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NORMAL PAO, = 100 min Hg (lungs) Pac 95 mm Hg (blood) oO; On ret Fe NF ZN. J S20, = 100% , content = 1.34 x Hb x Sa0, + PaO, RESPIRATORY ACIDOSIS PACO; = 80 mm Hg PAO, 60 mm Hig (lungs) 50 mm Hg (blood HEME 4 \ S20, = 50% (¥ 0% ann 134xHbx ¥ Sa0, +¥ PaiCARBON MONOXIDE POISONING ANEMIA. METHEMOGLOBINEMIA PAO, PAO, = 100 mm fig (ngs) 100 mm Hg (lungs) G PAO; = 100 mm Fig (lungs) Pa0; =95 mm Hg (blood) Pad, PaO; =95 mm Hg (blood) fo ™ a [\ A fe 7 Hea — aw Zo \ Re" Fe" Fee Fe! co oO, 0; $10,=50% 0; 1.34x9 Hb x SaO, + Pad, YO; content = 1.34 x Hb x¥ Sa0, + Pad, ¥O; content = 1.34x Hb x ¥Sa0,+ Pao, #0, content = 13414 Hb 00,4 Pad, 2 0, bi, Palost Tisabact™ gi. (me The freaks Leeper 4° “ Atick acbens pubew 1: lace rt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