GOLJAN NOTES: CELL INJURY 1-3 Hypoxia Causes: ischemia, hypoxemia (ventilatory defects), Hb related (anemia, carbon monoxide,

xide, methemoglobin, L-O2 curve, cytochrome oxidase, uncoupling agents) Low O2 to tissue (same as shock) Need O2 for mitochondrial oxidative phosphorylation O2 as finale e acceptor in ATP formation (1.34)(Hb)(O2 sat) + Parterial O2 = O2 supply to blood o O2 sat = how much Hb occupied (inside RBC attached to heme) o Parterial O2 = O2 dissolved in plasma o If PO2 decrease, then O2 sat decrease b/c since less in plasma, less diffuses into RBC Ischemia: decrease arterial blood flow o Thrombus in muscular artery most common cause MI o Decrease cardiac output, hypovolemia o Hypoxemia #2 cause of ischemia also cause hypoxia and decrease Parterial O2 When retain CO2, then PO2 decrease due to Daltons law of partial pressure (partial pressure all gases equals 760 mmHg total) Ventilation defect: RDS (hyaline membrane disease) lose ventilation, retain perfusion o Give 100% O2 but PO2 not change SHUNT Perfusion defect: no blood flow o PE #1 cause o Increase dead space o Give 100% O2 and PO2 increases b/c other areas of lung can make up Diffusion defect: smtg block O2 diffusion o Sarcoidosis cause fibrosis o Pulmonary edema o CHF due to fluid (J reflex due to CN 10) 1

Anemia: no decrease PO2 gas exchange normal o Decrease Hb cause hypoxemia

Carbon monoxide: hypoxia o Room heater, auto exhaust, house fire (also cause cyanide poisoning from polyurethane on upholstery) o High Hb affinity, freely diffuses o Cause decrease O2 sat b/c C1O1take up Hb space so O2 cannot bind o NOT see cyanosis b/c cherry red pigment mask blue lips o #1 sx: headache o Cytochrome oxidase: last enzyme before O2 acceptor inh by cyanide and C1O1 o C1O1 bind to Hb to prevent O2 binding and decrease O2 sat, L shift O2 curve, inh cytochrome oxidase

Methemoglobin: Fe3+ - cannot bind O2 cause decrease O2 sat o Chocolate colored blood b/c no O2 o Need Hb reductase to convert to Fe2+ o Give O2 and still cyanotic o H2O in mountains loaded with oxidizing agents (nitrite and nitrate) o Rx: IV methylene blue, vit C as anxillary o Increase Fe3+: dapsone (leprosy, sulfa drug)

Sulfa and nitro drugs: produce G6PD deficiency, hemolysis, methemoglobin oxidizing agents (increase peroxidase in RBC and cause hemolysis) R-O2 curve shift: 2,3-DPG, fever, high H+, high altitude L-O2 curve shift: Hb-F, methemoglobin, carbon monoxide, alkalosis, low 2,3-DPG Uncoupling: mt cannot synthesize ATP o Inner mt membrane permeable to H+ (go into matrix from intermembranous space) o Rxn making NADH and FADH2 deliver H+ need to increase to make up for H+ loss incrase body temp and hyperthermia 2

o Uncoupling agents: salicylate toxicity, alcohol Respiratory acidosis: decrease O2 sat, decrease PO2, Hb unaffected Anemia: decrease Hb, O2 sat and PO2 nl Carbon monoxide and methemoglobin: affect O2 sat only When ATP decrease due to hypoxia, then go to anaerobic glycolysis produce lactic acid o All cells can do anaerobic glycolysis including RBC produce 2 ATP o Increase lactic acid inside and outside cells increase anion gap o Increase acid in cell denatures proteins/enzymes coagulation necrosis b/c cell cannot digest itself Digoxin: block Na/K pump to keep Na in cell and allow intracellular Ca2+ release to increase force of contraction Intracellular swelling if no aTP b/c Na kept in cell no ATP to drive 3Na/2K pump Irreversible tissue changes in prolonged hypoxia o Ca2+ enter cells b/c no ATP to pump it out active PL in cell membrane, enzymes in nucleus (pyknosis), destroy mt, acute pancreatitis due to enzyme activation o Cell membrane damage bad exposed to environment increase AST/ALT, CKB, amylase, lipase

Free Radicals Produce lipofuscin undigestible lipids o Arranged around nucleus o Due to oxidation unsaturated FA o Due to uncoupled e o Cause reperfusion injury in MI/thrombus o See in Fe overload Tylenol: CyP450 canc hange drugs to free radicals

o #1 cause drug induced fulminant hepatitis o Damage around central vein o N-acetyl cysteine as antidote: replenish GSH (N-acetyl cysteine is substrate) o GSH neutralizes free radicals from drugs and peroxide from HMP shunt o Kills renal medulla blood flow o ASA cause renal vasoconstriction via decrease PGE2 o ASA + acetaminophen kills kidneys

Apoptosis Programmed cell death part of aging Creates: lumen of GI, fingers, toes, thymus Kills neoplastic cells

Necrosis Coagulation necrosis: see in MI infarcts on gross exam o Increase lactic acid destroy enzymes and cannot break down cell Hemorrhagic necrosis: blood diffuse out to tissue that does not have good consistency Pale infarct: blood diffuse out to good consistency tissue Spleen emboli are pale infarcts Systemic infarcts due to L heart emboli o Rarely RF o Often mitral stenosis and AF (stasis and fibrillation) Dry gangrene: no pus, see in diabetic with popliteal artery problems (atherosclerosis) Bowel infarct: SI trapped in indirect inguinal hernia hemorrhagic infarct

Lung: hemorrhagic infarct, exudate and effusion, possible pleuritic chest pain Liquefactive necrosis: in CNS o TIA: plaques stuck in small BV of CNS cause transient motor/sensory abnormalities o Astrocytes = fibroblasts in brain give CNS structure, damaged in necrosis and hence brain liquefies o Usually due to inflammation involving polys (acute > chronic) if not due to infarct

Abscess due to coagulase from S. aureus break down fibrinogen to fibrin and trap polys Strep release hyaluronidase break down GAG infection spread through tissue = cellulitis Granulomatous necrosis in TB o Mediated by IL12 and TH1 cell o Caseous necrosis: systemic fungal infection or mycobacterial Lipid in cell wall cause cheesy look

Pancreatitis: pain to back b/c pancreas is retroperitoneal o Lipase more specific than amylase o Enzymatic fat necrosis: saponification with Ca2+ bound see on x ray alcoholics o Traumatic fat necrosis: see in breasts, can calcify, painful (vs painless cancer) o Ca2+ stains blue in damaged tissue

Fibrinoid necrosis: look like fibrin but isnt o Necrosis if immunologic disease o Palpable purpura: type 3 hypersensitivity, small vessel disease o Activate alternative complement C5a chemotactic for polys cause damage

o RA, SLE glomerulonephritis Liver: sinusoid organ along with spleen and BM o Gaps between endothelial cells o Nutmeg liver in R heart failure 5

o Hepatic vein empty to IVC Budd-Chiari: blocked hepatic vein liver congestion o Zone 2 damage: yellow fever o Zone 3 damage: prone to ischemia, fatty change here, Tylenol toxicity (least amount of O2 here so cannot combat free radical injury)

Fatty Liver NADH: part of alcohol metabolism o See lactic acidosis due to increased NADH (pyruvate lactic acid) o No gluconeogensis b/c all pyruvate converted to lactic acid o See ketone bodies (beta-hydroxybuteric acid) due to increased acetyl-CoA o In glycolysis, drive G3P formation G3P + 3FA = TG high VLDL o To decrease VLDL, restrict carbs Kwashiorkor: protein deficiency o No apoprotein to put on VLDL, so fat accumulate in liver b/c no way to get rid of TG ETOH: increase VLDL synthesis Ferritin: soluble circulating Fe used to diagnose Fe disease Hemosiderin: insoluble Fe, stored in macrophages, Prussian blue stain

Calcium Dystrophic calcification: dys = abnormal o Damaged tissue gets calcified o Enzymatic fat necrosis is an example o Reverse calcified plaques with Ornish diet o #1 cause of aortic stenosis, hemolytic anemia

Hypercalcemia: high PTH, malignancy Metastatic calcification: high Ca2+ or P o P drives Ca2+ into normal tissue

Cell Membrane Spherocyte: no central pallor o Spectrin deficiency cell membrane defect o Unable form biconcave disc

Ubiquitin Stress protein Marks intermediate filaments for destruction Keratin + ubiquitin = Mallory bodies in alcoholic hepatitis Jakob-Creutzfeld: can form neurofibrillatory tangles resembling amyloidosis Tau protein: ubiquinated neurofilament Parkinsons: Lewy body ubiquinated

Cell Cycle Labile: stem cells (BM, skin basement membrane, crypts of SI) Stable: in G0, mostly parenchymal organs, SM Permanent: can never enter cell cycle o Neurons, striated muscle, cardiac muscle o SM only non permanent muscle can undergo hyperplasia G1 phase most variable (like proliferative phase of menstrual cycle)

o Longer/shorter cell cycles due to G1 length variation CDK: phosphorylation usually activate something o Glucagon phosphorylates o Insulin dephosphorylates G1S: key checkpoint o Rb on Chr13q suppresses entering S tumor suppressor gene o Cyclin D cause P of Rb o P53 (Chr 17p): guardian of the cell give cell time to detect DNA defects Inh cyclin D so that it cannot P Rb not enter S See in most human cancers and Li-Fraumeni HPV inactivate P53 and Rb via E6 and E7

S: doubles everything 4N G2: make tubulin M: mitosis form 2x2N cells

Atrophy CNS: atherosclerosis, AD Muscle: ALS Endocrine: hypopituitarism cause atrophy adrenal fasciculate (cortisol) and reticularis (sex hormones) b/c no ACTH stimulation CF: atrophy exocrine glands b/c lumen blocked

Hypertrophy and Hyperplasia Hypertrophy of cardiac muscle: block before G2 still at 4N Hyperplasia o Usually predispose to cancer except in BPH

o Uterus: 50% hyperplasia and hypertrophy BM: usually 3:1 WBC:RBC o If increase RBC, see RBC hyperplasia see in COPD b/c hypoxemia cause Epo release (endothelial cell of peritubular capillaries) All hormones stimulate glands under HYPERPLASIA, not hypertrophy (BPH vs. hypertrophy of overworked heart)

Metaplasia and Dysplasia Cell replaced by another cell type o Barretts esophagus predispose to esophageal adenoCA Ciliated, pseudostratified columnar cells line bronchus metaplasia in smokers o Goblets cells usually present in mainstem bronchus but not terminal bronchioles o Squamous metaplasia dysplasia CA H pylori cause gastric adenoCA Dysplasia: atypical hyperplasia, disordered, preneoplastic Actinic keratosis precursor to skin SCC

INFLAMMATION Microbicidal Defects Oxidative burst o O2 converted by NADPH oxidase o No NADPH oxidase in G6PD deficiency see infection before hemolysis Chronic granulomatous disease of childhood o X linked Recessive, female carriers and give to 50% of sons o No respiratory burst, no superoxide, no H2O2 (b/c no NADPH oxidase convert O2 to H2O2) 9

o Can kill Strep b/c strep has no catalase, so when it produces H2O2, it goes to HOCl o Cannot kill Staph b/c catalase positive, so breaks down H2O2 after it produces it No myeloperoxidase: autosomal recessive, nl oxidative burst, but no HOCl made to kill bacteria

Inflammation Rubor: arteriole vasodilator histamine Calor: due to histamine induced vasodilation Tumor: increase venule permeability due to histamine cause exudate Dolor: bradykinin (kininogen system, activated by factor 12 and PGE2) degraded by ACE o ACEI cause decreased bradykinin metabolism leading to increased venule permeability and angioedema Polys in small vessels migrate: have type 4 collagenase for drilling through basement membrane of BV (cancer cells also have it) Chemotaxis of polys: C5a, LTB4 also make adhesion molecules on polys Opsonization: IgG and C3b Umbilical cord not fall off: adhesion molecule defect (integrin) o No inflammatory reaction involving polys polys unable to stick cord stays Histamine: acute inflammation king 5HT: from tryptophan, is a NT deficiency cause depression Anaphylatoxins: C3a and C5a stimulate mast cells to release histamine Prostaglandin: mostly dilate and increase vessel permeability NO: made in endothelial cells, potent vasodilator, role in septic shock IL1: fever, pyrogen (made in hypothalamus when cause fever) Steroids: inh PLA2 no arachidonic acid release from PL inh PG and LT Omega 6: linoleic acid

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Omega 3: linoneic acid block platelet aggregation like ASA Zileutin: block lipooxygenase and LT involved in bronchospasms and bronchoconstriction PGI2: enemy of TXA2, made in endothelial cell, vasodilator, inh platelet aggregation o Blocked by thromboxane synthase o Block TXA2 in dipyramidol sestamibi stress test

Steroids: decrease adhesion molecule synthesis o CBC show increased polys b/c no longer bound to endothelium (usually 50%) o Kills T and B cells via apoptosis o Decrease eos and lymphs, increase polys o Addisons: no cortisol opposite of steroids o MI: increase epinephrine increase cortisol increase polys

Usually CD4:CD8 cells is 2:1 Plasma cell: lots of rER to make Ig, from B cell, located in germinal follicle Charcot Leyden crystals: gdegenerated eos in asthmatic Type 2 hypersensitivity rxn: IgE receptors on eos release MBP to kill helminth Type 1 hypersensitivity: histamine and eos chemotactic factors released from mast cells o Eos neutralize LT and histamine indirectly

CD3: all T cells CD1: histiocytes CD10: CALLA antigen of ALL CD15/30: RS cell CD 21: EBV hook into CD21 on B cells CD45: all WBC Fever: IL1 and PGE2 released from hypothalamus o R shift O2 curve good b/c enable O2 burst to kill bacteria (and viruses) 11

Types of inflammation o Suppurative: pus, Staph o Abscess: Staph osteomyelitis from hematogenous spread o Sickle cell: Salmonella o Cellulitis: Strep pyogenes o Diphtheria: produce exotoxin pseudomembrane like C. diff o Fibrinoid pericarditis: Coxsackie o 3rd degree burns: pseudomonas

Fibronectin and granulation tissue needed for wound healing o Collagen type 3 found in initial wound repair (reticulin) zinc converts it to type 1 via collagenase activity o Zinc deficiency = poor wound healing

Collagen type 1: strong tensile strength in bones, skin, tendon, etc. Scurvy: no crossbridging of collagen o Vit C needed to hydroxylate proline and lysine for crossbridging and tensile strength

Keloid: excess type 3 collagen (reticulin) same as hypertrophic scar o Genetic predisposition o See in 3rd degree burns and skin SCC o Lots of turnover in scar tissue fibroblasts involved chance for squamous cancer o Also see SCC in chronic draining sinus tract

Acute inflammation: IgM activates classical complement needed for wound repair o Go all the way to C5-9 MAC o IgG only activates complement to C3 and then stops need 2xIgG to activate complement kick in after 10 days b/c heavy chain splicing of IgM

Chronic inflammation: IgG, monocytes, plasma cells, no pus Mast cells are in tissues, not BV so not part of acute inflammation 12

Granuloma: o Delayed type 4 hypersensitivity: macrophages process Ag and present to Th1 cells o IFN-gamma (activate macrophage to kill become epithelioid cells) and macrophage inhibitory factor (localize granuloma)

Macrophages produce IL12 activate Th1 become memory T cells PPD: Langerhans cells (macrophage of skin, CD1) Birbeck granules on stain o Phagocytose PPD present to memory Th1 cell induration o AIDS: no PPD response b/c no Th cells no granulation either o Aging: decreased PPD reaction

> 5 mm is positive PPD Scar/fibrous tissue: does not contract decreases ejection fraction after MI Straight part PCT and medullary TAL (Na/K/2Cl pump) are most susceptible to low O2 o 20 mL obligated water moves for every Na, K, Cl o Na/K/2Cl pump generates free H2O for ADH to absorb because TAL not permeable to water, so cannot follow blocked by Lasix

Type 2 pneumocytes: repair cell of lung, produce surfactant CNS: astrocytes are repair cells gliosis ESR: sed rate how many mm/hr RBC settles o If Rouleaux cells: fast sed rate o Due to increased IgG and fibrinogen o IgM cause RBC stick together RBC usually repel each other due to neg charge cold agglutinatinin Ab Raynauds

Cryoglobulin congeal in cold water associated with HCV Appendicitis: o Increased absolute polys o Toxic granulations (azurophilic from myeloperoxidase around bacteria creating O2 burst) 13

o L shift polys: >10% bands

HEMODYNAMICS 1-3 Edema Edema: fluid in interstitial space o Transudate cause pitting o Exudate and lymphatics NOT cause pitting MI: increased hydrostatic P, L heart failure transudate Bee sting and face swelling: due to histamine increase vessel permeability exudate o SQ epi for airway management Cirrhosis: decreased oncotic P to no albumin, increased hydrostatic P to portal HTN Lymphedema: peau dorange breasts, mastectomy can cause if damage lymphatics Must give 3L isotonic saline to retain 1L in BV (2L in interstitial space)

Osmolality Osmolality: measure solutes in fluid o 2Na + glucose/18 + BUN = approximately 2Na + 10 o Urea can equilibrate between ECF and ICF does not contribute to osmolality o Hyponatremia of CNS: H2O inside cells cerebral edema o Hypernatremia of CNS: brain cells shrink o Hyperglycemia: H2O to ECF b/c high glucose dilutional hyponatremia Increase osmolality cause ADH release Total body sodium: look at skin turgor, mucous membranes, mouth o Dehydration = low total body salt

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o Pitting edema = high total body salt restrict Na and H2O, give diuretics See in R heart failure: kidney reabsorb more H2O than Na

Tonicity Nl saline = 0.9% Diuretic: lose hypertonic fluid hypo Na fluid to ICF ADH: distal CD permeable to free H2O hypernatremia o Concentrates urine SIADH Rx: restrict H2O (total body Na still nl) Sulfunylurea: produce SIADH in DM2 Pitting edema: hypo Na b/c kidneys reabsorb more H2O than Na o Increase total body Na causes pitting edema fluid in interstitial space Hypertonic state: increased glucose or Na DI and SIADH opposites Baby diarrhea: hypotonic give Gatorade need glucose+Na for reabsorption Adult diarrhea: isotonic Hypovolemia o EABV = cardiac output o Losing Na cause hypovolemia o Hypovolemia: low P baroreceptors on venous side o Arterial baroreceptors innervated by CN9 and 10 o Hypovolemia: release NE, E constrict veins to increase return to R heart, increase contractility and HR due to beta 1, increase SVR to maintain diastolic BP, increase RAAS (AT2 constrict SVR arterioles, aldosterone reabsorb Na and H2O) o Na gets reabsorbed from PCT to peritubular capillaries due to increase oncotic P

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o Tilt test: decrease BP and increase HR when sit up from lying down due to NE/E effect gravity decreases venous return ANP: act as diuretic (get rid of Na) released in volume overload when LA or RA dilates Sweat: hypotonic salt solution o Tilt test will indicate hypovolemia o Infuse normal saline first to stabilize BP o Then infuse hypotonic salt solution (half normal saline) for hypovolemia Diabetic ketoacidosis o Osmotic diuresis losing hypotonic fluid o Give normal saline to stabilize BP need 6-8 L o Give half normal saline with insulin after BP stabilizes Diabetes insipidus o Hypernatremic o Give pure water (most likely 5% dextrose) to prevent aspiration

Shock Neurogenic: spinal cord injuries Hypovolemic: blood loss, diarrhea, salt loss o Skin cold, clammy vasoconstriction peripheral vessels due to AT2, NE, E o BP low b/c low cardiac output o HR high Cardiogenic: MI o Skin cold, clammy vasoconstriction peripheral vessels due to AT2, NE, E o BP low b/c low cardiac output o HR high 16

Septic: E. coli (due most commonly to indwelling urinary catheter) o Gram negative bacteria produce endotoxins in cell wall o Less common with gram positive bacteria o Endotoxins activate alternative complement release C3a and C5a mast cells release histamine histamine cause vasodilation of peripheral arterioles hot skin (like acute inflammation) o Endotoxins damage endothelial cells produce excess NO and PGI2 (prostacyclin) o Vasodilation cause decrease BP (low SVR) and hence faster blood return to heart increased cardiac output

Poiseuilles law: R = viscosity/radius4 Swan Ganz catheters: stick into R heart o Cardiac output: low in cardiogenic/hypovolemic, high in septic o SVR: high in cardiogenic/hypovolemic (vasoconstriction), low in septic (vasodilation) o Mixed venous oxygen content: low in cardiogenic/hypovolemic (plenty of time to extract O2 b/c no force pushing blood through), high in septic b/c blood flows so fast that no time to extract O2 o PCWP (measures LV EDV and EDP): separate cardiogenic and hypovolemic shock Cardiogenic: high EDP Hypovolemic: low EDP

Kidneys suffers most from hypovolemia (medulla) o Oliguria, high BUN/Cr o Cause ATN (coagulation necrosis cause casts to block urine flow causing oliguria)

CNS circle of Willis will distribute blood throughout brain even in hypovolemia Sickle cell trait can cause sickling in medulla and cause micro-infarcts of kidneys and ATN

Acid-Base H = PCO2/HCO317

Ventilation refer to CO2 levels Acid-base compensation is never 100% except chronic high altitude Respiratory center: medulla oblongata control RR Inspiration: increase negative intrathoracic pressure suck air into lungs and blood to R heart Respiratory acidosis o Barbiturate (depress respiratory center) o CNS injury to medulla o Any diaphragm injury o Upper airway obstruction o Paralysis muscles of respiration: Guillan Barre, polio o Obstructive lung disease

Respiratory alkalosis o Anxiety hyperventilation get tetany due to low ionized Ca2+ o Pregnancy: E2 and P stimulate respiratory center AV fistulas in lung blow off more CO2 per breath

o Endotoxins: stimulate respiratory center Also in metabolic acidosis due to lactic acid Hence pH is normal

o ASA: stimulate respiratory center, but also adding acid to body, so pH normal Acute epiglottitis: H. flu inspiratory stridor 3 month: croup tracheal obstruction

NUTRITION 1-2 Casons disease

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o For every 30 ft underwater increase 1 atm pressure o Alveolar oxygen = 0.21(Patm)-PCO2/0.8 o Bends: gas bubbles out from tissues pain, quadriplegia, loss bladder control, death Rx: hyperbaric O2 chamber

Eating disorders Anorexia nervosa o Body image problem: still think fat at 60 lbs loss of control o GnRH increases as lose 15-20% body weight low E2, P osteoporosis, no period o Die of heart failure o Rx: weight gain to bring period back Bulimia nervosa o No distorted body image o Binge and force vomit o Acid wears down enamel dentin show (brown stuff) o Metabolic alkalosis as a result L shift O2 curve resp acidosis to compensate get hypoxia can induce arrhythmia o Mallory Weiss: tear esophagus or stomach vomit up blood o Borhaus syndrome: air and acid can get into pleural cavity Hammonds crunch (hear crunch at mediastinum) Obesity o BMI to calculate = kg/m2 o > 30 = obese o > 40 = morbidly obese o Main complication: HTN mechanism unknown Cause LVH and risk heart failure 19

o Gallbaldder disease, cancer o Adipose aromatises 17-ketosteroids (T to E2) risk E2 related cancers (breast, endometrial adenoCA, colon) Marasmus: total calorie deprivation wasting away of muscle survive if get food Kwashiorkor: low protein diet anemia, immunity problems, fatty liver, low albumin, need to force feed likely to die o Pitting leg edema, dermatitis that flakes

Vitamins Fat soluble o Taken up by chylomicrons (DEAK) o Toxicity greater b/c stored in fat (not pee out) Vit A o Deficiency o Excess Big game hunter who eats bear liver, headaches (cerebral edema and papilledema), retinoic acid can cause liver toxicity Important in kids for growth cause FTT Follicular hyperkeratosis, nictolopia (night blindness) Usually prevents squamous metaplasia: eyes lined by cuboidal epithelium metaplasia can cause softening cornea and blindness (keratomalacia)

Vit D o Cholesterol: makes bile salts, hormones, converted to vit D in skin o Sunshine most important vit D source o Not present in breastmilk need to expose to sun o Reabsorbed in jejunum

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o Active vit D 1,25-OH vit-D 25 hydroxylated in liver 1 alpha hydroxylated in PCT (PTH responsible for synthesis 1 alpha hydroxylase) Reabsorbs Ca2+ and P to mineralize bone

o Vit D mineralize bone and cartilage Need osteoblasts vit D bind to receptor release Alk P

o Vit D deficiency: loss sunshine, poor diet, liver disease, renal disease Patient on phenytoin/alcohol/barbiturate with hyperCa2+: phenytoin induce CYP450 located in sER sER hyperplasia metabolize 25-OH vitD Woman on phenytoin and OCP and gets pregnant due to CYP450 induction sER: high gamma glutamiltransferase in CYP450 induction Cirrhosis: cannot hydroxylate vitD Chronic renal disease (DM2) need supplement 1,25-OH-vitD (not OTC vitD) Kids: rickets soft skulls so can see if there is recoil, rosary beads on ribs (excess osteoids) Type 1: missing 1 alpha hydroxylase Type 2: missing vit D receptor

Adults: osteomalacia (soft bone) not mineralized easily fractured

o Vit D excess Hyper Ca2+ kidney stones

o PTH: reabsorb Ca2+ in early DCT via Ca2+/Na channel (most reabsorb Na) Thiazides: risk hypercalcemia b/c Na now cannot be reabsorbed Use thiazides in calcium stone formers to suck Ca2+ out of urine Decrease P and HCO3- reabsorption in PCT Resorb bone

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PTH bind to osteoblast and release IL1 (osteoclast activating factor) IL1 inhibited by E2 and T Osteoporosis with low E2: IL1 unchecked and hence break more bone down

o Calcitonin receptor on osteoclast: use for osteoporosis and Ca2+ excess Vit E o Main function: maintain cell membranes, prevent lipid peroxidation not get broken down by PLA o 2nd function: neutralize oxidize LDL (more atherogenic) cardio-protection Macrophages phagocytose oLDL and become foam cells

o Deficiency o Excess > 1100 units Prevent synthesis of vit K dependent coagulation factors: 2, 7, 9, 10, protein C and S anticoagulating Synergy with warfarin (prevent gamma carboxylation) Uncommon See in kids with CF b/c malabsorption, so need to supplement DEAK Cause hemolytic anemia and myelin problems

Vit K

o Synthesized by anaerobes in GI o Hence give neonates vit K injection (none in breast milk and not colonized GI until day 5) o Make K2 (inactive form) converted to K1 (active) via epoxide reductase o K1 gamma carboxylates vit K dependent factors o 2, 7, 9, 10 must be bound by Ca2+ to work carboxylation allows Ca2+ to bind o Warfarin inhibits epoxide reductase, so all K2 and no K1 o Broad spec antibiotics: knock out anaerobes in gut no vit K synthesized 22

o Deficiency cause bleeding o Rat poison = warfarin antidote is IM vit K Water soluble o Pee out excess vitamins o Bright yellow urine due to vitamins o All cofactors of biochemical reactions Vit C o Deficiency: Unstable blood vessels rupture (hemearthrosis) resemble hemophilia A Corkscrew hair Ring around hair follicle

o Excess: renal stones (uric acid esp) o Reducing agent use for methemoglobin o Cofactor for making catecholamines convert NE to E Thiamine B1 o Cofactor for transketolase (HMP), all dehydrogenase in glycolysis Pyruvate dehydrogenase: pyruvate to acetyl-CoA (6 ATP) Carboxylase: pyruvate to oxaloacetate B1 deficiency: low acetyl-CoA low citrate and TCA low ATP TCA usually 24 ATP

o Dry beriberi: peripheral neuropathy b/c no ATP to make myelin o Korsakoff psychosis: cannot remember new things o Wernicke: confusion, ataxia, nystagmus o Wet beriberi: congestive cardiomyopathy, dependent pitting edema, LHF and RHF pulmonary edema, pitting edema, congestive heart failure reverse with IV B1 23

o Alcoholics commonly have B1 deficiency o Give IV thiamine before give IV glucose Comatose in ER: IV thiamine, IV glucose, naloxone (OD) Niacin B3 o Pellagra: niacin deficiency o Hyperpigmentation on sun exposed areas necklace o Cofactor for NAD+ and NADP reactions o Tryptophan can be used to synthesize B3 (and 5-HT) hence essential AA o Nicotinic acid: lipid lowering see flushing (take ASA before to avoid) used for familial combined hyperlipidemia (high cholesterol and TG) Riboflavin B2 o Co-factor for FAD and FMN reactions o Glutathione reductase need B2 as cofactor Pyridoxine B6 o Succinyl Co-A + glycine in heme synthesis need B6 cofactor o Transaminase (SGLT, SGPT) can produce pyruvate from alanine, oxaloacetate from aspartate via removing NH2 B6 cofactor o Neurotransmitters need B6 for synthesis o Deficiency: INH Pantothenic acid B5 used for making CoA Biotin o Deficiency: Cannot make oxaloacetate no gluconeogenesis Pyruvate build up lactic acid

Chromium: glucose tolerance factor help insulin do its job Copper: crossbridge collagen fibrils and elastic tissue 24

o Deficiency = dissecting aortic aneurysm Fluorine: prevent dental cavities, too much = white chalky teeth o Colorado water has fluorine o Excess: calcification of ligaments when inserts to bone subject to rupture Selenium: needed for GSH to neutralize H2O2 hence is antioxidant Zinc: o Metalloenzyme has a trace metal as a cofactor o Collagenase is metalloenzyme: has zinc in it that breaks down type 3 collagen so can form type 1 o Zinc deficiency = poor wound healing, rash on face, deficiency taste, anosmia o Diabetics all zinc deficient Soluble fiber: lower cholesterol o Oatmeal has insoluble fiber suck up water from gut and bad things that might be there (lithocholic acid causes cancer) o E2 is excreted in stool oatmeal will also decrease E2 recycling that is not needed Restrict protein: renal failure (so less ammonia and hence urea) and liver cirrhosis (defective urea cycle so cannot metabolize ammonia)

NEOPLASIA 1-3 Benign: usually not mets, except for invasive mole (goes to lung) Malignant: does metastasize Leiomyoma of uterus: most common benign tumor in women SM tumor (fibroid) o No transformation to leiomyosarcoma Lipoma: most common benign tumor in men Adenoma: functional glands o Tubular: most common precursor for colon cancer strawberry on a stick 25

Carcinoma: malignancy of epithelial tissue o Squamous, glandular, transitional o Squamous: squamous keratin pearls o Glandular: adenocarcinoma glands with things inside it o Transitional: from urinary system

Malignant melanoma: excise o Benign version = nevus o Most rapidly increasing cancer o S100 antigen popular o Of neural crest origin: neurosecretory granules on EM

Neurosecretory tumor (APUD): S100 positive o Bronchial carcinoid o SCC of lung o Tumor at tip of appendix o Neuroblastoma in kids in adrenal medulla can mets to skin

Sarcoma: from mesenchymal tissue o Osteogenic sarcoma: Codmans triangle, sunburst appearance o Rhabdomyosarcoma: necrotic mass coming out of vagina, vimentin negative, desmin positive see muscle striations, most common sarcoma of kids (vagina and penis) o Leiomyosarcoma: SM o Liposarcoma: fat

Mixed tumor in parotid: most common overall salivary tumor o 2 cell types from same cell layer (hence difference from teratoma which comes from all 3 cell layers)

Teratoma = germ cell tumor: stay in midline (ovary, anterior mediastinum, pineal gland) o RLQ pain on 64 year old woman with pelvic calcifications on xray (due to bone or teeth) 26

Auer rods for AML Leukemia: malignancy of stem cells in bone marrow can mets out H/S megaly, lymphadenopathy Lymphoma: malignancy of lymph nodes can mets out bone marrow o Most common lymphoma arising not in LN: stomach, can be produced by H pylori o Second most common occasion: Peyers patches in terminal ileum o Follicular B cell lymphoma most common: t(14;18) knock off apoptosis gene

Trophoblastic tumors: seen in pregnancy o Hydatidiform mole: present with pre-eclampsia in T1 complete mole, goes to chorioCa, cancer of chorionic villus o Mole = benign tumor of chorionic villus (lined by trophoblastic cells SCT on outside in contact with blood, then CT, then Whartons jelly, then umbilical vein) o ChorioCA: SCT and CT tumor mets to lung, respond to chemo, highly malignant o SCT makes hCG and hPL

Peutz-Jeger: hamartoma o No increased risk for cancer o Hyperplastic polyp of colon

Benign pancreatic tissue: heterotopic rest Meckels diverticulum: bleeding most common complications from ulcerated gastric or pancreatic mucosa Atypical mitotic spindle = cancer Increased mitotic rate does not necessarily mean cancer Cancer o Longer cell cycle than cell from which they are derivated o 30 doubling times before can detect tumor (10-9 in mass) o Immortal can live forever

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o Burkitt cells: test for immune complexes o Have collagenases and proteases to help invade Metastasis: hematogenous, lymphatic, seeding o Sarcoma: mets hematogenously directly o Carcinoma: hematogenous spread after spread through LN (subcapsular sinus) to BV o Follicular CA of thyroid: spread hematogenously even though is CA o Renal adenoCA: invade renal vein o Seeding: cancer in cavities Ovarian carcinoma seeding: pouch of Douglas in F = prostate in M

o Peripheral lung cancer can seed through pleura Is metastasis more common than primary cancer? o Lung: mets from breast cancer o Bone: mets from breast cancer (Batson is venous complex from vena cava that goes to the sacrum vertebral bodies) Vertebral column and femoral head most common sites

o LN most common site of mets o Liver: mets from lung (NOT colon) o Paraortic LN: testicular cancer (testes from abdominal cavity, so met to paraortic LN) o L supraclavicular LN (Virchows node): mets from stomach weight loss and epigastric distress o Radionuclei scan: look for bone mets o Lytic mets: break bone down MM has IL1 (osteoclast activating factor) Get hyper Ca2+ Lucency on Xray

o Blastic mets: build bone males with prostate cancer (lumbar vertebrae) High Alk P b/c making bone 28

Density on Xray

o Multiple lesion: due to mets o CNS: mets from lung o Adrenal gland: mets from lung o Always CT of hilar lymph nodes and biopsy adrenal glands Renal adenoCA is common primary Stains o Desmin: intermediate filaments stain for muscle o EM: used if stains dont work o APUD: neurosecretory granules o Histiocytic tumor: Birbeck granules (CD1) o Muscle: actin and myosin o Vascular: Weibel-Palade bodies (have vWF in them) Oncogenesis o Initiation = mutation o Promotion = make multiple copies of specific mutation o Progression = different cancer cells have different functions within group Proto-oncogenes growth genes (cell cycle) o EGF o Cis: make growth factor o Erb-B2: code for receptor o Ret: MEN syndromes, code for receptor o Ras: GTP as messenger o Abl: live in cytosol, messenger o Nuclear oncogenes: N-myc (NF) and c-myc (Burkitts) 29

Suppressor genes o Rb and p53 o All point mutations o Adenomatous polyposis coli, Wilms o BRCA 2: breast only o BRCA 1: breast or ovarian

Mechanisms of initiation/mutation o Point mutation most common: p53 and Ras o Amplification: Erb-B2 o Translocation: CML Abl from 9 to 22 (Bcr) t(9;22) Burkitts lymphoma: Myc from 8 to 14 (Ig heavy chain) t(8;14) EBV bind to CD 21 and cause B cells to become plasma cells (antibody cells) increased mitotic rate so higher likelihood of mutation B cell lymphoma: t(14;18) Acute granulomatous leukemia: t(15;17) Rx with retinoic acid (cause blasts to mature)

Chemicals main thing that induces mutations o Smoking o Anyline dye: transitional cell o Cyclophosphamide: hemorrhagic cystitis (prevent with mesna), carcinogen for transitional cell

EBV: Burkitt, nasopharyngeal CA Hepatocellular CA: HBV + aflatoxin B HIV: CNS lymphoma HPV: also anus CA 30

o E6 for p53 o E7 for Rb Radiation o CML t(9;22) o Papillary carcinoma of thyroid o Osteogenic sarcoma o Basal cell CA: multifocal due to non-ionizing radiation UVB cause thymidine dimmers o Arsenic cause SCC from actinic keratosis esp in Bangladesh due to H2O supply Retinoblastoma: Chr 13 o Sporadic: need 2 separate mutations o A-Dominant genetic: born with one mutation, only need one more o White eye reflex Congenital cataract: most common cause white eye reflex o Can be due to TORCH Steroids predispose to cataracts Xeroderma pigmentosum o Defect DNA repair enzymes DNA repair o Chromosome instability syndrome: Wiskott Aldrich, Fanconi, Atelangia-ectasia Lower lip: SCC Upper lip: basal cell CA H. pylori only bacteria associated with cancer: adenoCA and low grade lymphoma Grade: what does cancer look like o Low = well differentiated 31

o High = anaplastic Stage o T = tumor size (>2 cm great chance of mets) o N = node o M = metastasis o Mets most important prognostic factor CD8 T cell most important host defense system component o Stimulate caspase to kill cell Cachexia o Due to TNF alpha, irreversible Anemia chronic disease most common anemia in cancer Cancer causes hypercoagulability Trousseaus sign: vascular problem that jumps from site to site Cancer cause thrombocytosis Gram negative infection cause fever o Most common cause of death in cancer

Paraneoplastic syndromes Signs that say you might have underlying cancer present Hypercalcemia: o Mets to bone and produce IL1 or PGE2 that cause lytic lesions most common o Make PTH like peptide paraneoplastic!! Gastric adenoCA marker o Acanthosa nigricans, seborrheic keratosis: multiple outcroppings overnight, two black lesions 32

o Hypertrophic osteoarthropathy cause fingernail clubbing Collagen vascular disease o Dermatomyositis: Increased CK, raccoon eyes o Associated with leukemia, lung cancer, lymphoma Sterile MV vegetations marantic endocarditis o Benign o Associated with mucous secreting colon cancer can embolize o Maybe confuse with rheumatic fever (all other endocarditis are not as regular) Hyponatremia or Cushings: SCC of lung ADH and ACTH o S100, NCC origin, neurosecretory granules Renal adenoCA: PTH like peptide, make Epo Hypoglycemia or 2nd polycythemia: hepatocellular CA (insulin like and epo like factor) Hypocalcemia or Cushings: medullary tumor of thyroid calcitonin Tumor markers o Male + testicular cancer: hCG and AFP (yolk sac tumor = endodermal sinus tumor) o AFP = albumin of fetus o AFP elevated in hepatocellular CA, NTD, Trisomy 21 o Bence Jones protein = light chain of Ig see in MM o PSA: not specific for prostate cancer, but is sensitive (not increased after rectal exam b/c not enzyme) o Surface derived ovarian cancer: CA-125 o Surface derived breast cancer: CA15-3 o Colon cancer, small cell, breast: CEA can be part of immune complex o Mole: hCG Primary tumor of brain in kids: cerebellar cystic astrocytoma

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Primary cancer of brain in kids: medullo-blastoma from cerebellum Most common childhood cancer: ALL Ewings sarcoma: onion skinning, tumor of bone Incidence of cancer o Women: breast > lung > colon o Men: prostate > lung > colon

Cancer killers: o Men: lung > prostate o Women: lung > breast o Colon cancer biggest killer combined in men and women

Incidence gyn cancer: endometrial > ovarian > cervical (b/c PAP smear detects it) o Reverse for cancer killer: cervical > ovarian > endometrial

Cancer vaccine o HBV (also protects again HDV)

Eradicate hepatocellular CA in far east with HBV vaccine

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