Episode 48: In this episode, you’ll learn about cell death, types of necrosis and lots of examples of pathophysiologic states that exemplify each condition.
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Apoptosis – Programmed cell death
Normal functions of apoptotic genes – “programmed to die” (theory).
(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 pycnotic 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).
Pale vs hemorrhagic infarctions: look at consistency of tissue. 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).
B. Gangrenous Necrosis: dry and wet gangrene:
Picture of a dry gangrene – not wet/no pus. This commonly 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. 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.
Example: hemorrhagic infarction of small bowel due to indirect hernia. 2nd 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.
C. 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).
D. 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.
E. Fat Necrosis:
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 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.
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). Rheumatic 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 dibbs on O2 coming out of the sinusoids (zone 1). Zone 2 is where yellow fever will hit (midzone necrosis) due to ides egypti. Zone 3, around central vein, which will have least O2 (analogous to renal medulla, which only receives 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 O2, and therefore cannot combat free radical 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 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)!
2. Kwashiorkor – kind 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.
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). Essentially, 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 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.