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

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 plasmao If PO2 decrease, then O2 sat decrease b/c since less in plasma, less diffuses into RBC

Ischemia: decrease arterial blood flowo Thrombus in muscular artery most common cause – MIo Decrease cardiac output, hypovolemiao Hypoxemia #2 cause of ischemia – also cause hypoxia and decrease Parterial O2

When retain CO2, then PO2 decrease due to Dalton’s law of partial pressure (partial pressure all gases equals 760 mmHg total)

Ventilation defect: RDS (hyaline membrane disease) – lose ventilation, retain perfusiono Give 100% O2 but PO2 not change – SHUNT

Perfusion defect: no blood flowo PE #1 cause o Increase dead spaceo Give 100% O2 and PO2 increases b/c other areas of lung can make up

Diffusion defect: smtg block O2 diffusiono Sarcoidosis cause fibrosiso Pulmonary edemao CHF due to fluid (J reflex due to CN 10)

Anemia: no decrease PO2 – gas exchange normalo Decrease Hb cause hypoxemia

Carbon monoxide: hypoxiao Room heater, auto exhaust, house fire (also cause cyanide poisoning from polyurethane on

upholstery)o High Hb affinity, freely diffuseso Cause decrease O2 sat b/c C1O1take up Hb space so O2 cannot bindo NOT see cyanosis b/c cherry red pigment mask blue lipso #1 sx: headacheo 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 sato Chocolate colored blood b/c no O2o Need Hb reductase to convert to Fe2+o Give O2 and still cyanotico H2O in mountains loaded with oxidizing agents (nitrite and nitrate)o Rx: IV methylene blue, vit C as anxillaryo Increase Fe3+: dapsone (leprosy, sulfa drug)

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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 hyperthermiao 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 ATPo Increase lactic acid inside and outside cells – increase anion gapo 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 nucleuso Due to oxidation unsaturated FAo Due to uncoupled eo Cause reperfusion injury in MI/thrombuso See in Fe overload

Tylenol: CyP450 canc hange drugs to free radicalso #1 cause drug induced fulminant hepatitiso Damage around central veino N-acetyl cysteine as antidote: replenish GSH (N-acetyl cysteine is substrate)o GSH neutralizes free radicals from drugs and peroxide – from HMP shunto Kills renal medulla blood flowo 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

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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 RFo 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 abnormalitieso Astrocytes = fibroblasts in brain – give CNS structure, damaged in necrosis and hence

brain liquefieso 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 cello 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 amylaseo Enzymatic fat necrosis: saponification with Ca2+ bound – see on x ray – alcoholicso 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 isn’to Necrosis if immunologic diseaseo Palpable purpura: type 3 hypersensitivity, small vessel diseaseo Activate alternative complement C5a chemotactic for polys cause damageo RA, SLE glomerulonephritis

Liver: sinusoid organ along with spleen and BMo Gaps between endothelial cellso Nutmeg liver in R heart failureo Hepatic vein empty to IVC

Budd-Chiari: blocked hepatic vein liver congestiono Zone 2 damage: yellow fevero 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

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o See ketone bodies (beta-hydroxybuteric acid) due to increased acetyl-CoAo In glycolysis, drive G3P formation G3P + 3FA = TG high VLDLo To decrease VLDL, restrict carbs

Kwashiorkor: protein deficiencyo 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 calcifiedo Enzymatic fat necrosis is an exampleo Reverse calcified plaques with Ornish dieto #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 defecto 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 Parkinson’s: 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 muscleo 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 somethingo Glucagon phosphorylateso Insulin dephosphorylates

G1S: key checkpointo Rb on Chr13q suppresses entering S – tumor suppressor geneo Cyclin D cause P of Rbo P53 (Chr 17p): guardian of the cell – give cell time to detect DNA defects

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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 cellsAtrophy 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 BPHo Uterus: 50% hyperplasia and hypertrophy

BM: usually 3:1 WBC:RBCo 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 Barrett’s 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 bronchioleso Squamous metaplasia dysplasia CA

H pylori cause gastric adenoCA Dysplasia: atypical hyperplasia, disordered, preneoplastic Actinic keratosis precursor to skin SCC

INFLAMMATIONMicrobicidal Defects Oxidative burst

o O2 converted by NADPH oxidase o No NADPH oxidase in G6PD deficiency see infection before hemolysis

Chronic granulomatous disease of childhoodo X linked Recessive, female carriers and give to 50% of sonso No respiratory burst, no superoxide, no H2O2 (b/c no NADPH oxidase convert O2 to

H2O2)o Can kill Strep b/c strep has no catalase, so when it produces H2O2, it goes to HOClo 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

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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 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 synthaseo Block TXA2 in dipyramidol sestamibi stress test

Steroids: decrease adhesion molecule synthesiso CBC show increased polys b/c no longer bound to endothelium (usually 50%)o Kills T and B cells via apoptosiso Decrease eos and lymphs, increase polyso Addison’s: no cortisol – opposite of steroidso 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) Types of inflammation

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o Suppurative: pus, Stapho Abscess: Staph – osteomyelitis from hematogenous spreado Sickle cell: Salmonellao Cellulitis: Strep pyogeneso Diphtheria: produce exotoxin pseudomembrane like C. diffo Fibrinoid pericarditis: Coxsackieo 3rd degree burns: pseudomonas

Fibronectin and granulation tissue needed for wound healingo Collagen type 3 found in initial wound repair (reticulin) zinc converts it to type 1 via

collagenase activityo 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 predispositiono See in 3rd degree burns and skin SCCo Lots of turnover in scar tissue – fibroblasts involved – chance for squamous cancero Also see SCC in chronic draining sinus tract

Acute inflammation: IgM activates classical complement – needed for wound repairo Go all the way to C5-9 MACo 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 Granuloma:

o Delayed type 4 hypersensitivity: macrophages process Ag and present to Th1 cellso 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 indurationo AIDS: no PPD response b/c no Th cells – no granulation eithero 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, Clo 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 rateo Due to increased IgG and fibrinogen

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o IgM cause RBC stick together RBC usually repel each other due to neg charge cold agglutinatinin Ab Raynaud’s

Cryoglobulin congeal in cold water – associated with HCV Appendicitis:

o Increased absolute polyso Toxic granulations (azurophilic from myeloperoxidase around bacteria creating O2 burst)o L shift polys: >10% bands

HEMODYNAMICS 1-3Edema Edema: fluid in interstitial space

o Transudate cause pittingo 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 d’orange 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 + 10o Urea can equilibrate between ECF and ICF – does not contribute to osmolalityo Hyponatremia of CNS: H2O inside cells cerebral edemao Hypernatremia of CNS: brain cells shrinko 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 salto 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

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o EABV = cardiac outputo Losing Na cause hypovolemiao Hypovolemia: low P baroreceptors on venous sideo Arterial baroreceptors innervated by CN9 and 10o 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 Po 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 hypovolemiao Infuse normal saline first to stabilize BPo Then infuse hypotonic salt solution (half normal saline) for hypovolemia

Diabetic ketoacidosiso Osmotic diuresis – losing hypotonic fluido Give normal saline to stabilize BP – need 6-8 Lo Give half normal saline with insulin after BP stabilizes

Diabetes insipiduso 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, Eo BP low b/c low cardiac outputo HR high

Cardiogenic: MIo Skin cold, clammy – vasoconstriction peripheral vessels due to AT2, NE, Eo BP low b/c low cardiac outputo HR high

Septic: E. coli (due most commonly to indwelling urinary catheter)o Gram negative bacteria produce endotoxins in cell wallo Less common with gram positive bacteriao 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 Poiseuille’s law: R = viscosity/radius4

Swan Ganz catheters: stick into R heart o Cardiac output: low in cardiogenic/hypovolemic, high in septico SVR: high in cardiogenic/hypovolemic (vasoconstriction), low in septic (vasodilation)

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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/Cro 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/HCO3

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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 obstructiono Paralysis muscles of respiration: Guillan Barre, polioo Obstructive lung disease

Respiratory alkalosiso 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 breatho 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 Cason’s disease

o For every 30 ft underwater increase 1 atm pressureo Alveolar oxygen = 0.21(Patm)-PCO2/0.8o 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

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o GnRH increases as lose 15-20% body weight low E2, P osteoporosis, no periodo Die of heart failureo Rx: weight gain to bring period back

Bulimia nervosao No distorted body imageo Binge and force vomito 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 bloodo Borhaus syndrome: air and acid can get into pleural cavity – Hammond’s crunch (hear

crunch at mediastinum) Obesity

o BMI to calculate = kg/m2

o > 30 = obeseo > 40 = morbidly obeseo Main complication: HTN – mechanism unknown

Cause LVH and risk heart failureo 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 dieo 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 Ao Deficiency

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)o Excess

Big game hunter who eats bear liver, headaches (cerebral edema and papilledema), retinoic acid can cause liver toxicity

Vit Do Cholesterol: makes bile salts, hormones, converted to vit D in skino Sunshine most important vit D sourceo Not present in breastmilk – need to expose to suno Reabsorbed in jejunum o Active vit D 1,25-OH vit-D

25 hydroxylated in liver

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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 fracturedo Vit D excess

Hyper Ca2+ kidney stoneso 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 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 Uncommon See in kids with CF b/c malabsorption, so need to supplement DEAK Cause hemolytic anemia and myelin problems

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)

Vit Ko Synthesized by anaerobes in GIo 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 reductaseo K1 gamma carboxylates vit K dependent factorso 2, 7, 9, 10 must be bound by Ca2+ to work – carboxylation allows Ca2+ to bind

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o Warfarin inhibits epoxide reductase, so all K2 and no K1o Broad spec antibiotics: knock out anaerobes in gut – no vit K synthesizedo Deficiency cause bleedingo Rat poison = warfarin – antidote is IM vit K

Water solubleo Pee out excess vitaminso Bright yellow urine due to vitaminso 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 methemoglobino Cofactor for making catecholamines – convert NE to E

Thiamine – B1o 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 myelino Korsakoff psychosis: cannot remember new thingso Wernicke: confusion, ataxia, nystagmuso Wet beriberi: congestive cardiomyopathy, dependent pitting edema, LHF and RHF –

pulmonary edema, pitting edema, congestive heart failure – reverse with IV B1o Alcoholics commonly have B1 deficiencyo 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 AAo 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 reactionso Glutathione reductase need B2 as cofactor

Pyridoxine – B6o Succinyl Co-A + glycine in heme synthesis need B6 cofactoro Transaminase (SGLT, SGPT) can produce pyruvate from alanine, oxaloacetate from

aspartate via removing NH2 – B6 cofactoro Neurotransmitters need B6 for synthesiso Deficiency: INH

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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

o Deficiency = dissecting aortic aneurysm Fluorine: prevent dental cavities, too much = white chalky teeth

o Colorado water has fluorineo 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 cofactoro Collagenase is metalloenzyme: has zinc in it that breaks down type 3 collagen so can form

type 1o Zinc deficiency = poor wound healing, rash on face, deficiency taste, anosmiao Diabetics all zinc deficient

Soluble fiber: lower cholesterolo 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 Carcinoma: malignancy of epithelial tissue

o Squamous, glandular, transitionalo Squamous: squamous keratin pearlso Glandular: adenocarcinoma – glands with things inside ito Transitional: from urinary system

Malignant melanoma: exciseo Benign version = nevuso Most rapidly increasing cancero S100 antigen popularo Of neural crest origin: neurosecretory granules on EM

Neurosecretory tumor (APUD): S100 positiveo Bronchial carcinoido SCC of lung

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o Tumor at tip of appendixo Neuroblastoma in kids in adrenal medulla can mets to skin

Sarcoma: from mesenchymal tissueo Osteogenic sarcoma: Codman’s triangle, sunburst appearanceo Rhabdomyosarcoma: necrotic mass coming out of vagina, vimentin negative, desmin

positive – see muscle striations, most common sarcoma of kids (vagina and penis)o Leiomyosarcoma: SMo Liposarcoma: fat

Mixed tumor in parotid: most common overall salivary tumoro 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) 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 pylorio Second most common occasion: Peyer’s patches in terminal ileumo Follicular B cell lymphoma most common: t(14;18) – knock off apoptosis gene

Trophoblastic tumors: seen in pregnancyo Hydatidiform mole: present with pre-eclampsia in T1 – complete mole, goes to chorioCa,

cancer of chorionic villuso Mole = benign tumor of chorionic villus (lined by trophoblastic cells – SCT on outside in

contact with blood, then CT, then Wharton’s jelly, then umbilical vein)o ChorioCA: SCT and CT tumor – mets to lung, respond to chemo, highly malignanto SCT makes hCG and hPL

Peutz-Jeger: hamartomao No increased risk for cancero Hyperplastic polyp of colon

Benign pancreatic tissue: heterotopic rest Meckel’s 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 derivatedo 30 doubling times before can detect tumor (10-9 in mass)o Immortal – can live forevero Burkitt cells: test for immune complexeso Have collagenases and proteases to help invade

Metastasis: hematogenous, lymphatic, seedingo Sarcoma: mets hematogenously directlyo Carcinoma: hematogenous spread after spread through LN (subcapsular sinus) to BVo Follicular CA of thyroid: spread hematogenously even though is CAo Renal adenoCA: invade renal vein

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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 cancero 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 metso Liver: mets from lung (NOT colon)o Paraortic LN: testicular cancer (testes from abdominal cavity, so met to paraortic LN)o L supraclavicular LN (Virchow’s node): mets from stomach – weight loss and epigastric

distresso Radionuclei scan: look for bone metso 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 Density on Xray

o Multiple lesion: due to metso CNS: mets from lungo Adrenal gland: mets from lungo Always CT of hilar lymph nodes and biopsy adrenal glands

Renal adenoCA is common primary Stains

o Desmin: intermediate filaments – stain for muscleo EM: used if stains don’t worko APUD: neurosecretory granuleso Histiocytic tumor: Birbeck granules (CD1)o Muscle: actin and myosino Vascular: Weibel-Palade bodies (have vWF in them)

Oncogenesiso Initiation = mutationo Promotion = make multiple copies of specific mutationo Progression = different cancer cells have different functions within group

Proto-oncogenes – growth genes (cell cycle)o EGFo Cis: make growth factoro Erb-B2: code for receptoro Ret: MEN syndromes, code for receptoro Ras: GTP as messengero Abl: live in cytosol, messengero Nuclear oncogenes: N-myc (NF) and c-myc (Burkitt’s)

Suppressor geneso Rb and p53

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o All point mutationso Adenomatous polyposis coli, Wilm’so BRCA 2: breast onlyo BRCA 1: breast or ovarian

Mechanisms of initiation/mutationo Point mutation most common: p53 and Raso Amplification: Erb-B2o Translocation:

CML – Abl from 9 to 22 (Bcr) – t(9;22) Burkitt’s 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 Smokingo Anyline dye: transitional cello 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

o E6 for p53o E7 for Rb

Radiationo CML t(9;22)o Papillary carcinoma of thyroido Osteogenic sarcomao Basal cell CA: multifocal – due to non-ionizing radiation – UVB cause thymidine

dimmerso Arsenic cause SCC from actinic keratosis – esp in Bangladesh due to H2O supply

Retinoblastoma: Chr 13o Sporadic: need 2 separate mutationso A-Dominant genetic: born with one mutation, only need one moreo White eye reflex

Congenital cataract: most common cause white eye reflexo 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

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H. pylori only bacteria associated with cancer: adenoCA and low grade lymphoma Grade: what does cancer look like

o Low = well differentiatedo High = anaplastic

Stageo T = tumor size (>2 cm great chance of mets)o N = nodeo M = metastasiso Mets most important prognostic factor

CD8 T cell most important host defense system componento Stimulate caspase to kill cell

Cachexiao Due to TNF alpha, irreversible

Anemia chronic disease most common anemia in cancer Cancer causes hypercoagulability Trousseau’s 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 commono Make PTH like peptide – paraneoplastic!!

Gastric adenoCA markero Acanthosa nigricans, seborrheic keratosis: multiple outcroppings overnight, two black

lesionso Hypertrophic osteoarthropathy – cause fingernail clubbing

Collagen vascular disease o Dermatomyositis: Increased CK, raccoon eyeso Associated with leukemia, lung cancer, lymphoma

Sterile MV vegetations – marantic endocarditiso Benigno Associated with mucous secreting colon cancer – can embolizeo Maybe confuse with rheumatic fever (all other endocarditis are not as regular)

Hyponatremia or Cushing’s: SCC of lung – ADH and ACTHo 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 Cushing’s: medullary tumor of thyroid – calcitonin Tumor markers

o Male + testicular cancer: hCG and AFP (yolk sac tumor = endodermal sinus tumor)o AFP = albumin of fetuso AFP elevated in hepatocellular CA, NTD, Trisomy 21o Bence Jones protein = light chain of Ig – see in MM

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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-125o Surface derived breast cancer: CA15-3o Colon cancer, small cell, breast: CEA – can be part of immune complexo Mole: hCG

Primary tumor of brain in kids: cerebellar cystic astrocytoma Primary cancer of brain in kids: medullo-blastoma – from cerebellum Most common childhood cancer: ALL Ewing’s sarcoma: onion skinning, tumor of bone Incidence of cancer

o Women: breast > lung > colono Men: prostate > lung > colon

Cancer killers:o Men: lung > prostate o Women: lung > breasto 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 vaccineo HBV (also protects again HDV)

Eradicate hepatocellular CA in far east with HBV vaccine

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