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Audio file 1 Cellular Injury 1

By Audrey Marshall,2014-12-06 15:26
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Medullary segment of thick ascending limb where the NaK-2Cl pump isthis is also where Na is reabsorbed, and thiazides block this channel.

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     Nut Audio file 1: Cellular Injury 1

    CHAPTER 1: CELLULAR REACTION TO INJURY

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 for oxidation 2

    phosphorylation pathway where you get ATP from inner Mito membrane (electron transport system, called oxidative phosphorylation). The last rxn is O to receive the electrons. Protons are being kicked off, 2

    go back into the membrane, and form ATP, and ATP in formed in the mitochondria

    A. Terms:

    1. Oxygen content = Hb x O satn + partial pressure of arterial oxygen 2

    (these are the 3 main things that carry O in our blood) 2

    In Hb, the O attaches to heme group (O sat‟n) 22Partial pressure of arterial O is O dissolved in plasma 22

    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 on it, the O sat‟n is 100%. 22

    2. O sat’n is the O IN the RBC is attached TO the heme group = (measured by a pulse 22

    oximeter)

    3. Partial pressure of O is O dissolved in PLASMA 22

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

    RBC on the Hb, which is the Osat‟n 2

    Therefore if partial pressure of O is decreased, Osat‟n HAS to be decreased (B/c O came 22 2

    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. nd2. 2 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 (O dissolved in arterial plasma, therefore, when the particle pressure of O is decreased, this 222

    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, CO, and nitrogen; nitrogen 22

    remains constant therefore, when you retain CO, this is resp acidosis; when COgoes up, 22

    pO HAS to go down b/c must have to equal 760; 2

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    Therefore, every time you have resp acidosis, from ANY cause, you have hypoxemia b/c low arterial pO; increase CO= decrease pO, and vice versa in resp alkalosis). 222

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 for 20 minutes, and pO did not increase, 22

    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 for a perfusion 2

    defect, pO will go UP (way to distinguish vent from perfusion defect), b/c not every single 2

    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 and see whether the pO 22

    stays the same, ie does not go up (shunt) or increases (increase in dead space).

d. Diffusion defect something in the interphase that O cannot get through…ie fibrosis. 2

    Best exampleSarcoidosis (a restrictive lung disease); O already have trouble getting 2

    through the membrane; with fibrosis it is worse. Another examplePulmonary 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). There is 2

    NO hypoxemia in anemia, there is normal gas exchange (normal respiration), therefore normal pO and Osaturation, but there is a decrease in Hb. That is what anemia is: 22

    decrease in Hb. If you have 5 gm of Hb, there is not a whole lot of O that gets to tissue, 2

    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 SAT‟N will be decreased 2

    b/c its sitting on the heme group, instead of O (remember that CO has a 200X affinity for Hb). 2

(Hb is normal its NOT anemia, pO (O dissolved in plasma) is normal, too); when O 222

    diffuses into the RBC, CO already sitting there, and CO has a higher affinity for heme. To treat, give 100% O. Decrease of O sat‟n = clinical evidence is cyanosis 22

    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:

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Methemoglobin is Fe3+ on heme group, therefore O CANNOT bind. Therefore, in 2

    methemoglobin poisoning, the only thing screwed up is O saturation (b/c the iron is +3, 2

    instead of +2). Example: pt that has drawn blood, which is chocolate colored b/c there is no O on heme groups (normal pO, Hb concentration is normal, but the O saturation is not 222

    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, and he was still 2

    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 did not correct 2

    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, so it can release Oto 22

    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, leading to a right shift b/c there is an increase in synthesis of 2

    2,3 BPG).

Left shift CO, methemoglobin, HbF (fetal Hb), decrease in 2,3-BPG, alkalosis

    Therefore, with CO, there is a decrease in Osat‟n (hypoxia) and left shift. 2

    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 Osat (hypoxia), (2) left shifts (so, what little you 2

    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 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).

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    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, Osat‟n decreased, partial pressure of Odecreased (O2 2 2

    sat decreased b/c pOis decreased) 2 b. anemia only Hb is affected (normal Osat‟n and pO) 2 2

    c. CO/methemoglobin Hb normal, Osat‟n decreased, pOnormal 2 2

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

    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 Oat the end of the electron 2

    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.

     nd2. 2 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 Oback, and will pump it out therefore it is REVERSABLE). 2

    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 Oleads to irreversible changes. 2

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

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    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, and Ocan give free radicals. If give a person 50% Ofor a 22 2

    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.

    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

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    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.

    (b) Loose consistency of tissue= hemorrhagic infarct: bowel, testes (torsion of the testes),

    especially the lungs b/c is has a loose consistency and when the blood vessels rupture, the

    RBC‟s will trickle out, leading to a hemorrhagic appearance.

     ndExample: hemorrhagic infarction of small bowel due to indirect hernia. 2 MCC of bowel

    infarction is getting a piece of small bowel trapped in indirect hernial sac. MCC of bowel

    infarction is adhesions from previous surgery.

    Example: In the Lung hemorrhagic infarction, wedge shaped, went to pleural surface, therefore

    have effusion and exudates; neutrophils in it; have pleuritic chest pain (knife-like pain on

    inspiration). Pulmonary embolus leads to hemorrhagic infarction.

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B. Liquefactive Necrosis:

    Exception to rule of Coagulation necrosis seen with infarctions: brain.

    MC site of infarction from carotid artery why we listen for a bruit (hearing for a noise that is

    going thru a vessel that has a narrow lumen place with thrombus develops over atherosclerotic

    plaque and leads to stroke); leads to transient ischemic attacks is little atherosclerotic plaques

    going to little vessels of the brain, producing motor and sensory abnormalities, that go away in 24

    hrs. Brain with „meshwork‟ – in brain, astrocytes is analogous to the fibroblasts b/c of

    protoplasmic processes. Therefore, acting like fibroblast (can‟t make collagen), but its

    protoplasmic processes gives some structure to the brain. Therefore, infarction of the brain

    basically liquefies it (has no struct), and you see a cyst space liquefactive necrosis.

    Therefore, exception to the rule of infarctions not being coagulative necrosis is the brain and it

    undergoes liquefactive necrosis (no struc, therefore leaves a hole). Cerebral abscess and old

    atherosclerotic stroke -both are liquefactive necrosis.

    Liquefactive liquefies; think neutrophil, b/c their job is to phagocytosis with their enzymes (to

    „liquefy‟); liquefactive necrosis relates to an infection with neutrophils involved (usually acute

    infection producing an abscess or an inflammatory condition, which liquefies tissue). Therefore,

    liquefactive necrosis usually applies to acute inflammation, related to neutrophils damaging the

    tissue. Exception to the rule: liquefactive necrosis related to infarct (not an inflammatory

    condition, it just liquefies) (slide shows liquefactive necrosis due to infection in the brain). So, if

    you infarct the brain, or have an infection, or have an abscess it is the same process

    liquefactive necrosis.

    Example: Abscess gram “+” cocci in clusters. Why are they in clusters? Coagulase, which

    leads to abscesses with staph aur. Coagulase converts fibrinogen into fibrin, so it localizes the

    infection, fibrin strands get out, resulting in an abscess. Strep: releases hyaluronidase, which

    breaks down GAG‟s in tissue, and infection spreads through the tissue (cellulitis). From point of

    view of necrosis, neutrophils are involved, therefore it is liquefactive necrosis.

    Example: ABSCESS: Lung yellowish areas, high fever and productive cough; gram stain

    showed gram “+” diplococcus, which is strep pneumoniae. (MCC of bronchopneumonia.). Not

    hemorrhagic b/c its pale, and wedged shaped necrosis at the periphery, which leads to pleuritic

    chest pain.

    Example: pt with fever, night sweats, wt loss M tb, which has granulomatous (caseous) necrosis.

    Pathogenesis of granuloma (involves IL-12 and subset of helper T cells and “+” PPD).

C. Caseous (cheesy consistency) Necrosis: either have mycobacterial infection (any infections,

    including atypicals, or systemic fungal infection); these are the ONLY things that will produce caseation in a granuloma. It is the lipid in the cell wall of the organism‟s leads to cheesy appearance.

    Sarcoidosis get granulomas, but they are not caseous b/c they are not mybacterium or systemic fungi (hence „noncaseating‟ granulomas)

    Crohn‟s dz – get granulomas, but not caseous b/c not related to mycobacterium or systemic fungi.

D. Fat Necrosis:

    1. Enzymatic Fat Necrosis: unique to pancreas

    Example: pt with epigastric distress with pain radiating to the back pancreatitis (cannot be

    Peptic Ulcer Dz b/c pancreas is retroperitoneal), therefore just have epigastric pain radiating to

    the back. A type of enzymatic FAT necrosis (therefore necrosis related to enzymes). Enzymatic

    fat necrosis is unique to the pancreas b/c enzymes are breaking down fats into FA‟s, which

    combine with Ca salts, forming chalky white areas of enzymatic fat necrosis (chalky white areas

    due to calcium bound to FA‟s – saponification (soap/like salt formation)); these can be seen on

    xrays b/c have calcium in them. Example: A pt with pain constently penetrating into the back,

    show x-ray of RUQ. Dx is pancreatitis and esp seen in alcoholics. Histo slide on enzymatic fat

    necrosis bluish discoloration, which is calcification (a type of dystrophic calcification-calcification

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    of damaged tissue). What enzyme would be elevated? Amylase and lipase (lipase is more

    specific b/c amylase is also in the parotid gland, small bowel, and fallopian tubes). What type of

    necrosis? Another example: Enzymatic fat necrosis. Underlying cause? Alcohol produces a thick

    secretion that will lead to activation of enzymes; which leads to pancreatitis. Therefore, whenever

    you see blue discoloration and atherosclerotic plaque in a pancreas, it will be calcium.

    2. Traumatic Fat Necrosis: Example: woman with damage to breasts is TRAUMATIC FAT

    necrosis (not enzymatic); it can calcify, can look like cancer on mammogram. Diff btwn that and

    calcification in breast cancer is that it is painFUL. (cancer = painless). Traumatic fat tissue

    usually occurs in breast tissue or other adipose tissue

E. Fibrinoid necrosis: (the -oid means: looks like, but isn‟t)

    Therefore, looks like fibrin, but is not fibrin….it is the necrosis of immunologic dz:

    Examples of immunologic dz:

    Palpable purpura = small vessel vasculitis (immune complex type III).

    Fibrinoid necrosis has immune complex deposition of small vessel.

    Pathogenesis of immune complex: damage of type III HPY (an immune complex is an Ag-Ab

    circulating in the circulation; it deposits wherever circulation takes it ie glomerulus, small vessel,

    wherever). It activates the complement system (the alt system), which produces C5a, which is

    chemotactic to neutrophils. Therefore, damage done as a result of type III HPY is done by

    neutrophils. And they are there b/c the immune complex activated the alternative complement

    system. The complex has little to do with the damage, it‟s the neutrophils do eventual damage)

    Henoch-Scholein purpura feel person‟s legs, and see palpable purpura (due to type III HPY).

    Rhematic fever (vegetations off the mitral valve) have fibrin like (fibrinoid necrosis) materials

    (necrosis of immunologic dz). Morning stiffness = rheumatoid arthritis, see fibrnoid necrosis b/c

    immunologic damage. Therefore, fibrinoid necrosis is necrosis of immunologic damage (in vessel

    it‟s a vasculitis, in kidney it‟s a glomerulonephritis, and in lupus glomerulonephritis involving

    immune complexes).

    F. Liver: Triad area: portal vein, hepatic artery, bile duct. Liver is unique b/c it has dual blood supply and so hepatic artery and and portal vein will dump blood into sinusoids. Other examples of sinusoid organs are BM and spleen. Characteristic of sinusoids: gaps between endothelial cells, with nothing there so things can fit through (things like RBC‟s and inflammatory cells). GBM is fenestrated, have little tiny pores within the cells, for filtration. Sinusoids have gaps so large cells can get through them (not true with GBM b/c it is intact, and lil pores allow filtration). Portal vein blood and hepatic artery blood go through sinusoids, and eventually taken up by central vein, which becomes the hepatic vein. The hepatic vein dumps into the inf vena cava, which goes to the right side of the heart. Therefore, there is a communication between right heart and liver. Right HF (blood fills behind failed heart), therefore the liver becomes congested with blood, leading to nutmeg liver (aka congestive hepatomegaly). If you block the portal vein, nothing happens to the liver, b/c it is BEFORE the liver.

    Blockage of hepatic vein leads to budd chiari and liver becomes congested. Which part of liver is

    most susceptible to injury normally? Around central vein, b/c it gets first dibbies on O coming out of 2

    the sinusoids (zone 1). Zone 2 is where yellow fever will hit (midzone necrosis) due to ides egypti. Zone 3, around portal vein, which will have least O (analogous to renal medulla, which only receives 2

    10% of the blood supply, and the cortex receives 90%). Fatty change is around zone 3 (part around central vein). Therefore, when asking about acetaminophen toxicity, which part is most susceptible? Around the central vein b/c it gets the least amount O, and therefore cannot combat free radical 2

    injury.

    1. Alcohol related liver damage:

    (a) MCC fatty change: alcohol.

    (b) Metabolism of alcohol: NADH and acetyl CoA (acetate is a FA, and acetyl CoA can be

    converted to FA‟s in the cytosol). NADH is part of the metabolism of alcohol, therefore, for

    biochemical rxns: What causes pyruvate to form lactate in anaerobic glycolysis? NADH drove

    it in that direction, therefore always see lactic acidosis (a form of metabolic acidosis) in

    alcoholic‟s b/c increased NADH drives it in that direction. Also, in fasting state, alcoholic will

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    have trouble making glucose by gluconeogenesis b/c need pyruvate to start it off. However,

    you have lactate (and not pyruvate) therefore alcoholics will have fasting hypoglycemia.

    Acetyl CoA can also make ketone bodies (acetoacetyl CoA, HMG CoA, and beta

    hydroxybutyric acid). See beta hydroxybutyric ketone bodies in alcoholic‟s b/c it‟s a NADH

    driven reaction. Therefore, two types of metabolic acidosis seen in alcoholics are lactic

    acidosis (b/c driving pyruvate into lactate) and increased synthesis of ketone bodies b/c

    excess acetyl CoA; main ketoacid = beta hydroxybutyric acid. Why does it produce fatty

    change? In glycolysis, around rxn 4, get intermediates dihydroxyacetone phoshphate (NADH

    rxn) and is forced to become glycerol 3-phosphate. Big time board question! With glycerol 3

    phosphate shuttle, get ATP. Also imp to carbohydrate backbone for making tryglycerides

    (add 3 FA‟s to glycerol 3 – phosphate, and you get TG‟s). In liver, the lipid fraction if VLDL

    (endogenous TG is synthesized in the liver from glycerol 3 phosphate derived from

    glycolysis). Restricting fat will NOT decrease the synthesis of VLDL. Restricting carbs WILL

    decrease the VLDL synthesis b/c it is glucose intermediate it is made from. Glycerol 3

    phosphate is a product of glycolysis which is why fatty liver is MC‟ly due to alcoholism (this

    rxn)!

    Audio file 3: Inflammation 1

    2. Kwashiorker kid with fatty change. The mechanism: when you make VLDL, and to be able

    to get it out of the liver, the VLDL must be surrounded by apoproteins. In kwashiorkor, there is

    decreased protein intake; they have adequate number of calories, but its all carbs. Therefore,

    they cannot get VLDL that they made in the liver out b/c there are no apolipoproteins to cover it

    and put it out in the bloodstream and solubilize it in water. Lipid and water do not mix; therefore it

    is necessary to put proteins around the lipid to dissolve it in water. Therefore, the protuberant

    abdomen in these pts is there for two reasons: 1) decreased protein intake which decreases

    oncotic pressure, leading to ascites. 2) The biggest reason is that they have huge livers related

    to fatty change. The mechanism for fatty change is different from alcohol b/c in alcohol; the mech

    is due to increased synthesis of VLDL. In this case, there is a lack of protein to put around the

    VLDL and export it out of the liver.

    3. Hemosiderin and Ferrtin: brief discussion: Ferritin = soluble form of circulating Fe, and is a

    good marker for Fe in BM. It is the test of choice in dx‟ing any Fe related problem – Fe def

    anemia, or Anemia of Chronic Dz or Fe overload dz‟s such as hemochromatosis and

    hemosiderosis (would be elevated). Ferritin is a soluble form of Fe, while hemosiderin is an

    insoluble form of Fe storage, and is stored in macrophages and BM. Stain it with Prussian blue.

    V. Types of calcification: dystrophic and metastatic

    A. Dystrophic calcification: means abnormal calcification. The damaged tissue gets calcified.

    1. Example: Seen in enzymatic fat necrosis (chalky white areas on x-ray are a result of

    dystrophic calcification).

    2. Example: football player with hematoma in foot, that becomes calcified dsystrophically (Ca

    binds and co-produces dystrophic Ca deposits). Serum Ca is normal, but damaged tissue

    becomes calcified. Occurs in atheromatous plaques (causes serious tissue damage), therefore

    they are difficult to dissolve (need to be on the ornish diet a vegan diet).

    3. MCC aortic stenosis (MCC: congenital bicuspid aortic valve) = dystrophic calcification (also

    leads to a hemolytic anemia). Slide: the aorta has only 2 valves doing the job of three, and gets

    damaged, leading to dystrophic calcification which narrows orifice of valve, leading to aortic

    stenosis.

B. Metastatic calcification: In cases of Hypercalcemia or hyperphosphatemia, Calcium is actually

    made to deposit in normal tissues, non-damaged tissues.

    MCC hypercalcemia (outside of hospital) = primary hyperparathyroidism

    MCC hypercalcemia (inside the hospital) = malignancy induced hypercalcemia.

    With hypercalcemia, can put Ca in NORMAL tissues; this is called metastatic calcification. In dystrophic calcification there is damaged tissue with normal serum Ca levels. Metastatic calcification is when there is high Ca or phosphorus serum levels (actually when Ca is deposited into bone, it is

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    the phosphorus part of solubility product that drives Ca into bone). High phosphate levels (very dangerous) will take Ca and drive it into normal tissue. This is why have to put a pt with renal failure on dialysis (have high phosphorus serum levels) therefore need to dialyze the phosphate b/c the phosphate will drive Ca into normal tissue ie heart, conduction system, renal tubules, basement

    membrane (nephrocalcinosis) all lead to damage.

    VI. Cell Membrane Defects

A. RBC membrane defect: Spherocytosis is a defect in spectrin within RBC cell membrane; if you

    can‟t see a central area of pallor (if you don‟t see a donut) then it‟s a spherocyte. Absence of spectrin

    with in the RBC does not allow the RBC to form a biconcave disk; it is defective, and therefore forms a sphere.

    B. Ubiquitin stress protein. High ubiquitin levels are associated with high levels of stress. Some of the intermediate filaments (keratin, desmin, vimentin) are part of the superstructure of our cells (“frame of the cell”, upon which things are built). When these intermediate filaments get damaged, the

    ubiquitin marks then for destruction. The intermediate filaments have been tagged (ubiquinated) and marked for destruction. Some of these products have names, for example: there are open spaces

    within the liver tisse, these spaces are fat and they are probably due to alcohol. The ubiquinited products of the liver are called Mallory bodies. These are the result of ubiquinated filaments called

    keratin and these are seen in alcoholic hepatitis. Another example: Silver stain of neurofibilary

    tangles Jacob crutzfelt and alzheimers dz. Tau protein is associated with neurofib tangles; this is an example of a ubiquinated neurofilament. Example: Substantia nigra in Parkinson‟s Dz – include

    inclusions called Lewy bodies, neurotransmitter deficiency is dopamine. Lewy bodies are ubiquinated neurofilaments. Therefore, Mallory bodies, Lewy bodies, and neurofib tangles are all examples of ubiquintation.

    VII. Cell Cycle- very very important: big big big time

A. Different types of cells:

    1. Labile cells cell where the division is via a stem cell. Three tissues that has stem cells: bone

    marrow, basement membrane of skin, and the base of crypts in the intestine. These cells have

    the tendency of being in the cell cycle a lot. In pharm: there are cell cycle specific and cell cycle

    nonspecific drugs. The cells that are most affected by these drugs are the labile cells b/c they are

    in the cell cycle. Complications of these drugs are BM suppression, diarrhea, mucocidis, and

    rashes on the skin (there are stem cells in all these tissues!).

    2. Stable cells in resting phase, G phase. Most of perenchymal organs (liver, spleen, and o

    kidney) and smooth muscle are stable cells. Stable cells can ungo division, but most of the time

    they are resting, and something must stimulate them to get into the cell cycle and divide ie a

    hormone or a growth factor. For example: estrogen in woman will help in the proliferative phase

    of the menstrual cycle. The endometrial cells are initially in the G phase and then the estrogen o

    stimulated the cells to go into the the cell cycle. Therefore, they can divide, but they have to be

    invited by a hormone or a growth factor.

    3. Permanent cells can no longer get into the cell cycle, and have been permanently

    differentiated. The other types of muscle cells: striated, cardiac and neuronal cells. Only muscle

    that is NOT a permanent tissue = smooth muscle; hyperplasia = increase in #, while hypertrophy

    = increase in size. Would a permanent cell be able to under hyperplasia? NO, b/c that means

    more copies of it. Can it go under hypertrophy? Yes. A smooth muscle cell can undergo

    hyperplasia AND hypertrophy.

B. Different phases of cell cycle:

    1. G phase: The most variable phase of cell cycle is the G phase. Compare with menstrual 11

    cycle: The most variable phase is the proliferative phase (not the secretory phase). The

    prolifertive phase varies with stress; however, once ovulation has occurred, it is 14 days.

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