don’t
thrombose. Another reason phlebotomies are done are to create iron deficiencies; b/c if
you make them iron deficient, it’s going to take longer time to make RBCs (slowing
down the process).
• 2nd H = hypervolemia. It’s the only polycythemia where there’s also an increase in
plasma volume that matches the increase in RBC mass. Both RBC mass and plasma
volume can be measured by radioactive techniques.
• 3rd H = histaminemia. All cells are increased. Pts. w/polycythemia very commonly will
come with a history like: take a shower and they itch all over body. Itch b/c mast cells
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are increased and they’re in the skin; temperature changes can degranulate mast cells
causing release of histamine (generalized itching). Increased redness in face is not due
to increased RBC, but to increased histamine (vasodilation); they also get headaches like
migraines.
o Sidenote: very few things that produce generalized itching; one is bile salt
deposition on the skin in pts. withobstructive jaundice. Another is mast cell
degranulation.
• 4 H = hyperuricemia b/c nucleated hematopoietic cells are elevated (like neutrophils)
th

and when they die, nuclei have the purines in them. The purines go into the purine
metabolism (the end product is uric acid).
o Sidenote: Tumor lysis syndrome
 When you have cancers and you treat someone with a chemotherapy
drug. A lot of cancer drugs are going to die, you have to give
allopurinol (block xanthine oxidase) to prevent them from going into
renal failure from urate nephropathy (from increased uric acid).
 Myeloproliferative disease sidenote:
• is a stem cell disease where it’s neoplastic, where the stem cell has lost all regulation
(nothing can inhibit it anymore). Four diseases sometimes considered under this
definition: Polycythemia, Chronic Myelogenous Leukemia (only leukemia put under this
category), Agnagenic Myeloid Metaplasia (bone marrow is replaced by fibroid tissue),
essential thrombocytenia (stem cell that makes platelets goes crazy). Myelodysplastic
syndrome is sometimes put under this category (it’s a pre-leukemia type of syndrome).
o It would be inappropriate to have normal blood gas, no evidence of tissue hypoxia, and have an increase
of RBC mass.
o Second one would be a tumor or somekind of cyst with an excess production of erythropoietin (a renal
adenocarcinoma making erythropoietin). This is an inappropriate thing; it’s a tumor that’s
inappropriately making it.
o Over a period of years, the bone marrow may burn out, and the marrow space is replaced by fibrosis. In
this circumstance, hematopoiesis (including production of neoplastic cells) moves to extramedullary sites,
predominantly the spleen and the liver. This process is called myeloid metaplasia with myelofibrosis
(MMM).
o Review
 Polycythemia ruba vera
• RBC mass increased, plasma volume increased, oxygen saturation is normal
(inappropriate), O2 content (1.34 x Hb x O2 sat. + pO2), erythropoietin is low (have lots
of O2 b/c you have lot of RBCs which suppress erythropoietin).
 Chronic obstructive pulmonary disease, tetralogy of fallot, someone in a high altitude place
(hypoxic state)
• RBC mass increased, plasma volume normal, O2 sat. decreased (appropriate b/c it
relates to hypoxic stimulus), erythropoietin level is decreased
 Renal adenocarcinoma (could be a cyst; not necessarily a carcinoma)
• RBC mass increased, plasma volume normal, O2 sat. is normal, erythropoietin
increased (ectopically produced).
 Relative polycythemia
• RBC mass normal, plasma volume decreased, everything else is normal.

Leukemias
- It’s a malignancy of stem cells in the marrow; it metastasizes anywhere it wants (always gonna have generalized
lymphadenopathy, hepatosplenomegaly, …).
- You’re going to have abnormal cells in the peripheral blood (-blasts; myeloblasts, lymphoblasts, monoblasts,
megakaryoblasts, … –blasts).
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- Always have anemia; because it’s arising in the bone marrow, it’s going to crowd out all the normal
hematopoietic cells. Almost always thrombocytopenia, b/c you’re crowding out the normal megakaryocytes for
making platelets. Usually an increase in WBC count with these abnormal cells present.
- To separate acute from chronic
o Check out bone marrow.
o 30% -blasts
 If it turns out that the number of blasts isless than 30% of the WBCs in the marrow, then that
would qualify as chronic.
 If % blast is over 30%, then it’s acute.
- Age brackets (MUST KNOW)
o If 0-14 y/o = ALL (acute lymphoblastic leukemia)
 The most common type is Common ALL antigen B-cell leukemia. There’s a CALLA
antigenwith a cluster designation of 10 (CD10).
 It’s CD10+, cala antigen +, …
o 15-39 y/o = Acute myelogous leukemia; myeloblasts with Auer-rod (looks like red splinters in the bone
marrow) in peripheral blood
o 40-59 y/o = Acute myelogous leukemia and Chronic myelogous leukemia (has philadelphia
chromosomet(9:22) ….); separate the two with bone marrow.
 Leukocyte alkaline phosphatase stain could be done to confirm for Chronic myelogenous
leukemia; mature neutrophils all have alkaline phosphatase in them, but neoplastic neutrophils do
not. If there’s no stain, it’s neoplastic. Score is low b/c there’s no stain.
o 60 and over y/o = Chronic lymphocytic leukemia (is the most common overall leukemia regardless of
age). It’s the most common cause of generalized non-tender lymphadenopathy in someone over 60
(it’s b/c it metastasizes to lymph nodes).
 Have hypogamma globinemia b/c of neoplastic B cells; can’t change into plasma cells to make
gamma globulin. The most common cause of death is infection related to
hypogammaglobinemia.
- Extramedullary hematopoiesis
o When hematopoietic cells go somewhere else to make their cells; usually in the spleen.
o Agnogenic myeloid metaplasia (Splenomegaly and “Tear drop cells”)
 Some of the biggest spleens you will ever see are in Agnogenic myeloid metaplasia (used to be
called myelofibrosis and myeloid metaplasia). Megakaryocytes go back to bone marrow and
produce collagen to fibrose the bone marrow.
 Some cells that remain in the fibrotic bone marrow. To get out into the sinusoids they have to
go through strands of fibrous tissues that damages their membranes; they come out into the
peripheral blood looking like “Tear drop cells”.
- Acute monocytic leukemia – likes to infiltrate gums.
- Acute promyelocytic leukemia
o ALWAYS have DIC.
o Has a translocation t(15:17).
o Treat it with retinoic acid – it causes blasts to mature into benign cells.
- Hairy Cell leukemia (TRAP stain)
o Hepatosplenomegaly. Cells have projections off cytoplasm.
o Special TRAP (tartrate resistant acid phosphatase) stain to diagnose.
- French-American British Classification (M0-M7) is NOT ASKED.

Lymph Nodes (If there’s pain, it’s not malignant)

- If you have a lymphadenopathy and it hurts, it’s never malignant. What it means is that you have an
inflammation causing it. It doesn’t always mean infection (lupus has generalized lymphadenopathy). Pain comes
from stretching the capsule.
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- If you have non-tender lymphadenopathy, always think malignancy. First thing you think about is metastasis;
second thing is primary lymphoma.
- Generalized painful lymphadenopathy = systemic (inflammatory) disease. In HIV, they have generalized
adenopathy; same in Epstein Barr, Lupus, …
- Bruton’s Agammaglobinemia
o Germinal follicle area (where B cells are) would be absent.
- DiGeorge’s
o Paratrabecullar (where T cells are) area would be absent.
- Histiocytosis X (Letterer-Siwe syndrome, Hand-Schuller-Christian disease, and eosinophilic granuloma)
o Is a true histocytic CD1 positive tumor. You would see it in the sinuses.
- Severe Combined Immunodeficiency (due to adenine deaminase deficiency)
o Would have histiocytes, but no germinal follicles and paratrabecullar areas.
- Reactive lymphadenopathy
o Could be Lupus, something draining your tonsillitis, ….
o It’s benign.
- Malignant lymphoma
o Everything in the lymph node looks the same, even though there’s it’s forming follicles.
o Originates from follicular lymphoma (B-cells).
 It’s the most common (NHL) non-Hodgkin’s malignant lymphoma.
 Translocation (14;18); the apoptosis gene was knocked off.
- Lymphoma
o “Fish-flesh”
o Sidenote: Cartilage and elastic tissue are resistant to invasion by cancer cells.
- Burkitt’s Lymphoma
o Due to Epstein-Barr virus.
o Translocation is (8;14). Translocated myc oncogene from 8.
o “Starry sky” appearance. Stars are normal benign macrophages.
o About number 3 most common cancer in kids.
o In the U.S., it’s the most common lymphoma in kids. It’s in the abdomen.
- Mycosis fungoides
o Plaque-like lesions.
o Neoplastic cell is a helper T-cell. Usually involves skin, organs, as well as other lymph nodes.
o Sezary syndrome is when one of the malignant helper T-cells gets into the peripheral blood and you
have systemic involvement.
- Malignant histiocytic lesion (Letterer-Siwe syndrome)
o Can present as a child with a rash on the skin (eczemanous rash), generalized non-tender
lymphadenopathy, hepatosplenomegaly, and a biopsy showing monomorphic infiltrate of cells CD1
positive.
o Birbeck granules (looks like a tennis racket) in the cytoplasm of a histiocyte are characteristic.
 Sidenote: There’s a bacteria that’s a spore former that has a terminal end spore that also looks
like a tennis racket – Clostridium tetani.
- Hodgkin’s disease
o Biopsy of lymph nodes show a Reed-Sternberg cell (“owl-eye”; so is CMV, Giardia, Aschoff nodule of
rheumatic fever,...); it’s the neoplastic cell of Hodgkin’s.
o Prognosis depends on the number of the cells.

Hematology 6

Lymph nodes
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- Most common primary cancer of a lymph node is malignant non-hodgkin’s lymphoma (it’s a follicular B-cell
lymphoma; t(14;18); apoptosis gene was knocked off)
- Hodgkin’s disease
o There’s four types, you only need to know one (the most common one; Nodular sclerosing Hodgkin’s)
o Nodular Sclerosing Hodgkin’s
 It’s more common in women than men
 It would obviously be a hard, non-painful node. You’d see collagen in the node; it would look
pink.
 Recognize it by it’s usually a woman and she’ll have lymph node involvement in 2 places:
Anterior mediastinum, somewhere above the diaphragm (cervical nodes, supraclavicular, …)
say in the neck.
o The malignant cell is Reed-Sternberg cell.

Serum Protein Electrophoresis

- Albumin is the one that migrates the furthest b/c it has the most negative charges. Gamma globulin just sits
there.
- Polyclonal and monoclonal
o Polyclonal – many clones of plasma cells.
 Gamma Globin
• GAM is for the order of the most common globulin: IgG, IgA, IgM, IgD later.
 When we do a protein electrophoresis and we look in the gamma globulin region; when we see a
little peak, we know that it’s got to be an increase in IgG (b/c that’s the most abundant
immunoglobulin). Also, remember that in chronic inflammation, the primary immunoglobulin
was IgG; in acute it’s IgM.
• When you have chronic inflammation and when you have an increase in IgG, that’s
going to cause the gamma globulin region to show an elevation like a round mountain
(polyclonal gammapathy: many benign plasma cells are making IgG, IgM, …).
 It means benign, chronic inflammation; in an acute inflammation, you’re not going to see
polyclonal gammopathy (nothing in the gamma globulin region).
o Monoclonal gammopathy – one clone of plasma cells are making immunoglobulin
 When you see a monoclonal peak, it almost always means malignancy of a plasma cell. All the
other plasma cells are suppressed by immunologic mechanisms.
 Most of the times it’s an IgG malignancy. They make lots of immunoglobulin and light chains
(when they get into the urine, they’re called Bence Jones proteins).
 Multiple Myeloma is an example.

Multiple Myeloma
- Incurable. Usually seen in people over 50 (elderly). Most common type is an IgK type of multiple myeloma.
- Plasma cells have interleukin-1 (osteoclast activating factor).
- “Punch-out” lytic lesions in the skull are clear-cut [contrasts with Paget’s disease (also has lytic areas but
they’re fuzzy-looking)] is b/c Il-1 activates osteoclasts and they bore a hole through the bone to produce lytic
areas.
- Pathologic fractures are extremely common (if you had a lytic lesion in the rib and you coughed, you could
fracture it).
- Plasma cells have a bright blue cytoplasm and the nucleus is eccentrically located. An electron microscopy of a
plasma cell would show layers of ribosomes and Rough ER.
- Remember Bence-Jones proteins (when light chains get into urine).

Amyloidosis
- Amyloid protein looks like a non-branching linear compound with a hole in the center.
o Many different kinds of proteins can be converted into it (pre-albumin, calcitonin, light chains).
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- Is in the differential diagnosis for multi-system disease.

- Down’s Syndrome
o If you had trisomy 21 (chromosome 21 codes for beta-amyloid protein) would result in a little morebeta-
amyloid protein.
o Beta-amyloid protein is toxic to neurons. You’ll be losing more neurons.
o They’ll ask the question of a person who dies at age 40 and an autopsy is done and reveals atrophy in the
brain and reveals senile plaques in the frontal and temporal lobe. They’ll ask who is the patient – it’s
someone with Down’s syndrome (they’ll all get Alzheimer’s disease if they live that long).
 Down’s syndrome die around childhood b/c of cardiac diseases (endocardial cushion defects
[combo of atrial septal and ventricularseptal defect]) or Alzheimer’s in adulthood.

Lysosomal storage diseases

- Macrophages have a crinkly appearance in the cytoplasm. The lysosomes are filled with glucose cerebroside
(the disease would be Gaucher’s; an autosomal recessive with a missing glucose cerebrosidase)
- A cherry-red spot in the macula = Tay Sach’s disease; the build-up process in the lysosomes is sphingomyelin.
- Niemann-Pick’s disease = has severe mental retardation and a missing sphingomyelinase (so sphingomyelin is
what is increased). Niemann-Pick’s has a bubbly cytoplasm.
- The only glycogen storage disease that is lysosomal storage is Pompeii’s b/c it’s missing an enzyme to break
glycogen down in the lysosomes; they die by excess deposition of normal glycogen in the heart and that’s what
kills them.

Hemostasis
- If you had little clots developing in your small blood vessels it could lead to thromboses, DIC, TTP, or hemolytic
anemic syndrome.
- We don’t form clots in our small blood vessels (arterioles, venules, and capillaries; a small airway is a terminal
bronchiole, respiratory bronchiole, alveolar duct, alveolus).
- Preventing hemostasis
o We have heparin (it’s a glycose aminoglycan [GAG]). It enhances antithrombin III (made in the liver);
aminothrombin III neutralizes a lot of the coagulation factors.
o PGI2 (prostacyclin) made by endothelial cells (it’s a vasodilator). Because it’s a vasodilator, it’s hard
for things to stick b/c it gets blown away so fast; it’s antagonistic to forming thrombi and also platelet
aggregation.
o Protein C and S (vitamin K dependent factors); they inactivate factors V and VIII (antithrombin III
can’t inhibit those; it can only inhibit serine proteases).
o Tissue plasminogen activator – activates plasminogen which produces plasmin (plasmin eats
everything in site).
o If any of these were deficient, we’d form clots.
- Birth Control Pills
o A birth control pill is thrombogenic b/c it increases the synthesis of factors V and VIII; it also increases
fibrinogen and inhibits antithrombin III. The risk is from the estrogen in a birth control pill.
o The deadly duo is a woman on a birth control pill that smokes; smoking is in of itself thrombogenic b/c it
damages endothelial cells.
- Stopping bleeding when we cut small vessels
o Bleeding time: it’s used to evaluate platelet function. It has absolutely nothing to do with coagulation
factors.
 Once you inflict a small wound, you start a stop watch, and every 30 seconds you dab the wound
with a piece of filter paper. When no blood comes off on the filter paper, stop the stopwatch.
 Normal is about 7-9 minutes.
o Once you cut a vessel, it releases tissue thromboplastin will be released (it does activate the extrinsic
activation system that starts the coagulation system).
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o Collagen is going to be exposed in the wound and factor XII (Hageman’s factor) is activated; the
intrinsic system will also be started but it has nothing to do with the bleeding time either.
o Endothelial cells as well as megakaryocytes make von Willebrand’s factor (an adhesion product
whose purpose is to stick to platelets) that’s part of the factor VIII molecule. Von Willebrand’s factor is
made in two places: the megakaryocyte in the bone marrow and also in the endothelial cells, so
platelets carry a little bit of von Willebrand’s factor with them. When you damage endothelial cells, von
Willebrand’s factor is also exposed. Platelets also have receptors for von Willebrand’s factor (basically
an adhesion molecule).
o When the platelet sticks, it causes the platelet to release chemicals (the most important chemical is
ADP, a platelet aggregate) to help form a thrombus in that vessel; this is called the release reaction.
o Once the platelet has its release reaction, it begins synthesizing its own substance, thromboxane A2;
platelets are the only cell in the entire body that have thromboxane synthase (can convert PGH2 into
thromboxane A2).
 Thromboxane A2 is a potent vasoconstrictor (if you slow up the rate of blood flow, it makes it
easier for platelets to stick together; they don’t get washed away); it’s what causes the
vasoconstriction of a coronary artery in Printzmetal’s angina.
 Thromboxane A2 also is a bronchoconstrictor; it has some activity in asthmatics. Once
thromboxane A2 is released, the bleeding time is stopped.
o Platelets, Mast cell analogy
 Platelets do two interesting things that another cell also does (release reaction and then it made its
own unique thromboxane A2).
 A mast cell releases histamine, serotonin, and eosinophil chemotactic factor; it started the
inflammatory reaction in a type I hypersensitivity. Later the mast cell activates the release of
arachidonic acid from its membrane and we end up making prostaglandins and leukotrienes.
o The platelet plug is a bunch of platelets stuck together held by fibrinogen (carried by every platelet). It’s
not very stable.
o Causes of bleeding time prolongation
 Thrombocytopenia
 von Willebrand’s disease; the most common genetic disease (it’s autosomal dominant).
 Aspirin; the most common cause of prolonged bleeding time. The mechanism is blocking
platelet cyclooxygenase (thromboxane synthase is blocked by dipyramidole).
 Endothelial cells have cyclooxygenase too; the aspirin didn’t inhibit the endothelial cell
cyclooxygenase from making PGI2 b/c the platelet cell cycle cyclooxygenase vs. the endothelial
cell cycle cyclooxygenase reacts differently than aspirin.
 Aspirin and other NSAIDS affect platelet cyclooxygenase to a greater degree than they do
endothelial cell cyclooxygenase.
 Aspirin is irreversible; other NSAIDS are reversible (48 hours). When you take aspirin, even a
baby aspirin, no platelets work (bleeding time is increased).
o The end factor of the coagulation system is thrombin. Thrombin is supposed to convert fibrinogen
into fibrin. A little later after the bleeding time is over, thrombin that’s generated will convert fibrinogen
(holding the platelets together) into fibrin.
o The platelet plug is then removed from the vessel by plasminogen.
o The bleeding time goes up to the formation of a temporary hemostatic plug (platelets held together
by fibrinogen) that is unstable. Thrombin (the result of the coagulation system pathway) is what
makes the plug stable.
 This is important for distinguishing a platelet abnormality from a coagulation factor
deficiency.
• If one has a platelet problem, bleeding time is going to be prolonged (can’t form a
temporary hemostatic plug).
• Also the integrity of the vessels is disrupted; you get petechiae (pinpoint hemorrhages of
capillaries) that are only seen in platelet abnormalities. Ecchymoses, purpura, or
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epistaxis may also be present; epistaxis is the most common manifestation of platelet
abnormalities.
• None of these presentations of platelet abnormalities (petechiae, ecchymoses,
epistaxis, or bleeding from superficial scratches) occur in a coagulation deficiency.
• If you had hemophilia A (deficient in factor A), bleeding time would be normal. The
kind of problems they run into are late re-bleeding (ex. after an appendectomy, they
move around and blood starts to come out of the wound).
o The best question to see if a patient has a coagulation problem is to ask whether
or not they had bleeding problems after having a wisdom tooth removed
(imposes the greatest hemostatic stress on your system; some people can choke
to death on their own blood).
• Features more common in coagulation deficiencies are menorrhagia, hemarthrosis
(bleeding into closed spaces), and G.I. bleeds.
• Tests for platelet abnormalities:
o Platelet count (not changed by aspirin or NSAIDS, however they don’t work)
o Bleeding time (mainly for platelet function)
o Ristocetinco-factor assay = test for von Willebrand’s factor (adhesion glue
for platelets)
• On boards will ask it as:
o Person goes into surgery that had osteoarthritis (more than likely was on
NSAIDS; it’s assumed, not told) is bleeding to death afterwards. Platelet count
and coagulation factor tests are normal; Bleeding time is missing. What do you
do?
o Because of the NSAIDS assumed to have been taken, you assume their platelets
don’t work and give them a platelet pack transfusion (donor platelets are
working).
Hematology 7

Coagulation System
- Extrinsic vs. Intrinsic
o Extrinsic system has factor VII
o Intrinsic system has XII, XI, IX, and VIII (the four on equal sides of ten)
o Both systems share the same final common pathway = factor X.
o Remaining factors (common for both) are X, V, II (prothrombin), I (fibrinogen) for clot.
- PT (prothrombin time)
o Evaluates extrinsic system down to the formation of the clot (only detecting and dealing with VII, X, V,
II, and I).
o End stage of the test is the clot in the test tube.
- PTT (Partial thromboplastin time)
o Evaluates intrinsic system down to the formation of the clot (XII, XI, IX, VIII, X, V, II, and I).
- If PT is prolonged, but PTT is normal: factor deficiency is VII
- If PTT is prolonged, but PT is normal: odds are factor VIII (hemophilia A); after von Willebrand’s factor, it’s the
most common factor deficiency
- Warfarin blocked epoxide reductase. By doing this, it prevented the gamma carboxylation of II, VII, IX, and X.
So usually use PT (it doesn’t evaluate IX). PTT is also prolonged b/c of X and II, but PT does a better job
evaluating it because ¾ are in the prothrombin time.
- Heparin (increases the effectiveness of antithrombin III) therapy is followed with PTT. Antithrombin III
knocks off XII, XI, VII, X, II (prothrombin), and thrombin. PT is prolonged, but PTT does a better job.
- PT and PTT are both prolonged whether you’re on Warfarin or Heparin.

Fibrinolytic System
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- Plasmin breaks down fibrinogen, especially fibrin, coagulation factors, …

- Plasmin breaks things apart and leaves degradation products.
- Best screening test for DIC is D-Dimer.
o When you form a fibrin clot, there’s a factor XIII (fibrin stabilizing factor); it stabilizes fibrin by linking
them. Collagen is made stronger by linkage. D-dimer is detecting only the fibrin fragments that have a
link; it proves there was a fibrin clot (you would see it in DIC).
o If you broke apart a platelet thrombus (a bunch of platelets held together by fibrin) in the coronary artery,
the D-dimer assay would be increased if you broke apart that clot.
o Test is also used for a pulmonary embolus along with ventilation perfusion scans.
o It’s also used for seeing whether you have reperfusion after you’ve given tissue plasminogen activator (if
D-dimers are present, a fibrin clot was there).

Platelet and Vessel Abnormalities

- Vessel Abnormalities
o Senile purpura is an age-dependent finding. It should only be present in places that normally bump into
things (shins, back of hands, …).
o Osler-Weber Rendu Disease (aka Hereditary Telangectasia)
 Present with chronic iron deficiency anemia related to persistent G.I. bleeds. Always bleeding
b/c little telangectasias rupture.
 A physical exam will show red dots (telangectasias) on their fingers. Red dots on lips, tongue,
and throughout G.I. tract (if do endoscopy).
 It’s the most common genetic vascular disease.
o Scurvy is also a vascular instability disease.
- Platelet abnormalities
o Remember signs and symptoms: can’t make a temporary hemostatic plug; epistaxis (nose bleeds) is the
most common, the second is petechiae and ecchymoses, and last bleeding from superficial cuts
o Clinical situation
 A kid w/a resp. infection now has epistaxis. Physical exam shows lesions. You press on them
and they don’t blanch. A petechiae doesn’t blanch when you press on it; b/c it’s bleeding. A
spider angioma will go away when you press on it b/c it’s an arterio-venus fistula. Platelet count
is 220,000
• Diagnosis is Idiopathic Thrombocytopenic Purpura (ITP); the mechanism is IgG
antibody against the platelet. It’s a type II hypersensitivity reaction. The platelets are
being removed by macrophages in the spleen b/c they have IgG (similar to autoimmune
hemolytic anemia except it’s autoimmune thrombocytopenia).
• Treatment is corticosteroids or leave it alone.
o TTP-HUS (Thrombotic Thrombocytopenic Purpura – Hemolytic Uremic Syndrome)
 Both have similar pathophysiology.
 IT’S NOT DIC. Coagulation factors are not consumed. PT and PTT are NORMAL.
 Something in the plasma damages small vessels throughout your body. Platelets stick,
disaggregate, and eventually form firm platelet plugs in all the vessels (small vessels in entire
body). You end up with thrombocytopenia and you will bleed. In every small vessel, RBCs in
peripheral blood get smashed (schistocytes) and you get a microangiopathic hemolytic anemia.
 Have to have schistocytes in peripheral blood with hemolytic anemia or you can’t make the
diagnosis.
 Hemolytic Uremic Syndrome has two causes:
• One is the 0157 serotype E. coli (present in undercooked beef). The toxin damages the
vessels and produces the disease; the hemolytic part deals with the schistocytes and the
uremic focuses on the renal failure part.
• HUS is one of the most common causes of renal failure in children.
• The other cause is Shigella toxin.
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 In TTP-HUS syndrome, we should see low platelet count, bleeding time prolonged, but the PT
and PTT are normal (not consuming coagulation factors, only platelets).
- When you have an operation and you start bleeding out the wound, the most common cause is not a coagulation
factor deficiency. The most common cause is sutures split or you just have a bleed. When you have a coagulation
deficiency you have excessive bleeding.

Hemophilia A vs. Von Willebrand’s

- Hemarthrosis doesn’t occur in platelet abnormalities, you only see it in coagulation factor deficiencies. Of all the
coagulation deficiencies, you must know the difference between Hemophilia A vs. Antithrombin III deficiency.
- Von Willebrand’s disease leads to platelet adhesion defect which tells you that they get all the signs and
symptoms one would see with a platelet problem.
o They also have a factor VIII deficiency as well (very mild, never severe).
o They have a platelet defect and a coagulation factor defect. This is why they can have symptoms of
both.
o There’s 3 parts to the factor VIII molecule.
 Von Willebrand’s (vW) factor
 VIII coagulate
 VIII antigen – it’s a chauffer that carries vW and VIII coagulate around in the blood.
 All three can be measured
- In patients that have hemophilia A, the genetics is sex-linked recessive (affects males). Von Willebrand’s is
autosomal dominant (only one parent has to have abnormality).
- Hemophilia A only has one thing deficient – VIII coagulate; they have normal vW and normal VIII antigen.
- Von Willebrand’s deficiency has VIII antigen decreased, VIII coagulant is mildly decreased, and von
Willebrand’s decreased.
o DDADP (desmopressin; from ADH) can increase the synthesis of all of the factor VIII molecule
components. It will help treat MILD hemophilia A and is the treatment of choice of von Willebrand’s
disease.
o Women with von Willebrand’s disease will have menorrrhagia that is bettered by anticonception drugs;
estrogen increases the synthesis of all the factor VIII molecules. PT and PTT are not the proper tests for
von Willebrand’s disease; Ristocetin co-factor assay is the proper test for this.
o Two things that can increase the synthesis of vW: desmopressin and birth control pills (have
estrogen).

Antiphospholipid Syndrome
- One of the causes of spontaneous abortion.
- Includes lupus anticoagulant (means the opposite; you are thrombogenic) and anticardiolipid antibodies (both
cause vessel thromboses).
o Anticardiolipid antibodies are known for producing biological false positives in syphilis serologies (can
get a VDRL positive). To double check, do a FTAAbS (fluorescent treponema antibody absorption test);
a negative FTAAbs makes the VDRL a false positive because the confirmatory test was negative. It was
false positive because the test antigen is beef cardiolipid and syphilis antibodies react against it but some
do anticardiolipid antibodies.
o If you have a woman who has a biological false positive syphilis serology, the first test you should get
after FTAAbs is serum antinuclear antibody because she’ll develop lupus. Anticardiolipid antibodies are
a very common feature of lupus; in fact it’s a criteria for diagnosing lupus.

DIC
- Easier to diagnose clinically than laboratory wise.
- Clots are formed throughout the body in small vessels.
- Fibrinogen, V, VIII, II (prothrombin), and platelets are consumed in making the clot and in DIC.
- When we do a clot tube (draw blood into a clot tube and form a clot and spin it down; the top is serum and it’s
missing all the things consumed in clots).
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- You have two diseases at once, thrombi in your vessels and at the same time you’re anticoagulating because all
you have circulating around is serum (coagulation factors have been consumed).
o It’s a hemorrhagic-thrombosis syndrome.
- Causes:
o Number one cause is septic shock (most common cause is E. coli)
o Snake bite; not neurotoxin types (cobras or coral snakes) but rattlesnakes
o ARDS
- Key is they bleed from EVERY ORIFICE.
- PT and PTT should be prolonged; platelet count should be decreased; D-dimer should be positive.
- D-dimer is the test of choice for evaluating the patient.
- Amniotic fluid embolism is a misnomer; the death is DIC (thrombosis) because of the thromboplastin in the
amniotic fluid, it precipitates DIC

Hereditary Thromboses
- Recognized by a young person with a deep vein thrombosis (DVT).
- The most common is factor V Leiden. It’s an abnormal factor V that protein C and S cannot break down so
therefore you always have an increase in factor V that would lead you to thrombose.
- Antithrombin III deficiency is the most asked.
o Most common cause is a woman on birth control pills.
o Diagnosing Antithrombin III
 If you have a patient with a DVT, you put them on warfarin and heparin. The PTT is normal
after heparin. They have antithrombin III deficiency because heparin isn’t what anticoagulates
you; it enhances antithrombin III.

Review
- If someone is on Aspirin
o Platelet count is normal; bleeding time is prolonged; PT and PTT are normal
- ITP (most common cause of thrombocytopenia in kids)
o Platelet count is low; bleeding time is prolonged; PT and PTT are normal.
- TTP and HUS
o Platelet count is low; bleeding time is prolonged; PT and PTT are normal
- Hemophilia A
o Platelet count and bleeding time are normal; PT is normal; PTT is prolonged
- Von Willebrand’s
o Platelet count is normal; bleeding time is prolonged; PT is normal; PTT is prolonged.
o Difference between Hemophilia A is bleeding time.
- If Warfarin or Heparin
o Platelet and bleeding time is normal; PT and PTT are prolonged (PT is better for warfarin and PTT is
better for heparin).

Blood Bank
- Blood Group O is the most common one
o They have Anti-A IgM, Anti-A IgM, and Anti-AB IgG
o Associated with duodenal ulcer
o Universal Donor b/c they have no A or B antigen
o Can only receive blood group O
- Blood Group A (second most common one)
o Have Anti-B IgM
o Associated with gastric cancer
- Blood Group B (third most common)
o Have Anti-A IgM
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- Blood Group AB (rarest)

o Have nothing floating around in the blood stream
o Universal recipient b/c have no antibodies to attack
- Newborns
o Have nothing floating around their blood. Newborns don’t begin synthesizing IgM until they’re born.
Only after 2-3 months that they begin synthesizing IgG.
- Elderly
o Have hardly anything in their blood. Levels of antibodies are so low that they don’t lead to hemolytic
transfusion reaction to foreign blood groups.
- Rh antigens
o Rh Positive = D antigen positive; vice versa
- Duffy antigens
o Missing in black population; b/c of that they’re not likely to get Plasmodium vivax malaria b/c the
antigen that the P. vivax needs to parasitize the RBCs is the duffy antigen.
o Sidenote:
 Anemias like (thalassemias, sickle cell, and G6PD) protect the black population from P.
falciparum b/c the RBCs have a shorter lifespan so the malaria parasites can’t live out their cycle.
- Major Crossmatch
o Patient’s serum with the donor’s RBCs; they’re mixed together to see if they’re compatible. Looking to
see if there’s anything in the patient’s serum that’s going to attack antigens in the donor RBC.
o An antibody screen (indirect Coombs) should have been done prior to this. If it’s negative, it’s almost
always compatible in a major crossmatch. A separate crossmatch for every unit of blood has to be done.
o It doesn’t prevent from a hemolytic transfusion reaction or developing antibodies at a later date. For
every unit of blood that you give a person, you increase the risk for developing antibodies (when the time
comes to get another blood transfusion, they have to go and find units of blood that are negative for the
antigen to which you have antibodies). Don’t transfuse unless absolutely necessary.

Hematology 8

Hypersensitivities
- Lupus (normally type III)
o is type II for hemolytic anemia and thrombocytopenia
- Penicillin rash is type I; Penicillin hemolytic anemia is type II (IgG antibody against penicillin group attached to
RBC membrane)

Antibodies
- Most common antibody is antibody skin CMV.

Getting a disease from a blood transfusion

- Getting HIV
o Probability is very low. ELISA tests are done (checking for anti gp120 Ab; it’s a gp120 antigen that
attaches to the helper T-cell molecule – CD4). Western blot assay is for 3 or 4 antibodies.
- Most common infection transmitted by a blood transfusion is CMV.
o In newborns, they want to prevent graft vs. host and CMV (they have no immune defenses against it) by
radiating the blood to kill all the lymphocytes and CMV (lives in the lymphocytes).
- Most common cause of post-transfusion hepatitis is Hepatitis C.
- Most common infection from an accidental needle stick is Hepatitis B.
- If you just drew blood from a person who was HIV positive and you accidentally stick your finger with it, your
chances of getting HIV positive are 1/300.
o What you do about it is you go on to therapy as if you were HIV positive (2 reverse transcriptase
inhibitors and a protease inhibitor for 6 months).
o You get constant checks with PCR tests (the most sensitive) looking for the RNA in the virus.
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- Don’t transfuse anything into a person unless they are symptomatic from whatever it is they are deficient
in. For example, if one has 10 grams of hemoglobin but has no symptoms, don’t transfuse; but if one has 10
grams of hemoglobin and has COPD and angina, then transfuse.
o Every blood product is dangerous b/c you can get infections from them.
- Fresh frozen plasma should never be used like isotonic saline (to raise BP); it’s too important a component and
you run the risk of transmitting disease.
o You use fresh frozen plasma predominantly for multiple coagulation factor deficiencies (for example
DIC, or a person bleeding to death b/c they’re over anticoagulated on warfarin). If you overdose on
heparin, you use protamine sulfate.
- Blood transfusion reaction
o Most common is allergic. Symptoms would be itching, hives, potential anaphylaxis; type I
hypersensitivity. Caused by plasma in the unit of blood received having something in it you were allergic
to (maybe penicillin). Treat with benadryl or antihistamine.
o Second most common is a febrile reaction due to HLA antibodies; the patient has HLA antibodies against
leukocytes from the donor unit. Pyrogens are released when leukocytes are destroyed.
 If one has never been transfused, one should not have HLA antibodies against anything.
 A woman is most at risk for having a febrile reaction with transfusion; b/c of pregnancy and a
fetal-maternal bleed: some of the baby’s leukocytes get into maternal blood stream and the
mother develops HLA antibodies. The more pregnancies a woman has, the more anti-HLA
antibodies she’s going to develop b/c of previous pregnancies (also true for abortions).
o Hemolytic transfusion reactions are rare.
 Could be caused by giving the wrong blood type to someone. Remember anti-A or anti-B
involves IgM (the most potent complement activator). As soon as that RBC hits the circulation,
IgM would attack it (complement), release of anaphylotoxins, and you’d end up in shock.
 Another cause is where a person has an antibody against an antigen in the RBCs in the unit
(remember antibodies may not be present [can have a normal crossmatch], but you may still have
memory B cells).
• Sometimes it may be in a couple of hours or a few weeks.
• Possible situation
o Woman postpartum transfused 3 units of blood. She left hospital and had a Hb
of 10; one week later she sees jaundice and feels tired and week. Doctor tells
her she has unconjugated hyperbillirubinemia and Hb is 8 (drop in Hb). Ask
which is most likely cause.
o Halophane – no (takes over a week). Hepatitis – no (takes 6-8 weeks). Answer
is delayed hemolytic transfusion reaction.
• May also ask what test would you give: it’s Coomb’s test (you would see the antibody
coating the patient’s RBCs).
o It’s a type II hypersensitivity reaction.

ABO and Rh incompatibilities

- ABO problems
o If a woman with Blood group O has a baby, she will have the problem with ABO incompatibility (already
have Ab that can cross the placenta).
o If you have a mother with blood group O- ; baby’s blood group A- (problems can arise in very first
pregnancy; unlike Rh sensitization)
 There’s an incompatibility of blood groups; not an incompatibility of Rh groups
 Anti-A attaches to baby’s A cells (IgG antibody); baby’s macrophages in the spleen will destroy
it (type II hypersensitivity) producing a mild anemia
 Unconjugated billirubin derived from macrophage is handled by mother’s liver; no problems
with kernictus or jaundice in the baby in utero.
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 When the baby’s born they’re going to have a mild anemia and w/in the first 24 hours, they will
develop jaundice.
• The most common cause of jaundice in a newborn baby w/in the first 24 hours is ABO
incompatibility not physiologic jaundice of the newborn (starts on day 3).
• Baby developed jaundice b/c the baby’s liver system for conjugating isn’t as good as an
adult’s and it has to handle all the unconjugated billirubin on its own (it builds up).
o Most of the time, when you put them under UV B light, that’s enough.
o UV B light converts the billirubin in the skin into a dipyrole (water soluble
and harmless; they pee it out).
• Anemia is mild b/c the antigen isn’t very strong. Coomb’s test on the baby’s RBC would
be positive.
- Rh incompatibilities
o Example: Mother is Rh- and baby’s Rh+. Mother is O- and baby’s O+; not ABO incompatible but Rh
incompatible.
 First pregnancy: baby is delivered and there’s a fetal-maternal bleed (some of the baby’s O+
cells got into bloodstream). An anti-D antibody is developed against the baby’s cells (now
mother is sensitized: mother is anti-D)
 Next pregnancy: Mother is O- and has anti-D and baby is O+. Now there’s a problem because
anti-D (an IgG antibody) will cross the placenta and attach to the baby’s D antigen positive
cells. Of all the antigens, the D antigen holds the worst hemolytic anemia. The baby will be
more severely anemic with Rh than with ABO incompatibility.
• Same thing happens as before: macrophages in spleen phagocytose producing anemia
and billirubin and mother’s liver will work harder. When the baby’s born, however, the
billirubin will be higher and the anemia will be worst; excellent chance that you will
need an exchange transfusion.
o Prevention:
 Prevented by doing an antibody screen on the Rh- mother.
 Around the 28th week, she will be given an Rh immune globulin (prophylactic and it’s anti-D; it
doesn’t cross the placenta, however, and stays inside the mother). It’s given at 28th week b/c you
can get fetal-maternal bleeds before delivery (a car accident, a fall, and some baby’s blood can
get into circulation).
 The anti-D antibodies sit on the D positive cells and destroy it so you don’t get sensitized.
 When the baby is born, you see if the baby is Rh+. If it is, then they have to do a Kleihauer-
Betke test (takes from the mother’s blood and does a special stain to identify the fetal RBCs in
her circulation). They can count them and determine the amount of bleed; it can help determine
how many vials of Rh immune globulin you give the mother again to protect her further. The
anti-D only lasts about 3 months so you have to give more at birth if you find the baby is Rh +.
o The test of choice to detect the presence of IgG (wamr agglutinin) anti-RH circulating in the mother’s
blood is indirect Coombs test.
 Serum is collected from the mother and mixed with Rh-positive RBCs, followed by incubation
with complement. If the mother had circulating IgG anti-Rh, it would bind to the Rh antigen on
the Rh-positive RBCs, fixing the complement and lysing the target cells.
 A titer of greater than or equal to 1:8 is considered diagnostic.
- If mother is O- and baby is A+, you have two problems: ABO incompatible and Rh incompatible but there isn’t
going to be a problem with sensitization.
o If after delivery, some of baby’s cells get into blood; they won’t last at all b/c of the anti-A IgM
antibodies. The anti-A antibodies will destroy the cells so fast that in the majority of the cases, they’re all
gone and there’s no opportunity for the mother to develop an antibody against the D antigen.
o ABO incompatibility protects against Rh sensitization.
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- In Rh incompatibility, a kid with erythroblastosis fetalis dies of heart failure (remember severe anemia
decreases the viscosity of blood: they get a high output failure [left heart failure first, then right heart failure
second]). Livers are huge b/c of extramedullary hematopoiesis in it.
- Kernicterus
o Causes yellow spots in the brain of a newborn.
o It’s an unconjugated hyperbillirubinemia b/c it’s a hemolytic anemia. The unconjugated means it’s lipid
soluble. Because the baby’s BBBarrier is immature and the lipid-soluble unconjugated billirubin gets
into the brain and is very toxic. You end up with a severe debilitating disease or death.

Respiratory 1

A-a gradient (normally 5mmHg; increased in primary lung disease)

- The alveolar oxygen (PAO2) and the arterial oxygen (PaO2) are never the same. The difference between these
two is called the alveolar-arterial gradient.
o The reason they’re never the same is:
 The ventilation-perfusion is not evenly matched in the lungs.
• Ventilation is greater than perfusion when you’re standing up in the apex.
o Reactivation TB is in the apex because it’s a strict aerobe.
• Perfusion is greater than ventilation in the lower lobe. This is why almost all
pulmonary infarctions are in the lower lobe.
- Normally, the alveolar is 100 and the arterial pO2 is 95; the gradient is normally about 5 mmHg.
- If you have an A-a gradient greater than 30 mmHg you more than likely have a lung disease. 30 mmHg is a
number set for a high specificity [positive predictive value]).
- You would expect the gradient between the alveoli oxygen and the arterial oxygen to be greater if you have
primary lung disease: ventilation defects (produce hypoxemia and prolong the gradient [decrease the arterial
pO2]), a perfusion defect (such as a pulmonary embolus), or a diffusion defect.
- If you had depression of respiratory center (by barbiturates) would not increase the A-a gradient.
- The A-a gradient tells you in patients with hypoxemia if it is related to something wrong in your lungs
(ventilation, perfusion, or diffusion defect) versus something outside your lungs (respiratory acidosis –
your pO2 goes down).
o You can have respiratory acidosis from pulmonary problems (COPD) but you can also have it because
you depressed the respiratory center.
- Anion Gap
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o Anion gap should always be calculated with electrolytes and the A-a gradient should always be calculated
when you’re given blood gases (just have to calculate the alveolar oxygen [PAO2] because the arterial
oxygen is measured).
o Alveolar oxygen PAO2 = {.21(713 mmHg [humidified air]) = 150 mmHg} – PCO2 (given to you in
the blood gas [normally 40]) /.8 (respiratory quotient) = 150-50 = 100
 Now that you calculated the alveolar oxygen, you just subtract from it the measured arterial pO2
(PaO2) and you get the A-a gradient.

Upper Airway Diseases

- Nasal polyps
o The most common is an allergic polyp.
 You don’t see allergic polyps in kids. Allergic polyps develop in adults that have long-term
allergies and allergic rhinitis.
o Scenario
 If you have a kid with a polyp, the first step in management is a sweat test because a kid with a
nasal polyp more than likely has cystic fibrosis.
o Triad asthma (aka Samter’s triad) = asthma, nasal polyps, and an allergic reaction to aspirin
 You have a person who takes an aspirin or a non-steroidal. They get asthma and they have nasal
polyps. The fact that they took aspirin and that they have a polyp is not given but implied.
 Scenario:
• A woman presents with chronic headaches or some chronic pain (hint at a NSAID).
She develops occasional bouts of asthma. The mechanism of this patient’s asthma is…
• The answer is she’s taking NSAIDs.
o NSAIDS or aspirin block cyclooxygenase (prostaglandins can’t be produced) but
the lipoxygenase pathway remains (LTC, LTE, and LTE4) leading to potent
bronchoconstriction. It’s not a type I hypersensitivity reaction; it’s a chemical
mediated non type I hypersensitivity type of asthma.
 Another scenario requiring assumption:
• An athlete (assumed to be on anabolic steroids) with intraperitoneal hemorrhage.
Anabolic steroids produce benign liver cell adenomas which have a tendency of
rupturing.
- Laryngeal carcinoma
o The false vocal chord (up) is lined by squamous epithelium.
o The true vocal chord (down) is lined by a ciliated pseudostratified columnar epithelium.
o Risk factors for squamous cancer (from esophagus to the mouth)
 The most common cause is smoking
 The second most common cause of squamous carcinoma in the larynx is alcohol.
 If you did both, you would have a much greater chance of developing it (synergism).
o Most common symptom is hoarseness of the throat.
- Epiglottis
o It can be infected by H. influenza. You’d have inspiratory stridor.
o Scenario
 A kid three months old dies. There was inflammation in the trachea and an inspiratory stridor.
• Diagnosis is croup caused by parainfluenza.
- Hyaline membrane disease (aka respiratory distress syndrome)
o There’s massive atelectasis (collapse of airways).
o Pathogenesis
 The airways throughout both lungs collapse because there’s no surfactant.
 Collapsing pressure in the airways is equal to surface tension (numerator) divided by the radius
of the airway (denominator)
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• On expiration, the caliber of the airways is smaller. If you decrease the radius, you
increase collapsing pressure, and would expect the airways to close.
• To counter the decrease in airway radius (that increases collapsing pressure), we have to
decrease surface tension (this is what surfactant does).
o Causes are:
• Prematurity.
o Surfactant begins synthesis early on but peaks at about 32-35th week; if you’re
born beforethat timeyou don’t have enough surfactant and run a risk for a
respiratory distress syndrome.
o To counter this and try to increase the surfactant in the baby, you can give the
mother glucocorticoids. Glucocorticoids stimulate surfactant synthesis;
thyroxine (thyroid hormone) along with prolactin also stimulates surfactant.
• Diabetes in pregnancy
o Gestational diabetes is a woman who was not diabetic when she’s not pregnant;
she gets pregnant and then develops glucose intolerance.
o Hyperglycemia in the mother transfers to hyperglycemia in the baby. If the baby
has hyperglycemia, it’s a stimulus for insulin release. Insulin decreases
surfactant synthesis.
• Caesarean section
o It bypasses stress and therefore ACTH and cortisol aren’t increased and
therefore they don’t make surfactant.
o Cortisol stimulates surfactant synthesis.
o Sidenote: Why are babies of women with poor glycemic control big (macrosomia)?
 The baby’s insulin is increased to keep the glucose down. Insulin increases fat storage (TG
storage is increased in adipose [most adipose is located centrally]). Insulin stimulates
triglyceride synthesis and deposition in fat (kids are a little fatter). Insulin increases the uptake
of amino acids in muscles (increases muscle mass too).
 The reason for macrosomia is an increase in adipose and muscle mass due to insulin. It also
explains why they frequently get hypoglycemia when they’re born.
o Oxygen (superoxide free radical) damage producing retinopathy, blindness, and pulmonary dysplasia in
premature babies.
o Patent ductus arteriosus
 Babies that have respiratory distress syndrome commonly have patent ductus arteriosus
because they have hypoxemia.
 When a normal baby takes a breath, it starts the process going for functional closure of the
ducturs; if they have hypoxemia after birth, it remains open (they have a “machinery”
murmur).
o Pathogenesis (cont.)
 Hyaline membranes are due to degeneration of the type II pneumocytes and leakage of
fibrinogen (they produce the membranes).
 The pathogenesis of the hypoxemia in a baby with respiratory distress syndrome is a massive
ventilation defect (everything is collapsing). With a ventilation defect you have a shunt
problem; they have massive intrapulmonary shunting.
o Treatment = PEEP and surfactant
 Treatment is PEEP (positive end-expiratory pressure) and surfactant. Because you have
collapsed airways, you have to get oxygen and surfactant into them. You hook them up to a
respirator (gives them oxygen) and set it for positive end-expiratory pressure; at the end of
expiration you puff in pressure that keeps the airways open on expiration (to keep oxygen).
o Type II pneumocytes
 Lamellar bodies (seen on EM) – look like an onion cross-section (like hyperplastic
arteriolosclerosis).
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• The lamellar bodies contain surfactant and identify the cell.

 They’re also the repair cells.
- ARDS (Adult Respiratory Distress Syndrome = due to neutrophils)
o Has the same pathophys as Respiratory Distress Syndrome, but it’s usually due to neutrophils.
o Most common cause is septic shock.
 Septic shock
• The most common cause of septic shock is E. coli due to sepsis from an indwelling
catheter.
• Septic shock is the most common cause of DIC.
• In an ICU, when you have septic shock, w/in 24 hrs.of having dyspnea, that’s ARDS.
If w/in 48 hours, they’re bleeding out of every orifice, that’s DIC.
o Neutrophils get into the lungs (in septic shock) and they start destroying all the cells in the lungs
(surfactant goes down and you get collapse [massive atelectasis]).
o The hyaline membranes are due to neutrophils getting to the lungs by going to the pulmonary
capillaries (they put holes in them). As the neutrophils get out of the bloodstream and into the lungs
and cause leaky capillaries (“leaky capillary syndrome”). Protein and fibrinogen get in there and
produce hyaline membranes.
o The major pathophysiology is intrapulmonary shunting.

Pneumothorax
- Spontaneous pneumothorax (rupture of a subpleural bleb)
o
o The most common cause of spontaneous pneumothorax is a ruptured subpleural bleb (causes a hole
in the pleura).
o Once there’s a hole in the pleura, that part of the lung will collapse. What keeps the lung expanded is the
negative intrathoracic pressure. When you have a rupture, the negative intrathoracic pressure
equilibrates with the atmospheric pressure.
o When parts of the lung collapse, the diaphragm goes up on that side to take up the space.
o If there’s a collapse, the trachea deviates to the side of the collapse.
o Scuba divers commonly get it when they come up too quickly.
- Tension pneumothorax
o Most commonly is due to a knife injury into the lung.
o There’s a tear of the pleura that produces a flap.
 When you breathe in, the flap goes up and the air goes into the pleural cavity.
 On expiration it closes so the air stays in the pleural cavity.
 Every time you take a breathe, you increase the pressure in the pleural cavity. The lung hasn’t
collapsed, but the increase in pressure starts pushing the lung and the mediastinum to the
other side; it compresses the lung and produces compression atelectasis.
 Blood return and breathing are compromised.
o You have a positive intrathoracic pressure.
o The diaphragm will be pushed down.

Pneumonia
- Typical
o You can wake up in the morning okay and then suddenly you have a fever, malaise, and a productive
cough.
o You have a productive cough because you have exudate (pus in the alveoli that produces consolidation
in the lungs).
 Physical findings of consolidation are:
• Decreased percussion note
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• Increased tactile fremitus

• Egophony: “eeee” to “aaa” sign; patient says eee and you hear aaa; called egophony
• Whispered pectoriloquy; patient whispers and you hear it loud through the stephoscope.
 Sidenote: a pleural effusion vs. a pneumonia
• A pleural effusion would just have decreased percussion, not the rest of the signs
mentioned above.
o Caused by S. pneumoniae (can present as a lobar pneumoniae)
 Treatment is penicillin G.
- Atypical
o You have a slow and insidious onset (takes a couple of days).
o Caused by Mycoplasma pneumoniae, followed by Chlamydia pneumoniae.
o Do not have productive cough. They don’t have as high a temperature.
o They’re interstitial pneumonias; the inflame the interstitium (there’s no exudate in the alveoli; don’t
cough and don’t have consolidation).
- Community Acquired and Nosocomial
o Nosocomial would tend to be E. coli, Pseudomonas, and S. aureus.
- Rhinovirus is the most common cause of the common cold.
o They’re acid labile; you’re never going to get gastric distress (it gets destroyed by acid). You’re never
going to have a vaccine because there’s over 100 serotypes of the virus.
- Respiratory Syncytial Virus
o The most common cause of bronchiolitis and pneumonia (in children); whenever you inflame small
airways you get wheezing.
- Influenza
o Drift vs. Shift
 Hemagluttinins help attach the virus to the nasal mucosa; Neuraminidase bores a hole through the
mucosa.
 Antigenic Drift
• Minor mutation in hemaglutinin or neuraminidase; doesn’t require a new vaccine.
 Antigenic Shift
• Major mutation in hemagluttinin or neuaminidase; you do need a new vaccine.
 The vaccine is against just Influenza A
- Chlamydia trachomatis
o Scenario
 A newborn at a week is wheezing. Has an increased A-P (antero-postero) diameter, a tympanitic
percussion sound, wheezing, but no fever. The eyes may be crusty on both sides (you may
suspect a conjunctivitis).
 The kid has a stacotto??cough.
 The newborn received it while traveling through an infected cervix.
o The most common cause of conjunctivitis in the second week is C. trachomatis. The most common
cause overall of conjunctivitis is inflammation from the erythromycin drops in the eye.
- Pseudomonas
o Water-loving bacteria
o We see it in patients in ICU’s and CCU’s when they’re on a respirator.
o Scenario
 Someone in an ICU with a productive cough with green color discoloration.
- Klebsiella pneumonia
o Famous in the alcoholic.
o Differentiating Klebsiella vs. S. pneumoniae
 Scenario
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• Patient who is an alcoholic has high spiking fevers, productive cough of mucoid
appearing sputum (aka “currant-jelly” sputum).
• It’s mucoid because the capsule of Klebsiella is very thick.
o It is also frequently cavitated in the upper lobes (frequently confused with TB).
- Legionella
o Considered an atypical type of pneumonia.
o You get a non-productive cough. It can kill.
o It’s a water-loving bacteria that can be found in water coolers.
o The mists in grocery stores over the vegetables is a common source for Legionella.
o Scenario
 A patient with a classical atypical pneumonia (non-productive cough, low-grade fever), but the
patient had hyponatremia.
• Legionella doesn’t just infect the lungs.
• You can get liver disease and also interstitial nephritis (infects the kidneys) and it
knocks off your juxtaglomerular apparatus (low renin levels, low aldosterone
levels).
• Because of low aldosterone levels, you lose salt in your urine and you end up with
hyponatremia.
o Treatment: erythromycin
- Fungi
o Systemic fungi
 Candida
• Normally get from in-dwelling catheter (usually are subclavian).
o Geography
 Midwest and Ohio-Tennessee Valley area (very humid) = Histoplasmosis
• They’re carried in bats and starlings (birds).
• Scenario:
o Person who goes cave exploring (or spelunking) and ends up with a non-
productive cough.
• They’re the only systemic fungus that has yeasts phagocytosed by macrophages.
 Where there are pigeons (New York), they have Cryptococcus.
• Yeast forms are narrow-based buds (have a “Mickey Mouse” appearance).
• Scenario
o New York executive that had pigeons on the air conditioner and he developed a
non-productive cough.
o Painters that were painting the Brooklyn bridge (pigeons or starlings can roost
there) developed a respiratory infection. However, they asked treatment which is
actinomycin.
 Southeastern United States = Blastomycosis
• Produces skin and lung infections.
• Key buzzwords are thick wall and a broad-based bud.
 Southwest = Coccidioides
• New Mexico, Arizona, and Southern California
• Spherules with endospores.
• Scenarios:
o In Los Angeles earthquake, people develop non-productive cough.
 The arthrospores (infectious agent) is in dust; when you get earthquakes,
dust comes up and you breathe it in.
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o A guy that’s an Indian artifact explorer in the Senoran desert (in Arizona) who
was a cave explorer (throws you off as Histo; it’s in the Midwest, not the
Southwest [it’s too dry in the southwest for Histo to live]). Developed non-
productive cough.
Respiratory 2

Rheumatic Fever
- Looks like marantic vegetation (you would need history in order to distinguish the two); marantic vegetation has
a history of a cancer
- Fibrinoid necrosis; it’s the necrosis of all immunologic diseases

Histoplasma
- Is the only systemic fungus that has its yeast-form phagocytosed by macrophages.

Aspergillus
- 3 Different Diseases
o Fungus Ball
 Aspergillus loves to inhabit abandoned TB cavities.
 It’s a common cause of massive hemoptysis.
o Vessel Invaders
 It’s a vessel invader and can invade the vessels in the lung and then produce thrombosis and
infarction of those vessels.
o Extrinsic Asthma (Type I hypersensitivity)
 You can have allergies to the molds.
- Septate hyphae with 45 degree angles (narrow angle) and has coronas (“halo sign”) on CT scan.

Pneumocystis (previously classified as a protozoa; is now found to be a fungus)

- It’s the first AIDS defining lesion (the most common lesion); when the helper T-cell count gets to 200, it seems
to be there.
- Can be treated with or prophylactically guarded against by the use of trimethoprim-sulfamethoxazole (all AIDS
patients with CD4 counts <200 should be put on this). It is also prevents Toxoplasmosis (the most common cause
of a space occupying lesion in the brain of a patient with AIDS).
- You use a silver stain for it (also used for Bartonella henselae [causes bacillary angiomatosis], Legionella, and
Pneumocystis carinii)
- Under microscope it looks like ping pong balls and in the alveoli it produces a foamy alveolar infiltrate (“ground
glass” haziness on cross chest cross section).
- Patients have severe dypnea.
- It’s not just in the lungs.

Tuberculosis
- Primary TB
o Is in the lower part of the upper lobe or the upper part of the lower lobe (near the middle section) and
out near the pleura.
o They have a Ghon focus and a Ghon complex.
- Reactivated TB
o Most recover from primary TB and if you get immunocompromised, you get reactivation and it goes to
the apex and produces a cavitary lesion.
o There’s no Ghon focus or Ghon complex in reactivation TB.
- Differential Diagnosis
o Histoplasmosis
o Squamous Cell Caricinoma of the lung can cause cavitation of the lung.
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o Klebsiella (with a big mucous wall around it) can also produce cavitation in the upper lobe.
o Sidenote: Acid Fast Stain stains for mycolic acid.

Foreign Bodies
- If you’re standing or sitting up
o It will go to the postero-basal segment of the right lower lobe (it’s the most posterior segment of the
right lower lobe).
- If you are lying down
o This is the most common position for aspiration.
o It will go to the superior segment of the right lower lobe.
- If you’re lying on your right side (only one that’s upper lobe)
o It can go either to your middle lobe or the posterior segment of the right upper lobe.
- If you’re lying down on your left
o It will go to the lingula.

Abscesses
- The most common cause is aspiration of oral pharyngeal material; seen commonly in people who don’t have good
dentition (may be drunk and the oral pharyngeal material can get aspirated).
- Oral pharyngeal material has aerobes and anaerobes so it’s very putrid.
- You can also get them from pneumonias, but not as common as aspiration. Staph aureus and Klebsiella can cause
it.

Pulmonary Emboli
- Can be small or large
o Small emboli produce wedge-shaped hemorrhagic infarctions if you have underlying lung disease.
o Large emboli such as the “Saddle embolus” blocks off the orifices of the pulmonary vessels.
 If you knock off 3/5 orifices of the pulmonary vessels, you have instant death. There’s no
infarction because you don’t have enough time. You have acute right heart strain and immediate
death.
- Most pulmonary emboli originate from deep veins of the lower leg (it’s the most common site for deep venous
thrombsis). The most common site for embolization is the femoral vein because venous clots propagate to the
heart. The femoral vein is a larger caliber vessel so is more likely to chip off.
- Screening and Confirmatory Tests
o The screening test of choice initially is the ventilation perfusion scan; you’ll have ventilation, but not
perfusion.
o The confirmatory test is a pulmonary angiogram.
Restrictive Obstructive Lung Disease (decreased lung volume and capacity)
- Compliance and Elasticity
o Compliance (an inspiration term; filling up the lungs with air)
o Elasticity (an expiration term; the recoil of the lung)
- Compliance is decreased. What prevents it from filling up is fibrosis (most commonly interstitial fibrosis).
Elasticity is increased.
- All volumes and capacity are equally decreased (Total Lung Capacity, Residual volume, Tidal volume, …).
- The FED1/FVC (takes it in and lets it’s out; it’s the amount of air you got out in one second) is normal or
higher. FED1is increased (normal is 4 L; restrictive have it around 3L), but the FVC (normally 5 L) is the same
as FED1 most times (b/c of increase in elasticity) or increased.
- Examples:
o Pneumoconiosis
 These are air-born and dust-born diseases.
 Coal worker’s
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• They get anthrocotic pigment that sets up a fibrous reaction in their lung. Then they end
up in restrictive lung disease.
• They have an increased incidence of TB, but not cancer.
 Silicosis
• These people are usually sandblasters or work in foundries (dealing with rocks and
quartz). They have the possibility of breathing in the dust.
• They have big nodules in the lung hard as rock because they have quartz in them. It can
look like metastatic disease in the lung.
• If you happen to have rheumatoid arthritis and a pneumoconiosis, you have a tendency
for Caplan’s syndrome (rheumatoid nodules in the lung with fibrosis).
• Silicosis also increases the incidence of TB; cancer is still under dispute.
 Asbestos
• Asbestos fibers look like dumbells. The asbestos fibers can be covered by iron; they can
be called ferruginous bodies.
• The most common pulmonary lesion associated with asbestos exposure is not cancer,
but a fibrous plaque of the pleura (benign).
• The most common cancer is primary lung cancer. The second most common cancer is
mesothelioma (a malignancy of serosal lining of the lungs).
o Mesotheliomas take 25 to 30 years to develop. Lung cancers usually only take
10 years to develop.
• If you’re a smoker and have asbestos exposure, you have a increased chance of getting
primary lung cancer (synergism). There’s no relationship between smoking and an
increased incidence of mesothelioma.
• Scenario
o A roofer for 25 years (25 years ago all the insulation material had asbestos in it)
is asked about what he would most likely get. Primary lung cancer.
o Risk for exposure is usually presented as a roofer or someone working in a
shipyard (all the pipes of the ships are insulated with asbestos).
o Sarcoidosis
 It’s the second most common cause of restrictive lung disease.
 It’s a (“non-casseating”) granulomatous disease. It has no relationship to infection.
 The lungs are always involved. Hilar adenopathy is also associated with it.
 The second most common area hit is the face: uveitis (inflammation of the uveal tract producing
blurry vision) or the salivary glands (get enlarged).
 It’s more common in blacks.
• Scenario
o A black person with dyspnea and a x-ray showing hilar adenopathy.
 Skin lesions in sarcoidosis are nodular lesions. If biopsied you’d see non-casseating granulomas.
 This is a diagnosis of exclusion (anything that causes granulomas: TB, histo, …) because the
treatment is going to be steroids.
 ACE is very high because the granulomas have a lot in it.
 Hypercalcemia occurs and the macrophages in the granulomas (the epitheliod cells) make 1-
alpha hydroxylase.
• The mechanism of the hypercalcemia is hypervitaminosis D; you are second
hydroxylating more of the vitamin D and therefore you have excess amounts of vitamin
D (it increases reabsorption of calcium and phosphorous).
 It’s the most common non-infectious cause of granulomatous hepatitis (TB is the most common
of infectious). The second most common is pneumoconiosis.
o Hypersensitivity Pneumonitis
 Farmer’s Lung and Silo-Filler’s Disease
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• Silo-Filler’s Disease
o Produced by exposure to nitrogen oxides that are released from fermenting
organic matter in freshly filled, poorly ventilated farm silos (a closed space).
o Scenario
 A farmer went into a room in his barn and suddenly developed wheezing
and dyspnea.
• Farmer’s Lung
o Results from exposure to molds: either Thermoactinomyces vulgaries or
Actinomyces micropolyspora faeni. The molds are usually blown up in the air
(farmer riding a tractor) and breathed in. They end up getting dyspnea and
hypersensitivity pneumonitis ending up in a restrictive obstructive lung disease.
• Byssinosis
o Occurs in textile factory workers.
o Goodpasture’s
 Begins in the lungs with coughing up of blood and ends up shortly with the renal disease.

Obstructive Lung Disease (decreased FEV1/FVC)

- Problem isn’t getting air in, but getting it out.
- There’s no problem getting air in because elastic tissue support is destroyed. Also, because the elastic tissue
support is destroyed, it’s hard to get air out because it collapses on expiration.
- Residual volume is increased and total lung capacity is increased.
- Diaphragm is going to go down since the lungs are overinflated; A-P diameter is increased.
- After a certain point of expansion, the air begins to compress (and decrease) the other volumes aside from
residual (tital, vital capacity,…).
- Overall, your residual volume and total lung capacity increase, but everything else decreases.
- On a spirometer, FEV1 is very low (trouble getting out); compared to restrictive the FEV1 is better (you can at
least get air in). FVC is also decreased (the complete opposite to restrictive).
- The FEV1 is the thing to evaluate in a patient before surgery if they have an underlying lung disease (whether
they will be on a respirator for a long period of time).
- Small toddlers can have obstructive lung disease caused by bronchiolitis due to RSV. A newborn can have
obstructive lung disease due to C. trachomatis pneumoniae.
- There are four types of obstructive lung disease:
o Chronic bronchitis
 It’s a clinical diagnosis; if a patient has a productive cough for 3 months out of the year for 2
consecutive years.
 Terminal Bronchioles
• The disease actually is in the terminal bronchioles (prior to terminal bronchioles, you
have turbulent air; from this point on, you have parallel branching).
• The terminal bronchioles (aka “non-respiratory bronchioles) are the primary place for
small airway disease and the origin of expiratory wheezing.
• Most small airway diseases are in the terminal bronchioles (asthma, bronchiolitis,
chronic bronchitis).
• Inflammation of the terminal bronchioles produces wheezing.
• Proximal to that you get mucous gland hyperplasia, goblet cell hyperplasia, and this
contributes to the productive part of the cough; but the actual point of obstruction is the
terminal bronchiole. Past the point of obstruction, the many parallel branches that follow
(after the terminal bronchiole) suffer from ventilation-perfusion mismatch.
• Because of the ventilation-perfusion mismatch they can be known as blue bloaters
(they’re cyanotic and can’t get rid of CO2 b/c they have mucous plugs in the terminal
bronchioles).
o Emphysema
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 It occurs in the respiratory unit (where you can actually exchange gas; you can’t exchange gas in
the terminal bronchiole [aka “non-respiratory bronchiole”]).
 Gas exchange occurs in the respiratory bronchiole, alveolar duct, and alveoli (all after the
terminal bronchiole).
 Emphysema and the inflammation associated with it destroys not only the respiratory unit, but
the vasculature associated with it (you have an even loss of ventilation and perfusion); you don’t
have retention of CO2 in these patients (not known as blue-bloaters but pink puffers). Many
have respiratory alkalosis.
 Central Lobular Emphysema
• Most often associated with smoking
• It’s an upper lobe emphysema.
• The primary portion of the respiratory unit that is destroyed is the respiratory
bronchiole (the first thing that smoke hits).
o Neutrophils cause damage (increased in smoking because smoke is chemotactic
for neutrophils).
o Sidenote: alpha-1 antitrypsin
 It’s an anti-elastase; it destroys elastases produced by neutrophils.
 Smoking denatures alpha-1 antitrypsin and causes acquired alpha-1
antitrypsin deficiency.
o Neutrophils have no problem in destroying the elastic tissue support of the
respiratory bronchiole (the patient has alpha-1 antitrypsin deficiency).
 Panacinar
• The entire respiratory unit is destroyed.
• It’s associated with no alpha-1 antitrypsin; it’s an autosomal recessive genetic disease.
The liver doesn’t make it at all.
• At an early age you develop destruction of the entire respiratory unit in the lower lobes.
• Smokerscan gettwo emphysemas central lobular emphysema (upper lobes and
respiratory bronchioles) and then in the lower lobes a panacinar pattern.
o Bronchietasis
 Bronchi extend further than the hyaline (toward the pleura).
 Mechanism is infection, destruction of the elastic tissue support, and dilatation of the airways.
It affects the segmental bronchi and bronchi; they then fill up with pus.
• Scenario
o Someone has a productive cough of cupfulls of pus.
 In the U.S. the most common cause is cystic fibrosis. In third world countries, it’s TB.
o Asthma
o The ones associated with smoking are bronchitis and emphysema.

Respiratory 3

Bronchiectasis
- In the U.S.,cystic fibrosis is the most common cause.
- In third world countries, TB is the most common cause.
- Another cause is immotile cilia syndrome (Kartagener’s syndrome)
o In Kartagener’s syndrome, there’s an absent dyenin arm. The 9 microtubules in the 9 +2
configuration are missing dyenin arms causing the cilia to not be able to move.
o Places affected include sinuses (why you have sinusitis), bronchiectasis (b/c of the cilia in the
pseudostratified columnar), and infertility (the tail of the sperm is a modified cilia and the fallopian
tube needs cilia to carry fertilized eggs down).
o Dextrocardia (not complete transposition; just a normal heart on the other side).
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Asthma
- Extrinsic (Type I hypersensitivity)
- Intrinsic
o Involves chemicals often times.
o “Triad asthma” related to taking NSAIDs.
o Athletes when they run can develop wheezing (exertional asthma). Cromolyn sodium is the DOC for
exertional asthma.
o Cold temperatures can cause asthma.
o Wheezing
 Due to inflammation in the terminal bronchioles.
 Caused by factors like LTC4, LTD4, LTE4 and prostaglandins causing inflammation

Cancer
- Centrally located cancers (have the highest association with smoking)
o Squamous
 Can be recognized with a PAP smear (of the sputum); it stains keratin bright red.
o Small Cell
 Difficult to differentiate from lymphocytes.
 The most malignant cancer of the lungs; can only do radiation and chemotherapy (no
surgery).
 These are output tumors (a bronchial carcinoid tumor is also an output tumor but less
malignant) with neurosecretory granules in them. S100 antigen positive. They can make
ADH or ACTH.
o They are located more in mainstem bronchus.
- Peripherally located
o Adenomocarcinomas
 The most common primary cancer followed closely by squamous.
 It goes to the periphery because of filters in cigarettes. The large carcinogens were
eliminated, but the small ones remained.
 There’s 3 types
• Bronchiolo-alveolar
• Large cell
• Scar
- Bronchial carcinoids
o It’s a low grade malignancy of the same kinds of cells that produce small cell carcinoma.
o They can invade and metastasize and can produce carcinoid syndrome if they make increased
amounts of serotonin.
- The most common cancer of the lung is metastasis; breast is the most common metastasic cancer to the
lung.
- Horner’s Syndrome (aka Pancoast or Superior Sulcus tumor)
o Tumors usually in the upper lobe posteriorly (usually in the posterior mediastinum); it can be called
squamous cancer in the posterior mediastinum.
o The tumor is locally invading into the lower part (lower trunk of the brachial plexus); you can get
lower trunk brachial plexus types of findings.
o The superior cervical ganglion can also be knocked off (it’s in the posterior mediastinum) and end up
with Horner’s Syndrome (knocking off sympathetic activity: ptosis, miosis, anhidrosis, and
enopthalmos).
o Don’t confuse with Superior Vena Cava syndrome.
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Mediastinum
- Pleural fluid
o Transudate = protein < 3 gms.; hardly any cells in it. Most common cause is heart failure.
o Exudate = protein > 3 gms. and has cells in it; can be caused by pneumonias or pulmonary
infarctions.

G.I. Tract 1

Mouth to Butt

- Herpex Simplex
o Primary Herpes is a systemic infection
 Viremia, fever, lymphadenopathy (generalized) at first but then goes away and stays in
sensory ganglion
o Recurrent Herpes
 Remains in sensory ganglion (Herpes Zoster also remains latent in sensory ganglion and
recurs); stays dormant and can come out and form vesicles in the same spot but no more systemic
effects (no viremia, fever, or lymphadenopathy)
o Histological examination of vesicle (Tzanck test) would show inclusions (multinucleated cell with
intranuclear inclusions)
- Hairy Leukoplakia
o Pre-AIDS (couple months before helper T-cell gets to 200) type of infection (like thrush and
shingles)
o On lateral border of the tongue
o Due to an infection of EBV (can be treated with acyclovir)
- Thrush (Oral Candidiasis)
o If an adult, has to be an immuno-compromised patient with a defect in cellular immunity
o Kids (newborns) commonly have this (pick it up on the way out)
o Not an AIDS defining lesion, but like Hairy Leukoplakia does occur with it
- Exudative Tonsilitis
o 30% chance that it’s Group A Beta Hemolytic Strep (Strep. pyogenes)
 Prove this by Latex-agglutination test or by culture
 If Group A Strep and 3 weeks later, patient went into bibasilar rales, polyarthritis, and had a
pansystolic murmur at apex radiating into the axilla – Rheumatic Fever (if blood culture done,
nothing found because not an infective endocarditis)
o 70% chance that it’s a virus (adenovirus, EBV, …)
- Invasive Cancer on Tongue
o Leukoplakia – white lesion, plaque-like; doesn’t come off when you try to scrape it off (and
cannot be characterized clinically or pathologically as any other disease)
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 First step in management is always biopsy (also true if in vulva area or penis area if you see
a white plaque-like or reddish plaque-like lesion) to rule out dysplasia and/or invasive cancer
 The use of tobacco is the most common antecedent to leukoplakia (and erythroplakia)
o Smoking is the most common cause of squamous dysplasia and cancer; second most common cause
is alcohol.
o Invasive Squamous Cancer (picture)
 Color change present, midline is curved
- Lower Lip = squamous
- Upper Lip = basal cell
- Chewing tobacco causes cancer (ferrucous carcinoma; human papilloma virus is also related)
- Hyperpigmentation
o Addison’s Disease (diffuse hyperpigmentation)
 Low cortisol levels (increased ACTH; ACTH has melanocyte stimulating properties)
 First place you see hyperpigmentation is buccal mucosa
o Peutz-Jeuger’s (Splotchy hyperpigmentation)
 Polyps are in small intestine (exception to the rule for polyps in the small intestine colon;
most polyps in the entire G.I. tract are located in the sigmoid colon)
 Hamartomas (non-neoplastic)
- Pleomorphic adenoma a.k.a mixed tumors (picture looks like mumps)
o Two different types of tissues, same cell layer
o Most common salivary gland tumor; most common location – parotid
- Mumps (caused by paramyxovirus)
o Amylase enzyme is elevated
o Mumps orchitis incidence is not high
 If you do have it, it doesn’t lead to infertility; because it’s unilateral most of the time (if
bilateral incidence increases)
 Usually in older (teenager or adult) men
 In women, like in males, more commonly unilateral than bilateral; infertility is not usually a
problem with mumps
- Dysphagia – difficulty with swallowing
o Clues:
 Patient has a problem with swallowing foods
• Solids and not liquids, an obstructive lesion
o Possibilities are esophageal web, Plummer Vinson Syndrome (iron
deficiency anema, glossitis, and esophageal dysphagia), or Cancer
• Solids and liquids = peristalsis problem
o If in upper third = myasthenia gravis (affects striated muscle
o If lower third = scleroderma (progressive systemic sclerosis and CREST
syndrome) or achalasia (when they go to bed at night they vomit food they ate)
o Clues in general
 Palpable Purpura = small vessel vasculitis (immunocomplex type III; odds are Henoch-
Schonlein purpura)
 Epistaxis = platelet problem (don’t think hemophilia)
 Physical Diagnostic Findings show pansystolic murmur increases intensity on inspiration =
tricuspid regurgitation; on expiration = mitral regurgitation
- Odynophagia (painful swallowing – always abnormal)
o Most common cause in an HIV positive patient is Candida esophagitis (AIDS defining; Candida is
the most common fungal infection in HIV and when it gets in the esophagus it’s AIDS defining, but when it
produces thrush it’s pre-AIDS lesion)
- Tracheoesophageal Fistula (always asked)
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o Embryology: blindly ending esophagus (proximal esophagus ends blindly but distal esophagus arises
from the trachea)
 Mother has polyhydramnios (excess amniotic fluid = baby urine)
• Babies swallow amniotic fluid and it’s reabsorbed in the small intestine; so if you
have obstruction in esophagus or proximal portion of duodenum, mother will have
polyhydramnios)
• Polyhydramnios is associated with tracheoesophageal fistula and duodenal
atresia (in Down’s syndrome); block the ability to reabsorb amniotic fluid
 When kids eat or drink for first time, reflux gets in trachea and they cough and sputter
(because the distal esophagus arises from the trachea and they have distention of the stomach; very
characteristic symptom).
 Vater’s syndrome – part of which has tracheoesophageal fistula
- Zenker’s diverticula
o Area of weakness is the cricopharyngeus muscle
o Mucosa and submucosa (a false diverticula; true is all)
o Pouch collects things
o Tend to regurgitate things and they can come out of nose
- Achalasia (peristalsis problem)
o Problem with failure of relaxation of the LES (spasm all the time)
o Biopsy would show that ganglion are missing (like Hirschsprung’s disease)
 Ganglion cells have VIP (vaso-intestinal peptides) to relax esophageal sphincters; therefore
destruction of ganglion cells not only destroys movement of the lower esophagus, but you also
reduce VIP levels (constant constriction of LES)
o “Bird’s beak” (proximal portion is dilated) on barium study
o Chagas’ disease (Leishmania) can produce acquired achalasia
 Parisites can invade ganglion cells of LES and rectum to produce acquired achalasia and
acquired Hirschsprung’s
 Vector = reduviid bug (kissing bug)
 Swelling of the eye (Romana’s sign)
 Gives myocarditis and chronic heart failure
 Also gives congestive cardiomyopathy
 One of more common causes in heart failure in South America
- Barrett’s esophagus
o Shows glandular metaplasia, goblet cells, and mucous cells (shouldn’t be there) there because
esophagus can’t protect itself from acid injury
o Runs risk of adenocarcinoma of distal esophagus (squamous cell carcinoma affects mid
esophagus)
- Esophageal varices
o Results in patients with cirrhosis and portal hypertension
o Vein involved is left gastric vein (drains distal esophagus and proximal stomach; the left gastric vein
drains into the portal vein)
 Azygous vein drains into left gastric vein (comes from further up)
- Hematemesis (vomiting blood)
- Hemophysis (coughing up blood)
- Hematochezia (blood pouring out of anus; not blood-coated stools = internal hemorrhoids)
o Most common cause is diverticulosis, not diverticulitis (because vessel is right next to diverticular
sac and if it was diverticulitis it would be scarred off but in diverticulosis it’s eroded)
- Mallory-Weis tear (tear at esophago-gastric junction)
o Found in bulimia (not anorexia); bulimics are the ones that throw up.
o Also found in wretching (extreme vomiting) in alcoholics
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- Boerhaave’s syndrome
o Puncture of esophagus
o More in a bulimic than an alcoholic
- Squamous Esophageal Cancer (CT, MRI like picture)
o Most common cause is smoking, second is alcohol
o Dysphagia would be solids but not liquids initially
o Also presents weight loss
- Congenital Pyloric Stenosis
o Vomiting at 3 wks of age non-bile stained fluid
o Knot in upper right quadrant upon palpation
o Hyperperistalsis
o Does have multifactorial inheritance (can be increased in future children)
o Pyloroplasty (enter via slit in belly button and split muscle) to treat
- Duodenal Atresia (Down’s Syndrome)
o Vomiting at birth and bile-stained fluid
o “Double bubble” sign
 Atresia (lack of development of lumen) is distal to where the bile duct comes in (bile can still
empty into proximal portion of duodenum – why bile stained); because there’s no movement
there’s air trapped in there and the stomach (look like a bubble in the stomach and a bubble in the
proximal duodenum)
 Mother has polyhydramnios
- NSAID ulcers
o Non-steroidals will block PGE2 (responsible for the mucus barrier of the stomach)
o Ulcers are responsible for the vasodilatation of the vessels, mucus secretions, and the secretion of
bicarbonate into that mucus barrier
o Usually not very deep but can cause blood loss over time
- H. pylori
o Silver stain (Legionella, pneumocystis, Bardonella henselae)
o Comma-shaped organisms (resembled Campylobacter)
o Make urease (convert urea to ammonia to allow them to burrow through mucous layer) and
cytokines
o Use urea test to diagnose
o Serologic tests are useful only for the first time (useless against recurrent infections because
antibodies remain)
o Parietal Cells (found in body and fundus); H. pylori is found in pylorus and antrum (lesser
curvature); destroys that mucosa and produces an atrophic gastritis of pylorus and antrum (where most
cancers are – along the lesser curvature of the pylorus and antrum)
o Implicated as the most common cause of stomach cancer and can also cause malignant
lymphoma (not most common cause)
o Gastric and duodenal ulcers
 Duodenal ulcers aren’t biopsied because they’re not malignant
 Only reason they biopsy a gastric ulcer is to rule out cancer (3% chance)
 H. pylori is more associated with duodenal ulcers than gastric ones
- Melena
o Upper G.I. bleeding; upper g.i. is above from where duodenum meets jejunum
o Black because acid acts on hemoglobin and converts it to hematin (black pigment; nonprotein
portion of the hemoglobin molecule wherein the iron is in the ferric Fe3+ state rather than the ferrous Fe2+
state)
o Black tarry stools have a 95% chance that it’s an upper g.i. bleed and chances in that are
duodenal ulcer
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- Vomiting of coffee ground material = blood clots acted upon by acid changed into hematin
- Pt. executive under great stress with severe epigastric pain which radiates into left shoulder
o First step in management on the patient is a flat plate of the abdomen (because he has a
perforated ulcer; odds are duodenal); in 85% of the time you will see air under the diaphragm
o Shoulder pain because air got out and settled under the diaphragm and irritated it (4th nerve)
and you have referred pain to the shoulder (shares same dermatome)

G.I. Tract 2
- Stomach & Ovary slide
o History: 52 yr. old woman w/weight loss and epigastric distress. She had an upper gastrointestinal series.
Noted that the stomach did not move (peristals). She died and now slide shows stomach and ovary.
 Stomach didn’t move because stomach had linitis plastica (“leather bottle”): an
adenocarcinoma of the stomach (unique type that the cells that are invading the wall of the
entire stomach are called signet ring cells; stained with mucin-carbine stain)
• In signet rings (like a diamond ring), the diamond is the nucleus pushed to the periphery
by the mucous (like in fatty change in the liver; except these are malignant neoplastic
glandular cells). These signet rings are characteristic of linitis plastica type of gastric
adenocarcinoma.
• These signet cancer cells can diffusely infiltrate the wall of the stomach and gives the
appearance of a “leather bottle”
 Krukenberg tumor
• Gastric cancer involving the stomach is not seeding (falling on the ovaries and invading
it from that; you would see ometum metastases; also the cancer cells would be on the
outside invading in) but spread hematogenously to the ovaries.
• Signet rings adenocarcinoma of the ovaries aren’t primary; they are metastasized from
the stomach.
- Cancers of stomach
o Most are ulcerated type of lesions in the lesser curvature in the pylorus and antrum; krukenberg is not
common
o Gastric cancers declining because of triple therapy treatment of H. pylori
o Stomach cancer is the primary cancer in Japan
 It’s related to the smoked products (bar-b-que’s) because there’s carcinogens
(polyhydrocarbons) in smoke (charcoal)
- Ethnically (National) associated cancers
o Nasopharyngeal carcinoma – China
o HTLV-1 (human T-cell leukemia lymphoma virus) in Japan and in the Caribbean
 Scenario
• It can present as a generalized lymphadenopathy, hepatosplenomegaly, skin rash,
hypercalcemia, and an increased WBC. What does it predispose?
• It can lead to T-cell Leukemia 20-30 years after infection.
o Burkitt’s lymphoma - Africa
- If a non-tender mass in the left supraclavicular area, then the patient that had epigastric distress and weakness:
o 1st choice is metastatic gastric adenocarcinoma
o Cervical cancer can also metastasize to the supraclavicular node
 The left supraclavicular node drains abdominal organs; the right supraclavicular node
doesn’t; so lung cancers go to right usually
- Malabsorption (of everything: fats, carbs, and proteins)
o malabsorption of fat (steatorrhea) is necessary for diagnosing malabsorption; diagnose by stool sample
test for fat
o Fat absorption
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 Lipases are needed to break fat down into 2 monoglycerides and fatty acids (need a functioning
pancreas)
 Need villi in the small intestine (otherwise small intestine would have to extrophy to compensate)
to increase absorption
 Need bile salts to emulsify the fat into micelles (making absorption easier)
• Bile salts are made in the liver from cholesterol (it can’t be degraded: is either solubilized
in bile – runs risk of cholesterol stones, or it’s converted into bile salts (bile acids))
• Bile salt deficiencies can be caused by:
o liver disease
o Anything obstructing bile flow
o Bacterial overgrowth; they love salts and can eat them and break them down
o Terminal ileal disease (Crohn’s disease) you can’t recycle bile salts
o Cholestyramine bile acid resins (for treating hyperlipidemia)
 They bind bile salts on purpose to excrete them (if they’re not recycled,
more has to be made, and in the liver there’s an up regulation of LDL
receptor synthesis – they take cholesterol out of blood and reduce it)
 It can upset you and it also takes drugs with it (digitalis for example)
o If malabsorption is confirmed (positive steatorrhea test), overall, the best choice is small bowel
 Celiac disease [picture of small bowel lesion and a skin zit (caused by dermatitis herpetiformis)]
• Is an autoammine disease against gluten in wheat (specifically gliadin); antibodies
destroy the villi when attacking gluten (therefore you can’t absorb)
• It is the most common cause of malabsorption in this country
• The glands underneath are fine, but the villous surface is gone
• There is a 100% association with dermatitis herpetiformis (HLA-B8 antigen may be
present)
o It is also an autoimmune type of disease involving skin, but it’s not herpes
o It does have vesicular lesions (kind of looks like herpes of the skin)
 Whipple’s Disease (rare)
• An infection of the intestine due to Trophermya whippelii.
• Can only be seen by electron microscopy (can’t be gram stained or cultured)
o Shows bacteria that look like defective rods.
• Histology will show flat, blunt villi. Lamina propria will show foamy looking
macrophages (looks like Niemann-Pick disease and can be confused for something
else in an AIDS patient
o Acid Fast Stain in an HIV positive person with a 100 T-helper cell count would
show foamy macrophages caused by Mycobacterium avium intercellularae
(more common than MTB)
• Being an infection has systemic signs and symptoms: fever, polyarthritis, generalized
painful lymphadenopathy, peculiar color to the skin (usually males). Since it’s an
infection, it can be treated with antibiotics.
o Other diseases could involve pancreas
 Chronic pancreatitis – more common in alcoholics
• If an alcoholic has malabsorption, there’s two possible reasons: 1) chronic pancreatitis or
2) cirrhosis (could have bile salt deficiency)
- Diarrhea (3 subtypes)
o Invasive (bacteria invade)
o Secretory (bacteria produce a toxin that stimulate cAMP or other mechanisms causing the small bowel to
secrete excess amounts of isotonic fluid – NaCl)
o Osmotic (lactase deficiency and laxatives can produce it)
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 Means there’s an osmotically active substance in the lumen that’s soaking water out of the bowel
causing a high volume hypotonic loss of fluid
 Lactase is a disaccharidase brush border enzyme. If you’re lactase deficient, any dairy product
(which breaks down into glucose and lactose) can’t be digested and goes down to the colon and
the anaerobic bacteria eat it and release gases (it’s the hydrogen gas that causes bloating and
distention) and acids to produce an acidy stool and explosive diarrhea
o Secretory and Osmotic Diarrheas are both high volume diarrheas, whereas Invasive is low volume
 Cholera (Vibrio cholera LT strain)
o One of best tests is a fecal smear for leukocytes (like a reticulocyte count in a patient with anemia)
 If there aren’t any neutrophils, you know it’s not invasive and it will eventually go away
 If there are inflammatory cells in it, you’re obligated to culture it (Campylobacter, Shigella, etc.)
o Know all the toxic E. coli
 ETEC (enterotoxigenic; causes secretory diarrhea)
• Heat stable toxin (ST) increases cGMP levels (causing ion and fluid secretion
• Heat Labile toxin (LT is almost identical to cholera toxin, and increases cAMP (Vibrio
cholera also increases cAMP)
 EHEC (enterohemorrhagic – E. coli 0157:H7)
• Shiga-like toxin, no invasion
 EIEC (enteroinvasive)
o Traveler’s Diarrhea (Enterotoxigenic E. coli)
 Unless bacteria is invasive, bowel biopsy will be negative
o Cholera
 When you give fluid replacement to patients for cholera, it has to have glucose (to be able to
co-transport with the sodium that you put in)
o Campyobacter jejuni
 Most common invasive bacterial infection in the U.S. is Campylobacter jejuni; Shigella is
second
 Case may sound like a person with a low-volume diarrhea with some blood in it. Gram-stain
shows a comma-shaped (or S shaped organism). This is Campylobacter jejuni
o Shigella
 Can produce pseudomembranes (so can Campylobacter; so not all pseudomembrane is caused
by C. difficile)
o Giardia
 Owl-eye that moves
 Found especially up in the mountains (streams).
 Most common cause of chronic diarrhea due to a parasite in the U.S.
 Treatment: metronidazole
o Cryptosporidium parvii
 Most common organism associated with AIDS diarrhea
 Partially acid-fast organism
 Will kill you if you’re immunocompromised
 Comes in around the end when helper T-cell counts are 50 or 75(along with Mycobacterium
aviium, Toxoplasmosis, and CMV)
• Pneumocystis cariniii is when you’re up in the 200s
 Sticks on surface of the colon
o Pseudomembranous colitis
 Case may present as an autopsy of older woman in the hospital for a pneumonia (she’d be on
antibiotics) and she developed a diarrhea.
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• Antibiotic (most commonly ampicillin, not clindamycin – it’s number two) is wiping
out the good guys and leaving behind Clostridium dificile (present in everyone but E.
coli and Bacteriodes fragilis are keeping it in check)
o Clostridium dificile makes toxin and it damages the superficial layers of the
colon; it doesn’t invade, the toxins do (analogous to Corynebacterium
diphtheriae)
 Corrynebacterium diptheriae
• Its toxin damages and produces psuedomembranes; the toxin
ADP-ribosylates elongation factor 2 (EF-2), thereby inhibiting
protein synthesis in the cell
 First step in management is toxin-assay of stool (screening test)
 Treatment is metronidazole (ironically itself can cause pseudomembranous colitis); vancomycin
used to be used but it produced resistant strains
o Diagnosis is small bowel obstruction (step ladder affect: air-fluid levels)
 When you have a hollow viscous that peristalsis, you get cholicky pain (not crampy pain –
without intervals) whichis pain followed by painfree intervals, then pain. It doesn’t have to be
within minutes of each other (can be up to 1 hour apart)
• Bile duct doesn’t peristalse, therefore it can’t have colicky pain but crampy; it has to
peristalse (move) in order to have colicky pain
 Because it can’t peristalse, you end up with ileus and it doesn’t move at all – so you get
stagnation of the food (wherever the obstruction is, proximal to it) and you get air-fluid levels
 Distal to the area of obstruction there is no air.
 In an obstruction, you can have constipation and obstipation
• Constipation is when you just have a problem with stooling; doesn’t mean obstruction
• Obstipation means you have constipation and you can’t pass gas; means you have
complete obstruction (remember his passing gas joke)
 Down’s syndrome
• Doesn’t have to be trisomy 21 (due to nondisjunction: unequal separation in the 1st stage
of meiosis); could be 46 chromosomes from Robertsonian translocation:
o one of the chromosome 21s would have another one attached to it (still count as
one, but you get three functioning chromosomes)
o The mother is the one who usually has the abnormality (usually has 45
chromosomes: her chromosome 21 is actually one chromosome with the two
attached together and when she gives that to her baby, you end up with 46
chromosomes but three functioning ones
• Associated with duodenal atresia (also associated with Hirshsprung’s)
o Hirshsprung’s Disease
 Ganglion cells are missing in rectal area causing stools not to be able to go by (no
peristalsis).
 You end up with dilatation of the proximal colon (has ganglion cells). A rectal ampulla has no
stool on it.
• If there’s a child that didn’t pass the meconium in 24 hours and you did a rectal
exam with pinky, and no stool came out = diagnosis is Hirschsprung’s (if stool did
come out, the diagnosis would be a tight sphincter)
o Most common cause of obstruction (slide shows watermelon pits with narrowing). Most common cause is
adhesion from previous surgery. If patient never had surgery and they have classic colicky pain, the
answer is the bowels attract in an indirect inguinal hernia (male weight lifter developing colicky pain in
right lower quadrant area, who never had a history of surgery – answer being indirect inguinal hernia)
o Intussuseption (most are in toddlers)
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 Where terminal ileum intusussepts (goes into the) cecum; it gives a colicky pain (because
you’re obstructing) and compromises blood flow and it gives bleeding
 They’re not going to say currant jelly stools; they’re just going to say bloody stools, colicky pain,
2 year old kid and might say oblong mass in the right upper quadrant called Dancer’s sign
 Most times it spontaneously comes out in kids; if not, radiologist can everts it with a barium
enema
o Volvulus
 Twisting of the colon around the mesentery because there’s too much of it.
 Also produces a complete obstruction along with infarction (compromises blood supply).
o Gallstone Ileus (seen in older people)
 Stone falls out of fistula (serves as communication between gall bladder and small bowel to
allow air to get into the gall bladder and biliary tree) and into ileocecal valve usually to produce
obstruction (seen usually in older women); signs are colicky pain and obstruction
 Diagnosis is by flat plate of abdomen reveals air in the biliary tree
o Meconium Ileus
 Means Cystic Fibrosis
o Vascular Lesions
 Small bowel more commonly infarcts than the large bowel (because of one blood supply –
superior mesenteric artery)
 Superior mesenteric artery
• Supplies entire small bowel, ascending colon, and transverse colon
• When it changes to inferior mesenteric, there is no double blood supply, but a little island
between the two irrigated areas that does not get any blood; here is where you get pain
when you have ischemic disease (near splenic flexture)
 Small bowel infarct (Slide)
• Can be entrapped in small bowel in indirect hernial sac; can cause a severe pain (at
splenic flexure area) 30 minutes after eating and blood in stools
• Patient presents sudden onset of severe generalized pain (whole abdomen hurts)
and bloody diarrhea; if it’s the colon (the pain is at a particular point)

- Difference in Small Bowel infarct vs. Bloody Diarrhea related to Ischemic Ulcer (in Splenic Flexure)
o Both can have bloody diarrhea, but small bowel will be diffuse abdominal pain, whereas ischemic
ulcer (small infarct in colon) can be pointed out
- Other Vascular Lesions (picture on cecum looking like angiodysplasia
o Angiodysplasia is the second most common cause of hematochesia (number one being diverticulosis)
 It’s in cecumbecause of Law of LaPlace (tension in the wall of a cylinder is a function of
intraluminal pressure and diameter, therefore the cecum develops the greatest wall tension
because it has the widest diameter of the colon)
 Wall stress (being greater in cecum) puts stress on the vessels of the wall and pulls them apart a
little bit forming plangictasia (if one ruptures to surface, you can end up with significant
bleeding)
 It’s a very common cause of hematochezia in older people (behind diverticulosis)
 In USMLE 2, know that it’s associated with aortic stenosisand relationship of angiodysplasia
with Von Willenbrand’s disease
o Meckel’s diverticulum
 2 feet, 2 inches, 2 percent of the population, and from the terminal ileum.
 The most common complication is bleeding
 Because it is a diverticulum, you can get inflamed (diverticulitis)
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• Question where patient had hematemesis, melena, and pain in the right lower quadrant
area. Choices included Crohn’s and Ulcerative Colitis… Because of hematemesis and
melena, it’s not Crohn’s disease. Answer being Meckel’s diverticulitis.
• Because of bleeding and vomiting, some fluid from neck can get acid involvement and
become melena; bleeding aspect is associated and location seems right because it’s about
2 feet from ileocecal valve
 Embrology question: Newborn had a sinus on the umbilicus ….???
• It’s formed from persistence of the vitelline duct (aka omphalo-mesenic)
• Sometimes it can go all the way through (communication between small bowel [ileum]
and umbilicus = vitelline fistula)
o Feces can come out of umbilicus = persistence of vitelline duct
o If urine comes of umbilicus = persistence of urachus
 Sigmoid Colon
• Is the most common location for cancer, polyps, and diverticulii.
o Diverticula
 Area of weakness (where blood vessels penetrate the valve)
 Mucosa and submucosa is going to herniated right next to vessel
 When feces gets stuck in there (called a fecola) and you can erode the area around the vessel; this
is why diverticulosis is the most common cause of hematochezia (massive lower G.I. bleed)
 Barium study can be confused with familial polyposis; polyps go into the lumen (not out),
diverticulosis extend outside of the lumen
 Common complication is diverticulisis; presents as left-sided appendicitis (right lower
quadrant pain, rebound tenderness, fever, neutrophilic …)
 Also a common cause of fistula (a communication between two hollow organs) in the G.I. tract
• Most common fistulas are colovesicle fistula (between colon and the bladder); you get
pneumaturia (air in urine)
• Can rupture and produce pertinitis
- Inflammatory Bowel Disease
o Crohn’s and Ulcerative Colitis
o Crohn’s involves the terminal ileum 80% of the time; sometimes it may involve terminal ileum and
colon; and sometimes it just involves colon
o Crohn’s likes the anus (produce fistulas and fissures);
o Ulcerative colitis likes the rectum (bloody diarrhea)
o Crohn’s jumps around, is transmural, has noncasseating granulomas; Ulcerative colitis doesn’t
jump around but has continuity; it involves mucosa and submucosa
o Crohn’s
 Diagnosis of Crohn’s disease has a narrow lumen with colicky right lower quadrant pain and
diarrhea in a young person.
• If it’s in a third world country, it could be TB (Mycobacterium bovis because of lack
of pasteurization, not Mycobacterium tuberculosis.
• In theU.S.,if we were to get intestinal TB, it’s Mycobacterium tuberculosis from
swallowing a primary in the lung).
 String sign (in Barium study; as a result from edema, inflammation, fibrosis, and hypertrophy of
the muscularis propia); slides would show transmural inflammation (affecting all layers),
segmental bowel involvement, fissuring (“cobblestoning”) of the mucosa, linear ulcers
(“serpentine ulcers” with fissures in between “aphthous ulcers”). Noncasseating granulomas
(hard to identify) but it has multinucleated giant cells; characteristic of Crohn’s.
o Ulcerative Colitis
 Always begins in the rectum. It can stay there or it can move up in continuity and involve the
whole colon (pancolitis: highest incidence of cancer), but never involves the terminal ileum.
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 Pseudopolyps (in slide) are residual mucosa that’s inflamed and bloodied. Grey stuff in between
is totally ulcerated off (basically looking at submucosa).
 Has the highest association with cancer, ankylosing spondylitis, and is the most common
cause of sclerosi pericholangitis (sclerosis or fibrosis around the common bile duct producing
obstructive jaundice and high incidence of palangial carcinoma)
- Polyps
o The most common polyp in the entire GI tract is the hyperplastic polyp (hamartomas; no polyposis
syndrome or neoplasia with these) and are more commonly located in the sigmoid colon
o Tubular adenoma: looks like a strawberry on a stick (has a stock) on histological slide. Precursor
lesion for colon cancer.
 Size determines their malignant potential (if over 2 cm, they’re very dangerous).
o Slide shows polyp coming out of butt is a juvenile polyp (all are located in the rectum).
 If (reddish mass) was sticking out of the butt of an adult, it would be an internal hemorrhoid.
 Internal hemorroids bleed, external hemorroids thrombose (and are painful).
 When you have blood-coating stool, that’s from an internal hemorrhoid (they are not painful but
they do prolapse).
o Sessile polyp (associated with villous adenoma)
 Unusual because it looks like the villous surface of the small intestine.
 Have the greatest malignant potential of all polyps.
 Usually in the rectal sigmoid. Because they are villous-like, they often have a lot of mucous
coating the stool.
 Has a 50% chance of being malignant. Secretes lots of mucous and coats stool.
o Familial Adenomatous Polyposis (FAP)
 You have to have more than 100 polyps to call it familial.
 This is autosomal dominant; caused by mutations of the APC (adenomatous polyposis coli)
gene (Ras and p53 also is involved).
 Always get cancer in them; usually between 35-40 they prophylactically have to remove your
bowel.
 Autosomal dominant diseases are famous for late manifestations, concept of penetrance, and a
variable expressivity (patients with FAP don’t have polyps at birth but develop between 10 and
20 yrs of age); same for adult polycystic kidney disease and Huntington’s chorea (autosomal
dominant)
 Turcot’s syndrome
• Have polyps adenomatous colonic polyposis andtumors of the central nervous system
(mnemonic: Turbin for head and it sounds like Turcot’s)
• Is autosomal recessive
 Gardner’s syndrome
• Instestinal polyps and multiple benign soft tissue tumors (desmoids, osteomas in jaw)
- Carcinoid tumors
o All carcinoid tumors are malignant, but they have low-grade potential and a lot of it depends on
their size (whether they’re going to metastasize). If greater than 2 cm, they have the ability to
metastasize.
o The most common location for carcinoid tumor is thetip of the appendix.
 They have a bright yellow color.
 They are never the cause of carcinoid syndrome because if they’re at the tip of the appendix
they usually won’t be greater than 2 centimeters.
o The location of the most common carcinoid tumor that can be associated with carcinoid syndrome is
terminal ileum (they’re always greater than 2 cm).
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o Carcinoid tumors make serotonin; since the appendix and terminal ileum are drained by the portal vein,
the serotonin goes through the portal vein, through the hepatocytes (metabolize it to 5-
hydroxyindoleacetic acid [5-HIAA] and you pee it out so you don’t have it in your blood).
 There’s no signs of flush in your diarrhea because there’s no contact with your systemic
circulation, BUT if you metastasize to the liver (you can get signs). The metastatic nodules
that are making serotonin can dump some of it into the hepatic vein (it does have access to your
circulation)
 It can go into the inferior vena cava and right side of your heart which leads to right-sided lesions
(TIPS - tricuspid insufficiency pulmonic stenosis).
 Serotonin (a vasodilator in some cases and vasoconstrictor in others); in terms of carcinoid
syndrome, it’s a dilator (it produces flushing, the most common symptom of carcinoid
syndrome; followed by diarrhea).
 Screening test of choice is 5-hydroxyindoleacetic acid(because it’s the metabolite of
serotonin).
 Tryptophan could be deficient (because of all the excess serotonin) and you could have Niacin
deficiency (you could have pellagra).
 Neurosecretory granules (dense core bodies in cytoplasm) on an electron micrograph (require
history) to indicate colon cancer.
- Colon Cancer
o Left side obstructs, right side bleeds (in terms of colon cancer).
 Left colon has a smaller diameter than your right. Because of the smaller diameter, the cancer
when forming a polyp, it goes around (annular) to form a “napkin” ring (this produces
constriction). You would have signs of obstruction; more likely to present as constipation.
 In the right colon, because of a bigger diameter, it has a greater chance of going out and forming
a polyp and it will bleed. Right sided lesions are more likely to have iron deficiency.
o Tumor marker is CEA (carcino-embryonic-antigen); not used to diagnose but to follow for recurrence.
o Most common cause relates to diet (fiber helps get rid of colic acid). Age also is a risk factor (over 50).
Smoking also has an association. Polyps are also a risk factor.

Appendicitis
- The most common cause is a fecolith (an impacted stool).
o The impacted stool presses on the sides of an appendix to produce ischemia. The mucosa then breaks
down and E. coli gets in there. (The same mechanism for diverticulitis.)
- The pathogenesis of acute diverticulitis and acute appendicitis is exactly the same. Acute cholecystitis is
similar, but involves a stone instead of a fecolith; it pushes on the side to produce ischemia and acute
cholecystitis (E. coli).
- In children, the most common cause is measles and/or an adenovirus infection.
o You get acute appendicitis because there’s lymphoid tissue in the appendix. When you get an
adenovirus and measles, you get hyperplasia of the lymphoid tissue in the appendix. The
hyperplasia can obstruct the lumen and predispose to mucosal injury.
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Hepatobiliary 0
Starts at 29:33 of 4Gastrointestinal

Billirubin metabolism
- Most of the billirubin (almost all) is unconjugated billirubin derived from the RBCs when they got old,
phagocytosed, and destroyed. Unconjugated billirubin then went out into the bloodstream, joined albumin, went
to the liver, and was taken up.
- Since unconjugated billirubin is lipid-soluble it doesn’t show up in our urine.
- Once billirubin is taken up by the liver, it’s conjugated.
- (Anytime the cytochrome P-450 system in the liver conjugates or deals with any drug or any metabolite, it
renders it water soluble.) The lipid-soluble unconjugated billirubin is converted into a conjugated billirubin
(direct billirubin) that is water soluble.
- Once billirubin is taken up by the liver, it is not close to a vessel (it can’t get into a vascular channel). If
direct conjugated billirubin ends up in our urine, it’s because something happened in the liver or the bile ducts
because the direct conjugated billirubin shouldn’t have access to our bloodstream.
- Once in the liver, the conjugated billirubin is pumped into the ductules (go into the portal triads) and comes down
the common bile duct (some is stored in the gallbladder) and goes into the small intestine (via the common bile
duct).
o Bile contains conjugated billirubin, bile saltes, cholesterol, estrogen, …
o The conjugated billirubin then takes a long trip to the colon. The bacteria there then break it down back
into unconjugated billirubin. It is continued to be broken down to urobillinogen; urobillinogen gets
oxidized to urobillin which gives stool its color.
o A small portion of urobillinogen is reabsorbed (out of the colon); most goes back to the liver and a little
goes to the kidney and ends up in your urine (it’s oxidized into urobilin; responsible for the color of
urine).
o The same pigment that colors stool is the same pigment that colors urine; urobillin.
- If bile flow is obstructed (either in the liver or in the common bile duct) the color of your stool should be light
colored (was deprived of access to billirubin to make urobillin).

Jaundice
- By taking the billirubin and determining what the percentage of it is conjugated (direct) billirubin, you can
determine jaundice.
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- Three types:
o Conjugated billirubin < 20% (most is unconjugated)
 Primarily unconjugated hyperbillirubinemias
• Increased in hemolytic anemias, spherocytosis, sickle cell anemia, ABO and Rh
hemolytic disease of the newborn, physiologic jaundice of the newborn (can’t conjugate).
• If your conjugating enzymes are missing you have Crigler-Najjar syndrome.
o Conjugated billirubin 20%<50%
 These are hepatitis (an inflammation of all the liver).
 Your liver doesn’t want to take up unconjugated billirubin. The inflammation in the liver
destroys its architecture and probably breaks open some of the bile ducts that have
conjugated billirubin.
o Conjugated billirubin >50% (most is conjugated).
 Means you have obstruction of bile.
 Causes of obstruction
• Intrahepatic
o akaintrahepatic cholestasis.
o You’re blocking bile flow in the liver.
 Extrahepatic obstruction
• Means something is obstructing the common bile duct.
• Causes:
o Odds are a stone in the gallbladder and the common bile duct (from the
gallbladder).
o Carcinoma of the head of the pancreas; the ducts of Wirsung go through the head
of the pancreas. Bile duct is completely obstructed.
 If bile flow is blocked, it’s backed up to the liver cells. It bubbles outside the liver cells and now
has access to the sinusoids and it gets in your bloodstream.
 The excess conjugated billirubin (water-soluble) in the bloodstream will cause you to have very
yellow urine but pale stool.
- Other causes of jaundice:
o Gilbert’s Syndrome
 Presents if you fast for more than 24 hours.
• The best test is the fasting test.
o You get a baseline billirubin when not jaundiced.
o In 24 hours, if you get the blood (they’re already jaundiced) and you get double
the baseline billirubin you have Gilbert’s.
 It’s autosomal dominant and benign.
 It’s a problem in taking up billirubin and a problem in conjugating billirubin; produces a
predominantly unconjugated type of hyperbillirubinemia.
 The second most common cause of jaundice; the most common cause is hepatitis A.
o Dubin-Johnson syndrome
 You lose the ability to remove conjugated billirubin in the bile ducts.
 Predominantly a conjugated type of hyperbillirubinemia.
 They have a black colored pigment that builds up in the liver; you get black livers.

Liver Function Tests

- Transaminases are used because they’re indices of liver cell necrosis (i.e.).
o AST
 It’s present in muscle, RBCs, and in liver.
 In alcoholics, AST is elevated.
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• AST is present in the mitochondria of hepatocytes (ALT is in the cytosol of hepatocytes).

Since alcohol is a mitochondrial poison and AST is predominantly in there, when you
have alcoholic hepatitis, AST is higher than ALT.
• Could be fatty change, alcoholic hepatitis, or cirrhosis.
o ALT
 Is more specific; it’s only found in the liver.
 If you had a hepatitis (viral) with massive liver cell necrosis, you would see ALT as the
predominant transaminase elevated.
 The main enzyme elevated in any kind of diffuse liver cell necrosis.
- Enzymes of obstruction (of bile ducts) are alkaline phosphatase and gamma-glutamyl transferase.
o Gamma glutamyl transferase is located in smooth endoplasmic reticulum.
 When the smooth endoplasmic reticulum is revved up (underwent hyperplasia due to drugs such
as alcohol, phenytoin, and barbiturates), you not only increased the metabolism of the drug given
but you also caused increased synthesis of gamma glutamyl transferase.
 Scenario
• What would be the classic thing you’d see in any alcoholic liver disease?
• AST > ALT and an increase in gamma glutamyl transferase
o Alkaline phosphatase
 It’s also in bone (with osteoclastic activity), placenta, and other places.
 If it is elevated along with gamma glutamyl transferase, then there is a bile duct obstruction.
 If it is elevated alone, it means the disease is not of liver origin.
- Albumin Protime
o Markers of severity of liver damage
o Albumin is made in the liver; therefore if you have severe liver disease (i.e. cirrhosis) the albumin
should be decreased.
o An even better marker for severity of liver damage is the prothrombin time (the majority of coagulation
factors are made in the liver [not von Willebrand’s]); if you have severe liver damage you would show a
prolonged prothrombin time.
o Albumin can be used in determining the prognosis for a portal-systemic shunt.
- Anti-mitochondrial antibody
o For primary biliary cirrhosis.
- Tumor markers
o Alpha-feto protein is a marker for hepatocellular carcinoma.
o Alpha-1 antitrypsin can be used as a marker; it’s made in the liver and will be increased in
hepatocellular carcinoma.

Hepatobiliary-Pancreas 1

Hepatitis
- The most common HAV; the incidence follows alphabetical order (A most common, B 2nd most, C 3rd most, ….)
- HAVand HEV are not transmitted parenterally
- HAV never produces a chronic carrier state. HEV can produce a chronic carrier state if patient is pregnant
(Robins says otherwise).
- HDV is dependent on the genetic information from HBV (can result in coinfection or superinfection).
- HAV can be transmitted in day-care centers and in jails.
- HBV is common in IV drug users and post-transfusion hepatitis; it’s also the most common hepatitis in accidental
needle stick.
- HBA
o Anti-HAV IgM = Hepatitis A
o Anti-HAV IgG = you had Hepatitis A and won’t get it again (you’re protected).
 Only protective antibodies are those for HAV, HBV (surface antibody), and HEV
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o Note: HCV and HDV are not protected by antibodies

 Anti-HCV IgG doesn’t mean you had Hepatits C, rather that you have it presently. The
same non-protection of antibodies occurs in HDV; Anti-HDV IgG = active Hepatitis D infection
- HBV
o First marker is surface antigen (HBsAg) about a month or so after the infection.
o The second markers are the infectiveantigens: E antigen (HBeAg) and HBV-DNA.
o After the infective antigens comes the first antibody; the core antibody IgM (IgM-anti-HBc).
o The majority of people with HBV recover (about 90%); those who are HIV positive all go chronic.
o If you recover, the first thing to go away is the infective antigens. The last to go away is HBsAg (it’s
the first one to come and the last one to leave).
 It’s impossible to be E antigen (HBeAg) positive and surface antigen (HBsAg) negative.
o Serologic gap
 The surface antibody doesn’t come up until about a month or so after surface antigen is gone.
 You can determine if the patient had HBV b/c core antibody IgM (IgM-anti-HBc) doesn’t
leave; it eventually becomes core IgG (IgG-anti-HBc) over time.
 The marker during the period where all the infective antigens and surface antibody hasn’t
arrived yet, IgM-anti-HBc tells you that you had HBV and are in the process of recovery.
You’re not infected during this period b/c E antigen and HBV-DNA aren’t there.
o If you had HBV, you should have two antibodies: IgG-anti-HBc (core IgG) and IgG-anti-HBs
(surface antibody).
o Vaccinations only leave surface antibody as a marker (it’s a protective antibody).
o Chronic Hepatitis = having surface antigen for more than 6 months.
 Carrier (Healthy or Infective)
• Infective chronic carriers
o Are E antigen (HBeAg) and HBV-DNA positive
o Intimate contacts all have to be immunized (you can potentially transmit the
disease sexually to those people or IV).
o Are candidates for alpha-inteferon therapy.
 Sidenote: never give corticosteroids to patients with chronic viral
hepatitis.
• Healthy Carrier
o Are negative for E antigen and HBV-DNA but are positive for surface antigen
(HBsAg).
o Still have chronic hepatitis B but have excellent chances of recovery; w/in a year
or a year and a half the surface antigen will disappear along with surface
antibody.
o Markers and HBV Scenarios (Review)
 Markers would be HBsAg, HBeAg, HBV-DNA, and IgM-anti-HBc
 During the window period, we would see IgM-anti-HBc.
 If we had HBV and we have long since recovered from it, we’d have IgG-anti-HBc and IgG-
anti-HBsAg.
 If we had vaccination, we would only expect IgG-anti-HBsAg.
 If at the end of six months, we have HBsAg, IgM-anti-HBc, you are a healthy carrier.
 If after six months, we have HBsAg, HBV-DNA, HBeAg, and IgM-anti-HBc you are an
infective carrier.

Amebiasis
- Entamoeba histolytica
o The organism is resistant to acid so you could swallow and it exists in the cecum where there’s an
alkaline environment.
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o It has a chemical that can drill a hole through your mucosa and you get “flask-shaped” ulcers. You
have bloody diarrhea related to this.
o Because the cecum is drained by the portal vein, there’s a chance that the organism can get into a
portal vein tributary and be distributed to the right lobe of your liver where it will produce an abscess
(“anchovy past abscess”).
o It could drill a hole in your right diaphragm and go up into your lungs and produce an effusion or
get into your systemic circulation and go anywhere.
o Treatment
 Metronidazole (Used in Giardiasis, Entamoeba histolytica, Clostridium difficile, and
Trichomonas)
o Trophozoites have RBCs in them; it’s the only protozoal that can phagocytose RBCs.

Hydatid Disease
- Caused by Echinococcus
- Definitive vs. Intermediate Host
o Definitive means you have the sexually active worms that have the ability to mate and lay eggs.
o Intermediate Host doesn’t have sexually active adults; only the larval form (ingest eggs that develop
into larva but no further).
o Cycle is adult, egg, and larva. Can’t jump stages (in a human); if you have larval stage it can’t become
anything else (it’s an end stage form in humans).
- Could cause “Sheepherder’s Disease” (caused by Echinococcus multilocularis)
o It’s transmitted from sheep (an intermediate host with the larval form in the meat) to the dog.
o In the dog, the larval form can transform to an adult (so the dog becomes the definitive host). In the
dog, the adult lays eggs and when the sheepherder pets the dog, and receives eggs from the dog.
o The sheepherder somehow eats the eggs. In the sheepherder, the egg forms the larva and it stays there
(the sheepherder is the intermediate host).
o If the cysts rupture, the fluid would get into the abdominal cavity and you’d go into anaphylactic shock.

Taenia solium (also deals with definitive and intermediate host)

- It’s a tapeworm found in pork (the larval form); the pig is the intermediate host.
- When a human eats it, the larval form develops into an adult (the human is the definitive host).
- The eggs from an infected human (who didn’t wash his hands) can pass it on to other humans (it’s fecal-orally
contamination).
o The egg again forms larva in a human; the larval form are called cystercosi.
o The larva don’t form adults (in this case the human is the intermediate host); they cause cystercosis in
humans.
- The larva penetrate bowel and go to the eye and the brain (can cause seizure activity).
- If a human eats pork with larva in it, the larva can develop into adults (the human is the definitive host,
whereas if a human eats eggs (transferred via fecal-oral contamination) then the human is the intermediate
host (the eggs stop at the larval stage).

Nutmeg liver
- Most common cause was right-heart failure.
- Thrombus in Portal Vein (Pre-hepatic) vs. in Hepatic Vein (Post-hepatic)
o Portal Vein
 A thrombus in the portal vein would not produce nutmeg liver b/c it’s before the portal vein
emptied into the liver.
 You would, however have ascites, the potential for portal hypertension, and varices.
 Your liver isn’t big and congested.
o Hepatic Vein
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 A thrombus in the hepatic vein (Budd-Chiari Syndrome). The most common cause is
polycythemia rubra vera followed by birth control pills.
 You would have a nutmeg liver b/c the hepatic vein empties the liver.
 You’d get a huge liver.
 It’s a medical emergency; without surgery, you die.

Alcoholism
- Most common manifestation is fatty change; this occurs because of alcohol metabolism.
o Alcohol metabolism
 You have increased amounts of NADH. The NADH can change pyruvate into lactate and you
get fasting hypoglycemia and metabolic acidosis.
 You can have increased amounts of acetate (can make beta-hydroxybutyric acid [possible by the
increased amounts of NADH]). The increased acetate is another reason for increased anion gap
metabolic acidosis.
 You have increased amounts of acetyl coA. With the acetyl coA you can make fatty acids for
fatty change or make ketone bodies.
- Fatty change is reversible in an alcoholic if they stop drinking.
- Alcoholic hepatitis can cause death. It can cause hepatic encephalopathy, ascitis, and more.
o Alcoholic hepatitis differs from fatty change in that there’s fever, neutrophilic glucocytosis, high
enzymes (AST>ALT, gamma glutyrate, …).
o If you don’t stop drinking, you’ll die (b/c it’s systemic).
- You see Mallory bodies here (and in other disease). They’ve been ubiquinated keratin microfilaments.
- The toxic compound in alcohol that does the damage to the liver is acetaldehyde bound to a protein.
- Ito cell normally is the cell in the liver that stores retinoic acid (vit. A).
o When you’re an alcoholic, the acetaldehyde-protein complex stimulates the Ito cells to make fibrous
tissue (collagen). This is responsible for the cirrhosis that one sees.

Cholestasis (Obstruction to bile flow)

- Mechanism after obstruction
o Liver takes on a deepgreen color b/c bile is blocked (has conjugated billirubin) and is backed up into the
liver.
o The bile then refluxes into the sinusoids.
- Signs and Symptoms
o You get jaundice and lots of billirubin in the urine (b/c conjugated billirubin is water-soluble).
 Your stools come out pale
 In the urine, you don’t get urobilinogen, but the urine is bright yellow (it’s due to the conjugated
billirubin).
o Alkaline phosphatase and gamma glutamyl transferase are the elevated enzymes.
o Hypercholesterimia is possible as well because cholesterol can’t be eliminated (it’s normally eliminated
in bile).
o Bile salts are refluxed as well and they end up depositing in the skin (cause itching).
- Causes:
o Primary Sclerosing Cholangitis (associated with Ulcerative Colitis)
 Scenario
• Bile duct is surrounded by fibrous tissue (obstructing the bile duct and producing
jaundice). Patient has bloody diarrhea with left lower quadrant crampy pain and now has
jaundice. What inflammatory bowel disease is this?
• Ulcerative Colitis
o Sidenote: Cholangiocarcinoma
 Ulcerative colitis is the most common cause of this.
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• It will predispose cholangiocarcinoma since it involves a bile duct.

 In third world countries (Asia), the most common cause of cholangiocarcinoma is infection
Clonorchis sinensis (a biliary tree fluke).
o Primary Biliary Cirrhosis (an autoimmune disease)
 Scenario
• 50 y/o woman complaining of generalized itching. Examination shows hepatomegaly.
Blood studies shows normal billirubin, but increased alkaline phosphatase and gamma
glutamyl transferase. No jaundice is evident.
• She has primary biliary cirrhosis.
• She doesn’t present with jaundice b/c this disease is an autoimmune disease with
granulomatous destruction of the bile ducts in the portal triad.
 Jaundice doesn’t occur because it destroys the bile ducts in the portal triads little by little
(you maintain a reserve of triads for a while); you get jaundice late.
 The antibody that you order in this patient is anti-mitochondrial antibody (not anti-microsomal
for Hashimoto’s thyroiditis).
o Drugs
 Aldamet, Halophane, acetaminophen, birth control pills, and anabolic steroids can cause a
hepatitis-like picture.
 Birth control pills and anabolic steroids
• Have the same effect.
• Both produce intrahepatic cholestasis.
• Scenario
o A weight-lifter (have to assume he’s on anabolic steroids) presents with
jaundice. Viral serologies are negative. Alkaline phosphatase and gamma
glutamyl transferase are high.
o The cause of this is anabolic steroids or simply drug effect.
• Sidenote: Benign Intrahepatic Cholestasis
o One of the most common causes of jaundice in pregnancy is benign intrahepatic
cholestasis.
o The estrogen during pregnancy causes intrahepatic cholestasis. Estrogen is
also the cause behind birth control pills causing jaundice.
• Hepatic Adenoma (Liver Cell Adenoma)
o Both of these drugs also predispose to a benign liver tumor called Liver Cell
Adenoma (aka Hepatic Adenoma).
o It’s benign, but it has a habit of rupturing and could lead to intraperitoneal
hemorrhage (which could kill you).
o Scenario:
 Weight lifter becomes hypotensive and collapses. He’s brought into the
emergency room and they find his abdomen is distended and find there’s
blood in there. Upon exploration they find the spleen is okay and other
organs are okay.
 The most likely cause is a ruptured Liver Cell Adenoma that was put
there b/c the patient was on anabolic steroids.

Iron Overload Disease

- In general about iron:
o Iron can be stained with Prussian blue.
o Screening for iron overload is serum ferritin. Serum iron would be high, transferring synthesis is
decreased (TIBC is decreased), % saturation is increased, and serum ferritin is increased.
o Treatment: phlebotomy
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- Locations it can deposit and complications

o Iron can also go to the pancreas
 You have exocrine and endocrine problems. You get malabsorption problems and type I
diabetes.
o Iron can deposit on your skin and give you a “bronze” look. It’s due to a combination of iron deposited
on your skin and also iron stimulating melanocytes (increased melanin pigmentation).
o Iron can go into your joints (produce osteoarthritis), the pituitary (produce hypopituitarism), heart
(restrictive cardiomyopathy), …
- Hemochromatosis
o Bronze Diabetes
 Scenario
• An adult that is diffusely hyperpigmented and has diabetes.
• Bronze diabetes refers to hemochromatosis.
o It’s an autosomal recessive; it’s one of the most common autosomal recessive diseases.
 Instead of reabsorbing 10-15% of iron from foods each day, you reabsorb 100%.
o The target organ is the liver.
- Cirrhosis
o Iron damages via hydroxyl free radicals
 Whenever iron goes into cells, it produces hydroxyl free radicals.
 If you damage liver cells, you get fibrosis and end up with cirrhosis.
o Any iron overload disease results in cirrhosis. Iron overload also has a high incidence of hepatocellular
carcinoma.
- Hemosiderosis
o Acquired iron overload. Can be acquired by being an alcoholic (alcohol has lots of iron) or by taking
excess iron.
 Sidenote: Iron supplements are contraindicated in an elderly person (women don’t have menses
anymore).

Wilson’s Disease
- Kayser-Fleischer rings
o Eye lesionsthat are green to brown deposits of copper in the Descemet’s membrane (between the
endothelial layer of the cornea and the substantia propria) in the cornea.
- Hepato-lenticular degeneration
o Patient would have an abnormal movement disorder, dementia, and cirrhosis.
o Lenticular nucleus = globus pallidus and putamen (part of the basal ganglia of the cerebrum); the
putamen is especially atrophied and may even be cavitated
- Pathogenesis
o It’s autosomal recessive and it’s a defect in getting rid of copper in bile.
o Copper builds up and accumulates in the liver; it’s very toxic. Over a period of months to years, you go
from a chronic active hepatitis to cirrhosis.
- Copper Levels (Total Copper Levels = Cerruloplasma + free copper)
o When you get a total copper level, it includes free copper and the binding protein for copper
(cerruloplasma).
o 95% of a normal total copper level is related to the copper attached to cerruloplasma. If you have a
high free copper level, you can end up with hepatolenticular degeneration.
o If you have cirrhosis, you don’t synthesize cerruloplasma and it’s levels decrease. Because you don’t
have a lot of binding protein for free copper, the free level copper level increases.
o The total copper level in patients with Wilson’s disease is decreased because cerruloplasma is
decreased (which accounted for 95% of the normal total copper) but the free copper level is increased.
o Treatment = penicillamine (it’s a copper binder).
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Cirrhosis
- Is always diffuse.
- The bumps are regenerative nodules.
- Liver tissue is stable (in a G0 phase) and something has to stimulate it to go into the cell cycle and divide.
- Regenerative Nodules
o Pathogenesis
 The liver has a regenerative capacity. A surgeon can remove a lobe and over time it will grow
back, but it’s not normal liver.
 All that’s being grown back are hepatocytes (not basement membrane or blood vessels).
o The hepatocytes are worthless because there’s no central vein, sinusoids, or triads. This is what the
regenerative nodules are in cirrhosis.

Hepatobiliary 2

Cirrhosis
- Portal Hypertension
o Because the regenerative nodules in a cirrhotic liver have no vascularity, the portal vein has problems
emptying blood into the liver; this is why you get portal hypertension.
- Complications
o Pitting edema
o Ascites
o Esophageal varices (related to portal hypertension)
o Metabolic problems
 Can’t metabolize estrogen (gynecomastia);
• Sidenote: gynecomastia is normal in males when they are newborns, when they hit
puberty, and in old age.
• Scenario
o 13 y/o boy has a unilateral subareolar mass. The management of this patient is…
o Leave it alone. Gynecomastia isn’t always bilateral; most of the time it’s
unilateral. The same asymmetry in breasts is also true for women.
• Palmar erythema can result (related to estrogen)
• Men can become impotent because of the high estrogen levels.
o Spider angioma (shows vitamin deficiencies are common in cirrhosis)
o Dupuytren contracture
 It’s the most common fibromatosis.
 You get increased fibrous tissue around the tendon sheaths that causes the fingers to coil in.
 It’s commonly associated with alcoholics, but not necessarily always.

Spontaneous Peritonitis
- In adults where it’s usually associated with cirrhosis, it’s usually caused by E. coli.
- Children with nephritic syndrome who also has ascites and gets spontaneous peritonitis; the organism is
Streptococcus pneumoniae.

Hepatocellular carcinoma
- Almost always develops a background of cirrhosis.
- The most common cause isn’t alcohol; the more common causes are pigment cirrhosis from hemochromatosis,
the post-necrotic cirrhosis in HBV and HCV,
- They have ectopic hormones (erythropoietin and insulin-like factors). The hormones can cause
hypoglycemia and secondary polycythemia.
- Tumor marker is alpha-feto protein.
o Scenario
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 Pt. has an underlying cirrhosis with ascites that is stable. Suddenly the ascites gets worst and the
patient is beginning to lose weight. A peritoneal tap shows hemorrhage (blood in the ascitic
fluid; don’t assume there’s trauma). Which of the following tests would you do?
 Alpha-feto protein

Metastasis
- Would see multiple things on the slide.
- Odds are it’s from lung.
- Scenario
o They’ll show you the slide. Patient is a non-smoker. What’s the most likely cause?
o Metastatic colon cancer; there’s less of a relationship with smoking. Don’t pick primary lung cancer (b/c
it’s a non-smoker).
- Sidenote: Bowel obstruction
o Scenario patient didn’t have surgery (rule out adhesions; it’s the most common cause). The next most
common cause is an indirect inguinal hernial sac.

Gallbladder Disease
- Pathogenesis of the stones:
o Too much cholesterol in bile (gives you cholesterol stones) or too little bile in salts.
o Any of the things that produce bile salts deficiency (cirrhosis, obstruction, choletyrasine, Crohn’s
disease).
o Colors
 Cholesterol stones are yellow
 Billirubin stones are jet black
o Scenario
 25 y/o female had right upper quadrant crampy pain, fever, neutrophilic leukocytosis, and point
tenderness on examination of the upper quadrant. Ultrasound revealed stones. They were
removed and CBC showed a mild normocytic anemia and a corrective reticulocyte count of 8%.
Splenomegaly was also present on the exam and there’s a family history of splenectomy.
Diagnosis?
 She’s got congenital spherocytosis b/c she’s been hemolysing RBCs all her life. There’s more
conjugation in billirubin into conjugated billirubin so she has supersaturated bile with billirubin
and she forms calcium billirubinate stones (are jet black).
o The screening test of choice for stones (esp. gallbladder) is ultrasound.
o The screening test of choice for anything in the pancreas is CT is that the bowel overlies the pancreas
and screws up ultrasound (not as sensitive).

Cystic Fibrsis
- Growth alteration in the pancreas is atrophied.
- When you block the lumens of the exocrine ducts, the pressure goes back to the glands. The pressure atrophies
the glands and you end up with malabsorption.
- They can develop type I diabetes (the islet cells get fibrosed).
- Molecular biology
o Chromosome 7 three nucleotide deletion. The three nucleotides are coded for phenylalanine.
o You are deficient for phenylalanine in the cystic fibrosis transmembrane regulator protein.
o The real problem is you end up having no CFTR (cystic fibrosis transmembrane regulator) receptor.
When it gets into the Golgi apparatus, it’s supposed to be modified so it can be secreted to the cell
surface but instead ends up being degraded in the cell.
- Sweat Glands
o In the sweat glands the CFTR would normally reabsorb sodium and chloride out of the sweat glands. The
deficiency then leads to salt loss; this is the basis of the sweat test.
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o Scenario
 3 y/o that has failure to thrive and has chronic diarrhea and respiratory infections. Mother states
that baby tastes salty when she kisses the baby (the give away).
- Hard secretions
o The secretions are thick (in the lungs, pancreas, and bile ducts) because the CFTR the salt in the
secretions is necessary to keep it viscous. Because you’re missing CFTR, sodium is reabsorbed out of
the secretions in the airway (it would cause them to be a little dehydrated). Also chloride can’t be
pumped into the lumen of the airway.
o Since you’re taking sodium out and you can’t put chloride back in, the secretions become hard.
The same is true for secretions in the pancreas.
- The most common cause of death is infection due to Pseudomonas aeruginosa.
- Fertility
o The percent chance for a male who has cystic fibrosis of having children is between 0-5%; most are
infertile.
o For females, they can get pregnant, but they only have about a 30% chance for getting pregnant. The
cervical mucous is thick and so the sperm can’t penetrate through.

Acute Pancreatitis
- Most commonly due to alcohol. Second most common is a little stone caught in one of the accessory ducts.
- Amylase is elevated and the pain is epigastric with radiation to the back (b/c the pancreas is a retroperitoneal
organ).
- Scenario
o History of pancreatitis, and after 10 days you feel a mass in the abdomen. What tests do you do and
what is it?
o CT; it’s probably a pseudocyst. In a pancreatic pseudocyst, there’s a lot of fluid that develops around
an inflamed pancreas and it then accumulates to form a false capsule. It has a potential for rupture.
- Consequences
o It can cause steatorrhea (it’s one of the causes of malabsorption).
o You wouldn’t have bile salt deficiencies.
o They could have a hemorrhagic situation b/c of vitamin K deficiency (related to malabsorption).

Carcinoma of the Head of the Pancreas

- The head of the pancreas is the most common location for cancer in the pancreas.
- Smoking is the most common cause; the second most common cause is chronic pancreatitis.
- Scenario
o Patient will present with “painless” jaundice, light-colored stools, and palpable gall-bladder. The
jaundice will be primarily due to conjugated billirubin.
- C-sign = the duodenum looks like a C on x-ray
- Scenario
- Localized Ileus and Sentinel Sign
o Peristalsis of the bowel near the pancreas (localized ileus) stops because inflammation of the pancreas.
Because of the lack of peristalsis, there would be just air there (sentinel sign).
o Sidenote: appendicitis
 If you had a segment of bowel that was distended in the right lower quadrant, it has to be
inflammation, which could be appendicitis.
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Kidney 0
Starts at 24:37 of Hepatobiliary-pancreas2

Urinalysis
- Casts
o A cast is a mold of whatever is going on in the nephron. Tamm-Horsfall protein (a mucoprotein
produced by the ascending limb of the loop of Henle) is solidify around whatever is present in the tubule
at the time; it makes a mold of it that’s passed in the urine and can be seen under the microscope.
o Examples:
 If you had glomerulonephritis (inflammation of the glomerulus) you would damage the
capillaries and get hematuria; you could expect to see RBCs in the nephron that would be trapped
in the cast (you’ll have an RBC cast). RBC cast = glomerulonephritis.
 If you had renal tubular necrosis, you would see renal tubular casts. Renal tubular casts = renal
tubular necrosis.
 If someone had acute pyelonephritis, neutrophils would be infiltrating the interstitium in the
tubules. You would see casts of the neutrophils or WBCs indicating an infection in the kidney.
 If you had nephrotic syndrome and were spilling lipid in the urine, you would form a fatty cast
that you could see and polarize in the urine.
o Hyaline cast (Benign)
 Is a cast of a protein that is hard to spot and looks like a ghost.
- When you have renal failure, the first thing that disappears is the ability of the kidney to concentrate urine.
- Specific Gravity
o Specific gravity of the urine in the first morning void (after sleeping overnight) can tell you whether the
urine is concentrated or dilute.
o If specific gravity> 1.023, it would mean that the patient’s concentrating urine and the kidneys are
normal; the urine of someone sleeping overnight should be concentrated.
o If 1.010 (a hypotonic urine), it means that the patient could not concentrate urine and the patient is in
renal failure (would follow up with BUN and creatine clearance).
- Crystals
o Uric Acid crystals
 The pH of the urine has to be acidic to form a uric acid crystal.
 If you had a patient with gout and you wanted to stop these crystals from forming, you would
want to alkalinize the urine (by carbonic anhydrase inhibitor).
o Calcium Oxalate crystals
 They look like an x in a box.
 Scenario
• Person comes in a stuperous state and has an increased anion gap metabolic acidosis.
You do a urinalysis and you see a lot of calcium oxalate crystals. What did he drink?
• Ethylene glycol
 Calcium oxalate is the most common stone that we past.
o Sidenote:
 The inferior mesenteric artery restricts the movement of a horseshoe kidney (it goes over the
kidney and traps the kidney behind it).

Cystic Diseases of the Kidney

- Infantile Polycystic Kidney Disease (Autosomal Recesssive)
o They’re present at birth (b/c they’re autosomal recessive).
o You have oligohydramnios (an abnormally small amount of amniotic fluid). The kid is in an amniotic
sac without hardly any amniotic fluid (the lack of normal kidneys leads to lack of normal urine output,
and therefore has malformations related to pressure); his nose is flat and ears have prominent
infraorbital folds (“Potter’s facies”).
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o Potter’s facies is a sign of oligohydramnios in a child with polycystic kidney disease.

o Breathing is difficult because there’s hardly any fluid; the lungs are hypoplastic because they could not
fill them up quick enough.
o Cysts are not only in the kidneys; they’re in the liver, pancreas, and other.
o They are incompatible with life.
- Adult Polycystic Kidney Disease (Autosomal Dominant)
o Cysts are not present at birth; autosomal dominant disease have delayed manifestations.
 Penetrance (the frequency of manifestation of a hereditary condition in individuals) could mean
that you have the abnormality when they look for it on the gene, but you wouldn’t have cystic
kidney disease; you have the genetic abnormality but never expressed it (incomplete
penetrance). You may transfer it to your children.
• Sidenote: Marfan’s
o You can have the abnormality on chromosome 15 and have no symptoms. That
person can pass it on to the kid.
o Marfan’s has incomplete penetrance.
• Familial Polyposis has 100% penetrance; if you have the gene, you got the disease.
o Cysts show up by about 10 y/o.
o Hypertension
 You will always develophypertension. The hypertension will predispose to two kinds of bleeds
in the brain: 1) Charcot-Bouchard aneurysms, 2) a berry aneurysm (it can rupture and bleed into
the subarachnoid space [described as “the worst headache”])
 Subarachnoid hemorrhages can lead to death in patients with Adult Polycytic Kidney
Disease
o Mitral Valve Prolapse (occurs in about 20-25%)
 Scenario:
• History of pt. w/hypertension, abnormality in ultrasound of the renal pelvis area, and
who had a click murmur (mitral valve prolapse). What was the patient’s kidney disease
that caused the hypertension?
• Adult polycystic disease
o Diverticulosis
 There’s a high incidence of diverticulosis in patients with adult polycystic kidney disease.
 Scenario:
• Pt. w/hypertension, abnormality on ultrasound in the renal pelvis area, and loss 600 mL
of blood all of a sudden from stools (hematochezia).
• The most common cause of hematochezia is diverticulosis.

Glomerulonephritis
- If it ends in –itis, it’s a type III hypersensitivity reaction.
- Terms
o Diffuse = every glomeruli is affected
o Focal = not all the glomeruli are involved
o Segmental = only one part of the glomerulus is abnormal.
o If the disease is focal and the disease in the glomerulus is focal, it would be called focal segmental.
o Proliferative = more than 100 nuclei in a glomerulus consistently, it’s a proliferative type of
glomerulonephritis.
o Membranous = demonstrated as a thick membrane
o Membrano-Proliferative = you see both an increased number of cells and a thick membrane.

Renal 1
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Anatomy of glomerular capillary

- From inside to outside, you have the endothelium, basement membrane, and the visceral epithelium (have
podocytes; the spaces between the podocytes are called slit pores).
- Flow is from blood, through endothelial cell, basement membrane, visceral epithelial cells, and parietal epithelial
cells (line the Bowman’s capsule).

Basement membrane
- The basement membrane is made by the visceral epithelial cell (podocyte).
- Albumin is normally kept out of the urine by the negative charge of the glomerular basement membrane (due
to a glycosaminoglycan – heparan sulfate).
- If the visceral epithelial cell was immunologically damaged, we also damage the basement membrane (you will
spill a lot of protein in your urine). If you spill > 3.5 gm/day, you could have nephrotic syndrome.

Tests one does on a renal biopsy for evaluating glomerular nephritis

- Routine H&E, Silver stains, …
- Immunofluorescent stains
o You take the biopsy and have antibodies with a fluorescent take on them.
 If you wanted to see if there was IgA in the glomerulus, you have anti-IgA antibodies with a
fluorescent tag. If there was any IgA, the anti-IgA would attach to it and produce fluorescence
there.
 There’s also tags for IgG, C3, fibrinogen, …
o Patterns
 Linear
• Are due to immune complexes or antibodies detected.
 Granular (“Lumpy bumpy”)
o It doesn’t tell us where the different antibodies or immune complexes are; it just tells us that they’re
there.
 In order to find out where immune complexes are located, we need electron microscopy.
- Electron microscopy
o Used in order to find out where in the glomerular capillary immune complexes and antibodies are
located.
o Also used to tell whether or not podocytes are fused because they’re so small.

Antibody-mediated glomerulonephritis
- Goodpastures (Type II hypersensitivity)
o IgG anti-basement membrane antibodies.
 They’re in the blood, they get into the glomerular capillary and are directed against the basement
membrane.
 They line up all every space in the basement membrane (b/c there’s millions and millions of the
IgG).
o A fluorescent tag for IgG would show a linear pattern of the whole basement membrane.
Goodpasture’s is the most common cause of a linear pattern on an immunofluorescence.
- Immune-complex (Type III hypersensitivity)
o An immune complex is an antigen and an antibody attached to it. It is circulating in your blood.
o Examples:
 Lupus: The antigen is DNA, the antibody is anti-DNA.
o They’re larger than individual antibodies (you have antigens and antibodies attached together).
 They have different solubilities.
 They have different charges.
 They don’t deposit in a neat and continuous fashion.
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 If the complex is too big it will deposit under the endothelial cell nucleus (subendothelial
deposit). Lupus is like this; they can’t get through the basement membrane and stay under the
endothelial cells.
o Post-streptococcal glomerulonephritis
 The immune complexes (due to bacterial antigen and the antibody against it) are very small and
very soluble.
• They go all the way through the basement membrane and can deposit on the epithelial
side but under the epithelium (subepithelial deposit).
• We have to do an electron microscopy to detect subepithelial deposits. They are also
electron dense on electron microscopy.
o Granular (“lumpy bumpy”) Pattern
 Since immune complexes have different solubilities, charges, and are randomly going underneath
the endothelium or the subepithelial surface, you get a granular pattern.
• The granular pattern (“lumpy bumpy”) can be attributed to any immune complex
(type III hypersensitivity) disease: lupus, post-streptococcal, IgA glomerulonephritis.
o IgA glomerulonephritis is the only glomerulonephritis that can be diagnosed with
immunofluorescence (it’s the only mesangial).

Glomerulonephritis
- Two types: Nephritic and Nephrotic
o You can’t have both, but you can start out nephritic and go to nephrotic.
o Nephritic (Post-strep, Lupus, and Crescentic Nephritis)
 It has a unique cast – a RBC cast. You have hematuria.
 Because you have inflammation of the glomerulus, you are going to spill protein, but not > 3.5
gm/day b/c if it did, then it’d be nephrotic. It has mild to moderate proteinuria;< 3.5 gm/day.
 You would not have pitting edema and ascites.
 Because you’re inflaming the glomerulus, you would have oliguria (the glomerular capillaries
are all swollen up and therefore the GFR would decrease).
 The reabsorption of sodium is decreased b/c you’re not filtering as much. Sodium is then
retained and you run the risk of hypertension.
 Post-streptococcal glomerular nephritis
• Glomeruli looks diffuse. It has proliferative glomerular nephritis.
• Scenario
o Patient had scarlet fever two weeks ago and now presents with hematuria, RBC
casts, mild to moderate proteinuria, hypertension, some periorbital puffiness
(always see if you retain a little bit of salt). What’s the diagnosis?
o Post-streptococcal nephritis
• It presents dense immune complexes (bacterial antigen-antibody complexes)
subepithelially.
• Treatment: corticosteroids
 Lupus
• Scenario:
o 35 y/o woman who has a positive serum ANA with a rim pattern (anti-dsDNA
antibodies = lupus).
• Lupus presents as a diffuse proliferative glomerulonephritis (the most common overall
lupus disease affecting the kidneys).
• The electron micrograph shows complexes subendothelially.
 Crescentic Glomerular Nephritis
• Worst glomerular nephritis you can have b/c within about three months, you go into
acute renal failure and you’ll die unless you’re on dialysis.
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• Many diseases (PAN, Wegener’s granulomatosis, etc.) can have crescentic glomerular
nephritis; the only one we need to know is Goodpasture’s syndrome.
o Goodpasture’s syndrome classifically produces a crescent on biopsy.
o Nephrotic
 Associations
• It has a fatty cast (not RBC).
• You have > 3.5 gm/day of protein. You would have pitting edema and ascites.
• Podocytes (slit pores) are fused.
• Maltese crosses may show up on polarized urine; it’s really cholesterol in the urine; it is
the pathognomonic cast of nephrotic syndrome.
• Decreased albumin levels
• Hypercholesterolemia and casts (malteses crosses) with cholesterol in the urine (only in
nephrotic syndrome)
 You can use these signs to tell if you’re moving from nephritic to nephrotic.
 You run the risk of spontaneous peritonitis (if you’re a kid, it’s caused by Strep. pneumonia; an
adult, caused by E. coli)
 Lipoid nephrosis (aka Minimal Change Disease)
• Occurs because the patient has lost the negative charge on the glomerular basement
membrane (albumin now can get through and its levels are increased in urine).
• Most common cause of nephrotic syndrome in kids.
• Scenario
o 8 y/o boy had an upper respiratory infection 1 week ago and now has pitting
edema all over the body and ascites. He’s normotensive and doesn’t have a high
blood pressure. Renal biopsy and H&E stain showed no abnormalities in the
glomerulus; immunofluorescence showed no abnormalities. Electron
micrograph showed a majority of fused podocytes. Maltese crosses shows in the
urine. What does the kid have?
o Lipoid nephrosis (aka minimal change disease)
• Treatment is corticosteroids; may come recur, but after a year it goes away
 Focal Segmental Glomerulosclerosis
• Is the most common cause of nephrotic syndrome in AIDS patients and IV drug
abusers.
• Scenario
o Patient who’s HIV positive has pitting edema. Urinalysis shows protein > 3.5
gm/day, fatty casts, and hypertension. Biopsy shows some normal glomeruli.
Others are abnormal, but only a part of it (focal segmental).
Immunofluorescence and electron microscopy didn’t show electron dense
deposits.
o It’s called focal segmental glomerulosclerosis
• Next to Rapidly Progressive Crescentic Glomerulonephritis, the next worst glomerular
disease you can have.
 Diffuse Membranous Glomerulonephritis
• The most common cause of nephrotic syndrome in adults.
• It involves subepithelial deposits. Silver stains and magnification shows “hair on
end” (or epimembranous spikes) which are actually the immunocomplexes under silver
stain.
• Electron microscopy shows
• Scenario
o Pt. presents with pitting edema and nephrotic syndrome. Basement membranes
are thick.
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• Causes are numerous. NSAIDs, HBV, Captopril, Malaria, Syphillus, Cancer (colon
cancer [immune complex is CEA-anti-CEA antibodies].
• It eventually leads to renal failure and death is possible unless a renal transplant.
 Membranoproliferative Glomerulonephritis
• Type I Membranoproliferative Glomerulonephritis
o Has a relationship with HCV. (Cryoglobinemia is also related with HCV; PAN
is also related with HBV).
o It’s a subendothelial deposit.
o It produces nephrotic syndrome
• Type II Membranoproliferative Glomerulonephritis
o There’s an antibody against C3 (the C3 Nephritic Factor [C3NeF]). It causes C3
convertase to become overactive and it constantly breaks complement down.
o It presents with the lowest complement levels in any glomerulonephritis
(dense deposit disease b/c the entire basement membrane is an immune
complex).
• Presents as “tram track”
o The mesangial cell extends itself between the basement membrane and the
endothelial cell; this is what causes the “tram track”.
 Diabetic glomerulosclerosis (Diabetic Nephropathy)
o Presents big red “Christmas balls” in the glomerulus
• Hyaline Arteriolosclerosis(occurs in diabetics)
o Excess Red = hyaline arteriolosclerosis; It’s a small vessel disease in
hypertension and diabetes
o Hyalinization of the Efferent Arteriole
 The first vessel hyalinized is theefferent arteriole(away from the
kidney).
 If the lumen is narrowed in the efferent arteriole, the GFR will be
increased. The creatinine clearance is increased.
• Pathogenesis
o In early diabetic nephropathy, you have increased creatinine clearance and GFR
b/c the efferent arteriole is hyalinized and it’s obstructed. After time, the
glomerulus will be damaged (hyperfiltration damage).
o If non-enzymatic glycosylation also occurs in a diabetic, the glomerular
basement membrane is also being glycosylated. The basement membrane
now becomes permeable to proteins.
o The combination of pressure on the glomerular capillary (b/c of the efferent
arteriole) and glycosylated basement membrane contributes to protein in the
urine (microalbuminuria). The standard dipstick for protein will not detect this.
o When a diabetic patient has a positive dipstick for microalbuminuria
requires an ACE inhibitor to stop the progression.
 The afferent arteriole’s caliber is controlled by PGE2. The efferent
arteriole’s caliber is controlled by angiotensin II (it normally
constricts it).
 If you gave a person an ACE inhibitor, the angiotensin II levels decrease.
The lumen would open up a little and take the pressure off the
glomerulus and decrease the glomerular filtration rate and also decrease
the amount of damage.
 You obviously have to tell the patient to get his/her glycemia controlled
or they may go into chronic renal disease.
o Nodular Glomerulosclerosis (Kimmelstiel-Wilson lesion)
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 In patients who have diabetes, type IV collagen builds up in the

mesangium (looks pink). This is called nodular glomerulosclerosis (or
Kimmelstiel-Wilson lesion).
 It is the most specific lesion of diabetic glomerulosclerosis for the
purposes of the USMLE.
 The lesions are ovoid, hyaline, PAS-positive structures in the
mesangial core at the edge of the glomerulus.
 Amyloid
• It can deposit in the kidneys.
• It’s a protein that when stained with Congo Red and then polarized, it has an apple-green
birefringence.
o IgA Nephropathy (Berger’s Disease)
 It is the most common glomerulonephritis.
 Is probably a variant of Henoch-Schonlein purpura
• They’re both immunocomplex diseases with IgA and anti-IgA antibodies.
• Sidenote: Henoch-Schonlein purpura
o Palpable purpura in buttocks and legs
o Polyarthritis
o GI bleed
o Hematuria and RBC casts (both have this)
 When you do immunofluorescence, all is taken up in the mesangium (where the immune
complexes are).
 In kids, it presents with episodes of gross hematuria, goes away and may come back years later.
 In adults, it usually presents as episodic bouts of microscopic hematuria. It’s on again and off
again. It may have a little proteinuria. There’s no hypertension.
 It is a type III hypersensitivity disease.

Renal 2
BUN/Creatinine
- Allows you to differentiate pre-renal azotemia vs. renal failure.
- BUN = blood urea nitrogen; creatinine is the end product of creatine metabolism.
- Urea and Creatinine
o Urea can be filtered and reabsorbed in the proximal tubule.
o Creatinine is only filtered in the kidney and it’s either reabsorbed or secreted.
 Creatinine is commonly used for creatinine clearance; inulin clearance, however, is a lot better.
 Creatinine can be secreted in other places like the gut in high levels.
- If you take the normal BUN level (~ 10) and the normal creatinine level (1mg/dL), you have a normal ratio of
10:1.

Pre-Renal Azotemia
- When you have pre-renal azotemia (an increase in BUN), there’s nothing wrong with the kidney, but your
cardiac output is decreased.
o Any cause of a decrease in cardiac output (congestive heart failure, myocardial infarction,
cardiomyopathy, hypovolemia, …) will produce a pre-renal azotemia.
o It will cause pre-renal azotemia b/c the GFR will decrease.
 The decrease in GFR will give the proximal tubule more time to reabsorb more urea than it
normally would with a normal GFR.
 Creatinine is not reabsorbed; however, since the GFR is decreased, there will be a backup of it
and you won’t be able to clear it as fast. There will be an increase in serum creatinine, however,
not as much compared to the increase in urea.
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- There’s a disproportionate increase in BUN/creatinine.

- 15:1
o If you have a ratio greater than 15:1 (BUN/creatinine) means you have pre-renal azotemia.
- Scenario
o Pt. has congestive heart failure. Serum BUN = 80; Creatinine = 2.
o Both are elevated, but the BUN/Creatinine = 40:1. This means there’s pre-renal azotemia and the patient
does not have acute tubular necrosis.

Renal Failure
- If you really have renal failure, you have oliguria, and renal tubular casts in the urine.
- The patient’s kidneys have failed and you have acute renal failure. This is going to affect the urea and the
creatinine equally. Both increase, but proportionate to each other (since they both have the same problem).
- Scenario
o BUN = 80 and Creatinine = 8.
o The ratio is 10:1 and it means you have renal failure.

Review: Pre-Renal Azotemia vs. Renal Failure

- If you maintain the normal ratio of 10:1 though urea and creatinine are increasing, it means you have renal
failure.
- If the ratio of BUN:creatinine is greater than 15:1 you have pre-renal azotemia.

Acute Renal Failure (Ischemic Acute Tubular Necrosis)

- The most common cause is ischemic acute tubular necrosis.
o This is what you worry about most when a patient’s cardiac output decreases and they develop oliguria (it
is also present in pre-renal azotemia).
o If pre-renal azotemia is not taken care of, they can develop acute renal failure (ischemic acute tubular
necrosis).
o The most common cause of ischemic acute tubular necrosis is not reading pre-azotemia.
o In ischemic ATN, you have a BUN/creatinine ratio ~ 10:1.
- Pathogenesis
o You have coagulation necrosis and cells will slough off and block the lumen and contribute to the
oliguria.
o In the urine, you would see casts. The casts would show renal tubular cells in them (called renal
tubular casts).
- Ischemic acute necrosis shows BUN/creatinine ratio ~ 10:1, oliguria, and renal tubular casts.
- Basement Membrane Damage
o The reason ischemic acute necrosis has a bad prognosis is when you have an ischemic cause for tubular
necrosis, not only are you killing the tubular cells, but the basement membrane gets damaged.
o The basement membrane is essential for retaining integrity and regenerating it even after acute
tubular necrosis (as long as the basement membrane is present; renal tubular cells cannot be regenerated
where there’s no basement membrane).
- The two parts of the nephron most susceptible to ischemia are the straight portion of the proximal tubule and
the thick ascending limb in the medullary segment. These are the parts of the nephron that undergo the
coagulation necrosis and sloughing off.

Drugs that are nephrotoxic

- Gentamicin, aminoglycosides, ….
- The first thing they hit when they get filtered from the glomerulus is the proximal tubule.
- Nephrotoxic tubular necrosis related to drugs just involves the proximal tubule. The basement membrane
remains intact so the prognosis in nephrotoxic tubular necrosis is better than ischemic ATN.
- The most common cause of nephrotoxic tubular necrosis is aminoglycosides. The second most common cause is
intravenous pyelograms (dye).
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- In the elderly, the GFR and the creatinine clearance are decreased. If you’re giving a drug that has no
nephrotoxicity and you give the dose of the drug in the same amount as you would for a young person (with a
normal GFR), you can kill them. You have to adjust the dose for elderly.

Pyelonephritis
- Lower urinary tract infections are more common in women b/c of a short urethra.
- Pyelonephritis is a systemic infection and an infection of your kidney proper.
- Vesicoureteral Junction
o Normally a muscle squeezes on the vesicoureteral junction so there’s no reflux of urine from the bladder
into the ureter; not all people have a normal vesicoureteral junction.
o If you get a bladder infection and the vesicoureteral junction is incompetent, you get vesicoureteral
reflux and infected urine can reflux (esp. when you’re micturating) up into ureters and you get an
ascending infection that can go all the way up into the kidneys.
o The mechanism of all urinary tract infections (urethritis, cystitis, ….) is ascending infection from
the beginning of the urethra due to an incompetent vesicouretereal junction.
- Acute cystitis vs. Pyelonephritis
o When you have acute cystitis, you have dysuria (painful urination), increased frequency, suprapubic pain,
but you don’t have fever. You don’t have flank pain. You don’t have WBC casts b/c they develop in the
renal tubule (not in the ureter or bladder).
o Fever, flank pain, and WBC casts mean there’s an acute pyelonephritis.

Chronic Pyelonephritis
- Constant and recurrent attacks of acute pyelonephritis can lead to chronic pyelonephritis
- With chronic pyelonephritis, you run the risk of hypertension and eventual renal failure related to it (in both
kidneys).
- Indicators of Chronic Pyelonephritis
o Scarred kidney
o Blunted calyxes (normally concave); it occurs where the scar is; You can see this with an intravenous
pyelogram

Acute drug-induced interstitial nephritis

- You get a fever when you take the drug, a rash, and oliguria; they may even have eosinophiluria (pathognomonic
for acute drug-induced interstitial nephritis).
- Possible drugs that can do this are lasix, all the penicillins (methicillin is the prototype of acute interstitial
nephritis related to drugs).
- It’s a combination of type I and type IV sensitivity; if your patient develops the signs and symptoms of acute
drug-induced interstitial nephritis, you should never give them that drug again.

Analgesic Nephropathy
- Ring sign:
o A pale infarct in the renal medulla; the renal papilla is missing.
o Other causes:
 A different cause is diabetic nephropathy b/c of ischemia.
 Acute pyelonephritis can also cause this b/c of abscess formation.
 Sickle cell trait and disease can do this as well but for different mechanisms.
- Due to a combination of acetaminophen plus aspirin over a long period of time.
- Pathogenesis
o Acetominophen produces free radicals and b/c of the poor circulation in the renal medulla, it does free
radical damage on the tubular cells in the medulla.
o Aspirin then blocks PGE2 (a vasodilator); the renal blood flow falls to the control of angiotensin II (a
vasoconstrictor of the efferent arteriole). \
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o The peritubular capillaries derive from the efferent arteriole so by vasoconstricting the efferent arteriole,
you also affect the peritubular capillaries that go around the collecting tubules in the renal medulla; you
get ischemia.
o Free radical damage and ischemia are what cause renal papillary necrosis.

Chronic Renal Failure

- You have a BUN/Creatinine ratio of 10:1 for more than three months.
- If both kidneys fail:
o We can’t excrete things normally; we would probably retain salt.
o We can’t make erythropoietin (we end up with normocytic anemia and a corrected reticulocyte count
less than 2%).
o The organic acids we normally eliminate will lead to metabolic acidosis (increased GAP).
 Because of the metabolic acidosis, bones try to buffer the acid and you could develop bone
disease (like osteoporosis).
o The proximal tubules are screwed up and 1-alpha hydroxylase doesn’t function properly (normally it
hydroxylates vitamin D); you get hypovitaminosis D.
 Because of the hypovitaminosis D you get hypocalcemia, hypophosphatemia, and you get
osteomalacia.
 Parathyroid glands try to compensate by increasing release of parathyroid hormone (secondary
hyperparathyroidism).

Hyaline Arteriolosclerosis
- Scenario
o A patient had essential hypertension for over 10 years and not well controlled. You get a kidney with a
cobblestone appearance = nephrosclerosis.
- It decreases blood flow, you get tubular atrophy (glomeruli are fibrosing off), and renal function goes down (can
go into renal failure).

Malignant Hypertension
- Scenario
o A patient with essential hypertension for over 10 years and not well controlled wakes up with a headache
and blurry vision. The person gets dizzy and has malaise. Blood pressure is 240/140. The patient shows
papilledema with flame hemorrhages, hard or soft exudates, grade IV hypertensive retinopathy, and BUN
creatinine ratio 80:8.
o He has malignant hypertension.
- The kidney has a “flea-bitten” appearance (petechiae visible on the surface of the kidney). There’s vessel
changes such as hyperplastic arteriolosclerosis (“onion skinning”) and the blood vessels are rupturing.
- Treatment is intravenous nitroprusside.

Infarction
- Kidney shows pale areas with depressions. The kidney, since it’s a solid organ, doesn’t have hemorrhagic
infarctions, but pale infarctions (coagulation necrosis).
- Scenario
o Kidney is pale and depressed. The patient also had an irregular irregular pulse. What would you see?
o Pale infarction with coagulation necrosis (infarcts in the kidney aren’t hemorrhagic but pale since the
kidney is a solid organ).
o The mechanism for the infarction was atrial fibrillation (irregular irregular pulse). Atrial fibrillation is
most dangerous for embolization.
o Don’t confuse with pyelonephritis.
o Pyelonephritis doesn’t have diffuse pale areas; it would have little white dots due to
microabscesses.
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Hydronephrosis
- An increased pressure pressing on the cortex and medulla; you get ischemia, kidney atrophy (compression
atrophy) and dilated renal pelvises and calyces.
- It’s similar to cystic fibrosis; ducts are filled with mucous and the pressures impact back on the glands (undergo
compression atrophy).
- The most common cause is a kidney stone.

Staghorn calculus (stone)

- The urine pH is alkaline and it smells like ammonia.
- A urease producer would have to be present (b/c of the ammonia smell). It most commonly is Proteus.
o The urease producers break urea down into ammonia (you get an alkaline pH).
- The stones are composed ofmagnesium ammonium phosphate.
- It only develops in patients with infections due to urease producers.
- These stones aren’t passed.
- Treatment is surgical extraction.

Sidenote: The treatment for Cryptococcus is amphotericin.

Tumors of the Kidney

- If you see a mass in the kidney and it’s a kid, it’s Wilm’s tumor.
- If you see a mass in the kidney and it’s an adult, it’s a renal adenocarcinoma.
- Renal Adenocarcinoma
o They’re derived from the proximal tubule and the most common cause is smoking.
o They make lots of ectopic hormones: erythropoietin and parathyroid-like hormones (produce
hypercalcemia).
o They invade the renal vein.
o They’re very clear cells (full of glycogen).
- Wilm’s Tumor
o Scenario
 Kid has a flank mass and hypertension.
 He has Wilm’s Tumor. The hypertension is due to the production of renin.
o It’s usually unilateral and produces a flank mass usually.
o The histology shows a duplication of the embryogenesis of a kidney.
o It likes to metastasize to the lung.
o Certain types are autosomal dominant (may involve chromosome 11).
o They have 2 physical diagnostic findings consistent on exams:
 Aniridia – an absent iris.
 Hemihypertrophy of an extremity – one extremity will be bigger than the other.

Lower and Upper Urinary Tract Infections

- In urine, you can see neutrophils, RBCs, and bacteria (odds are E. coli).
- Dipstick analysis
o Picks up neutrophils, RBCs, and bacteria.
o The dipstick has a portion that picks up blood.
 When you can see blood in your urine, it’s called hemorrhagic cystitis (most of the time it’s E.
coli, but sometimes it’s adenovirus).
o The dipstick has leukocyte esterase to measure the enzyme in leukocytes.
o The dipstick has a section for nitrites (E. coli is a nitrate reducer).
 Most urinary pathogens are nitrate reducers (convert nitrate to nitrite).
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- If you have a patient that has dysuria, increased frequency, suprapubic pain, and a urine sediment showing
neutrophils, RBCs, and bacteria or dipstick findings of hematuria, leukocyte esterase positive, nitrate positive, it’s
a urinary tract infection.
- Lower vs. Upper Urinary Tract Infection
o If the patient has fever, flank pain, or WBCs = upper. If none of these are present, then it’s lower.
o Scenario
 A patient with urine increased frequency and neutrophils in the urine. No bacteria are present;
culture is negative for bacteria. The patient does have dysuria and positive leukocyte esterase,
nitrite is negative. Standard urine culture. The person is sexually active. What is it?
 Chlamydia
• Causes non-specific urethritis in men and called the acute urethral syndrome in women.
 Normal urine cultures don’t pick up Chlamydia trachomatis; it’s the most common sexually
transmitted disease.
o Sterile pyuria means bacteria isn’t present but neutrophils are. Routine bacterial cultures are negative.
One cause of sterile pyuria is a Chlamydial infection but another is tuberculosis (the most common
organ that miliary TB goes to is the kidney).

Transitional Cell Carcinoma

- Papillary lesion in the bladder.
- The most common cause of transitional cell carcinoma is smoking. It can also be caused by aniline dye.
- The chemotherapy agent used in treating Wegener’s is cyclophosphamide; it can cause hemorrhagic cystitis (can
be prevented with mesna). Hemorrhagic cystitis increases the risk for bladder cancer.

Penis
- Embryology
o Hypospadia – opening on the ventral surface due to failure of closure of the urethral folds.
o Epispadia – opening on the dorsal surface. It’s due to a defect in a genital tubercle.
- Perines disease – the penis goes in different directions
- Priapism
o You have a permanent erection and is common in sickle cell disease (RBCs get trapped in the vascular
channels). It is very painful.
- Cancer
o The most common cancer for penis is squamous.
o The most common reason is lack of circumcision (that has poor hygiene); the person has smegma (that’s
carcinogenic).

Testicles
- Cryptorchidism
o Undescended testicles.
o Phases of descent
 First phase is a transabdominal migration (possible by Mullerian inhibitory factor).
 Second phase is androgen dependent (testosterone and dihydrotestosterone).
o The testes have to descend into the scrotal sac by a minimum of 2 years of age b/c of the risk of
seminomas.
 Even if it did get down to the scrotal sac before 2 years, you’re still at risk.
 If you remove a pathological testicle, the normal testicle is at risk as well; the testicle has to be
examined once a year to make sure seminoma (a germ cell tumor) doesn’t develop.
o Analogy:
 In Turner’s syndrome, the person is infertile. They have menopause before they have menarchy
b/c by 2 y/o they have no follicles in their ovaries (streak gonad).
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 Like cryptorchidism predisposes to seminomas, so does the streak gonad predispose to a germ
cell tumor (except in a woman it’s not called seminoma but dysgerminoma). This is why girls
with Turner’s syndrome have both of their ovaries surgically removed.
- Epididymitis
o Less than 35, it’s caused by sexually transmitted diseases (Neisseria and Gonorrhorrea).
o Greater than 35, Pseudomonas and E. coli.
- Varicocele
o Enlargement of the veins of the spermatic cord; it commonly occurs above the left testicle.
o Left side predisposition
 It’s located on the left side because the spermatic vein on the left is connected to the left renal
vein; the spermatic vein on the right is connected to the inferior vena cava.
 The pressures tend to be greater on the left and serve as predisposition to a varicocele on the left.
o It can produce increased heat and is one of the most common causes of male infertility.
o Scenario
 What would happen if you blocked the left renal vein?
 You’d develop a varicocele; it would increase the pressure in the spermatic vein and you’d get a
varicocele.
- Torsion (of the spermatic chord)
o When there’s a torsion of the spermatic chord, it shortens it (the testicle goes up a little bit into the
inguinal canal).
o It hurts and you lose your cremasteric reflex (if you scratch a scrotum, it won’t contract).
- Hydrocele
o Is persistence of the tunica vaginalis.
o When you have a big scrotum, you transilluminate. If it transilluminates, it’s a hydrocele; if it doesn’t,
it’s cancer.
o The differential diagnosis for a painless enlargement of the testicle is only cancer (why biopsies aren’t
even done, they’re simply removed).
- Seminoma
o The most common cancer of the testicle.
o It has the best prognosis.
o It is the exact same as a dysgerminoma (in a female).
o They can melt with radiation.
o They have no tumor markers.
o They metastasize to your paraortic lymph nodes (b/c it came from the abdomen and will go back).
- Yolk Sac Tumor
o The most common testicular tumor in a kid.
o The tumor marker is alpha-fetoprotein.
- Choriocarcinoma
o The worst carcinoma you can get in a man. It is associated with HCG.
o Scenario
 25 y/o man has unilateral gynecomastia and dyspnea. Chest x-ray reveals multiple nodular
masses in the lung. Where is the primary tumor?
 In the testicle (choriocarcinoma).
 Gynecomastia comes from the beta-HCG; it’s a luteinizing hormone analog (it acts just like
lutein hormone) and therefore stimulates progesterone in the male which does increase duct
growth and breast tissue.
- Metastases
o If an older man had testicular cancer, it would most likely be malignant lymphoma (as metastasis).
Leukemias and especially lymphomas commonly metastasize to the testes.

Prostate
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- Hyperplasia occurs in the periurethral portion of the prostate gland. This is why you get dribbling and urinary
retention as the most common symptom.
- Prostate cancer is in the periphery of the prostate gland. If you press on the prostate with your finger and it
feels hard, that’s prostate cancer.
- Scenario
o A 75 y/o man has urinary retention and his bladder is enlarged. He has dribbling, …. What is the most
likely cause?
o NOT PROSTATE CANCER; for prostate cancer to cause this, it would have had to invade through the
prostate gland to around the urethral or the bladder neck.
o This is prostate hyperplasia b/c it already is around the urethra; this is the most common cause.
- Dihydrotestosterone (not testosterone) is responsible for prostate hyperplasia and prostate cancer. In
embryogenesis, it was DHT that fused the labia together to form a scrotum, extended the clitoris to form a penis,
and formed the prostate glands.
- If you use a 5-alpha reductase inhibitor (a treatment for cancer), it would decrease dihydrotestosterone. The
testosterone is increased and you get hair on your head.
- Prostate cancer is a dihydrotestosterone dependent cancer. It is the most common cancer in men and likes to
metastasize to the bone where it produces osteoblastic metastasis.

Gynecology 1

Virilization and Hirsutism

- Virilization is hirsutism plus male secondary sex characteristics (acne, deeper voice, clitoromegaly [the
pathognomonic sign]).
- Hirsutism
o Pathogenesis
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 Testosterone (free testosterone, dihydrotestosterone) is predominantly synthesized in the ovary

(some is synthesized in the adrenal).
 DHEA sulfate (an androgen) is 95% from the adrenal.
o If a person has hirsutism, you only have to get two tests: testosterone level and DHEA sulfate.
 If it’s predominantly testosterone that’s elevated, it comes from the ovary (most common); if
DHEA sulfate is predominantly elevated, it comes from the adrenal (you have hydroxylase
deficiencies).
o Possible causes of increased testosterone in the ovary
 Polycystic ovarian syndrome is a common cause of elevated testosterone in the ovaries.
 Sometimes the increase in testosterone is due to stromal hyperplasia.

Polycystic Ovarian Syndrome

- It’s a hypothalamic pituitary abnormality where FSH is suppressed and luteinizing hormone (LH) is
increased.
- Luteinizing Hormone (LH)
o Luteinizing hormone in a woman is responsible for hormone synthesis around the developing follicle of
the month (the theca interna).
o In the theca interna during the proliferative phase of the cycle, what is predominantly synthesized are
the 17-ketosteroid (DHEA and androstenedione [converted by oxidoreductase into testosterone]).
o The testosterone then goes across the membrane of the developing follicle into the granulosa cells
(there’s aromatase that FSH put in there).
o Aromatase in the granulosa cell converts the testosterone into estradiol; this is how the woman gets
her estradiol.
o Luteinizing hormone is responsible for the synthesis of 17-ketosteroids and testosterone in the ovaries.
- Obesity and Estrogens
o Obesity is also associated with polycystic ovarian syndrome.
o Aromatase can be found in adipose tissue.
o Sex hormones like testosterone and androstenedione can be converted into estrogens in these patients;
androstenedione is aromatized into estrone (a weak estrogen) and testosterone is aromatized into estradiol
(the strong estrogen).
o The increased estrogens can predispose endometrial hyperplasia and endometrial carcinoma.
- These women have a combination of increased androgens and increased estrogens.
- Repetitive Cycle
o Theincreased estrogens maintain the suppression of FSH (estrogens have a negative feedback on FSH
and a positive one on LH); this causes the cycle to repeat itself.
o The cycle can be broken by giving a birth control pill; the progestins in it block FSH.
- Pathogenesis of Cysts
o The cysts in the ovary are due to FSH.
o If FSH is constantly suppressed, then the follicle degenerates and it leaves behind a cystic space where
the follicle used to be.

Menstrual dysfunction
- Dysmenorrhia – painful menses.
o Primary
 The most common cause is having too much PGF2 (a prostaglandin that increases contracture of
the uterine musculature).
o Secondary
 Most common cause is endometriosis.
- Dysfunctional Uterine Bleeding
o It’s not a bleeding abnormality related to an organic or anatomical cause.
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o Is a hormone imbalance that’s causing an abnormality in bleeding.

o Three causes:
 Anovulatorycycles
• It’s the most common cause of abnormal bleeding in a young woman from
menarchy to ~ 20 y/o.
• There’s a persistent estrogen stimulation on the mucosa and not enough
progesterone stimulation.
o They develop a little hyperplasia. There’s a buildup of the mucosa as the month
progresses and then when the stroma can’t hold it, it sloughs off.
 The woman can ovulate and have problems with bleeding
• Inadequate luteal phase
• Irregular shedding of the endometrium
- Amenorrhea
o Due to hypothalamus-pituitary, ovarian, or end organ problem
 Hypothalamic-pituitary
• The hypothalamus may not be putting out gonadotropin releasing hormone (GnRH). The
pituitary may not be putting out FSH and LH?
 Ovarian
• Maybe it’s not making enough estrogen.
 End organ Dysfunction
• Maybe she doesn’t have a vagina or an imperforated hymen (there’s blood behind it).
• She could have cervical stenosis or DES exposure. These are less common causes.
• Asherman’s syndrome – secondary amenorrhea due to repeated endometrial scarring
(repeated D&C [dilatation and curettage]). They scrape away the stratum basalis.
o Differentiating via LH and FSH
 If you have a hypothalamic or pituitary problem, the FSH and LH would be low.
 If you had a primary ovarian problem, LH and FSH would be high.
 If you had an end organ defect, LH and FSH would be normal.
o The first workup of any patient with amenorrhea is a pregnancy test.

Turner’s Syndrome
- It’s a very common cause of primary amenorrhea
- The majority are XO (not XX; they don’t have a barr body).
- They have defects in lymphatics.
o You would see defects at birth such as swelling of the hand and feet (lymphedema).
o The webbed neck is related to lymphatic abnormality.
 They get cystic hydromas. These are dilated lymphatics in the neck area and they fill up with
lymphatic fluid and stretch the skin.
- Other associated signs and symptoms
o The fourth metacarpal is commonly underdeveloped (instead of a bump, they have a dimple: the knuckle,
knuckle, dimple, knuckle).
 Knuckle, knuckle, dimple, dimple is pseudohypoparathyroidism.
o They have preductal coarctation.
o They don’t have mental retardation.
o They have menopause before menarchy before two years of age.
o All the follicles in their ovaries are gone (streak gonad); it’s susceptible to dysgerminomas.
- They can be mosaics: can be XOXX (or XOXY) and there’s a possibility they can be fertile.

Adenomyosis vs. Endometriosis (both deal with glands and stroma)

- Adenomyosis is glands and stroma w/in the myometrium.
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oIt’s a common cause for dysmenorrhea, dyspareunia (pain in labia, vagina, or pelvis after or during
intercourse), amenorrhagea, hysterectomy.
o It does not predispose to cancer.
- Endometriosis is functioning gland and stroma outside the confines of the uterus (the myometrium is in there).
o Most common location is ovary. It produces bleeding in the ovary (aka “chocolate cysts” or
endometriomas [not to be confused as a tumor]).
o It can be in the tube or the pouch of Douglas (rectouterine pouch).
o A question to diagnose endometriosis is:
 When you’re having period and you go to the bathroom, does it hurt when you defecate? When
your period’s gone?
 If it hurts when she defecates and when goes away when her period’s gone, she has
endometriosis.
 They have bleeding endometrial implants in the pouch of Douglas (the pouch between the
anterior rectal wall and the posterior uterine wall) so the rectum when it’s filled up with stools is
going to be stretching the pouch and it causes pain.
o Theories for endometriosis
 Reverse menses
• The endometrial tissue when it’s being sloughed up might reverse up the fallopian tubes
and spread out in different places and implant itself.
 Coelomic metaplasia
• The surface epithelium in the peritoneum could metaplastically make endometrium
mucosa.

Endometrial Hyperplasia and Cancer

- Due to unopposed estrogen (no progesterone effect); persistent estrogen stimulation on the mucosa and not
enough progesterone stimulation is also involved in anovulatory cycles (a common cause of abnormal bleeding in
young women).
- You run the risk for endometrial cancer.
- The most common cause of endometrial cancer is endometrial hyperplasia (unopposed estrogen).
o It occurs in early menarche (as opposed to late menarche). The earlier woman has estrogen going.
o It occurs in late menopause (b/c there’s more estrogen exposure).
o It prefers obesity b/c there’s more aromatase in the tissues.
- Diabetes isn’t really a risk factor for endometrial cancer; what really is the risk factor is obesity (80% of type II
diabetics are obese).
- Cancers in Age brackets
o Endometrial is the most common, followed by ovarian.
o 45 = cervical
o 55 = endometrial (post-menopausal)
 Any woman that has been in menopause for over a year and then has re-bleeding has endometrial
cancer until proven otherwise.
 First step in management is endometrial biopsy.
o 65 = ovarian

Leiomyoma
- The most common benign tumor in a woman.
- Leiomyosarcoma differs by a mitosis count.
o It’s the most common sarcoma of the uterus.
o It’s a big and bulky tumor.
- They’re not a precursor for leiomyosarcoma.

Ectopic Pregnancy
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- Scenario
o Young lady who has a sudden onset of severe lower abdominal pain.
o Think about doing a pregnancy test (beta-HCG) to rule out an ectopic pregnancy.

Ovarian Masses
- Surface derived: they’re derived from the lining of the ovary.
- Germ-cell: Same as the ones men get (in women, they’re called dysgerminomas); yolk-sac tumors, teratomas, …
- Sex chords stromal tumors
o Are uncommon, but they can make estrogens (granulose cell tumors).
o A woman can have hyperestrinism and bleeding and endometrial cancer.
o Some make androgens (sertoli-leydig tumors). It’s associated with hirsutism and virilism.
- Guys, only share germ-cell tumors with women.
- The most common cause of an ovarian mass in a young woman is a follicular cyst.
o Rupture of the cyst is a very common cause of sudden onset of pain in a woman.
o The fluid from the cyst can lead to peritonitis.
o When it occurs on the right side, it can be confused with a number of things (appendicitis, ruptured
ectopic, pelvic inflammatory disease, follicular cyst, …).
o Ultrasound and beta-HCG would help in diagnosing.
- Under 35 y/o, most ovarian masses are benign. Over 35 y/o most ovarian masses have a greater potential of
being malignant.
- Surface Derived
o Overallmost common ovarian tumors; they’re also the most common benign and malignant
tumors.
o Serous cystadenoma is benign.
o Serous cystadenocarcinoma is malignant.
 Have Psammoma bodies (bluish concretions); they represent apoptosis of tumor cells replaced
dystrophic calcification.
• Psamomma bodies are also present in papillary carcinoma of the thyroid and
meningiomas.
 These kind of tumors can be identified by CA-125.
o Scenario
 65 y/o woman who got bilateral ovarian enlargement. What does she have?
 She has serous cystadenocarcinoma.
o The most commonly bilateral.
- Any woman over 55 who has palpable ovaries on either side is cancer till proven otherwise.
- Cystic Teratoma
o It’s the most common overall germ cell tumor.
o It’s usually benign.
o They can make thyroid hormones (struma ovarii).
- Fibromas
o The most common sex chord tumors.
o They’re benign.
o They cause Meigs’ syndrome: an ovarian fibroma (benign), ascites, and a right-sided pleural effusion. If
you take the tumor out, it goes away.
- Granulosa Cell Tumor of Ovary
o Low-grade malignant tumor
o It normally aromatizes androgens and estrogens.
o It would more than likely be estrogen producing.
- Krukenberg’s tumor
o Signet ring cells indicate metastasis from another place (the stomach).
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o There’s no primary ovarian cancer that has signet rings.

- Chorionic Villus
o The outside layer is called syncytiotrophoblast (make hormones such as beta-HCG and human placental
lactogen [“growth hormone of pregnancy”])
o The clear cells underneath are the cytotrophoblasts.
o Vessels eventually coalesce into the umbilical vein and have the highest oxygen content.
o Neoplasms
 Hydatidiform mole; can be complete or partial
• Complete are 46 XX (both X chromosomes come from the father [androgenesis])
• Partial mole is a triploid (have 69 chromosomes) and can have a fetus present in them.
• The complete moles have the greater propensity for becoming a choriocarcinoma.
• They’re benign tumors of the chorionic villus.
 Choriocarcinoma
• Choriocarcinomas are a malignancy of the trophoblastic tissue.
• You do not see chorionic villi in a choriocarcinoma, only trophoblastic tissue.
• It tends to go to the lungs.
• Responds very well to chemotherapy (even when metastases has occurred).

Breast Lesions
- Locations of lesions
o Nipple = Paget’s disease of the breast
o Lactiferous duct = intraductal papilloma (the most common cause of a bloody nipple discharge in a
woman under 50).
o Major ducts in the breast = most of the breast cancers
o Terminal lobules (where breast milk is normally made) = lobular carcinoma; it’s bilateral (like serous
tumors in the ovary)
 Mammography doesn’t pick up lobular cancers
- Mass of the breast
o Fibrocystic change is the most common cause of a mass of the breast in a woman under 50.
 Are lumpy bumpy and kind of painful; gets worst as cycle progresses and dwindles down.
They’re hormone sensitive.
o Infiltrating ductal (not intraductal) carcinoma is the most common cause of a mass in a breast of a
woman over 50.
 It means we’re not picking up the cancer early enough by mammography and picking up in the
intraductal phase.
o Fibroadenoma
 Scenario
• Woman 35 y/o has a movable mass in the breast. It gets bigger as the cycle progresses.
What is it?
• Fibroadenoma
 The neoplastic component is the stroma, not the glands. As it grows, it compresses the ducts
(they have slit-like spaces).
o Ductal Hyperplasia
 Can’t see it.
 Is the precursor lesion for cancers.
 They’re the estrogen-sensitive epithelial cells. The epithelial cells lining the ducts are estrogen
sensitive (like the glands in the endometrium are also estrogen sensitive).
o Sclerosing adenosis
 In the terminal lobules.
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 Confused with invasive cancer.

o Breast cancer
 When they invade stroma, they elicit a fibroblastic and elastic tissue response to it; it makes it
hard and palpable.
 Scenario
• A woman over 50 has a painless, palpable mass. What is it?
• It’s cancer. If it’s painful and they’re under 50, it’s rarely cancer.
 The outer quadrants of the breasts are the most common location b/c that’s where most breast
tissue is. The second most common site is around the areola.
 A stellate appearing whitish mass is classic for invasive cancer. On a mammography it would
appear as a density and spicules coming out (it’s probably fine calcification); it’s highly
predictive for cancer.
 First step in management of a palpable mass in the breast is fine needle aspiration (not
ultrasound or thermography, …). With this you can make a diagnosis and tell whether it’s solid
or cystic.
• This is also the first step in management of a cold nodule in the thyroid.
 Intraductal cancer
• Has a net-like arrangement. Called “comedocarcinoma” b/c it has a lot of junk in it.
• Has erb-B2 oncogene
 Invasive Cancer
• Tumor cells invade stroma.
• Invasive lobular cancer
o Have an “Indian-file” appearance; it’s a sign of invasive lobular cancer (you
can also see it in infiltrating ductal.
 Paget’s disease
• Whenever you see a rash on the nipple = Paget’s disease.
• It’s a cancer of the duct underneath that has spread up into the skin and produced a rash.
• On biopsy, it looks like Paget’s in the vulva.
 Inflammatory Carcinoma
• The worst cancer.
• Peau d’orange
o The skin gets dimpled because the lymphatics are plugged with cancer and the
lymphatic fluid has leaked out. The ligaments attached to the skin are still there
but you increase the fluid in interstitium (as it expands out, it dimples looking
like an orange = peau d’orange).
 Lobular Carcinoma
• The most common cancer of the terminal lobules (the end of the ducts).
• It’s known for bilaterality.
 Post-radical mastectomy
• Lymphedema can occur.
• In a modified mastectomy, you remove the entire breast (including nipple). You leave
the pectoralis major; you do an anxillar resection and usually take the pectoralis minor
too.
• Most common complication is the winged scapula (you cut the long thoracic nerve).
 Lumpectomy??
• Lumpectomy removes the underlying tumor. A few nodes from the lower axillary chain
are taken (use for staging). This is followed by radiation.
• It has the same prognosis as a radical mastectomy.
• This is good for breast conservation.
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• If it’s too big for tumors, then you have to do a modified radical.
 ERA and PRA
• Estrogen receptor and progesterone receptor assay
• There’s a relationship between the presence of estrogen and its receptor synthesis.
o If estrogen was abundant, the receptors would be down regulated. (Why women
who are young and in the reproductive period of their life, when they have a
breast cancer, they’re usually ERA and PRA negative.)
o If you’re post-menopausal (estrogen levels are a bit lower) then you get up-
regulation of your receptors. This is why most post-menopausal women are
ERA and PRA positive.
• Analysis and Tamoxifen
o If you have a person that’s ERA and PRA positive, it means that the tumor is
responding to estrogen.
 You need to take away the estrogen b/c it’s feeding the tumor.
o Tamoxifen
 You decrease the tumor’s response to estrogen by giving them
tamoxifen (you can’t give estrogen to a woman who is ERA and PRA
positive).
 Tamoxifen is a weak estrogen that hooks into the receptors on the breast
tumor so that the normal estrogen in a woman can’t get into that and feed
the tumor.
 Tamoxifen then works as a receptor blocker.
 Symptoms associated with it are menopausal type symptoms after you’re
on it and it has estrogen so you have the risk of endometrial cancer.
 A benefit of tamoxifen in a post-menopausal woman with an ERA
positive tumor is that it does prevent osteoporosis.
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Endocrinology1

Nomenclature (primary, secondary, and tertiary)

- Hashimoto’s thyroiditis with destruction of thyroid gland = primaryhypothyroidism (the gland is the
cause of the hormone decrease)
- Hypopituitarism and hypothyroidism = secondary hypothyroidism (you don’t have TSH to stimulate
gland
- If you had hypothalamic disease (sarcoidosis destroying thyroid releasing hormone) then you have
tertiary
- Hypoparathyroidism
o If you had an adenoma on your parathyroid gland making parathyroid hormone (hypercalcemia) it
would be primary hyperparathyroidism.
o If you had hypocalcemia (Vit D. deficiency …. ) and it asked the parathyroid to increase the calcium
level and it underwent hyperplasia = secondary hyperparathyroidism
o If after long period of time that parathyroidism is making hypercalcemia, then it’s called tertiary
hyperparathyroidism (rare).
Overactivity/Underactivity of the gland
- Stimulation tests
o If you have an underactive test, you would probably do a stimulation test to see if it can get going
again;
o If you have an overactive gland, you would try a suppression test to see if you can suppress it.
o Most of the time, the things that cause overactivity, we can’t suppress them. Two only notable
exceptions where we can (both deal with tumors in the pituitary gland which are very common:
 Prolactinoma – can be suppressed; it can prevent the tumor from making prolactin; The
treatment – bromocriptine (a dopamine analog; it’s even used in treating parkinson’s disease
because that’s what’s missing) is what suppresses it. Why women don’t have galactorrea is
they have dopamine inhibiting prolactin.
 Pituitary Cushing’s – a benign tumor in the pituitary gland making too much ACTH; it can
be suppressed by a high dose of dexamethasone.
o ACTH Stimulation Test
 Patient with hypocortisolism; Do an ACTH stimulation test. IV drip with ACTH and let it
drip for a couple of days; collecting urine for 17 hydroxycorticoids (the metabolic end
product of cortisol; 11-deoxycortisol and cortisol)
• If nothing happens (it never increases), it was hypocortisolism due to Addison’s
disease- the gland was destroyed
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• Say after 2 or 3 days we start seeing an increase in 17 hydroxycorticoids; the cause

of hypercorticolism is hypopituitarism (it was atrophic because it wasn’t being
stimulated by ACTH but when you gave it ACTH over a period of time it was able to
regain its function again and so you were able to distinguish by that simple test what
the cause of hypocorticolism was).
o ACTH Test
 If you have Addison’s causing hypercorticolism, ACTH would be high; if it
washypopituitarism, ACTH would be low.
Hypopituitarism
- Pituitary Adenoma
o The most common cause in adults is a pituitary adenoma. Sella turcica is in the sphenoid bone
(surgery is transsphenoidal surgery).
 If it’s non-functioning, it basically over time destroyed all the normal pituitary as it
grows; you end up with hypopituitarism.
- Sheehan’s Post-Partum Necrosis
o If you have a pregnant woman and she has a ruptured placenta and goes into hypovolemic shock but
you get her out of it; she’s doing fine feeding her baby breast milk and her breast milk stops, she has
Sheehan’s post-partum necrosis.
o It means she’s infarcted her pituitary (coagulation necrosis with residual pituitarism; the
mechanism is ischemic necrosis). [Liquifaction necrosis occurs in the brain, but not the
pituitary.]
o Mechanism
 The mechanism is because if you’re pregnant right now your pituitary gland is 2 times the
normal size (because a lot of prolactin is being synthesized).
o Sidenote:
 A woman that’s pregnant doesn’t have galactorrhea because estrogen and progesterone
inhibit it from being released; the moment you give birth (inhibitory effect is released) you
start having galactorrhea and start expressing milk.
o Sheehan’s is the second-most common cause of hypopituitarism in an adult. The most common
is non-functioning pituitary adenoma.
o For a child the most common is craniophryngioma (of Rathke’s pouch origin).
 Rathke’s Pouch
• Rathke’s pouch is part of the embryological development of the pituitary gland.
• When little pieces of Rathke’s pouch remain, it can become neoplastically
transformed into a craniopharyngioma; it’s not a malignant tumor but benign).
 Craniopharyngioma is most commonly suprasella (above the sella). It goes down and
eventually destroys the pituitary. It likes to go forward and bumps into the optic chiasm
(producing bitemporal hemianopsia).
• Case may present as a kid with headaches and visual field defects (or may show a
schematic showing defect).
- When you have a tumor expanding in the sella turcica, the different releasing factors or hormones
decrease in a certain succession:
o 1st are the gonadotropins (FSH and LH)
 Women would have amenorrhea (secondary amenorrhea).
 Men would have impotence (impotence is to a male as amenorrhea is to a female);
impotence is failure to sustain an erection during sexual intercourse.
o 2nd is Growth Hormone
 Growth Hormone has two functions
• It increases amino acid uptake and is involved in gluconeogenesis.
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• Insulin Growth Factor 1 (IGF-1 aka somatomedin) (present in the liver) is involved
in producing bone growth and soft tissue growth.
• Growth Hormone when it’s released has to signal to liver to release IGF-1 to cause
the growth of bones (linear) and soft tissue.
 Symptoms of Deficiency
• Adult
o An adult with growth hormone deficiency will not get smaller.
o You will start losing muscle mass and they’re going to have fasting
hypoglycemia (growth hormone was normally gluconeogenic).
• Child
o You’d see a pituitary dwarfism. It’s an exampled of hypoplasia because of
lack of hormone; it’s an incomplete development of something (pituitary
dwarfism is an incompletely developed child; the child looks normal but
everything is smaller)
 Best stimulation test to see if you’re GH or IGF-1 deficient is sleep.
• Growth Hormone comes out at about 5 a.m. when we sleep.
• All we have to do is collect blood at 5 a.m. in the morning and see if IGF-1 is
increased (better test than GH).
 Arginine and Histidine are essential amino acids for normal growth of a child (they
stimulate growth hormone); why weight lifters go to store and get arginine supplements
 Sleep is the best and then arginine stimulation test is the second best
o 3rd hormone that goes is TSH
 Manifest as hypothyroidism (Low TSH and Low T4)…cold intolerance, fatigue, brittle hair,
etc.
o 4th is ACTH
 Hypocortisolism: is like growth hormone. It would manifest as fatigue with a low cortisol
level (cortisol is also gluconeogenic – fasting hypoglycemia)
o 5th (last) is Prolactin
o Don’t need to know order of succession but do need to know manifestations if absent.

Diabetes Insipidus
- How to distinguish it:
o Central vs. Nephrogenic
 Central = lacking ADH
• It’s common cause is a car accident (stalk is staying still and severed).
o One of first things that goes is ADH because it is made in the supraoptic
and paraventricular nucleus of hypothalamus.
o In the same nerve that it’s made in, it goes down the axon through stalk and
is eventually stored in the posterior pituitary (same big nerve).
• Not only is ADH deficient but releasing factors made in the hypothalamus that
stimulate the pituitary are also deficient (you’ll be hypopituiary too).
o Initially, however, you’ll have signs and symptoms of diabetes insipidus
(polyuria and thirst).
 Nephrogenic = have ADH but it doesn’t work on the collecting tubule to make it
permeable to free water.
- In Diabetes Insipidus, you’re missing ADH or it doesn’t work.
- You’re missing water (not salt, pure water).
o You’re constantly diluting and never going to be able to concentrate urine (opposite of inappropriate
ADH where you constantly concentrate).
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o When sodium goes up, that equates with an increase in plasma osmolality (because most of the
plasma osmolality is sodium).
o Other causes or differential diagnosis (diarrhea)
 Diabetes mellitus: mechanism is osmotic diarresis
 Polydypsia (drinking too much water) is usually a psychological problem
 Hypercalcemia – produces polyuria
o To test, restrict water
 Normal person with water restriction, plasma osmolality goes up to 292 (upper limit of
normal)
• A 750 urine osmolality means it’s concentrating; water deprivation should be
concentrating urine (getting water out to add back to ECF and bring serum sodium
into normal range)
 319 and 312 osmolality in plasma is elevated (>292) = hypernatremia;
• Urine osmol 110 (normal) and 98; both have diabetes insipidus (can’t be anything
else)
• To know which is which is give them ADH and see what happens to urine
osmolality
o If it increases greater than 50% from the baseline, then it’s central
o If it’s less than 50% it’s nephrogenic.

Acromegaly
- Cheapest way of screening for acromegaly is comparing old and recent picture.
- In an adult with excess growth hormone (and excess IGF) you don’t get taller because the epiphyses are
fused but you can go wider (esp. frontal bones).
o Frontal sinuses, hands, feet, and every organ gets bigger than it should (including your heart which
produces a cardiomyopathy and that’s how they die).
Gigantism:
- Occurs in a kid whose epiphyses have not fused; excess of growth hormone and IGF you have an
increase in linear growth
Galactorrhea
- Men don’t get it because they don’t have enough terminal lobules to get it.
- Many drugs can stimulate prolactin synthesis and release: birth control pills, hydralizine, calcium
channel blockers, different kinds of psychotropic drugs.
- The main cause is primary hypothyroidism (have to get a TSH)
o Because if you have Hashimoto’s, not only is TSH increased, but also the releasing hormones
increase (TRH) and TRHis actually used as a stimulation test for prolactin.
- When everything else is negative, and you have high prolactin, then the diagnosis is prolactinoma.
o Any prolactin level over 200 is always a prolactinoma; there’s no drug that can do that.
- Common cause for galactorrhea in women is a bra rubbing on the nipple (tactile stimulation of the
nipple will cause breast milk).
- Patients that have a prolactinoma develop secondary amenorrhea because prolactin inhibits
gonadotropin-releasing hormones (think of it as a cheap birth control pill during breast-feeding)

Thyroid studies
- Don’t have to know resin P3 uptake to diagnose these diseases. Don’t need to know 3T4 indexes
- Only three things you need to know: T4, TSH (most important), and I131 uptake
o If TSH is normal, your thyroid is normal
o If TSH is decreased, you can hyperthyroidism or hypopituitarism
o If TSH is increased, then you have high primary hypothyroidism
- Thyroxine-binding globulin (TBG)
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o Is the binding protein for thyroid hormone.

 Other binding proteins
• The binding protein for cortisol is transcortin.
• The binding protein for calcium is albumin.
• The binding protein for iron is transferring.
• The binding protein for copper is ceruloplasmin; binding sites are roughly occupied
about 30% by whatever it has
o There’s nine binding sites on TBG; when we measure total T4 it’s bound and free (the part that’s
metabolically active – gets diverted into T3).
- Birth Control Pill
o If you’re on a birth control pill (increase in estrogen), TBG (increased synthesis) and
transcortin increase
 It’s going to be 1/3 occupied (comes from free hormone loss) but because everything is in
equilibrium, thyroid gland senses it’s gone down a little bit and it replaces those three
immediately; Free T4 level has not altered at all, TSH is normal, but T4 is going to be
increased
o Summary is if you have an increase in T4 with a normal TSH = you’re on estrogen. Same goes
for cortisol.
- Steroids (anabolic steroids)
o Steroids break down proteins that normally would be used for making other things to build up to put
into muscle.
 Target proteins are binding proteins (TBG in this case is decreased) because the amino
acids that would have been used to make it are used to go into muscle.
o Total is decreased but free hormone level is normal (TSH is also normal).
- Review
o Low T4 (due to low TBG) and normal TSH = Anabolics
o Remember, woman with high T4 (due to high TBG) and normal TSH = estrogen
o High T4 and low TSH = hyperthyroidism
o Low T4 and increased TSH = primary hypothyroidism
- I131 uptake
o Radioactive test; remember thyroid hormone is tyrosine with iodine (you can also get melanin,
dopamine, and catecholamines)
o Hyperthyroidism
 If we had hyperthyroidism because of an overactive gland (Graves’ disease) we would be
making more thyroid hormone and would need more iodine to do that.
 If a person was given radioactive Iodine, there would be an increase uptake in the
overactive gland.
o Excess Intake of Thyroid Hormone
 If one was taking excess thyroid hormone (to lose weight probably), TSH would be
suppressed and the gland atrophies (there would be a decrease uptake); Think of weight
loss clinic – they give cow thyroid hormones.
- Midline cyst = thyroglossal cyst
o Thyroid gland originates at the base of the tongue and migrates down the midline to current location.
o A cyst in the antero-lateral portion of the neck = brachial cleft (know everyone of them)
- Thyroiditis (inflammation of the thyroid)
o Hashimoto’s is the most important one (De Quervain’s doesn’t come up)
- Graves’
o Exophthalmos is unique (pathognomonic) to Graves’.
 Reason is excess glycosaminoglycans deposited in the orbital fat is pushing the eye out.
o All people who have Graves’ have apathetic Graves’
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o All people with Graves’ disease have heart problems with atrial fibrillation (they get heart
manifestations more than anything else); any patient with atrial fibrillation you absolutely must get a
TSH to rule out Graves’ disease
o Treatment
 Initial treatment of Graves’ disease is beta blocker (to block the adrenergic response).
Then you give propyldiuracyl to stop the gland from making it.
 You can stop all the symptoms except sweating with a Beta-Blocker.
- Hyperthyroidism
o Signs and symptoms: heat intolerance, sinus tachycardia, sometimes atrial fibrillation, brisk reflexes,
diarrhea, systolic hypertension, and potentially can have hypercalcemia (mechanism is increased
bone turnover)
o All the symptoms of hyperthyroidism are adrenergic (catecholamine things) because T4 increases
the synthesis of beta receptors (catecholamines are the cousin of thyroid hormone and have the
same tyrosine origin)
o Laboratory findings: T4 is high, TSH is low, I131 uptake is high
- Hypothyroidism
o Look at periorbital area because there’s always puffiness (glycosaminoglycans)

Endocrinology2

Hypothyroidism
- Periorbital puffiness (edema), hoarse throat, pretibial myxedema (all have an increase in
glycosaminoglycan deposition); remember mitral valve prolapse also has an increase in
glycosaminoglycan (increase in dermatan sulfate responsible for causing an excess and redundancy of the
valve)
- Graves’ and Hashimoto’s both have an increase in glycose aminoglycans
o Graves’ disease is due to IgG antibody against the TSH receptor; when it hooks into it, it causes
the gland to continue to synthesize (this is a type 2 hypersensitivity – antibody against the receptor;
another example is myasthenia gravis – antibody attaches to and destroys receptor)
o Hashimoto’s thyroiditis has an IgG antibody against a TSH receptor as well except that instead
of activating the gland, it inhibits it
o Both are autoimmune diseases but one stimulates (Graves’) and the other inhibits (Hashimoto’s)
o Overlapping signs and symptoms are pretibial myxedema and glycosaminoglycan deposition
o A decrease in glycosaminoglycans could be found in a problem metabolizing glycosaminoglycans
 Lysosomal storage diseases:
• Hurler’s disease lacks alpha-L-iduronidase.
• Hunter’s disease lacks iduronate sulfatase.
• Both lack lysosomal enzyme for breaking down dermatan sulfate and it accumulates.
- Signs and symptoms: Most common is muscle weakness (all patients have proximal muscle myopathy),
others are brittle hair, coarse skin, slow indentation, periorbital puffiness, delayed Achilles’ reflex,
constipation, diastolic hypertension
- In biopsy of Hashimoto’s thyroiditis, a germinal follicle would indicate an autoimmune destruction of the
gland (cytotoxic T cells in there destroying); also you’ll be synthesizing antibodies (IgG)
o Low T4, high TSH, if they did an I131 uptake it would be low

Estrogen, pregnancy, and thyroid effects on fetus/newborn

- Someone on estrogen would have increased T4, TSH would be normal.
- An I131 would not be done because it would also go to fetus’ thyroid and it would produce hypothyroidism
(lead to cretinism)
- Brain is not fully developed when a baby is born.
o It takes about another year to a year and a half to be fully developed.
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o Thyroid hormone is responsible for this development (this is why it’s important to do newborn
screening – to rule out cretinism or hypothyroidism in newborn; they’re guaranteed to be severely
mentally retarded).
Thyroid summary
- Graves’ disease manifest as high T4, low TSH, I131 normal
- Someone on anabolics: low T4, normal TSH
- Hashimoto’s thyroiditis: low T4, high TSH, I131 low
- Factitious hyperthyroidism: high T4, low TSH, I131 low
Goiter
- Anytime the thyroid is big; found in Graves’ (diffuse enlargement of thyroid)
- Most common cause of a goiter is iodine deficiency (have hypothyroidism or borderline hypothyroidism)
- Treatment of choice is thyroxine
- A sudden increase in a goiter can be from a nodule hemorrhaging within a cyst in the goiter; can diagnose
with a fine-needle aspiration and blood would come out (benign cells)
- In the United States, the Great Lakes area around Chicago is a very iodine poor area.
- Graves’ disease could involve an increase in T3 (not T4) because of an iodine deficiency.
“Cold” and “Hot” nodules
- Involves whether nodule is taking up I131 or not.
- Hot Nodule
o A “hot” shows up as a black dot (because if that nodule was constantly making thyroid hormone,
TSH would be decreased and that would suppress the normal portion of the thyroid gland – it would
atrophy and not take I131; the active nodule, however, does take I131 and is black).
- Cold Nodule (Cancer in anyone other than a woman)
o A “cold” nodule doesn’t take up I131 and shows up as a lucid areasurrounded by a working
(black and taking up I131) gland.
o The chance that a cold nodule is malignant in a woman is about 15-20%; most cold nodules in a
woman (older woman) are benign, in fact most are cysts, a small percentage are follicular
adenomas (benign)
o Any cold nodule on a man is cancer till proven otherwise as well as in a child (cancer until
proven otherwise).
o Any person who’s had their neck and neck area exposed to radiation, cold nodule is cancer (papillary
carcinoma of the thyroid)
Thyroid Cancers
- Papillary carcinoma:
o Shows up as a cold nodule. Papillary means it has papilla; psammoma bodies present as little blue
thing scattered throughout
o Normally metastasize to cervical lymph nodes (commonly do)
o Very good prognosis and most common one
o Only one associated with radiation exposure.
o Don’t need to know about Orphan Annie nuclei and nuclear grooves
- Follicular cancer:
o Second most common type
o Invades vessels (when surgery is done on known follicular cancer, node picking is not done because
they don’t go to lymph nodes); they go hematogenously (to lungs and bone)
- Medullary Carcinoma
o Some cases are sporadic; some have autosomal dominant (relationship to MEN – multiple endocrine
neoplasias – syndromes)
 MEN I: pituitary tumors, parathyroid adenoma, pancreatic tumor (usually Zollinger Edison);
the three P’s
 MEN IIa:medullary carcinoma and pituitary pheochromocytomas
 MEN IIb:medullary carcinoma, pheochromocytoma, mucosal neuromas
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 RET proto-oncogene mutations (associated with MEN syndrome) can be used to see if
there’s a potential for developing medullary carcinomas; RET proto-oncogene codes for
receptors unique to MEN syndrome.
o Can be stained with Congo Red, then polarized, and an apple-green birifrengence = amyloid
(comes from tumor marker which is calcitonin); This is the screening test of choice for Medullary
Carcinoma
 Would be asked as where would the cancer be located with a tumor marker is converted into
amyloid
o Lower survival rate than previous two
Calcium Sidenote
o A person can have tetany and a normal total calcium
o Calcium is bound and free (it’s the free ionized calcium that’s metabolically active – true of any
hormone; the bound part is totally inactive) So calcium would be interacting with parathyroid hormone: if
the free T4 (calcium?) level was low, then the parathyroid hormone would be high; vice versa.
o Calcium has 3 fractions: 1) ionized, 2) protein bound, and 3) phosphate and citrate complexed.
Ionized and complexed calcium is filtered (60%), protein bound is not. Of the protein bound fraction,
albumin binds 90%.
o Roughly 1/3 of albumin binding sites are occupied by calcium (so in other words, roughly 40% of
total T4 (calcium?) is the calcium bound to albumin). Roughly about 47% is ionized calcium (metabolically
active). So total calcium is 4 + 5 + 5 (ionized) = 10 (think 100%)
o Most common overall cause of hypocalcemia is hypoalbuminemia; BUT IT’S
NONPATHOLOGIC (similar to TBG being decreased and it decreased total T4 but didn’t do anything to
the free hormone level)
Alkalosis
o Doesn’t matter whether respiratory or metabolic (a little more common in respiratory)
o In an alkalotic state you don’t have a lot of hydrogen ions around (it’s basic = high pH = decreased
hydrogen ion concentration)
o Acidic Amino Acids: glutamate, aspartate (because of COOH groups; where basic amino acids have
more NH groups)
o Albumin is a great binder of calcium because it has the most negative charges of any protein in the
body (has the most acidic amino acids).
 So if you have an alkalotic state with less hydrogen ions, then those COOH groups become
COO- groups, so it has even more a negative charge in an alkalotic state which means it can
bind more calcium (haven’t altered total, but has decreased ionized calcium level; so you’re
gonna have tetany)
o Mechanism of tetany
 A decrease in ionized calcium level lowers the threshold for activating the nerve of the
muscle (in other words you’re partially depolarized)
 In hypercalcemia is the opposite, you’re raising the threshold and it takes more ionized
calcium in order to activate the nerve
Parathyroid and Calcium disorders
- Expect a question in graph form: Serum PTH in y-axis and total calcium on x-axis (height = serum PTH and
width = serum calcium level)
- Situation 1: Low serum calcium level and low PTH
o Primary hypoparathyroidism
o Most common cause is previous thyroid surgery (chance that all the glands left behind because of
rxn. to injury infarcted). Nowadays autotransplant (if they take most of thyroid out, they’ll take it out
and put it in the forearm – won’t be rejected)
- Situation 2: Newborn with cyanosis and irritable and on X-ray of chest there’s no anterior mediastinum
shadow
o DiGeorge’s syndrome: hypoparathyroidism along with absent thymus.
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- Situation 3: Low serum calcium and high PTH

o Secondary hyperparathyroidism
o What is causing hypocalcemia is causing a compensatory increase in PTH = secondary
hypoparathyroidism
o Most common cause is renal failure: because hypovitaminosis D (decreases calcium and increases
PTH)
o Any cause of hypocalcemia (assuming parathyroid glands are normal) will cause a compensatory
increase in PTH
- Situation 4: High serum calcium and high PTH = gland is not obeying negative feedback
o Primary Hyperparathyroidism would be the most common cause of hypercalcemia in a
community.
o If you were in a hospital, it would most likely be malignancy induced
o Most primary hyperparathyroid patients are asymptomatic; if they are symptomatic they usually
have stones (calcium stones; the most common symptomatic presentation)
o Laboratory changes:
 PTH high, calcium high, low phosphorous (PTH normally increases calcium reabsorption
and decreases phosphate reabsorption)
o Little more common in women; almost always greater than 50 years
- Situation 5: high calcium, low PTH (should be that way)
o Causes: all of the causes of hypercalcemia except primary hyperparathyroidism; most commonly
due to malignancy
o PTH-like peptide causes of hypercalcemia increases calcium reabsorption and phosphorous but
when you measure PTH it’s not the same molecule (a PTH-like peptide tumor producing it like a
squamous of the lung, renal adenocarcinoma, metastases to bone which breaks down the bone,
sarcoidosis-producing hypercalcemia, or multiple myeloma producing hypercalcemia) so the
PTH levels are low
o Easiest way to determine the cause of hypercalcemia in a patient is PTH levels
 If PTH is high, diagnosis is primary hyperparathyroidism
 If PTH is low, all the other causes
 Play odds, malignancy
Cushing’s
- Purple striae, thin extremities and central obesity
- Most common cause of cushings: long-term steroid therapy (patient’s that had a renal transplant, using an
immunosuppressant, has lupus, etc.)
- If that’s excluded, think pituitary Cushing’s (accounts for 2/3 of Cushings), adrenal Cushings, and ectopic
Cushings’ (small cell carcinoma)
o Highest ACTH levels are found with ectopic adenomas (small cell carcinoma)
o Lowest ACTH levels are found with adrenal adenomas (it’s not making ACTH, but cortisol; cortisol
suppresses ACTH)
- Screening tests (2) (once you eliminate steroid therapy):
o 24 hour urine for free cortisol (means that it’s cortisol that’s in your urine not attached to any
protein, so it’s free and it means that you had a lot of excess of it); This is the single best screening
test for Cushings
 About 99% sensitivity and specificity; if it’s increased, then it’s Cushings
o Supression test: Dexamethasone suppression test (low dose and high dose)
 Dexamethasone is a cortisol analog (suppresses ACTH and cortisol level should be low,
which should mean that you were suppressable)
 If you use a low dose of dexamethasone in a patient with Cushings, their cortisol will not be
suppressed (positive screening test but doesn’t tell you which of the types it is)
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 Exceptions to the rule for an over productive type of endocrine disease that you can’t
suppress are pituitary
 If you gave a high dose, you are able to suppress the ACTH released by a pituitary tumor
and cortisol goes down, not so for adrenal Cushings or ectopic Cushings (small cell)
o To determine which type of Cushings it is, first look at the high dose dexamethasone suppression test
(if suppressed, it’s pituitary Cushings)
- Mechanism of action:
o Cortisol is gluconeogenic so you need substrates of gluconeogenesis. Main substrate from
gluconeogenesis is amino acids from muscle (arms and legs).
o So, you get a break down in muscle in the extremeties (thin arms and legs), and then the alanine,
which gets transaminated to give pyruvate.
o Because it’s gluconeogenic, glucose will be high (increases insulin release). Insulin increases fat
storage. Most adipose is in face and trunk and so you basically get from an insulin effect, an increase
in deposition of triglyceride (moon face, back for buffalo hump, and trunk)
o Stretch marks are due to normal obesity, and they’re purple because cortisol decreases collagen
synthesis (you get structurally weaker collagen like senile purpura – purpura within the stretch
mark). Vessels are broken down because of the increase in cortisol and that’s why they’re purple and
why it’s a very good marker.
- Trousseau’s sign – means tetany.
o If patient has hypertension, hypernatremia, hypokalemia, and metabolic alkalosis, the diagnosis is
primary aldosteronism.
o Tetany is present because when you have alkalosis, the negative charge on albumin increases, and the
ionized calcium levels decrease (tetany).
o Remember, Conn’s syndrome (aka primary aldosteronism) is tetany, with hypertension,
hypernatremia, hypokalemia, and metabolic alkalosis.

Pheochromocytoma
- Associated with adult hypertension, and adrenal medulla tumor (benign).
- In kid with hypertension think neuroblastoma (malignant).
- Both are in the adrenal medulla, of neural crest origin, produce hypertension, except
pheochromocytoma more common in adults and neuroblastoma more common in kids.
- Clinical signs and symptoms to recognize are: a patient with very unstable hypertension, anxiety, and they
sweat a lot.
o Think of Goljan’s “Danny DeVito syndrome”
o A person with these symptoms, you do a 24 hour urine test for metanephrines (best test) and 24 hour
urine for vanillylmandelic acid (VMA); they’re the metabolic end products of epinephrine and
norepinephrine
- Other associations are MEN IIa, MEN IIb, and a HIGH association withneurofibromatosis.
Waterhouse-Friderichsen syndrome (Neisseria meningitis)
- Presented as a gram negative diplococcus. A child (about 12) with high fever, nuchal rigidity (a spinal tap
found neutrophils in there), and gram negatives. The kid crashed all of a sudden and starts getting petechial
lesions all over the body and went hypovolemic and died.
- Autopsy showed both adrenal glands hemorrhage.
- Neisseria meningitis is the most common causeof meningitis from 1 month to 18 years of age. It’s the only
meningitis with petechial lesions.
- Clues are the hypovolemic shock (because of the adrenal hemorrhage), they have no cortisol, and no
mineral corticoids.
Addison’s disease
- A cause of hypocortisolism that’s chronic.
- By far and away, the most common cause is autoimmune destruction of the gland (used to be tuberculosis
in the old days).
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- It destroys the entire adrenal cortex (mineralcorticoids and glucocorticoid aspects)

o Low cortisol and high ACTH (increasing melanocytes and causing hyperpigmentation)
o No aldostolerone. Think of the sodium-potassium pump and proton potassium pump. No
aldostolerone causes losses of salt and hyponatremia. Potassium is retained (hyperkalemia –
peaked T waves). Won’t be able to get rid of protons into the urine (causes metabolic acidosis).
- Summary is: hyponatremia, hyperkalemia, metabolic acidosis, and hyperpigmentation.

Ambiguous genitalia (pseudohermaphrodite)

- First step is chromosome analysis (find out genetic sex).
- Odds are it’s an adrenal genital syndrome (21-hydroxylase deficiency).
- Know what 17 ketos are, 17 hydroxy’s are, 21, and 11-hydroxylase are.
- 17-hydroxylases are responsible for 17-ketosteroids (include DHEA and androstendione; they’re weak
androgens)
o Androstendione can be converted into testosterone and to dehydrotestosterone.
o 17 ketosteroids include DHEA and androstendione (testosterone is not a 17 ketosteroid)
- 17-hydroxycorticoids are 11-deoxycorticosol and cortisol (because there’s a 17-hydroxylase that forms 17-
hydroxyprogesterone and that’s where they develop from [21-alpha hydroxylase is necessary for 11-
deoxycortisol and this then is converted to cortisol by 11-Beta-hydroxylase])
o So if there’s an increase in 17-hydroxycorticoids, there’s an increase in 11-deoxycortisol and cortisol
- An increase in 17-ketosteroids = an increase in DHEA and androstendione

When you have an enzyme deficiency, things distal to the block decrease and things proximal to the block increase.
- 21 hydroxylase deficiency
o Things distal to the block decrease = mineralcorticoids and 17-hydroxycorticoids decreased
o 17-ketosteroids (proximal) are increased
o If you’re a female baby and you have excess androgens (this causes you to have ambiguous
genitalia); a little boy is going to look like he has precocious puberty (excess in androgens; they
cause the appearance of secondary sex characteristics before 8 in girls and 9 in boys).
o 17-hydroxys are decreased and the mineralcorticoid part is missing so you’re going to lose salt (salt-
loser)
o Basically, you’re like an Addison’s; ACTH level is high (why children are hyperpigmented)
- 11-hydroxylase deficiency
o Cortisol, corticosterone, and aldosterone are decreased.
o 11-deoxycorticosterone (a mineralcorticoid), 11-deoxycortisone, and 17-hydroxycorticoids are
increased
o You get hypertension and female with ambiguous genitalia or male with precocious puberty.
- 17 hydroxylase deficiency
o 17-ketosteroids are absent, 17-hydroxycorticoids are absent
o You’ll have an increase in mineralcorticoids; patient has hypertension
 If it’s a little boy with low 17-ketosteroids, no testosterone (looks like a little girl) and his
external genitalia would look female
 If it’s a little girl, she’s going to be underdeveloped.
Zonas
- Zona glomerulosa – has mineralcorticoids
- Zona fasciculate – has glucocorticoids
- Zona reticularis – has 17-ketosteroids and androgens
Islet Cell tumors (insulinomas and Zollinger-Edison syndrome)
- Insulinomas (tell the difference between this and injected insulin)
o Insulin when you break pro-insulin down into insulin you release C-peptide, so for every insulin
molecule you release, you have a C-peptide that corresponds to it.
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o So if you inject human insulin into yourself and produce a low glucose level, your insulin will be
elevated because you’re injecting, but your C-peptide will be suppressed.
o An islet cell tumor would have hypoglycemia, a high insulin level, but C peptide would be
increased.
Endocrinology3

Diabetes
- Type I
o Absolute insulin deficiency
o Antibodies against island cells (aka insulitis)
o Ketoacidosis
o HLA relationship; HLA means that you’re at a propensity for developing something. It doesn’t
necessarily mean you’re gonna get Type I, but if a certain environmental factor (infection (usually
viral), such as Coxsackie, Mumps, EBV, etc.) comes into the picture and you have that certain HLA
type, you could potentially develop that disease.
 HLA B27: ankylosis spondylitis can be “triggered” by chlamydial infection, ulcerative
colitis, shigellosis, or psoriasis.
o Always requires insulin
- Type II
o Family history of Diabetes
o Obesity
o Hyperosmolar nonketotic coma
o Amyloid in the beta islet cells (implies chronic disease)
o Can require insulin (because they can develop resistance to sulfonylurea)
- Pathogenesis
o Relates to osmotic damage
 Tissue has to have aldose reductase in it – converts glucose into sorbitol (osmotically
active)
 Two tissues that have it: Lens and Schwann cells.
• Lens: Sorbitol sucks water into lens. If pericytes in retinal vessels are destroyed,
then the retinal vessels are weak and you get microaneurysms (can rupture and
produce blindness).
• Schwann cells: Mechanism of peripheral neuropathy. The most common cause
of peripheral neuropathy in the U.S. is diabetes. (Mechanism being osmotic damage
and non-enzymatic glycosylation)
o Non-enzymatic glycosylation: glucose attaches to amino acids and proteins and renders whatever
that protein is (usually basement membrane) permeable to proteins. It’s operative in hyaline
artheriosclerosis and diabetic nephropathy.
o Hemoglobin A1C is a classic example of glycosylation and gives you an idea of long term glycemic
control.
- Diabetic nephropathy can show hyaline artheriosclerosis but not the “Christmas ball effect” (present in Type
IV collagen in there). Dry gangrene is present because of increased incidence of atherosclerosis.
- Microaneurysms is commonly seen in diabetes. Proliferative retinopathy where there has been rupture
and separation of the retina (can go blind).
- Example of a 50 year old patient who has blurry vision and goes to an ophthalmologist who gives them a new
prescription for a new set of glasses, but two weeks later they have blurry vision and goes again, but the
refractive index is different and gets a new prescription and gets it filled. One month later blurry vision again
so there’s a constant change in refraction and the diagnosis is diabetes. What’s happening is you’re
converting glucose into sorbitol and water is going in and altering the refraction of the lens.
o It’s absolutely classic: anyone having to change their glasses on a frequent basis, you have to get
a blood glucose level.
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- Laboratory tests:
o Fasting glucose is a classic way:
 If it’s greater than 126 mg/dL on two separate occasions you have diabetes.
 In the old days, the fasting glucose cut-off was 140 mg/dL, but now it’s 126 mg/dL. The
sensitivity of the test is increased (by making it lower or closer to the normal range, then you
can pick up more people that had diabetes). When it was set at 140, it was set for high
specificity (less false positives); if greater than 140 you unequivocally had diabetes. But now
because the glucose level determine the severity of pathology, the sensitivity has been
increased (lowered reference interval).
 Make sure you go over positive and negative predictive value, etc. If you have two tests,
what’s the percent chance that one will be a false positive = 10%.
o Glucose intolerance don’t have to worry about.
- Gestational diabetes is a woman who didn’t have diabetes before she got pregnant, but now she does.
o Risk factors for the baby if the mother doesn’t have good glycemic control are respiratory distress
syndrome. Sometimes premature deliveries, etc.
o Women who do have gestational diabetes are at risk for developing diabetes further on down the road
(have to watch these women).
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Musculoskeletal 1

- Have to know how to interpret crystals in the synovial fluid.

Arthritis
- Two diseases that both have crystals in the synovial fluid: Gout and pseudogout.
- Crystals in pseudogout;
o Rhomboid-shaped (chunky) crystal in the synovial fluid, that’s an automatic diagnosis of pseudogout
(problem is it can also have needle-shaped crystals like monosodium urate).
- Differentiate crystals by getting a sample of synovial fluid and put a red filter into it (makes the background red)
and makes the crystals yellow or blue depending upon an analyzer on the base of the microscope.
o If analyzer is in the north-south direction, look at all the crystals in the same direction of the analyzer and
look at what the color it is. If it’s yellow and parallel to the analyzer, by definition it’s negatively
birifringent and it’s monosodium urate.
o Think of a case of an older person with a swollen knee (think more pseudogout than gout). Do analysis
and see needle-shaped crystals and this time put the analyzer in an east-west direction. The color of the
crystal is blue; when it’s blue and parallel to the way you had set the analyzer that by definition is
positively birifringent crystal and it defines pseudogout.
o So when it’s yellow and parallel to the analyzer it’s gout. When it’s blue and parallel to the way you set
your analyzer it’s pseudogout.
- Osteoarthritis (aka degenerative arthritis)
o Most common type of arthritis.
o It’s not an inflammatory type of arthritis (rheumatoid arthritis and alkylosing spondylitis are).
o It’s a wearing down of articular cartilage.
o A reaction to injury occurs at the margin of that joint to wearing down of cartilage. The reaction to injury
produces a little bit of bone formation at the edge of the joint (called an osteophyte aka spur).
 Heberden’s node is basically an osteophyte that presents in distal interphalangeal joints as a
bump.
 Bouchard’s node are similar nodules that present on the proximal interphalangeal joints.
o Remember osteoarthritis involves DIP (distal interphalangeal joints) and PIP (proximal interphalangeal
joints). Rheumatoid arthritis would involve MCP (metacarpophalangaeal joints) and PIP. Both can
involve PIP.
- Rheumatoid arthritis
o Remember swelling of the MCP joints (usually 2nd and 3rd are the ones that start off).
o It is an inflammatory joint disease. The inflammation is set up by rheumatoid factor (an IgM antibody
against IgG) and set up in the synovial fluid and form immune complexes that activate the complement
system (neutrophils and stuff come in) and start damaging the joints. Synovial tissue starts getting
inflamed from all this and starts getting hyperplastic and starts grows over the articular cartilage and
starts destroying the cartilage.
o The synovial tissue growing over surface articular cartilage is called pannus (NOT to be confused with
tophus which is in gout). The pannus also destroys the articular cartilage while it grows over it and
because of its destruction, it produces fibrosis eventually (as a reaction to injury).
o The joints in rheumatoid arthritis can be ankylosing (fixed, don’t move) which doesn’t occur in
osteoarthritis. If rheumatoid arthritis sufferers don’t keep moving their joints and they’re not being
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treated properly (anti-inflammatories) eventually they’ll get ankylosing of the joint and they can’t move
at all.
o Ulnar deviation of the joints (which is usually symmetrical) is a classic symptom of rheumatoid arthritis.
o Rheumatoid nodules can also be seen in rheumatic fever.
o Case of patients with rheumatoid arthritis may also have trouble eating and swallowing crackers. They
may feel like there’s sand in their eye.
 When you look at their tongue it’s dry and when you look at their eyes it’s dry.
 Diagnosis is Sjogren’s syndrome (patient with rheumatoid arthritis that develops autoimmune
destruction of their lacrimal glands). End result can be keratoconjunctivitis (dry eyes) and also
minor salivary glands can be destroyed (dry mouth).
o Rheumatoid nodules in lung accompanied by pneumoconiosis (inhalation of dust particles) = Caplan’s
syndrome.
o Methotrexate is now used to treat rheumatoid arthritis; by hitting them early you get less damage in the
long run.
 May get a case of a patient with rheumatoid arthritis that develops a macrocytic anemia with
hypersegmented neutrophils. Neurologic exam is normal. What drug is he on? Methotrexate.
 Another complication of methotrexate is interstitial fibrosis in the lung.
Gout (aka Podagra)
- Usually the first joint involved in acute gouty arthritis is the big toe (almost always happens at night).
- Mechanism is precipitation of the monosodium urate crystals in the synovial fluid. The neutrophils are
phagocytosing that and release their chemicals and enzymes (produce the inflammatory reaction).
- An elevated uric acid level does not automatically mean you have gout.
- Gout is defined by an inflammatory joint and have to have stuck a needle into it and documented that there are
monosodium urate crystal in it. Some cases can have normal levels of uric acid.
- Most of the time they treat the initial disease with an anti-inflammatory agent (colchicine is not used now because
it’s too toxic). Most of the time indomethacin is used to control the inflammation. Once the gout is controlled,
the source is sought out.
- Causes of Gout can be due to overproduction of uric acid or underexcretion of uric acid (over 90% of cases are
these).
o Drugs used for gout are: Allopurinol (inhibts xanthine oxidase), Probencid and sulfinpyrazone (uricosuric
agents that increase uric acid excretion by inhibiting tubular re-absorption).
o If patient is an underproducer: the drug of choice would be probenecid or sulfinpyrazole.
o If patient is an overproducer: the drug of choice would be allopurinol (blocks xanthine oxidase).
- If you have gout and don’t take care of it, it can become chronic (identified by tophus).
o If you stuffed a tophus with a lance, crystalline material would come out. A section through it etc., it
would be polarized, have multinucleated giant cells, and have a foreign body reaction against it.
o A tophus is the deposition of monosodium urate in soft tissue.
o Can be seen in the hand and ear. You can have disfiguring collections in soft tissue.
o It’s very destructive when it’s next to a joint. It actually erodes away the joint.
o Once you have a tophus, the only treatment available is allopurinol. No other drugs are used for chronic
gout.
- Genetics: multifactorial inheritance (a little bit of genetics and a lot of environmental factors)
o Environmental factors:
 Red meat – full of purates
 Red wine
 Alcohol – (involves metabolic acidosis)
• Uric acid and all acids in our body have to compete with each other for excretion in the
proximal tubule. Alcoholics have lactic acidosis and beta hydroxybutyric ketoacidosis.
Uric acid is going to have to compete with those two acids for excretion in the proximal
tubule. Lactic and beta hydroxyl win because there’s more of it; and it builds up as it’s
waiting and waiting.
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Ankylosing spondylitis (associated with HLA B-27)

- Person looks like they’re looking down for something because of a hunched over back. It has a great effect on
their ability to breathe (restricts movement of chest cavity and have blood gas abnormalities).
- Patient when young (20-21) in the morning would have tremendous pain in the sacral iliac. On X-rays, sacral iliac
would show inflammatory reaction. Classically they wake up with severe lower back pain (around the sacral
iliac) and as day progresses they start feeling better.
- Eventually what happens is the inflammation involves vertebral column and you get fusion of the vertebral
columns (“bamboo spine”) and that’s when they start hunching over.
- Other associations aortitis (inflammation of the aorta and commonly have aortic regurgitation) and commonly
have uveitis and iridocyclitis (inflammation of the iris and ciliary body) with blurry vision and can potentially go
blind.
Alcaptonuria (autosomal recessive disease: homogentisate oxidase is absent)
- Degenerative arthritis in the vertebral column and other places. If an autopsy was performed, the cartilage in
between the vertebra would be a black color. Patients urinate and once it’s exposed to sunlight it turns black.
- Buildup of homogentisic acid and on exposure to light it turns black and when it deposits into cartilage it destroys
them (and gives a black pigment in them).
Case:
- Boy with dysuria, increased frequency, urinalysis showed lots of neutrophils (but couldn’t see bacteria at all).
Glucocyte esterase was positive but nitrite was negative. Culture urine and nothing in it (sterile pyuria). If the
boy was sexually active, then it’s nonspecific urethritis Chlamydia. After treatment a couple of weeks later he
starts getting a sterile conjunctivitis (no Chlamydia) and he’s starting to get some pain down in his Achilles
tendon.
o He has Reiter’s syndrome (urethritis, conjunctivitis, and arthritis). He’s essentially B27 postive and his
environmental trigger that pushed him into developing ankylosing spondylitis was Chlamydia (the most
common one of all).
o The Achilles tendon (Achilles tendonitis) is pathognomonic for Reiter’s syndrome.
o Ulcerative colitis can be a trigger in a person B27 positive in pushing them into ankylosing spondylitis
(others are psoriasis, Chlamydia, ulcerative colitis, shigella, etc.).
Case:
- Boy with a hot joint (knee). Has a pustule on his palm; upon aspiration, the pustule shows gram negative
diplococci with neutrophils.
- This patient has disseminated gonococcemia
o Remember STDs summarizes what you see in him: S for synovitis (inflammation of the joints –
specifically the knee), T for tenosynovitis (inflammation of a tendon sheath; joints in the hands and the
feet), and D is for dermatitis (pustules) on hands and feet; commonly on aspiration you can see the GC
right in them.
o If you’re missing C5-C9 (final common pathway), you’re at a predisposition to disseminated GC. The
reason is you need those complement components to phagocytose Neisseria gonorrhea. So if you’re
missing them and you get GC, you can get disseminated GC.
o The most common cause of septic arthritis in the US is gonorrhea.

Lyme’s disease with Erythema cronica migrans

- Pathognomonic: May present as a walking “watermelon pit” that’s bit someone and now it looks like dropped a
pebble on water (has concentric circles)
- Is caused by Borrelia burgdoferi, a spirochete found in the Ixodes tick.
- Once recognized, treat with tetracycline.
- If not treated early, and they go into chronic phase.
o Disabling joint disease doesn’t compare to myocarditis.
- Don’t walk in the woods in Long Island, you’re guaranteed to get Ixodes ticks on you.
- Bell’s Palsy:
o Usually idiopathic Bell’s Palsy is due to Herpes Simplex. It presents unilaterally.
o When it’s bilaterally, it’s Lyme’s disease until proven otherwise because the most commonly involved
cranial nerve involved in chronic Lyme’s disease is the seventh nerve; It’s literally pathognomonic.
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- If this person developed a hemolytic anemia, and you looked at the peripheral blood and you saw something
abnormal. You saw the Babesiosis. Remember the tick Ixodes dammini (found in the white-tailed deer) has a
reservoir for the Borrellia burgdoferi. Also, the white-tailed deer has the Babesiosis in them; so this tick can
carry two diseases: Borrelia burgdoferi (Lyme’s) and Babesia microti (an intraerythrocytic parasite that produces
a hemolytic anemia). Babesia microti looks very similar to the ring form that you saw in Plasmodium. About
20% of people with Lyme’s disease have Babesiosis as well.
- If you have chronic disease, you treat them with Ceftriaxone. If you have early form you treat with tetracycline.

Osteogenesis imperfecta
- They present a picture that looks like a foreign body (horseshoe) in the eye. There’s a blueish discoloration to the
sclera.
- The defect is they can’t make Type I collagen.
- The mechanism of the blue sclera is:
o Light-skinned people have blue veins. There’s collagen in sclera and since your Type I collagen is
defective, it’s thin. What you’re seeing is it’s so thin there because you don’t have collagen there that
you’re seeing the underlying choroidal veins. Basically it’s the reflection of the veins underneath there.
It’s the choroidal veins that gives the blue color to the sclera.
- Remember the picture presents as a kid with an eyeball.
- Should be considered a diagnostic possibility when there seems to be only small amounts of soft tissue damage
despite the presence of a serious fracture.
- Exuberant callus formation around healing may mimic the appearance of an osteosarcoma.

Osteogenesis petrosa (“Brittle bone disease”)

- Defect in osteoclasts so you can’t break bone down and you have no marrow. You have severe anemias and
different nerves etc. gets caught in there.
- Sometimes try to pass that off as Osteogenesis imperfecta.

Osteoporosis
- Articular cartilage is thin between vertebral column. A hump may be present (“Dowager’s hump” – a
characteristic dorsal kyphosis).
- Mechanism in an elderly woman is breaking more bone down than putting in. This is because you don’t have
enough estrogen to inhibit IL-1 (osteoclast activating factor) from breaking your bone down.
- It’s an overall reduction in bone mass (mineral and organic component of bone). Osteomalacia is decreased
mineralization (the organic part of the bone is totally normal – cartilage is okay and osteoid is okay).
- Diagnose it with dual beam absorptiometry (Cecil’s says dual energy x-ray absorptiometry – DEXA) to measure
the density of bone in different areas (somewhere around the hand area). It’s a noninvasive and easy test to do.
- The most common fracture is a compression fracture. You literally are collapsing in your vertebral column. You
will lose stature; the weight of your head is causing you to lean forward and your back to go out because of the
weakness of your bone.
- The second most common fracture is a Colles’ fracture of the distal radius (causes characteristic “dinner fork”
deformity).
- Swimming isn’t a good exercise to prevent osteoporosis. Reason is no stress on bone because the water is
holding you up. You have to stress bone to build it up (walking or weight training – is even better than walking
for a woman; a woman should walk with dumbbells). Side note is astronauts having to be carried off spaceship
when they come back because they have serious osteoporosis problems (lack of gravity).
- Women should be on (even if not postmenopausal) 1500 mg of Calcium everyday and 400 and 800 units of
Vitamin D everyday. Also you need a vitamin pill that contains iron. These are all normal primary prevention
things that every young woman in her reproductive period of life should be doing.

Bone tumors (not asked much)

- Osteochondroma
o Overall most common bone tumor. Osteochondroma can present as a knob on the bone. It’s a little
overgrowth (neoplasm of cartilage) capped by bone on the surface. Some people call it exostosis. If you
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have Ollier’s disease (you have exostosis all over your body) and you have a risk for developing
osteochondroma.
- Chondrosarcoma
o Most common malignant tumor.
- Osteogenic sarcoma
o Always think knee area, distal fever, proximal tibia, and adolescent.
o Develops in the metaphysis of bone. It has invaded into muscle and into periosteum (can see a little bit of
lifting of periosteum – on X-ray it would look like a triangle – Codman’s triangle). Spicules of bone can
present as a “sunburst” appearance on x-ray.
o RB suppressor gene on chromosome 13.
- Duchenne’s muscular dystrophy and Becker’s dystrophy
o Child can present with pseudohypertrophy (enlargement of an organ or structure owing to hypertrophy or
hyperplasia of tissue other than parenchyma). Child can also present with Gower’s sign (climbs on his
legs to stand up).
o Kid has elevated serum creatine kinase (CK) and has an absence of dystrophin.
o It’s a sex linked recessive disorder. Only dystrophin is missing.
o A variant of this disease is Becker’s dystrophy (still sex-linked recessive). Difference is they make
dystrophin but it’s abnormal dystrophin (defective).
o An analogy is α1-antitrypsin disease. The most common cause of hepatocellular carcinoma in children is
α1-antitrypsin deficiency. Also adults get panacinar emphysema. The reason there’s a difference is
there’s many different subtypes of antitrypsins. There’s a type where you don’t make antitrypsin at all
(in that case you will end up as a young adult with panacinar emphysema) but another type is you do
make α1-antitrypsin but you can’t get it out of your hepatocytes. When you do PAS stains of the
hepatocytes in these kids, you see lots of α1-antitrypsin except it can’t get out of the hepatocyte (it
damages the hepatocyte and predisposes to hepatocellular carcinoma).
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Skin

Myotonic Dystrophy
- Most common adult dystrophy
- Autosomal dominant
- Example of triplet repeat disease;
o Other examples of repetition of trinucleotides
 Huntington’s chorea
 Myotonic Dystrophy
 Friedreich’s ataxia
 Fragile X syndrome – where you have retardiation and macroorchidism (big testicles))
o In future generations, the disease gets worst = anticipation; in each generation, there’s more triplet
repeats added on (there’s more defective protein).
- Scenario
o A genetic counselor tells a couple that they have a type of disease where if they had children, it may
invariably be fatal, what is it?
o It was a triplet repeat disorder.
- Has frontal balding, muscle weakness in face (mouth may droop open)
o On boards, may present as a guy who can’t release his grip on his golf stick (myotonic part – can’t relax
muscle). They also have diabetes and cardiac abnormality.
Myasthenia Gravis
- Due to an antibody (IgG) to an acetylcholine receptor (example of a Type II hypersensitivity – as is Graves’
disease)
- Whether receptor is destroyed or blocked is irrelevant. You get muscle weakness. The first muscles are the eye
lids; you get lid lag and may get double vision (because the muscles of the eye). They may get dysphagia for
solids and liquids (because of striated muscle that is primarily affected). Eventually it progresses all over.
- When all the receptors go, you can give all the Acetylcholine esterase inhibitors you want (treatment), but it
eventually does no good when all the receptors are gone. At this point you could do a thymectomy. They may
try to trick you with thymoma (malignancy of the thymus, but only occurs in 15-20% of patients) being the most
common pathology in the thymus; what you actually see are terminal follicles in the thymus – B cell hyperplasia
(B cells should not be there; they’re the ones making the antibody). The antibodies aren’t made in the lymph
nodes, but in germinal follicles in the thymus. Why a thymectomy can help: 1/3 get completely cured, 1/3 get
partial cure, and 1/3 don’t get helped (probably waited too long and lost too many receptors).
Systemic Lupus Erythematosus
- a collagen vascular disease; has a butterfly distribution
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- Of all the autoimmune diseases, it’s the one that would most likely have a positive ANA (about 99%)
o The two antibodies that you should order when you have a positive ANA to prove it’s Lupus are the
Smith Antibody (has a 100% specificity for Lupus; means no false positives) and anti-ds DNA (if
positive it also means you have kidney disease as well; has about a 98% specificity)
- Morning stiffness is present; it simulates rheumatoid arthritis (photophobia), has a malar rash, associated with
pericarditis.
- LE cell preps should not be ordered. Neutrophil phagocytozing altered DNA; it’s not even specific for Lupus.
Progressive Systemic Sclerosis (Scleroderma) or CREST
- pt. may present with telangectasia, dysphasia, classic Raynaud’s, dystrophic calcification in hands, sclerodactyly
- Organ involvement differentiates: If kidneys are involved it may indicate progressive systemic sclerosis
Dermatomyositis
- presents with “raccoon eyes” and elevated serum CK.
- May present with a silvery rash (“Gottron’s patches”) over proximal interphalangeal joints.
- Has highest association with an underlying cancer
Sjogren’s syndrome
- Can be part of rheumatoid arthritis and antibodies that destroy minor salivary glands (dry mouth) and lacrimal
glands (dry eyes).
- A biopsy of the lower lip (confirmatory test) looks to see if there’s an inflammatory reaction destroying minor
salivary glands (would see a lot of lymphocytes)
- Antibodies are anti-SSA (anti-Sjogren’s syndrome A; aka anti-rho; patients with lupus can have this too and it
can cross the placenta and attack the baby’s conduction system) and SSB (aka anti-la)
Zit (lesion in the skin or pimple)
Basal Cell Carcinoma
Squamal Cell Carcinoma
Actinic Keratosis – rub it off and it comes back
Psoriasis
- Red and raised; has a silvery plaque; sometimes involves hands and scalp and not just the pressure point
- A black person with psoriasis would have the silvery plaque stand out.
Atopic Dermatitis
- How a kid with an allergic diaphysis usually starts their disease.
- Type I hypersensitivity
- Is a contact dermatitis; sometimes may be triggered by metal (nickel); is a Type IV hypersensitivity reaction
o On boards may say that the pathophysiology of this lesion would be equivalent to the pathophysiology of
positive PPD (also a Type IV hypersensitivity)
Seborrheic Dermatitis
- Associated with Malassezia furfur (also causes tinea versicolor)
- Think about an immunocompromised disease (AIDS)
- On a patient with a bald spot on their head, you use a black light (UVA light) and it fluoresces. The diagnosis is
Microsporrum canus (used to be the most common cause of tinea capitus, but now it’s Trichophyton tonsurans).
Because the fungus involves the inner portion of the shaft, there’s no fluorescent metabolites, it’s wood’s light
negative????
o The most common cause of tinea capitus (superficial dermatophytes) is not microsporum canus, but
trichophyton tonsurans. All the other superficial dermatophyte infections (including tinea corpus; aka ring
worm) with a red outer edge and a clear center, your first step for workup is to scrape the outside, do a
KOH prep, and look for hyphae and see the yeast forms. All other superficial dermatophyte infections
except tinea capitus are due to trichophyton rubra.
Molluscum contagiousum
- Common infection in children; children pick at them because they have sandy-like material in the middle of the
crater and they self-innoculate.
- Virus that produces these is pox virus (a DNA virus).
- Remember that basal cell carcinomas were also volcano-like crater forms.
Pityriasis rosea
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- Non-pruritic rash; oblong looking rash that’s red on the outside, pale on the middle. It is oblong looking as
opposed to circular. When you do a scratch and do a KOH prep, and there’s nothing. You put topical steroids
and it didn’t go away. He comes back days later and has rash and lines of langer and a Christmas-tree
distribution on trunk. Diagnosis is Pityriasis rosea (not an infectious disease); patch is a Herald patch.
- COMMON Board question; it’s not a fungus.
Nevi (dysplastic)
- This is a precursor lesion for malignant melanoma (dysplastic nevus)
- If more than 100 nevi on your body, then you have a dysplastic nevus syndrome; it’s very common. Have to
have your body looked at once a year by a dermatologist to check for dysphlastic nevus.
Malignant Melanoma
- 4 different types
- First step in management is excision, not punch biopsy, not partial excision.
- A superficial spreading malignant melanoma is the most common one.
- Lentigo malignant melanoma
o Seen on the face (sun-exposed area); seen commonly on older people. Have regular borders.
o Of all of the melanomas, it’s the least likely to metastasize.
- Black population doesn’t get malignant melanomas; the pigment in the skin prevents UV damage and the
propensity for cancers. There is one type of malignant melanoma that they can get:
o Board question – you have a black individual who has dyspnea. X-ray shows multiple metastatic lesions
throughout body. Biopsy shows malignant melanoma. Which part of the body to find the primary
disease? Answer is under the nails, palms, or sole of the feet.
o Called Acral lentiginous malignant melanoma. This is the most aggressive of all malignant
melanomas. Look under nails, palms, or soles because it has nothing to do with radiation.
o On gross observation, can be confused with Paget’s
- Most important thing determining prognosis is the depth of invasion. The magic number is 0.76 mm; less
than this, there’s no way it can metastasize.
Spiders
- Black Widow Spider
o Has a neurotoxin that commonly produces spasm of the muscles in the upper thighs and abdomen
(almost like tetanus). The bite is painful.
o Question would present as:
 Person went down into cellar and lifted up boxes and felt a sharp prick on their finger. Then over
a period of a couple of hours, contractions of the muscles…..
- Brown Recluse (“Violin”) Spider
o Common in Oklahoma
o Bite is not painful, but it’s a necrotoxin, not a neurotoxin. Can produce an ulcer in your skin. The most
potent of all venom in the world.
Sidenotes:
- Erector pilis muscle – structure responsible for piloerection.
- Receptor for Androgens in the skin
– sebaceous glands; where testosterone hooks in to.
– Men get more pimples (acne) because they have more testosterone; more stimulation of sebaceous glands to
release lipid-rich material
Spironolactone
- Drug that can be used to treat hirsutism; it is the same drug used to block aldosterone.
- It acts by blocking androgen receptors; it can also cause gynecomastia in males.

Extra:
Pemphigus Vulgaris
- An autoantibody directed against transmembrane cadherin adhesion molecules induces acantholysis
(breakdown of epithelial cell-cell connections) with resulting intrapeidermal blister formation.
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- It may develop spontaneously or following triggers such as drugs (thiols, penicilamine), physical injury (burns),
cancer, pregnancy, other skin diseases, and emotional stress.
- Pemphigus vulgaris is a relatively rare blistering disease; it is seen more commonly in patients with Jewish or
Mediterranean heritage. In addition to the usually prominent oral ulcers, uncomfortable skin erosions can also
occur when the blisters rupture rapidly and are not observed. The epidermis at the edge of these erosions is often
easily disrupted by sliding pressure (Nikolsky sign).
Bullous Pemphigoid
- Is characterized by deeper blisters than pemphigus vulgaris that occur at the dermal-epidermal junction.
Dermatitis herpetiformis
- Is characterized by severe, intense pruritis and groups of papules and vesicles.
Herpes Simplex I or II
It can show multin

CNS

Spinal fluid
- Derives from choroid plexus (are in the ventricles; in the lateral, third, and fourth).
- It’s an ultrafiltrative plasma. The difference between serum and spinal fluid is protein (grams/dL in serum and
milligrams/dL in spinal fluid). There are hardly any cells in spinal fluid.
o Glucose is also lower (about 60%) of what serum is.
 If it’s lower than 60% for example, that means that there’s something in there utilizing the
glucose for energy like bacteria, fungus, or cancer cells.
o Chloride is actually higher in spinal fluid than serum. On exam, they may ask you because of injuries to
head area:
 For example, a baseball hits you in the eye and you have an orbital blowout fracture, you could
potentially break your cribriform plate and have some dripping fluid out of there. You have to
know the differences between the two.
 For example, a kid practicing baseball and gets fluid coming out of ear (ottorrhea) and
hemorrhage behind the ear (Battle sign). It’s a fracture of the basilar plate and can end up with
spinal fluid there.
- CSF passes through Aqueduct of Sylvius. This is the most common cause of hydrocephalus in children;
Aqueduct of Sylvius gets blocked up and you get a buildup of spinal fluid in the third and lateral ventricles.
- After passing through Aqueduct of Sylvius it reaches fourth ventricle and has to get out to get into subarachnoid
space (via Foramen of Magendie).
o Membranes:
 Dura – is tightly adherent to periosteum
• Epidural hematoma (blood clot between bone and dura); the only pressure that could do
that is arterial pressure
o CSF gets into subarachnoid space to protect brain and spinal cord from injury (acts as a cushion)
o Arachnoid granulation is what helps us get rid of CSF; Menangiomas are tumors that derive from
arachnoid granulation.
o Once passes arachnoid granulation, it passes into dural sinuses and they all meet into jugular vein which
is emptied into right side of heart.
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 When you do a valsalva and neck veins distend, that pressure transmits all the way through dural
sinuses, arachnoid granulation, through spinal fluid, down to needle in subarachnoid space in L4
(pressure goes up; called Qweckesteck maneuver???? When doing a spinal tap to see if the entire
subarachnoid space is patent)
Tumors
- Tentorium cerebelli
o 70% of brain tumors in adults are supratentorial (involve cerebral cortex)
o 70% of primary brain tumors in kids are infratentorial
Hydrocephalus
- Communicating
o Communication of spinal fluid in the ventricles with the subarachnoid space.
o Causes:
 Benign tumor of choroid plexus (all papillary-looking); there would be a greater ultrafiltrate of
plasma and there’d be more spinal fluid (pressure would build up)
 Subarachnoid bleeding of meningitis. Arachnoid granulations are scarred off and you can’t drain
it out. This is the most common cause.
- Non-communicating (most common)
o Something is preventing spinal fluid from the ventricles from getting into the subarachnoid space.
o Most common cause is Aqueduct of Sylvius stenosis
o Other causes:
 Ependymoma in fourth ventricle (most common in kids)
 Meningitis at the base of the brain (TB) and you get scar tissue blocking the foramen of Luschka
(drains fourth ventricle laterally) and Magendie.
Arnold-Chiari Syndrome
- Spinal cord is pulled down and medulla (and maybe a little bit of cerebellum) is brought down into cervical
region.
- You get platybasia and hydrocephalus.
Andy-Walker Syndrome
- Cerebellar vermis and fourth ventricle never develops.
Herniation
- Would occur because of cerebral edema and it has nowhere to go
- Cerebellar herniation
o Part of the cerebellum has been squeezed into the foramen magnum.
o Death is very quick
- Uncal herniation
o Medial portion of the temporal lobe (uncus) herniates through the tentorium cerebelli and it presses
agains the midbrain.
o It can cause hemorrhage (Durrey’s) and nerve compression (oculomotor nerve – leading to
ophthalmoplegia)
 Oculomotor palsy – down and out (look at pupil); Down and in is trochlear nerve palsy; Lateral
rectus makes you look cross-eyed.
 thefirst sign of uncal herniation is mydriasis of the pupil (dilation) on the side of the
herniation; parasympathetic nerve stimulation constricts the pupil (sympathetic dilates it)
 Posterior cerebral artery can be compromised and you can get occipital lobe infarction
 Note: know where all the nerves arise from on the brain stem.
- Papilledema – any cause of intracranial pressure can do that; you normally see a sharp margin to the disc.
Vitamin A toxicity can cause this. Lead poisoning can cause this (increased vessel permeability because of delta
aminolevulinic acid)

Extra:
Central Pontine Myelinolysis
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- Is a specific, and nearly always iatrogenic condition characterized by demyelination of the central pons
following overly rapid correction of severe hyponatremia.
- Axons and neuronal cell bodies are relatively preserved. The lesion usually specifically involves the basis pontis
and portions of the pontine tegmentum.
- Clincially, patients may develop a rapidly evolving para- or quadriparesis, often accompanied by pseudobulbar
symptoms such as dysarthria or dysphagia.