Goljan Pathology Lecture Notes (Typed Pathology Notes) PDF

Goljan Pathology Lecture Notes (Typed Pathology Notes) PDF

Goljan Pathology Lecture Notes

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GOLJAN PATHOLOGY LECTURE NOTES very important resource to prepare for USMLE step 1 2018 ,they will help you to master and review all of the pathology beside usmle step 1 lecture notes pathology.
This file contains Typed Pathology Notes from goljan audio. 
There are many materials published by goljan which include:
1-goljan audio lectures (goljan pathology audio)
2-goljan rapid review pathology
3-Rapid Review Pathology
4-Rapid Review Pathology With STUDENT

(125 PAGES)


Day 1

Audio file 1: Cellular Injury 1


Key issues – hypoxia, cyanide poisoning, free radicals, apoptosis, growth alternations (i.e. hypertrophy, atrophy, hyperplasia, etc…)

I. Hypoxia = inadequate oxygenation of tissue (same definition of as shock). Need O 2 for oxidation phosphorylation pathway – where you get ATP from inner Mito membrane (electron transport system, called oxidative phosphorylation). The last rxn is O 2 to receive the electrons. Protons are being kicked off, go back into the membrane, and form ATP, and ATP in formed in the mitochondria

A. Terms:

1. Oxygen content = Hb x O 2 satn + partial pressure of arterial oxygen (these are the 3 main things that carry O 2 in our blood)

In Hb, the O 2 attaches to heme group (O 2 sat’n)

Partial pressure of arterial O 2 is O 2 dissolved in plasma

In RBC, four heme groups (Fe must be +2; if Fe+ is +3, it cannot carry O 2 ) Therefore, when all four heme groups have an O 2 on it, the O 2 sat’n is 100%.

2. O 2 sat’n is the O 2 IN the RBC is attached TO the heme group = (measured by a pulse oximeter)

3. Partial pressure of O 2 is O 2 dissolved in PLASMA

O 2 flow: from alveoli through the interphase, then dissolves in plasma, and increases the partial pressure of O 2 , diffuses through the RBC membrane and attaches to the heme groups on the RBC on the Hb, which is the O 2 sat’n

Therefore – if partial pressure of O 2 is decreased, O 2 sat’n HAS to be decreased (B/c O 2 came from amount that was dissolved in plasma)

B. Causes of tissue hypoxia:

1. Ischemia (decrease in ARTERIAL blood flow ……NOT venous)

MCC Ischemia is thrombus in muscular artery (b/c this is the mcc death in USA = MI, therefore MI is good example of ischemia b/c thrombus is blocking arterial blood flow, producing tissue hypoxia)

Other causes of tissue ischemia: decrease in Cardiac Output (leads to hypovolemia and cardiogenic shock) b/c there is a decrease in arterial blood flow.

2. 2 nd MCC of tissue hypoxia = hypoxemia Hypoxia = ‘big’ term

Hypoxemia = cause of hypoxia (they are not the same); deals with the partial pressure of arterial O 2 (O 2 dissolved in arterial plasma, therefore, when the particle pressure of O 2 is decreased, this is called hypoxemia).

Here are 4 causes of hypoxemia:

a. Resp acidosis (in terms of hypoxemia) – in terms of Dalton’s law, the sum of the partial pressure of gas must = 760 at atmospheric pressure (have O 2 , CO 2 , and nitrogen; nitrogen remains constant – therefore, when you retain CO 2 , this is resp acidosis; when CO 2 goes up, pO 2 HAS to go down b/c must have to equal 760;

Therefore, every time you have resp acidosis, from ANY cause, you have hypoxemia b/c low arterial pO 2 ; increase CO 2 = decrease pO 2 , and vice versa in resp alkalosis).

b. Ventilation defects – best example is resp distress syndrome (aka hyaline membrane dz in children). In adults, this is called Adult RDS, and has a ventilation defect. Lost ventilation to the alveoli, but still have perfusion; therefore have created an intrapulmonary shunt. Exam question: pt with hypoxemia, given 100% of O 2 for 20 minutes, and pO 2 did not increase, therefore indicates a SHUNT, massive ventilation defect.

c. Perfusion defects – knock off blood flow

MCC perfusion defect = pulmonary embolus, especially in prolonged flights, with sitting down and not getting up. Stasis in veins of the deep veins, leads to propagation of a clot and 3-5 days later an embolus develops and embolizes. In this case, you have ventilation, but no perfusion; therefore there is an increase in dead space. If you give 100% O 2 for a perfusion defect, pO 2 will go UP (way to distinguish vent from perfusion defect), b/c not every single vessel in the lung is not perfused.

Therefore, perfusion defects because an increase in dead space, while ventilation defects cause intrapulmonary shunts. To tell the difference, give 100% O 2 and see whether the pO 2 stays the same, ie does not go up (shunt) or increases (increase in dead space).

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d. Diffusion defect – something in the interphase that O 2 cannot get through…ie fibrosis. Best example–Sarcoidosis (a restrictive lung disease); O 2 already have trouble getting through the membrane; with fibrosis it is worse. Another example–Pulmonary edema; O 2 cannot cross; therefore there is a diffusion defect. Another example is plain old fluid from heart failure leads to dyspnea, b/c activated the J reflex is initiated (innervated by CN10); activation of CN10, leads to dyspnea (can’t take a full breath) b/c fluid in interstium of the lung, and the J receptor is irritated.

These are the four things that cause hypoxemia (resp acidosis, ventilation defects, perfusion defects, and diffusion defects).

3. Hemoglobin related hypoxia

In the case of anemia, the classic misconception is a hypoxemia (decrease in pO 2 ). There is NO hypoxemia in anemia, there is normal gas exchange (normal respiration), therefore normal pO 2 and O 2 saturation, but there is a decrease in Hb. That is what anemia is: decrease in Hb. If you have 5 gm of Hb, there is not a whole lot of O 2 that gets to tissue, therefore get tissue hypoxia and the patient has exertional dyspnea with anemia, exercise intolerance.

a. Carbon monoxide (CO) : classic – heater in winter; in a closed space with a heater (heater have many combustable materials; automobile exhaust and house fire. In the house fire scenario, two things cause tissue hypoxia: 1) CO poisoning and 2) Cyanide poisoning b/c upholstery is made of polyurethrane products. When theres heat, cyanide gas is given off; therefore pts from house fires commonly have CO and cyanide poisoning.

CO is very diffusible and has a high affinity for Hb, therefore the O 2 SAT’N will be decreased b/c its sitting on the heme group, instead of O 2 (remember that CO has a 200X affinity for Hb).

(Hb is normal – its NOT anemia, pO 2 (O 2 dissolved in plasma) is normal, too); when O 2 diffuses into the RBC, CO already sitting there, and CO has a higher affinity for heme. To treat, give 100% O 2 . Decrease of O 2 sat’n = clinical evidence is cyanosis

Not seen in CO poisoning b/c cherry red pigment MASKS it, therefore makes the diagnosis hard to make. MC symptom of CO poisoning = headache

b. Methemoglobin:

Methemoglobin is Fe3+ on heme group, therefore O 2 CANNOT bind. Therefore, in methemoglobin poisoning, the only thing screwed up is O 2 saturation (b/c the iron is +3, instead of +2). Example: pt that has drawn blood, which is chocolate colored b/c there is no O 2 on heme groups (normal pO 2 , Hb concentration is normal, but the O 2 saturation is not normal); “seat is empty, but cannot sit in it, b/c it’s +3”. RBC’s have a methemoglobin reductase system in glycolytic cycle (reduction can reduce +3 to +2).

Example: Pt from rocky mountains was cyanotic; they gave him 100% O 2 , and he was still cyanotic (was drinking water in mtns – water has nitrites and nitrates, which are oxidizing agents that oxidize Hb so the iron become +3 instead of +2). Clue was that O 2 did not correct the cyanosis. Rx: IV methaline blue (DOC); ancillary Rx = vitamin C (a reducing agent). Most recent drug, Dapsone (used to Rx leprosy) is a sulfa and nitryl drug. Therefore does two things: 1) produce methemoglobin and 2) have potential in producing hemolytic anemia in glucose 6 phosphate dehydrogenase deficiencies. Therefore, hemolysis in G6PD def is referring to oxidizing agents, causing an increase in peroxide, which destroys the RBC; the same drugs that produce hemolysis in G6PD def are sulfa and nitryl drugs. These drugs also produce methemoglobin. Therefore, exposure to dapsone, primaquine, and TMP-SMX, or nitryl drugs (nitroglycerin/nitroprusside), there can be a combo of hemolytic anemia, G6PD def, and methemoglobinemia b/c they are oxidizing agents. Common to see methemoglobinemia in HIV b/c pt is on TMP-SMX for Rx of PCP. Therefore, potential complication of that therapy is methemoglobinemia.

c. Curves: left and right shifts

Want a right shifted curve – want Hb with a decreased affinity for O 2 , so it can release O 2 to tissues. Causes: 2,3 bisphosphoglycerate (BPG), fever, low pH (acidosis), high altitude (have a resp alkalosis, therefore have to hyperventilate b/c you will decrease the CO 2 , leading to an increase in pO 2 , leading to a right shift b/c there is an increase in synthesis of 2,3 BPG).

Left shift – CO, methemoglobin, HbF (fetal Hb), decrease in 2,3-BPG, alkalosis Therefore, with CO, there is a decrease in O 2 sat’n (hypoxia) and left shift.

4. Problems related to problems related to oxidative pathway

a. Most imp: cytochrome oxidase (last enzyme before it transfers the electrons to O 2. Remember the 3 C’s – cytochrome oxidase, cyanide, CO all inhibit cytochrome oxidase. Therefore 3 things for CO – (1) decrease in O 2 sat (hypoxia), (2) left shifts (so, what little you carry, you can’t release), and (3) if you were able to release it, it blocks cytochrome oxidase, so the entire system shuts down

b. Uncoupling – ability for inner mito membrane to synthesize ATP. Inner mito membrane is permeable to protons. You only want protons to go through a certain pore, where ATP synthase is the base, leading to production of ATP; you don’t want random influx of protons – and that is what uncoupling agents do. Examples: dinitrylphenol (chemical for preserving wood), alcohol, salicylates. Uncoupling agents causes protons to go right through the membrane; therefore you are draining all the protons, and very little ATP being made. B/c our body is in total equilibrium with each other, rxns that produce protons increase (rxns that make NADH and FADH, these were the protons that were delivered to the electron transport system). Therefore any rxn that makes NADH and FADH that leads to proton production will rev up


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rxns making NADH and FADH to make more protons. With increased rate of rxns, leads to an increase in temperature; therefore, will also see HYPERTHERMIA. Complication of salicylate toxic = hyperthermia (b/c it is an uncoupling agent). Another example: alcoholic on hot day will lead to heat stroke b/c already have uncoupling of oxidative phosphorylation (b/c mito are already messed up).

These are all the causes of tissue hypoxia (ischemia, Hb related, cyto oxidase block, uncoupling agents). Absolute key things!

5. What happens when there is:

a. resp acidosis – Hb stays same, O 2 sat’n decreased, partial pressure of O 2 decreased (O 2 sat decreased b/c pO 2 is decreased)

b. anemia – only Hb is affected (normal O 2 sat’n and pO 2 )

c. CO/methemoglobin – Hb normal, O 2 sat’n decreased, pO 2 normal

Rx CO – 100% O 2 ; methemo – IV methaline blue (DOC) or vit C (ascorbic acid)

C. Decreased of ATP (as a result of tissue hypoxia)

1. Most imp: have to go into anaerobic glycolysis ; end product is lactic acid (pyruvate is converted to lactate b/c of increased NADH); need to make NAD, so that the NAD can feedback into the glycolytic cycle to make 2 more ATP. Why do we have to use anaerobic glycolysis with tissue hypoxia? Mitochondria are the one that makes ATP; however, with anaerobic glycolysis, you make 2 ATP without going into the mitochondria. Every cell (including RBC’s) in the body is capable of performing anaerobic glycolysis, therefore surviving on 2 ATP per glucose if you have tissue hypoxia. Mitochondrial system is totally shut down (no O 2 at the end of the electron transport system – can only get 2 ATP with anaerobic glycolysis).

Good news – get 2 ATP

Bad news – build up of lactic acid in the cell and outside the cell (increased anion-gap metabolic acidosis with tissue hypoxia) due to lactic acidosis from anaerobic glycolysis.

However, causes havoc inside the cell b/c increase of acid within a cell will denature proteins (with structural proteins messed up, the configuration will be altered); enzymes will be denatured, too. As a result, cells cannot autodigest anymore b/c enzymes are destroyed b/c buildup of acid. Tissue hypoxia will therefore lead to COAGULATION necrosis (aka infarction). Therefore, buildup of lactic acid within the cell will lead to Coagulation necrosis.

2. 2 nd problem of lacking ATP: all ATP pumps are screwed up b/c they run on ATP. ATP is the power, used by muscles, the pump, anything that needs energy needs ATP. Na/K pump – blocked by digitalis to allow Na to go into cardiac muscle, so Ca channels open to increase force of contraction (therefore, sometimes you want the pump blocked), and sometimes you want to enhance it.

With no ATP, Na into the cell and it brings H20, which leads to cellular swelling (which is reversible). Therefore, with tissue hypoxia there will be swelling of the cell due to decreased ATP (therefore will get O 2 back, and will pump it out – therefore it is REVERSABLE).

In true RBC, anaerobic glycolysis is the main energy source b/c they do not have mitochondria; not normal in other tissues (want to utilize FA’s, TCA, etc).

3. Cell without O 2 leads to irreversible changes .

Ca changes with irreversible damage – Ca/ATPase pump. With decrease in ATP, Ca has easy access into the cell. Within the cell, it activates many enzymes (ie phospholipases in the cell membranes, enzymes in the nucleus, leading to nuclear pyknosis (so the chromatin disappears), into goes into the mito and destroys it).

Ca activates enzymes; hypercalcemia leads to acute pancreatitis b/c enzymes in the pancreas have been activated. Therefore, with irreversible changes, Ca has a major role. Of the two that get damaged (mito and cell membrane), cell membrane is damaged a lot worse, resulting in bad things from the outside to get into the cell. However, to add insult to injury, knock off mitochondria (energy producing factory), it is a very bad situation (cell dies)…CK-MB for MI, transaminases for hepatitis (SGOT and AST/ALT), amylase in pancreatitis.

II. Free Radicals

Liver with brownish pigment – lipofuscin (seen on gross pic; can also be hemosiderin, bilirubin, etc; therefore need to have a case with the gross pic); end products of free radical damage are lipofuscin b/c certain things are not digestible (include lipids).

A. Definition of free radical – compound with unpaired electron that is out of orbit, therefore it’s very unstable and it will damage things.

B. Types of Free Radicals:

1. Oxygen: We are breathing O 2 , and O 2 can give free radicals. If give a person 50% O 2 for a period of time, will get superoxide free radicals, which lead to reperfusion injury, esp after giving tPA when trying to rid a damaged thrombus. Oxygentated blood goes back into the damaged cardiac muscle=reperfusion injury. Kids with resp distress syndrome can get free radical injury and go blind b/c they destroy the retina – called retinopathy prematurity; also leads to bronchopulmonary dysplasia, which leads to damage in the lungs and a crippling lung disease.



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2. Water in tissues converted to hydroxyl free radicals, leading to mutations in tissues. Complication of radiation therapy is CANCER (MC cancer from radiation is leukemia, due to hydroxyl free radicals). Fe2+ produces hydroxyl free radicals b/c of the fenton rxn. This is what makes Fe overload diseases so dangerous, b/c wherever Fe is overloaded, leads to hydroxyl free radicals which will damage that tissue (therefore, in liver leads to cirrhosis, in heart leads to restrictive cardiomyopathy, in pancreas leads to failure, and malabsorption, along with diabetes).

Audio file 2: Cell Injury 2

3. Tylenol (aka acetaminophen):

MCC drug induced fulminant hepatitis b/c free radicals (esp targets the liver, but also targets the kidneys). Cytochrome P450 in liver metabolizes drugs, and can change drugs into free radicals. Drugs are often changed in the liver to the active metabolite – ie phenytoin. Where in the liver does acetaminophen toxicity manifest itself? – right around central vein. Treatment: n-acetylcysteine; how? Well, the free radicals can be neutralized. Superoxide free radicals can be neutralized with supraoxide dismutase (SOD). Glutathione is the end product of the hexose/pentose phosphate shunt and this shunt also generates NADPH. Main function is to neutralize free radicals (esp drug free radicals, and free radicals derived from peroxide). Glutathione gets used up in neutralizing the acetaminophen free radicals. Therefore, when give n-acetylcysteine (aka mucamist); you are replenishing glutathione, therefore giving substrate to make more glutathione, so you can keep up with neutralizing acetaminophen free radicals. (like methotrexate, and leukoverin rescue – using up too much folate, leukoverin supplies the substrate to make DNA, folate reductase).

4. Carbon tetrachloride: CCl4 can be converted to a free radical in the liver (CCl3) in the liver, and a free radical can be formed out of that (seen in dry cleaning industry).

5. Aspirin + Tylenol = very bad for kidney (takes a long time for damage to be seen). Free radicals from acetaminophen are destroying the renal medulla *only receives 10% of the blood supply-relatively hypoxic) and renal tubules. Aspirin is knocking off the vasodilator PGE2, which is made in the afferent arteriole. Therefore AG II (a vasoconstrictor) is left in charge of renal blood flow at the efferent arteriole. Either sloughing of medulla or destroyed ability to concentrate/dilute your urine, which is called analgesic nephropathy (due mainly to acetaminophen).

III. Apoptosis

Programmed cell death. Apoptotic genes – “programmed to die” (theory). Normal functions: (1) embryo – small bowel got lumens from apoptosis. (2) King of the body – Y c’some (for men); MIF very imp b/c all mullarian structures (uterus, cervix, upper 1/3 of vagina) are gone, therefore, no mullarian structures. MIF is a signal working with apoptosis, via caspasases. They destroy everything, then wrap everything in apoptotic bodies to be destroyed, and lipofuscin is left over. (3) For woman – X c’some; only have one functioning one b/c the other is a barr body. Absence of y c’some caused germinal ridge to go the ovarian route, therefore apoptosis knocked off the wolfian structures (epidydymis, seminal vesicles, and vas deferens). (4) Thymus in anterior mediastinum – large in kids; if absent, it is DiGeorge syndrome (absent thymic shadow), and would also have tetany; cause of thymus to involute is apoptosis. (5) Apoptosis is the major cancer killing mechanism. (6) Process of atrophy and reduced cell or tissue mass is due to apoptosis. Ex. Hepatitis – councilman body (looks like eosinophilic cell without apoptosis) of apoptosis (individual cell death with inflammation around it). Just needs a signal (hormone or chemical) which activate the caspases, and no inflammation is around it. Apoptosis of neurons – loss brain mass and brain atrophy, and leads to ischemia. Red cytoplasm, and pynotic nucleas. Atherosclerotic plaque. Therefore, apoptosis is involved in embryo, pathology, and knocking off cancer cells.

IV. Types of necrosis – manifestations of tissue damage.

A. Coagulation Necrosis : Results often from a sudden cutoff of blood supply to an organ i.e. Ischemia (definition of ischemia = decrease in arterial blood flow). In ischemia, there is no oxygen therefore lactic acid builds up, and leads to coagulation necrosis. Gross manifestation of coagulation necrosis is infarction. Under microscope, looks like cardiac muscle but there are no striations, no nuclei, bright red, no inflammatory infiltrate, all due to lactic acid that has denatured and destroyed all the enzymes (cannot be broken down – neutrophils need to come in from the outside to breakdown). Therefore, vague outlines = coagulation necrosis (see color change in heart).

1. Pale vs hemorrhagic infarctions: look at consistency of tissue.

(a) Good consistency = grossly look pale: infarct: heart, kidney, spleen, liver (rarest of the organ to infarct b/c dual blood supply); ie coagulation necrosis. Example of a pale infarction of the spleen, most likely due to emboli from left side of heart; causes of emboli: vegetations (rarely embolize in acute rheumatic endocarditis); infective endocarditis; mitral stenosis (heart is repeatedly attacked by group A beta hemolytic streptococcus); and clots/thrombi. The worst arrhythmia associated with embolization in the systemic circulation is atrial fib b/c there is stasis in the atria, clot formation, then it vibrates (lil pieces of clot embolize).

Gangrenous Necrosis: dry and wet gangrene: Picture of a dry gangrene – not wet gangrene b/c there’s no pus. Occurs in diabetic’s with atherosclerosis of popliteal artery and possible thrombosis; (dry gangrene related to coagulation necrosis related with ischemia (definition of ischemia = decrease in arterial blood flow), which is due to atherosclerosis of the popliteal artery. Pathogenesis of MI: coronary thrombosis overlying the atheromatous plaque, leading to ischemia, and lumen is blocked due to thrombosis. MCC nontraumatic amputation = diabetes b/c enhanced atherosclerosis (popliteal artery = dangerous artery). Coronary is also dangerous b/c small lumen. In wet gangrene, it’s complicated by infective heterolysis and consequent liquefactive necrosis.


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