PATHOLOGY NOTES DR. GOLJAN GENERAL PATHg Note: This material is copyrighted. All rights reserved TABLE OF CONTENTS FOR GENERAL PATHOLOGY NOTES Prepared by Edward Goljan, M.D. Subject : Pages General Principles of Lab Medicine 1-8 Ic ell Injury a 98 22 | Inflammation oe 23-41 - Immunopathology 7 i 42-59 Fluids and Hemodynamics/Acid-Base _ | 60-92 i Nutrition a 7 a 93-117 Genetics 118-158 » Environmental Pathology a 1159-186 Neoplasia : 187-373 —_ a LNote: This material is copyrighted. All rights reserve GOLJAN HIGH YIELD NOTES FOR USMLE STEP 1 Note: This mi righted. All rig erved. No part of this publication may be repro 1 ny form or by any means, electronic or mechanical. including photocopy, recording, or any information ind retrieval system, without permission in writing from the publisher (Edward F. Goljan, M Abbreviations commonly used: AD = autosomal dominant, AR = autosomal recessive, COD = cause’ death, Dx = diagnosis, MC = most common, MCC = most common cause; Rx = treatment, S/S a mptoms, SXR = sex-linked rece High Yield Concepts in General Pathology General Principles of Lab Medicine Sensitivity of a test | “positivity in disease" A. TP = patient with the disease B. FN = patient with disease who has a negative test result C. formula for sensitivity TP /TP-+ EN use of a test with 100 % sensitivity— A. best used to screen for disease B. excludes disease when negative C. _imeludes people with disease when positive D. catch words: excludes and includes interpretation of a test with 100% sensitivity when it returns normal in a pati A ways has @ negative predictive value of 100% (PV-= TN// TN + EN B. it must be a TN test result (excludes disease) since there are no FNs: a TN isa tne tive or a normal test result in a person without disease " [ serum ANA has 100% sensitivity for SLE: a negative serum ANA excludes interpretation of a test with 100% sensitivity when it returns positive in a patient A. may bea TP or FP: 1) FP= false positive or a positive test result in a normal person note that FPs are not in the formula for sensitivity B. people with the disease are alw. e.g. a positive serum ANA result includes all people with SLE: it does not confirm S| since other diseases also have a positive ANA (e.g. rheumatoid arthritis, progressive Disease No Disease Positive test (TP) 100 (FP) 10 . Negative test (FN) 0 (TN) 90 @ Calculate sensitivity of the test: T 00 £ 100 = 0 = 1008 Calculate PV: TN / TN + FN = 90 10% Specificity of a test "negativity in health’ A. -TN=normal test result in a person without dis B. _ PP= patient without disease who has a positive teNote: This material is copyrighted, Al rights reserved CC. formula for specificity TN / TN + FP use of a test with 100% spe Positive test must be a TP interpretation of a test with 100% specificity when it returns positive in a patien A. confirms disease in that patient B. positive predictive value is always 100% (PV" = TP / TP + EP) must be a TP (confirms disease) since there are no FPs D. eg, anti-Sm for SLE has 100% specificity (no FPs): all patients with a positive anti have SLE 4. interpretation of a test with 100% specificity when it returns negative/normal in a patient A. may be a TN or FN: note that the FN rate is n B. _itdoes not exclude SLE C. eg, anti-Sm is negative in a patient (1) does not exclude SLE (2) _ use other tests to confirm fcity—- confirms disease: there are no FP test results, therefore, a in the formula for spe if your suspicions are high Disease No Disease Positive test (TP) 90 (FP) 0 Negative test (FN) 10 (EN) 100 Calculate specificity of the test: TN / TN + FP = 100 / 100+ 0= 100% Calculate PV": TP /TP + FP =90/90-+0= 100% ‘Calculate the reference interval of the test when given the mean of the test and 1 SD (standard deviation): 1. remember to double the SD- 2 SD covers 95% of the normal population example— A. — mean of the test = 100 mg/dL, and 1 SD=5 mg/dL. (2 SD= 10 mg/dL) B. reference interval = 90-110 mg/dL (100 - 10 = 90 and 100 + 10 = 110) 3. for each test, 5% of normal people will have test results outside the reference interval: A. chance of a FP increases when more than one test is ordered on a patient B. example, 2 tests on a patient increases the chance of a FP test result on one of those tests to~10% 4. SD is a marker of the precision (reproducibility) of the test it is not a marker of how accurate the test result is Accuracy: good ‘Accuracy: poor Precision: good Precision: good ‘ Bffect of test sensitivity/specificity of a test on prevalence: 1. test with highest sensitivity (not specificity) increases prevalence of disease (number of people in a population that have disease)~ A. it picks up more people with the disease since it is a good screening test B. tests with high specificity confirm disease and help differentiate a TP from a FP but they are poor screening testsE Note: This material is copyrighted. All rights reserved Effect of increasing the upper limit of normal of a test reference interval (c.g. raising a reference interval of 0-4 ng/mL to 0-10 ng/mL) on sensitivity, specificity, PV", and PV": 1. inereases specificity and positive predictive value A. higher values are more likely to represent. TPs than FPs B. specificity always increases, which automatically increases PV 2. decreases sensitivity and negative predictive value (PV>) A. increasing specificity of a test always decreases its sensitivity and PV B. _ EN rate increases, since more people with disease are encountered as the reference interval increases C. anormal test result is more likely to be a FN rather than a TN Effect of decreasing the upper limit of normal of a test reference interval (e.g., lowering the fasting glucose level for diagnosing diabetes mellitus [DM] from >140 mg/dL. to >126 mg/dL) on ficity, PV", and PV increases sensitivity and negative predictive value (PV) — A. dropping the upper limit to a lower value means that more people with a negative test result are likely to be TNs (not have DM) rather than FNs B. _ sensitivity and PV" always increase when the upper limit of a testis lowered 2. decreases specificity and positive predictive value (PV"}~ A. fewer people are likely to have DM, a test result >126 n than a TP test result B. summary schematic Lis more likely to be a FP Normal Disease 0 —> Interval 0 ~ 4 Sensitivity 100% (no FNs) PV" 100% Specificity decreases PV" decreases > Interval 0 ~ 10 Specificity 100% (no FPs) PV" 100% Sensitivity decreases PV" decreases Prevalence: |. Brevalence (number of people with disease in the population studied) = Incidence (aumber of new eases over a period of time) x Duration of the disease A. xD B. as duration (D) decreases, prevalence (F decreasesDISEASE COUNTRY —_—_____» i win Normal Disease Interval 0-10 Specificity 100% (no FPs) Sensitivity decreases (more FNs) PV" 100% PV" decreases (more FNs) Normal Disease 0 4 _ Interval 0-4 Sensitivity 100% (no FNs) Specificity decreases (more FPs) PV 100% PV* decreases (more FPs)Note: This material is copyrighted. All rights reserved C. as D increases, P increases D. incidence (1) isa constant in this relationship 2. prevalence caleulation— TP + FN (all people with disease)/ TP + FN + TN + FP. with and without disease) 3. example— if treatment for leukemis lengthens the survival period but does not lead to its cure, Prevalence (P) of leukemia increases owing to the increase in duration (D): no effect on incidence (number of new cases of leukemia) people Example of a calculation for sensitivity, specificity, PV+, PY-, prevalence: Disease No Disease Positive test (TP) 60 (FP) 40 Negative test. (FN) 20 (EN) 80 Sensitivity of the test: TP / TP + FN = 60 / 80 = 75% Specificity of the test: TN / TN + FP = 80 / 120 = 66% PV": TN/TN + FN = 80/100 = 80% (80% chance it isa TN and a PY": TP / TP+ FP = 60/100 = 60% (60% chance it isa TP and 40% Prevalence; TP + FN / TP + FN + TN + FP = 80 /200= 40% ‘Normal changes in pregnancy greater increase in plasma volume than RBC mass~ A. decreases hemoglobin (Hb) and hematocrit (Het): dilutional effect B. increases glomerular filtration rate (GFR) and creatinine clearance (Cr): due to . increased plasma volume decreases serum BUN/creatinine/uric acid: dilutional effect + increased clearance increased alkaline phosphatase— placental origin respiratory alkalosis— estrogen/progesterone effect on CNS respiratory center causi increased clearance of CO; per breath 4, inereased T, and cortisol A. increased synthesis of their binding proteins B. free hormone levels are normal C. _ no signs of hyperthyroidism/hypercortisolism D. eg, normal serum TSH and ACTH, respectively Main laboratory difference in adult male and female. 1. irom studies are all lower in women ¢.g., serum iron and ferritin 2. lower Hb concentration in women ~ © Children: 1. imcreased serum alkaline phosphatase (ALP)~ A. 3-5 times higher than adults B. osteoblasts release enzyme when stimulated by vita C. ALP increases bone mineralization increased serum phosphate required to drive calcium into bone, slight decrease in hemoglobin concentration when compared to adult levels Y% chance it is a FN) hance it is a FP) q in D ‘F Newborn; high hemoglobin (Hb) due to increase in HbF- 1. leftsh oxygen dissociation curve (ODC): causes tissue hypoxia> stimulus for erythropoietin (EPO) release—> increases RBC production with subsequent increase in Hb concentrationNote: This material is copyrighted. All rights reserved left shifts oxygen dissociation curve (ODC) protects newborns with sickle cell disease A. most of the RBCS at birth contain HbF: inhibits sickling B. less Hbs: (1) concentration not high enough for sickling (2) _HbS must be >60% in RBC for spontaneous sickling (3) dactyltis (bone infaretions of digits) begins in 6-9 mths protects newborn from severe -thalassemia— A. HDF contain 2c: and 2y chains B, adult HbA will be markedly decreased after a few months since B-chain synthesis is decreased: HbA = 20. and 28 HDF synthesis is increased with hydroxyurea— used to reduce sickle cell crises, HDF js resistant to alkali/acid denaturation— basis for Kleihauer Betke test in determining amount of fetal blood in maternal circulation after delivery Analytes inereased with hemolyzed blood sample secondary to venipuncture: 1. LDH A. LDH) isoenzyme fraction is primarily increased and is greater than LDH; isoenzyme fraction (LDHy/LDH: flip) B, false positive acute myocardial infarction C. LDEL isoenzyme is also in cardiac muscle potassium A. pseudohyperkalemia B. _K* is the major intracellular cation C. ECG will not show a peaked T wave Lipid most affected by fasting: 1, triglyceride (TG) component coming from chylomicrons— chylomicrons contain diet- derived TG 2. fasting or lack of fasting does not affect cholesterol (CH) and high-density lipoprotein (EDL) concentration— A. normally, CH is <3% of the chylomicron fraction B, fasting is unnecessary for an accurate CH or HDL fasting is necessary for an accurate calculated low-density lipoprotein (LDL)- A. LDL=CH-HDL-TG/S B. if TG is falsely increased by chylomicrons from the diet, it will falsely lower the calculated LDL Drugs enhancing the cytochrome system in the liver smooth endoplasmic reticulum (SER) 1. drugs A. alcohol B. _ barbiturates effect on SER- ER hyperplasia increased synthesis of y-glutamyltransferase (GGT): enzyme is normally located in SER decreases drug levels owing to increased metabolism of the drug ing eytochrome system in the liver: proton blockersNote: This material is copyrighted. All rights reserved 2. danger of drug tox ity Significance of erythrocyte sedimentation rate (ESR) in old age: probably indicates a disease 5 pre 1, not an age-related finding 2. not recommended as a general sereen for disease in the elderly Laboratory test alterations in alcohol Len \ancement of the liver cytochrome P-450 system. nereased synthesis of y- glutamyltransferase (GGT) B. excellent enzyme marker for alcoholic liver disease 2. imereased production of NADH in its metabolic breakdown causes biochemical reactions involving NADH to move in its direction resulting in the following— ‘A. lactic acidosis: pyruvate— lactate B. fasting hypoglycemia: pyruvate is unavailable for gluconeogenesis C. _ hypertriglyceridemia: 1,3 _bisphosphoglycerate-> dihydroxya phosphate: glycerol 3-phosphate-> TG increase in ketoacid synthesis A. acetyl CoA, the end product of alcohol metabolism is used in the following reaction acetyl CoA + acetyl CoA > cetoacetyl CoA HMG CoA-+ acetoacetic acid: increase in NADH converts it into fi hydroxybutyrie ac (6-OHB) 4, imerease in fatty acid synthesis due to the increase in acetyl CoA 5. hyperuricemia lactic acid/ketoacids compete with uric acid for excretion in the kidneys 6, _ imereased anion gap metabolic acidosis lactate + B-OHB B. zc D. Laboratory test alterations in smokers: 1, respiratory acidosis air gets in but cannot hypoxemia (low PaO;)- see Cell Injury notes inereased carbon monoxide (CO) levels CO is present in cigarette smoke secondary polycythemia— low PaO; stimulates erythropoietin release absolute neutrophilic leukocytosis- metabolites in smoke mobilize the neutrophil marginating pool in the circulation by decreasing leukocyte adhesion to endothelial cells ‘© Plasma/serum turbidity: 1. due to an inerease in tri cholesterol (CH) in plasma TG is carried by lipoproteins— A. chylomicrons: 85% B.__ very low-density lipoprotein (VLDL): 55% TG is falsely increased after eating due to diet-derived chylomicro chylomicrons form a supranate in plasma contain very little protein: less den: ut, so COs is retained lyeeride (TG)- turbidity does not occur with an increase in than VLDL VLDL forms an infranate (no supranate)— contains more protein than chylomicrons and does not float on the surface of plasma increased turbidity interferes with measurement of enzymes and serum Na false ‘enzyme values and sodium (pseudohyponatremia)Note: This material is copyrighted. All rights reserved Supranate Infranate (VLDL) (chylomicrons) XY Relation of serum albumin concentration with serum calcium concentration: albumin binds 40% of total calcium in blood. A. 13% of calcium is bound to other substrates B. 47% calcium is free, ionized calcium: metabolically active calcium low serum albumin decreases calcium bound to albumin— A. hypocalcemia B. no tetany is present, since the ionized levels are normal caleulation of sensitivity, specificity, PV’ and PV two tests are ordered on a patient, what is chance for a FP result- answer is ~10% increase/decrease upper limit of a test effect of sensitivity on prevalence ing triple therapy for HIV positive people and effect on prevalence it has extended the time interval (Duration) before an AIDS-defining condition occurs prevalence of HIV positive people has increased effect of pregnancy on serum cortisol~ answer is that it is increased due to an increase in the binding protein and not the free hormone level ‘Questions used in Board Review: F Assuming the use of 2 standard deviations to establish the reference interval of a test, ina test with a reference interval of 10-30 mg/dL, 1 standard deviation would equal A, B. c D. E 25 50 10.0 20.0 B- mean of the test is 20 mg/dL, 2 SD = 10 mg/dl, therefore 1 SD = 5 mg/dL. If the prostate specific antigen (PSA) test for prostate cancer is lowered from a reference interval of 0-10 ng/mL to 0-4 ng/mL, this will, increase the number of false negatives decrease the number of false positives increase the test’s specificity increase the PV increase the PV"Note: This material is copyrighted. All rights reserved Study the following schematic involving a control group and disease X correctly describes test results in the space occupied by each of the lettered gro\ A. Group A: true negatives + false negatives Group B: true negatives + false positives C. Group C: true positives + false positives Group D: true positives + false negatives C: group A =all TNs, group B = TNs + FNs, group C = FPs + TPs, group D= all TPs A pregnant woman in her first trimester complains of heat intolerance and palpitations. Physical exam reveals an enlarged, non-tender thyroid gland. Her serum T; is elevated and the TSH is normal Which of the following applies to this case? A. — Thyroid binding globulin is increased B. Free T, hormone levels are increased C. Estrogen increased the synthesis of thyroid hormone D. _ Progesterone increased the synthesis of thyroid binding globulin ANote: This material is copyrighted, All rights reserved Cell Injury Causes of tissue hypoxia (inadequate oxygenation of tissue): 1. ischem A. definition~ decreased arterial blood flow to tissue B. example (1) atherosclerosis in coronary artery: MCC (2) decreased cardiac output hypoxemia~ A. definition low arterial partial pressure of O3 (PaC (1) respiratory acidosis: whenever alveolar PCO; increases alveolar PO; must decn and PaO; must decrease (2) ventilation problems: e.g., atelectasis (3) perfusion problems: e.g., pulmonary embolus (4) _ diffusion problems: e.g., interstitial fibrosis in the lungs B. anemia C. CO poisonii D. _ methemoglobinemia E. _ left shifted oxygen dissociation curve (ODC) problems with oxidative pathway in mitochondria— A. _ carbon monoxide (CO) inhibits cytochrome oxidase B. _ cyanide inhibits cytochrome oxidase uncoupled oxidative phosphorylation in mitochondria— A. mitochondrial poisons (alcohol, salicylates) render inner mitochondrial membrane Permeable to protons B. decreases ATP synthesis arteriovenous shunting- A. AV fistula from trauma: (1) direct communication of arterial system with venous system (2) microcirculation is bypassed B. spider angiomas: due to hyperestrinism C. mosaic bone in Paget's disease of bone Ultimate effect of tissue hypoxia: decrease in ATP production by oxidative phosphorylation in the mitochondria 1, Osis normally the electron acceptor at the end of the oxidative pathway 2. all proximally located biochemical reactions must cease if O; is not present 3. no protons come off the oxidative pathway» no ATP production ‘Effects of a decrease in ATP in the cell: cell must utilize anaerobic glycolysis to generate ATP. A. phosphofructokinase (PFK), the rate limiting reaction in glycolysis, is activated by (1) low citrate (2) _ increase in adenosine monophosphate (AMP) net gain of 2 ATP no gain in NADH (1) NADH is converted into NAD” when pyruvate is converted into lactate (2) __NAD* generated by this reaction is used to produce 2 more ATP decrease in intracellular pH from lactate production: (1) denatures cellular enzymes and other protei 2) produces an sed anion gap metabolicNote: This material is copyrighted. All rights reserved 2. impaired Na"/K* ATPase pump~ A. water enters the cell producing cellular swelling B, reversible change if O; is restored 3. ribosomes fall off rough endoplasmic reticulum decreased protein synthesis O: content formula: 1. Oy content: A. definition: total amount of O, carried in’ blood B. formula: 1.34 (Hb) x PaO», where Hb = hemoglobin PaO; is the amount of O; dissolved in plasma = O» saturation, definition: amount of O> dissolved in plasma and not © is called the oxygen saturation (Sa0;) B. —PaOs is dependent on: (1) percent O; in inspired air (21%) 2) atmospheric pressure: decreases with high elevation even though O; percent is still ached to Hb in RBCs, which 3) on hed ventilation/perfusion in the lungs 4) diffusion of O; through the alveolar-capillary interface decreased alveolar PO, always leads to hypoxemia (1) must have adequate O, in the alveoli in order to diffuse into the pulmonary capillaries (2) lowalveolar O; always leads to low arterial PO: D. hypoxemia always e Hb in RBCs in the blood: (1) decreases SaO», which is the average percentage of heme groups in Hb occupied by Os 2) _ see discussion below E, PO; at the tissue level (1). driving force for diffusion of O2 from the capillaries into the tissue (2) capillary PO; must be higher than PO; in tissue for diffusion to occur A. definition: percentage of Qz attached to the 4 heme groups in Hb within the RBCs: normal range is 94-96% is dependent on: (1) P20; (2) valence of heme iron: must be ferrous (+2) to bind O; (3) if oxidized to ferric (+3), it cannot bind O and is called methemoglobin C. measurement of SaQ; (1) measured non-invasively with a pulse oximeter (2) calculated from measured PaO; (3) directly measured in arterial blood D. decreased SaO; correlates with cyanosis of skin/mucous membranes: SaO; <80% produces visible cyanosis Respiratory acidosis: 1. imerease PaCOy 2. low O; content— A. decreased B. reased SaQNote: This material is copyrighted. All rights reserved ® Anemia: 1. decreased O; content— A. decreased Hb concentration B. normal PaQ,/Sa0,: normal ©, exchange in the lungs so these parameters remain normal decreased Hb concentration A. most important component for carrying O» B. determines the amount of O; delivered to tissue 3. iron deficiency is MCC of anemia Carbon monoxide (CO) poisoning: decreased O; content A. normal Pat B. __decteased SaO: CO has a higher affinity for heme on Hb than O: additional causes of tissue hypoxia— ‘A. left shifts the O. dissociation curve (ODC) B. _ inhibits cytochrome oxidase causes CO poisoning- A. carexhaust gE B. space heaters (USMILE), C. smoke inhalation in fires D. wood stoves Rx (treatment) 100% O, sis A. headache first symptom B. cherry red color of earboxyhemoglobin masks eyanosis 6. long term effect- necrosis of globus pallidus leading to Parkinson-like findings Methemoglobinemia: 1, methemoglobin (metFfb) is heme with iron +3— heme cannot bind O; 2. Oz eontent decreased— A. normal P20, > B. decreased SaO.: decreased even though PaO; is normal cause~ heme oxidized by nitro/sulfa compounds Sis- A. cyanotic B. _ blood is chocolate colored from increased deoxyhemoglobin Rx A, IV methylene blue is gold standard for Rx: activates a methemoglobin reductase sy that is not normally operative B. ascorbic acid: reducing agent that is used as ancillary therapy Factors altering the oxygen dissociation curve (ODC): L. left shifted ODC- A. increased affinity for O;: does not release O; into blood B. examples: (1) 42,3 bisphosphoglycerate (BPG) @) co (3) met (4) HOF (5) _ hypothermia (6) alkalosisNote: This mat rial is copyrighted. All rights reserved 2. right shifted ODC- A reased affinity for O;: readily releases O, into blood B. examples: 1) 12,3 BPG ) fever ) acidosis Cytochrome oxidase inhibito lL co 2. eyanide clinical effects of inhibition A. blocks oxidative pathway in the mitochondria even though O; may be presen electron acceptor B. protons from the electron transfer system are no longer entering the intermem C. protons are not entering the proton pores in the inner mitochondrial membrane: no ATP is produced ® Causes of tissue hypoxia with a normal O; content: L. ischemia— MCC 2. eyanide poisoning 3. uncoupling of oxidative phosphorylation: A. uncoupling is where the inner mitochondrial membrane is rendered permeable to protons: protons are drained off without forming ATP B. examples of drugs that uncouple include: (1) aleohol Q) important in Reye syndrome) 3) dinitrophenol 4. possible outcome of uncoupling hyperthermia A. loss of protons into the mitochondria without forming ATP increases the rate of chemical reactions B. reactions increase production of NADH and NADPH to provide additional protons to the electron transport chain First histologic sign of tissue hypoxia: cellular sw 1, due to reduction in ATP and impaired Na°/K* ATPase pump 2. sodium and water enter the cell Causes of irreversible cell injury due to tissue hypoxia |. disruption of the cell membrane A. lipid peroxidation by free radicals: reversed by vitamin E € B. activation of phospholipase by calcium C. complement activation with damage to cell membrane 2. damage to mitochondria S& Role of calcium in irreversible cell injury: L. enters the cytosol 2. activates enzymes in following locations A. cell membrane phospholipase: enhances lipid peroxidation B. _ activates enzymes in the nucleus: produces nuclear pyknosis 3. enters mitochondria— produces electron dense deposits and destroys mitochondria 4. contributes to coagulation necrosis intracellular buildup of lactic acid also leads to coagulation necrosisThis material is copyrighted. All rights reserved Free radicals definition unpaired electrons in outer orbit examples— A. superoxide: Oy generated FR in superoxide dismutase (SOD) oH eroxide (1) inactivated by catalase and glutathione (GSH) GSH is synthesized in the hexose monophosphate shunt ‘chemicals: acetaminophen (inactivated by GSH) CCl, converted into CCl; (3) oxidized low density lipoprotein (LDL, greater iton.increases the synthesis of OH FRs via the Fenton reaction ‘damage in iron overload diseases: e.g, hemochromat Examples of FR injury: 1. normal aging process A. wear and tear theory B. lipofuscin accumulates in cells damaged by FRs. (1) indigestible lipid from lipid peroxidation (2) _ gives tissue a brown appearance Or-dependent myeloperoxidase (MPO) system. By Rost lethal bactericidal system present in neutrophils/monocytes: see Inflammation notes B. __ NADPH oxidase in cell membrane converts molecular O. inre superoxide FR O: toxicity— A. superoxide FR damage B. eg. retrolental fibroplasia: leads to blindness in newboms ionizing radiation fy generates hydroxyl (OH) FRs in tissue from radiolysis of water in cells B. _ damages DNA witl potential for cancer S-,sayamous cell sarwnomg of he skip Scetaminophen toxiity- inte drnelqeice + antisyshc ie 6 eile” ‘A: acetaminophen is converted'by the hepatocyte eftdehrathe ‘sybfem info FRs that ¢ sulfhydry! groups in hepatocyte cell membranes: MCC of fulminant hepatic necrosis © due to drugs Popa B.N-acetyleysteine therapy (Mucomyst) ? (1) replenishes GSH 2) GSH neutralizes the drug FRs CCl, poisoning~ A. dry cleaning industry B. CCl, converted by cytochrome system into CCl; FR» liver cell necrosis Apoptosis: d ition individual cell necrosis microscopic appearance. A. deeply eosinophil staining cytoplasm B. _ pyknotic nucleus Cc. no inflammatory infi D. cells "drop out" normal functions of apoptosis— A ‘olution of structures: cell/organ atrophy in old age/thymus1 Note: This material is copyrighted. All rights reserved B. apoptosis gene: progr C.— embryover B. _psammoma bodies: apoptosi C. cancer = Types of cell necrosis: of pol coagulation necrosis— — °{ [ B. pale types of infarction > Zeist! Aayea Ka let Corman yf : Zh C. hemorthagic types of infaretion:-Ziidas has ¢ ose crscttincey po LAD cell death am of Millerian structures in male fetus and Wolffian structures in female fetus es lumens for bowel @ (2) crea pathologic roles of apoptosis 3s in vital hepatitis of neoplastic cells with subsequent dystrophic calcification A. Councilman (acidophilic) b (1) _ inactivation of apoptosis gene in B cells leads to B cell follicular lymphoma Q ti Chins prin see Neoplasia notes, bacte, acidesi (Bye of Ranaeiobre gyeolpes A. widespread coagulation necrosis is called infat ()_ heart (BD Cant diffuse eadhy Q) kidneys wie dmboles fiom Mfr acy im? (3) _ liver (least likely to infarct due to ual portal vein/hepatic artery blood supply (4) spleen (Q) small bowel Lessee (2) Iungs G) testicles D. dry gangrene of infection (1) _ predominantly coagulation necrosis without eviden (2) example: diabetic foot CNS infarcts liquefactive not coagulative necrosis liquefactive necrosis ‘A. neutrophil destruction of tissue (1) abscesses/cellulitis 2). wet gangrene (infection superimpo: B, _ brain infarevinfection ed on dry gangrene) ‘A. cheese-like material noted on gross exam of tissue: represents lipid material granulomas from macrophage destruction of typic B. _ other types of granulomas are non-caseating: (1) Crohn's disease enzymatic fat necrosis apt A. key finding in acute pancreatitis mipnc’ B, release of amylase and lipase from damaged pancreas (A fibrinoid necrosis A. _ necrosis of immunologic in B, examples: (1) small vessel vasculitis (Henoch-Schénlein) (2) rheumatic heart disease vegetations on mitral valve G) _ immunocomplex types of glomerulonephrritis (systemic lupus e gummatous necrosis~ A. tertiary syphilis B. rubbery masses that are very destructive in tissue with protein material appearing like fibrinNote: This material is copyrighted. All rights reserved jn rhe BH suscep Ae . Zone > 4 q / . Fatty liver: 2" Poste rhe (ad Compassel 2 Zone {alcohol Mcc- A. inoreased NADH in the metabolism of alcohol causes a build-up of dibydroxyaceto phosphate (DHAP), an intermediate in glycolysis: DHAP produces glycerol 3-phosphat the carbohydrate backbone of TG B, _ increased acetyl CoA in alcoho! metabolism is used to increase fatty acid (FA) synthesis C. alcohol decreases B-oxidation of FAs in mitochondria kwashiorkor- fatty liver due to decreased synthesis of apolipoproteins neceShdry t6 coat vely lipoprotein (VLDL) CO poisoning shock drugs A. tetracycline B. amiodarone Reye's syndrome wed melanin pigment nevus~ benign melanocytic neoplasm malignant melanoma- malignancy of melanocytes increased ACTH- A. ACTH has melanocyte stimulating horm B, causes of increased ACTH: functioning pituitary ades 2) ectopic synthesis in small cell carcinoma of lung and medullary carcinoma o} @) n' ise with hypocortisolism (4) ir syndrome with enzyme deficiencies leading to hypocortisolism B. — melanosomes are larger and more numerous than in whites 1 albinism— AAR disease C. melanocytes present in the epidermis: devoid of melanc phenylketonuria (PKU)— phenylalanine hydroxylase: = Avid «2 Aion) tyrosine is the key amino acid substrate for melanin synthesis PKU children have blond hair = menia! Aleaptonukia I > det.Note: This material is copyright All rights reserved Melanin look-alikes anthracotic pigment A. coal dust B. inhaled as an environmental pollutant (1) phagocyti Jar macrophages ) called d black lung’ sis co A. _ black bowel syndrome B. deposition of black anthracene pigment in macrophages within the lamina propria of large bowel: sign of A. black pigment derived from acid effect on hemoglobin (Hb) B, black color of melena A. hemochromatosis: AR disease B. hemosiderosis: acquired excess 2. amemia of chronic disease (ACD)~ increased iron in macrophages that is unavailable for Hb 3. stasis dermatitis. A. deep vein thrombosis in the calf with hemorrhage of vessels around ankles B. _hemosiderin deposits in subcutaneous tissue give tissue a rusty colored appearance 4, sideroblastie anemia A. defect in heme synthesis B. iron accumulation producing 5. Prussian blue- stain for iron mitochondria Decreased iron: iron deficiency anemia- GI loss of blood is MC Glycogen excess states: glycogenoses~ see Genetics Glycogen depletion: fasting/starvation state (USMILE)— 1. glycogenolysis 2, electron microscopy (BM) on USMLE showed hepatocyte with black granules in fed state and another EM with a lack of the black granules in fasting state Excess glycosaminoglycans myxomatous degencration— pathogenesis of mitral valve prolapse mucopolysaccharidoses— lysosomal storage diseases (¢, 1 2 » Hurler’s disease) 3. pretibial myxedema- non-pitting edema noted in Hashimoto's thyroiditis and Graves disease Hemoglobin-derived pigments: 1 bilirubin— A. uncon type () lipid soluble 2) eg. extravascular hemolytic anemia B. conjugated type (1) water soluble (2) obstructive jaundiceNote: This material is copyrighted. All rights reserved hemosiderin— A. _ storage product of iron B. consists of packets of ferritin C. small circulating fraction of ferritin represents macrophage iron stores: serum the be -on disorders tin Decreased hemosiderin: first sign of iron deficiency anemia 2 ystrophie calcification 1. definition— ‘A. caleium deposition in damaged tissue B. normal serum caleium/phosphate 2. examples A. atherosclerotic plaques enzymatic fat necrosis: visible on plain films C. damaged cardiac valves D. _ psammoma bodies (1) _ serous cystadenocarcinoma of ovary 2) papillary adenocarcinoma of thyroid a G) meningioma (4) mesothelioma E, _ periventricular calcification in congenital cytomegalovirus infections ‘ 7 static caleification: 1. definition A. increased serum calcium and/or phosphate B. deposition of calcium in normal tissue 2. examples A hrocaleinosis in primary hyperparathyroidism: calcification of tubular basement ‘membranes B. calcification of-basal ganglia in primary hypoparathyroidism: high phosphorous levels in hypoparathyroidism drives calcium into the brain tissue Genetic example of a microtubule dysfunction: Chediak-Higashi syndrome AR disease 2. defect in microtubule polymerization _ Cylshicine > a dels used fo AReat-g apy REVERT ib 3. defective phagocytosis: increased susceptibility to infections ‘oom 4. giant red inclusions in peripheral blood leukocytes: represent giant lysosomes filled with ‘enzymes that have never been released Genetic example of a membrane defect: congenital spherocytosis cowie TAD disease 2, defect i spesteta fn he cell saembrame A. results in RBCs with too little membrane B. _ spherocytes develop in peripheral blood eztravascalay hemolyas of spherocyte by spleai macrophages Examples of intermediate filament defects 1. Mallory bodies A. ubiquinated (marked for destruction by ubiquitin) ke B. microscopic feature of alcoholic hepatitis Lewy body- ubiquinated neurofilaments from degenerated substantia nigra neurons in tin intermediate filam FRELCKLEREEETNote: This material is copyrighted. All rights reserved 3. neurofibrillary tangles~ ubiquinated n disease yrofilaments in the brain in old age/Alzheimer's Labile cells: contain stem cells—>1.5% of cells are in examples A. bone marrow stem cells B. skin; stratum basalis C. intestine: base of the glands 1 cell cycle at any one time 5. clinical significance most affected by radiation and S phase chemotherapy drugs due to high rate of mitoti activity of labile cells Stable cells 1. eells usually in Go (resting) phase— A, must be stimulated to enter (1) _ hormones (estrogen) (2) growth factors (epidermal derived growth factor) 3) _ loss of parenchymal tissue (removal of liver tissue) B, _ <1.S%of the cells are in the cell cycle at any one time Gy hase 2, examples~ A. most parenchymal cells in organs (2) liver (2) endothelial cells B, smooth muscle: not striated or cardiac cells CC. astrocytes/other neuroglial cells. 3. clinical significance capacity to under hypertrophy and/or hyperplasia Permanent cells: |. cells cannot enter the eell eycle~ permanently differentiated 2. examples: A. skeletal/cardiae muscle: can only hypertrophy B, neurons Cell eyele |. imaetive edk (cyclin-dependent kinase) is activated by cyclin D (see diagr: A. cyclin D is synthesized in the G, phase of the cell cycle: key phase of the cycle B. _ G; phase is the most variable phase Rb suppressor gene on chromosome 13 produces the unphosphorylated Rb protein A. Rb protein prevents the cell from moving from the G; phase into the $ phase: S ph functions include chromosome replication and organelle replication B. phosphorylation of the Rb protein by the active eyclin D/edk complex: allows the pass into the S phase and finish the cycle which includes the Gm phase (mitotic spindle synthesized) and the M phase (mitosis) C. inactivation of the Rb suppressor gene: (1) _ loss of the inhibitory effect of the Rb protein on the cell (2) cells constantly enter the S phase once they are phosphorylated p53 suppressor gene functions in cell eyele~ A. B located on chromosome 17 produces a protein product that inhibits the ive cyclin D/edk complex (1) prevents phosphorylation of the Rb protein (2) _ keeps cell in the G) phase I to repair any de! G) allow: in DNA ("guardianair in cell or ¢ p53 suppressor gene inhibits (allows DNA rej undergoes apoptosis) “a, > active cyclin D/edk complex ¥ cyclin D degraded av eii inactive cdk cyclin D cyclin D synthesized hormone, growth \_ factors inactive edk * edk = cyclin-dependeitt kinase * Rb (hypophosphorylated form) inhibits cell from going from G; to S phase * Rb phosphorylated form allows cell to go from Gy to S phase Inactive cdk is activated by cyclin D, which is synthesized in the G1 phase of the cell yele. The Rb'sippressor gene on chromosome’13: produces the Rb protein, which inhibits a cell from moving from the G1 phase into the § phase of the cell cycle. When the Rb protein is phosphorylated by the active cyclin D/cdk complex, the cell passes into the S phase and finishes the cycle. The p53 suppressor gene located on chromosome!17 produces a product that inhibits the active cyclin D/edk complex, hence preventing the phosphorylation of the Rb protein and keeping the cell in the G1 phase. Inactivation of the Rb suppressor gene results in the loss of the inhibitory effect of the Rb protein in keeping the cell from entering the S phase. Furthermore, inactivation of the p53 suppressor gene allows the active cyclin D/edk complex to continually phosphorylate the Rb protein, which allows the cell to complete cell division. Inactivation of either the Rb or pS3 suppressor gene leads to unrestricted cell growth and the potential for cancer.This material is copyrighted, All rights reserved (4) _ cells incapable of repair underg C. inactivation of the p53 suppresso: (1) active eyelin Diedk complex continually phosphorylates Rb proteins (2) cells continually mitose 4. important concept A. inactivation of either the Rb or p53 suppressor gene (1) unrestricted cell growth (2) _ potential for cancer B. sce Neoplasia notes for additional discussion apoptosis xamples of growth alterations: (f'9-Znt 2h 1. atrophy= J A. — decrease in cell/tissue mass B. organ less weight C. capsular surface wrinkled D. less mitochondria than normal cell E, increased lipofuscin in cells A. anlage (primordial tissue) is absent B. eg., renal agenesis aplasia anlage present but never develops fame b, tee 4. hypoplasia A. anlage develops incompletely B, tissue present is histologically norma 5. hypertrophy increased cell size (neT ue To Aormone teers ) 6. hyperplasia - A. increase in number of cel B. common in hormone excess state C. can progress to dysplasia and cancer if left unregulated 7. metaplasia replacement of one adult cell type by another adult cell type dysplasia— A. atypical hyperplasia with potential for evolving into cancer B, premalignant growth alteration Examples of atrophy 1, muscle in a east disuse of muscle leads to atrophy thyroid gland in someone taking excess thyroid hormone- decrease in TSH from inc in T, causes atrophy of thyroid renal artery atherosclerosis~ A. potential for secondary hypertension B. stimulation of renin-angiotensin-aldosterone system 4, compression atrophy of renal cortex by hydronephrosis 5. muscle atrophy in lower motor neuron disease 6. marasmus— A. tissue atrophy due to total calorie deprivation B. broomstick extremities carotid artery atherosclerosis— A. cerebral atrophy B. site for atherosclerotic stroke 8, atrophy of pancreatic ducts and islet cells in cystic fibrosis (USMILE)= A. thick ductal secretions obstruct the lumen leading to glandular atrophy and fibrosis 19Note: This material is copyrighted. All r B. fibrosis destroys islet cells ical examples of predominantly hypertrophy: left ventricular hypertrophy- A. causes due to increas (1) _ essential hyper 2) aortic stenosis B. causes due to volume over c cies: ¢.g, mitral or aortic valve insufficiency skeletal muscle in weight training removal of kidney and hypertrophy of remaining kidney (USMUR) Clinical examples of predominantly hyperp! 1. hormone excess— A. unopposed estrogen: endom ial hyperplasia/cancer B. increased ACTH (¢g., pituitary adenoma): adrenal cortical hyperplasia C. increased dihydrotestosterone + estrogen: prostate hyperplasia D. _prolactin-induced lactation (1) normal finding in postpartum state (2) _prolactinoma is benign neoplasm producing excess prolactin E. gynecomastia; excess estrogen develops male breast tissue F. acromegaly: excess growth hormone/insulin-like growth factor due 10 a pituitary adenoma secreting growth hormone G. RBC hyperplasia: erythropoietin stimulation by hypoxia H. secondary hyperparathyroidism: parathyroid gland hyperplasia due to hypocal gum hyperplasia— phenytoin therapy Persistent injury to tissue~e.g., 4. psoriasis— hyperplasia of squamous epithelium 5. increased goblet cells in bronchial epithelium in smokers~ example of met cells are found in terminal bronchioles erative noe ules in cirrhosis due to chronic injury ia if goblet cal examples of equal hyperplasia/hypertrophy: 1. uterine smooth muscle hyperplasia/hypertrophy~ pregnancy 2. iodine deficiency~ goiter Clinical examples of squamous metaplasia formation zone of cervix in human papilloma virus (HPV) infections— A. mucous secreting columnar cells normally undergo squamous metaplasia to replace exocervical epithelium B. may progress to squamous dysplasia/canc bladder transitional epithelium in schistosomi A. Schistosoma hematobium eges in submucosal venous plexus cause mucosal squamous if HPV is present sis— metaplasia B. may progress to dysplasia/cancer 3, true vocal cords/bronchial epithelium in smokers— A. epithelium is normally ciliated columnar epithelium B. carcinogens in cigarettes cornea in vitamin A deficieney- A. cornea is normelly cuboidal epithelium B. in vitamin A deficiency it undergoes squamous metaplasia: vitamin A normally prevents squamous metaplasia e/aleohol irritate mucosa: may progress to dysplasia/cancerNote: This material is copyrighted. All Clinical examples of glandular metaplasia: ights reserved ‘mucous secreting cells/goblet cells in the distal esophagus in acid injury (gastroesophage reflux disease)- A, normally squamous epithelium in distal esophagus B. acid injury due to gastric reflux causes glandular metaplasia: culled Barrett's esoph C. adenocarcinoma of esophagus due to Barrett's esophagus has replaced squamous cell carcinoma as the MC cancer of the esophagus goblet cells/Paneth cells in pylorus/antrum in chronic atrophic gastritis due to Helicobacter pylori A. goblet/Paneth cells are normally present in the small intestine B. cytokines released by A. pylori damage stomach mucosa and produce metaplasia: precursor of stomach adenocarcinoma USMLE scenarios: 1 cyanosis not relieved by oxygen in a patient coming home from a camping trip in the Rocky Mountains~ A. noglobinemia B. _ water in the mountains has nitrites that oxidize iron to ferric condition antioxidant that prevents lipid peroxidation of cell membranes— vitamin E USMLE pictures of coagulation necrosis~ A. acute myocardial infarction B. hemorrhagic infarct of small bowel incarcerated in inguinal hernia sac in a glycogen depletion- electron micrograph: present in fed state and absent in fasting st what happens to the other kidney if one is damaged or removed— undergoes hypertrophy dysplasia precursor to cancer fatty change in the liver— alcohol MCC first sign of tissue hypoxia in tissue swelling due to inactivation of the Na‘/k’ ATPase pump picture of adrenal cortex and asks what part is atrophied in a patient on corticosteroids— A. fasciculata and reticularis, are atrophied due to suppression of ACTH by the corticosteroids B, _ glomerulosa is normal: (1) where aldosterone is located (2) glomerulosa is stimulated by ATI not ACTH growth alterations see previous examples enzyme markers of cell death: transaminases: hepatitis creatine kinase: muscle CK:MB: cardiac muscle amylase/lipase: acute pancreatitis lactate dehydrogenase: (1). malignant lymphoma (2) disseminated cancer (3) intravascular hemolysis (4) V2 flip in myocardial inferetion CNS infaret— liquefactive not coagulative necrosis apoptosis~ see previous discussion free ra antioxidants see previous discussion moowD> als~ see previous discussionNote: This material is copyrighted, All rights reserved ‘Questions used during Board Review: D is primarily operative in which of the following growth A. Appearance of the affected kidney in renovascular hyp: B. —Thickened bladder wall in a patient with urethral obstruction C. Barrett's esophagus in a patient with gastroesophageal reflux D. Enlarged left atrium in a patient with severe mitral s E. — Galactorshea in a woman with a prolactinoma tension Which of the following disorders is an example of coagulation necrosis? A. Lobar pneumonia in an alcoholic B. Hepatic abscess in a patient with amebiasis C. Pseudomembranous colitis in a patient on ampicillin D. _ Diminished brain mass in a patient with Alzheimer’s disease ‘ E, _ Embolus to the superior mesenteric vein leading to bowel infarction In which of the following diseases would you expect a low arterial PO, and a low oxygen saturation (S20, A. Carbon monoxide poisoning B. Iron deficiency anemia « output D. Respiratory acidosis E. Cyanide poisoning Which of the following disorders is an example of metap! AL I goblet cells in the mainstem bronchus of a smoker B, Squamous epithelium in the mainstem bronchus of a smoker C. Proliferative endometrial glands in a woman on unopposed estr: D. _Hyperkeratosis of the skin in a patient with psoriasis E, Multinucleated giant cells in,a granulomaNote: This material i copyrighted. All rights reserved Inflammation/Repair Latin terms for acute inflammation. 1. ealor- A. heat B. _ histamine-dependent vasodilatation 2 bor A. redness B. _ histamine-dependent vasodilatation 3. tumor- A. tissue swelling B. _ histamine-dependent increase in vessel permeability in venules dolor A. pain B. due to prostaglandin E> and bradykinin 5. funetio Iaesa— A. loss of function B. sum total of the effects of a ammation ® Sequence of vascular events in acute inflammation: 1 B. increases blood flow/hydrastatic pressure 2. increased vessel permeability A. histamine-dependent B. histamine receptors on endothelial cells in venules stimulated to contract leaving a bare ‘basement membrane C. transudate initially moves into the interstitium D. lymphatics take up excess fluid Sequence of cellular events in acute inflammation |. neutrophil marginiation— ‘A. neutrophils pushed to periphery of the vessel B, due to adhesion molecule synthesis in neutrophils/endothelial cells neutrophil adhesion to endothelial cells (pavementing) A. adhesion molecules are CDj,/CDis complexes of glycoprotein and 1 and (32 integrins B. endothelial cell-derived adhesion molecul (1) _ leukocyte adhesion molecules (ELAM) (2) _ intercellular adhesion molecules (ICAM) (3) chemical mediators involved for synthesis of endothelial-derived adhesion nolecules are interleukin (IL)-] and tumor necrosis factor trophil adhesion mo thesis: CSa and LTB, mediated Cc. new 3. emigration of neutrophils— A. ~ neutrophils emit collagenase and destroy type IV collagen in bare basement membrane B. _protein/cell rich fluid accumulates in interstitium (called exudate) 4. directed chemotaxis~ A. receptor-mediated B. chemical mediators: Q) Ca Q) LTB, (3) _ bacterial productsNote: This material is copyrighted. All rights reserved phagocytosis monocyte/m (1) primary opsonizing agents IgG/C3b (2) _nonspecitic opsonizing agents: C-1 bacteria internalized by leukocytes into vacuoles (phagosomes), which become filled with lysosomal enzymes (phagolysosomes) bacteriocidal mechanisms in leukocytes A. neutrophils and monocytes have three systems: (1) Or-dependent myeloperoxidase (MPO) system (most potent system) (2) Oxdependent free radicals (3) lysosomal enzymes B. macrophages only have the latter two systems respiratory burst mechanism in neutrophils/monocytes 1. part of the O:-dependent myeloperoxidase (MPO) bacteriocidal system 2, NADPH oxidase A. enzyme located in the membrane of neutrophils and monocytes B. _ uses NADPH derived from the hexose monophosphate shunt as a cofactor C. converts molecular oxygen into superoxide free radicals: energy given off in this re is called the respiratory burst superoxide FRs~ A. located in the phagolysosomes B. _ converted by superoxide dismutase into peroxide myeloperoxidase (MPO)- combines peroxide with chloride anions to form bleach, which destroys bacteria NBT (nitroblue tetrazolium test) dye test~ A. evaluates the integrity of the respiratory burst B. neutrophils convert a colorless dye into a colored dye if the respiratory burst syst intact (lee Celie © dct + Fin # ) Mebsele prttnenia 9) Reslonones. 5) Nocedy wD Stentin wnetescons *) APES 6) Ec F)Salnonele — €)Candida albeuns Chronic granulomatous disease of childhood: 1. SXR disease~ microbicidal defect 2. absent NADPH oxidase A. absent respiratory burst: negative NBT dye test B. no peroxide is produced in phegolysosome C. MPO and chloride anions are present in phagolysosomes patients cannot kill catalase positive §. aureus- A. 5. aureus releases peroxide, which is all the leukocyte needs to synthesize bleach B. catalase is released by the bacteria, which neutralizes the peroxide Jeukoeytes can kill catalase negative streptococei peroxide released by streptococci is used by MPO to make bleach and kill the bacteria Summary of chemical mediators in acute inflammation: histamine— A. overall most important mediator B. _released/synthesized by basophils/mast cells C. __vasodilator/increases vessel permeability D. important in anaphylactic shock E. produces the "wheal and flare reactioCELL MEaVeRAVE Prachi bd | BitesPHOM PASE Ag CSTEROISS Rice) Wirohie AGG ——3, ATACH Oonmic Aad we CYchLoexy CEWAKE (ACPI /AEAOS a C a Breck i — SHeETe 7 LEUKOTRIENE Ay BERBRRREae aa. ARAB AREER a nana pe pageNote: This material is copyrighted. All rights reserved serotonin A. released/synthesized by basophils/mast cells/platelets B. _ synthesized from tryptophan C. functions: (1) vasodilator (can also be # vasoconstrictor)/increases vessel permeability (2) neurotransmitter (3) synthesized from tryptophan D. important in carcinoid syndrome: ) flushing 2) increases collagen synthesis (3) diarch 4) metabolized in the liver into 5-hydroxyindoleacetic acid C3a/C5a— A, — anaphylatoxins B. directly stimulate histamine release from basophils/mast cells C. important in tissue swelling and shock 3b A onizing agent B. __neutrophils/monocytes/macrophages have receptors for C3b cs A. _ adhesion molecule synthesis on neut B. chemotactic agent ophils C, anaphylatoxin 6. bradykinin: A. — vasodilator/increases vessel permeability B. _ bronchoconstrictor C. pain (dolor) of acute inflammation D. cough and angioedema with ACE inhibitors 7. prostaglandins in general feritiw Pethuecy A. derived from arachidonic acid (called eicosanoids): \ (1) _ teleased from phospholipids in cell membranes by activatio (2) synthesized from linoleic acid B. _ most prostaglandins are vasodilators/increase vessel permeability 8. PGH; products~ A. thromboxane A; (TXA2): (1) PGH) is converted by platelet-derived thromboxane synthase into TXA: (2) _ product of arachidonic acid metabolism (3) platelet aggregator (4) vasoconstrictor! bronchoconstrictor (USMILE) (5) TXBp is end-product of its metabolism: no biologie function B. _ prostacyclin (PGI2): (1) GH; is converted by endothelial cell-derived pros (2) prostacyclin synthase is not inhibited to any s \n of phospholipase A. -velin synthase into PGI; mificant degree by aspirin and NSAIDs (3) _ inhibits platelet aggregation (4) _ vasodilator C. PGE: (1) makes skin hypersensitive to pai (2) vasodilator in kidneys (blocked by NSAIDs but not a @G) taminophen) increases renal blood flow (counteracted by angiotensin II)Note: This material is copyrighted, All rights reserved (4) decreases renal reabsorption of sodium (S) increases gastric mucosal blood flow (important in gen barrier) mucosa (6) activates osteoclasts (important in producin 7) important in fever production (IL-1 hypothalamus) (8) _ inhibits platelet aggregation/IL-1 and IL D. PGF. (2) constricts uterine muscles (cause of primary dysmenorthea) (2) _ vasoconstricts/bronchoconstriets E. __PGDs: vasodilator/increased vessel permeability 9. LTB. A. derived from arachidonic acid ng hypercalcemia in malignancy) stimulates its synthesis in the anteri 2Mleukoeyte aggregation B. adhesion molecule synthesis on neutrophils C.__ chemotactic agent 10. LTC-D-E A. ~ derived from arachidonic acid B. bronchaconstrictor/vasoconstrictors C. important in asthma nitric oxide A. endothelial cell-derived B. _vasodilator/increase vessel permeability C. important in shock endothelin A. potent vasoconstrictor in endothelial cells B. important in shock 13. interleukin (IL)-1— Bier stimulates prostaglandin E, synthesis in anterior hypothalamus B. _ B cell stimulation to synthesize immunoglobulins C. activates osteoclasts: (1) called osteoclast activating factor (2) inhibited by estrogen in women and testosterone in men (3) _ release from osteoblasts is stimulated by parathormone gbresent in plasma cells (cause of lytic bone lesions in multiple myeloma) D. increases adhesion molecule synthesis by endothelial celle E, increases liver synthesis of acute phase reactants (1) coagulation factors (fibrinogen, V, VIII) (2) C-reactive protein 4, Hageman factor XTI- A. ivates intrinsic coagulation system B. activates plasminogen in fibrinolytic system C. activates kinin system: produces bradykinin D. important in the pathogenesis of disseminated intravascy lar coagulation Essential fatty acids (FAs): 1. linoleic acid (see below)~ C18:206 2. actinolenie (see below) C18:303 4 both are required in the diet- cannot be synthesized functions- A. synthesis of biologically active FAs