ED'S PATHOLOGY MELTDOWN Part II -- Systemic Pathology [This is the second half of my "high-yield facts" for pathology exam takers. On-line, they are available at http://www.pathguy.com/meltdown.txt http://www.pathguy.com/boildown.txt Since they do not explain the "why"'s, and are unreadable if you are not familiar with the material, they are worthless to anyone who has not had classroom or on-the-job pathology experience. As before, you would be stupid to use these while you are actually trying to learn. YOU WOULD BE EVEN STUPIDER TO USE THEM AS A SUBSTITUTE FOR YOUR OWN DOCTOR'S ADVICE. Brackets [] mark stray thoughts added for your enjoyment, rather than for testability. If you've used these notes, then drop me an E-mail message (erf@uhs.edu) and tell me what you think. I claim copyright, which as far as I'm concerned means you can share these notes freely in any medium so long as they're never altered, and never sold for a profit. THESE NOTES ARE DEDICATED TO MY STUDENTS. EVERYTING THAT I NOW DO RIGHT AS A TECHER, I'VE LEARNED HOW TO DO FROM THEM. HEALTH AND FRIENSHIP. * * * "Where there is love of medicine, there is love of humankind." -- Hippocrates] I do not teach tumors staging, to emphasize that it's the clinician's job. If this will be on your exam, grab a good medicine or surgery book. "Arteriosclerosis" is a word to avoid. It includes (1) atherosclerosis; (2) Monckeberg's medial calcific sclerosis; (3) hyaline arteriolar sclerosis; (4) hyperplastic arteriolar sclerosis; (5) intimal fibrosis. Intimal fibrosis: Dense, more-or-less uniform fibrosis of the intima, narrows the lumens, severity correlates with age and long-term high- blood pressure; worst in the kidney. Hyperplastic arteriolar sclerosis: Onion-skinning of the intima, concentric layers of cells. Typical of scleroderma, hemolytic-uremic syndrome, malignant hypertension, severe pulmonary hypertension. Hyaline arteriolar sclerosis: Increased basement membrane in the media. Typical of prolonged hypertension, prolonged hyperglycemia, old radiation injury. Monckeberg's medial calcific sclerosis: Non-disease, with dystrophic calcification of the media of arteries without compromise of the lumens. If widespread, loss of arterial compliance raises widens pulse pressure. Atherosclerosis is the great epidemic disease; the peak was the late 1960's, and all atherosclerosis-related problems are probably becoming less common. A stereotyped response of arterial intima to a variety of injuries. Accumulation of LDL-derived cholesterol-rich debris in intimal cells, and the resulting tissue reactions. Calcium, if present at all, is not the problem. Atherosclerosis causes harm by (1) occluding arteries slowly over time (angina, ischemic scarring of the myocardium, atherosclerotic dementia, leg claudication, intestinal angina, watershed infarct of splenic flexure); (2) occluding arteries suddenly by rupture of plaques (thrombosis, atheroembolization) or hemorrhages into plaques (myocardial infarct, atherosclerotic stroke, gangrene of the bowel); (3) weakening the walls of arteries (atherosclerotic aneurysms). The causes are mixed. Abnormal LDL's (oxidized-LDL as in smokers and maybe in iron-overloaded people, glycosylated-LDL as in diabetes, some variants of lipoprotein A, certain mutations of apolipoprotein E, and so forth) and LDL processed down the "bad" (non-apoprotein B receptor- mediated; remember that common familial hypercholesterolemia is a relative lack of apo-B-receptors) pathway aren't broken down fully in myointimal cells. Endothelial damage (turbulence, bifurcations, high pressure, smokers?) is an additional risk. Clotting (good platelet function, good or hyper-coagulability) places a person at risk. Women are protected during reproductive life. Eskimos are protected by dietary omega-three fatty acids, maybe. You can't do anything about your gender or heredity, but modifiable risks include, from most to least important (1) high LDL / low HDL-C (reflect heredity, lack of exercise, nephrotic syndrome, hypothyroidism, others); (2) cigarette smoking; (3) hypertension; (4) diabetes; (5) lack of exercise (exercise increases apo-B receptors). Expect, soon, to see (6) increased blood homocysteine from heredity or lack of folic acid / B12. I say obesity and stress are not independent risk factors. Fatty streaks: Lipid accumulated in myointimal cells. Ubiquitous and banal. Fibrous plaques: Cells proliferate, some scar tissue has formed around the fat deposits, which might have become necrotic by now. As the surrounding tissue continues to crack and heal, the lesions get Complicated plaques: (1) plaque ulcerates, and a clot forms; (2) plaque ulcerates, and debris embolizes; (3) a little vessel hemorrhage into the plaque, expanding it; (4) plaque blocks flow of nutrients to media, weakening it. Leukocytoclastic vasculitis: Type III immune injury of the venules. Common, often from drugs (haptens), lupus, other immune-complexes. Palpable purpura. Polyarteritis and Wegener's: Already covered; don't miss these. Remember that both feature lesions in various states of development and healing. Henoch-Schonlein is an IgA-based vasculitis. Cryoglobulinemia is usually either hepatitis B-antigen and antibody complexes, or rheumatoid factors; these precipitate in the cold as immune complex vasculitis. Temporal arteritis: Granulomatous attack on elastic of branches of external carotid system. Older folks. Headache worst over temples. Sudden blindness. Jaw claudication. Most have pain syndrome "polymyalgia rheumatica". All physical exam and lab findings normal except for high sedimentation rate. Treat with glucocorticoids. Takayasu's aortic arch syndrome: thickening of the wall of the arch and its main branches; most common in young Asian women. Raynaud's: Most are functional / idiopathic; in CREST-Scleroderma, the problem is intimal proliferation; rule out ergotism, Takayasu's, cryoglobulin, Buerger's. Kawasaki's: Mysterious process affecting kids, often of Japanese ancestry, following viral illness, ? carpet cleaning. Rash (includes mucosae, palms and soles), big lymph nodes, coronary vasculitis with aneurysms the most worrisome feature. Histology looks like polyarteritis nodosa, with three-layer vasculitis. Buerger's thromboangiitis obliterans: Young male heavy smokers; inflamed neurovascular bundles with thrombosis and gangrene. Mycotic aneurysm: Site where septic arterial embolus has lodged, caused a secondary infection, and inflamed the wall. Atherosclerotic aortic aneurysm: Usually distal abdominal aorta. Tension on wall becomes greater as the aneurysm gets bigger, hence the accelerated expansion. Embolization, occlusion by thrombus, and/or rupture. Syphilitic aortitis: Thoracic aneurysms; stretch-marks are "tree barking"; compromise of the coronary ostia leads to myocardial infarction; rupture into airways produces dramatic last moment to life. Dissecting hematoma ("dissecting aneurysms"): Marfanoids, some Ehlers- Danlos, copper deficiency, lathyrism folks, or anybody else may have a rip into a weak layer of the media ("cystic medial necrosis", a misnomer). Rupture back into the pericardial sac with tamponade. Successive occlusion of arteries. Widened mediastinum on x-ray. Venous insufficiency in leg veins: Varicosities (blow out one valve, the pressure on the next is greater making it likely to blow out, too). Stasis pigmentation is hemosiderin; stasis ulcers are venous infarcts. Thrombophlebitis: Blood clot, most common in leg veins. Budd-chiari: Thrombosis of hepatic veins; think polycythemia vera. Trousseau's migratory thrombophlebitis: Unexplained venous clots suggest cancer of the pancreas. Superior vena cava syndrome, from clot or cancer: Dusky face and upper body, headache. Inferior vena cava syndrome, from clot or cancer: Dusky lower body, curious collaterals. Coarctation of the aorta: Common, especially in Turner's. Rib-notching by collaterals. Lymphangitis: red streaks, typically strep infection. Lymphedema: After surgery, or carcinomatosis, lymphogranuloma venereum (wicked chlamydia in the perineum), or filariasis; Milroy's and Turner's feature lymphedema as a birth defect. Risk of lymphangiosarcoma. With epidermal hyperplasia and thickening of the connective tissue: elephantiasis. In breast cancer, "orange-peel" (peau d'orange) change. Port-wine stain follows a branch of the trigeminal nerve. Think of underlying hemangioma of the meninges (Sturge-Weber). Gorbachev's birthmark. Pyogenic granuloma: Neither pyogenic nor a granuloma, but a mass of granulation-tissue. Gums in pregnancy, anyplace else on anybody ("rotten cherry"). Thrombocytopenia from consumption in a large hemangioma: Kasabach- Merritt syndrome. Von Hippel-Lindau: Hemangiomas, notably of the retina; renal cell carcinoma, cerebellar hemangioblastoma. Deletion of a bit of 3p. Glomangiomas: Painful blue bumps at sites of glomi (coccyx, fingertips). Osler-Weber-Rendu: Multiple telangiectasias of the entire GI tract, with ability to bleed; autosomal dominant. Kaposi's "sarcoma": Misnamed proliferative response to infection by herpes 8 / KSHV. Little or no anaplasia; little sprouting vessels; epidemic in sub-Saharan Africa whether or not HIV is on-board; long a problem for the immunosuppressed (old men, renal transplant patients, others). Cirsoid (racemose) aneurysm: Huge tangle of blood vessels. Angiosarcoma of the liver: vinyl chloride workers. "What's a 'double-blind study'? Two pathologists trying to read an EKG!" -- Anonymous & baseless "Once I had brains, and a heart also; so having tried them both, I should much rather have a heart." -- The Tin Woodsman of Oz Words likely to cause trouble: (1) angina: chest-pain due to cardiac ischemia, in the absence of infarction; (2) stable angina: from narrow coronaries, i.e., when I climb stairs or walk against the wind, it hurts like this (fist sign); (3) Prinzmetal's angina: from spasm of the coronary arteries; (4) unstable angina: as when a thrombus on top of a plaque is forming, then lysing, then forming, then lysing; (5) forward failure: congestive heart failure considered as a vicious cycle involving salt retention, volume overload, and the inability to perfuse the kidneys; (6) backwards failure: congestive heart failure considered as a vicious cycle involving increased venous hydrostatic pressure and total-body salt and water overload; (7) contraction band: hypereosinophilic stripe crossing a freshly-dead myocardial cell, where the calcium got and clamped the sarcomeres; (8) sudden cardiac death: dropping over dead all-of-a-sudden from some heart-cause, most often ischemia without infarction, and with or without a fresh lesion in the coronaries; (9) syndrome X: an angina syndrome caused by failure of the small vessels to dilate appropriately, most typical in ill-controlled diabetics. Aerobic athletes get hypertrophy of the myocardium, which is good. Also increased mitochondria, increased vascular collaterals (little vessels develop). Good for helping you survive an infarct and/or avoid ischemia if something happens to your vessels. Plus, sports are fun. Unless you have septal hypertrophy / hypertrophic cardiomyopathy, or your coronary arteries are ruined by atherosclerosis already, or something else really unusual, aerobic exercise is good for you. Heart failure: Cannot pump enough blood. Tends to be a vicious cycle, with ischemic damage to the ventricle and/or alteration in its shape (i.e., stretched) so as to make pumping inefficient. Except in pure mitral stenosis or amyloidosis, the failing left ventricle will be hypertrophic. THE COMMON CUASES OF LEFT-SIDED FAILURE Ischemia (myocardial infarct, ischemic muscle disease) Aortic or mitral valve disease Systemic hypertension Myocardial disease THE COMMON EFFECTS OF LEFT-SIDED FAILURE -- Dyspnea (from pulmonary edema and total-body hypoxia) First, on exertion Later, PAROXYAMSL NOCTURNAL DYSPNEA ("cardiac dyspnea"); on lying down for a while, fluid redistributes itself in the body, resulting in pulmonary edema; patients may throw the windows open at night, or learn to sleep on various numbers of pillows; you the physician will hear rales; the pathologist may see "brown induration" and hemosiderin-laden "heart failure" macrophages; remember these?) -- Cough ("from the left atrium pushing on the bronchus"; this is common in mitral valve disease even in the absence of failure; why?) -- Prerenal azotemia -- Hypoxic encephalopathy -- Sodium overload and systemic dependent edema (from hypoperfused kidneys) HIGH-OUTPUT FAILURE is a special situation, glossed-over by "Big Robbins", in which the heart fails because it must pump an excessive among of blood. The causes Anemia Hyperthyroidism High fever Shunts between an artery and a vein Beriberi (arterioles open) Paget's disease of bone (abnormal bone vasculature) Iatrogenic (i.e., shunts in dialysis) THE COMMON CAUSES OF RIGHT-SIDED FAILURE Pulmonary emboli (acute or chronic) Any disease interfering with lung ventilation Emphysema Cystic fibrosis Most other bad, diffuse lung diseases NOTE: The mechanism, of course, is increased pulmonary vascular resistance due to fibrosis and/or the hypoxic vascular response Left-sided heart failure! Cardiac defects with left-to-right shunts (why?) Tamponade (some definitions) THE EFFECTS OF RIGHT-SIDED FAILURE Splanchnic congestion (you'll feel big livers & spleens; check for "hepatojugular reflux") Jugular venous distention (look carefully) Total-body dependent edema (from increased venous hydrostatic pressure, etc.) Effusions (transudates, of course; notably pleural, notably more on the right side than on the left; why?) NOTE: You'll never see "cardiac cirrhosis" except in prolonged severe tricuspid insufficiency. Atherosclerosis in the coronaries can produce (1) sudden death (ischemia makes ectopic foci arise); (2) infarct leading to sudden death, rupture, mural thrombus, pericarditis, cardiogenic shock (>40% of the muscle); (3) angina (stable, unstable). Infarcts can be due to rupture of a plaque with thrombosis, embolization to a coronary, or rupture of a small vessel into a plaque. Pathologists will diagnose sudden cardiac death in somebody who drops over dead and turns out to have bad coronary atherosclerosis. Tobacco and cocaine render the heart much more prone to die. Subendocardial infarcts arise in a setting of coronary ischemia, generally in systemic hypotension / shock /congestive heart failure. The subendocardium is farthest from the oxygen, so it dies first. This in turn hurts cardiac function. Remember cocaine, Prinzmetal's, lupus, rheumatoid vasculitis, polyarteritis nodosa, embolization (i.e., endocarditis), dissecting hematoma, and syphilis as the other causes of myocardial infarction. For some reason that I cannot explain, exam-writers often want you to be able to date myocardial infarcts. 0-30 minutes Wavy fibers at the edges, loss of glycogen from cytoplasm. 1- 2 hours Mitochondrial calcium, maybe contraction bands, maybe hydropic changes, maybe even a little fatty change. 4-12 hours Earliest nuclear changes, polys appear 8-24 hours First gross changes, i.e., pallor; good coagulation necrosis; often good contraction bands 24-72 hours Road-kill, lots of polys, fibers very dead; infarct feels soft and looks pale and yellowish (why?) 3- 7 days Macrophages, granulation tissue starts at rim; grossly you see the red granulation tissue around the infarct; wall is at its weakest, and this is time for rupture. 10 days Nice granulation tissue; cleanup team may be removing the dead fibers, or they may persist for weeks 7 weeks Nice scar. More words that can cause trouble: (1) atresia: the hole never opened; (2) clubbing: curious change of the tips of the digits, from cyanosis from any cause, and from other causes; (3) concentric hypertrophy: common hypertrophy of the left ventricle, as in an athlete, hypertensive, or aortic-valve disease patient; (4) congenital heart disease: malformations at or around birth; (5) cor triloculare biatriatum: no ventricular septum; (6) cyanotic congenital heart disease ("blue baby"): right-to-left shunt present at birth; (7) dilatation: the ventricle just can't empty fast enough, and ends up getting badly stretched; (8) Eisenmenger's syndrome: shunt reversal (left-to-right becomes right-to-left from increased resistance in damaged pulmonary arterial system; (9) endocarditis: non-ischemic damage to the endocardium sufficient to allow a fibrin mass to form; (10) pressure overload: the effect of vascular fluid overload and/or excess systemic vasoconstriction and/or an over-dynamic left ventricle, detrimental to the heart's function; (11) jet lesion: hyperplastic endocardium, i.e., little white ridges, where a jet of blood (flowing abnormally) strikes against it; (12) late cyanosis: Eisenmenger's; (13) paradoxical embolus: passes through the foramen ovale from the right atrium to the left atrium, or by some other route from the systemic venous to the systemic arterial circulation; (14): polycythemia: too- high hematocrit, enough to make the blood overly viscous; (15) hypertensive heart disease: the effects of pressure overload and maybe- more, in severe or longstanding high blood pressure; (16) reperfusion injury: calcium and oxygen damage ischemic myocardium when blood flow is restored. Jugular venous pulse: "A"-wave is atrial contraction; "C" wave is from the ventricle contracting and pushing blood back up out of the atria; "V" wave is the atrium filling before the tricuspid valve opens. "X" wave is the dip during early systole (i.e., tricuspid valve is sinking down), "Y" wave is the dip during diastole (i.e., the ventricle is filling). A couch potato's heart should not weight more than 350 gm, less for little folks. Left ventricle should not be more than 1.5 cm thick, right ventricle not more than 0.5 cm thick. Hypertensive's heart exhibits big, thick fibers with large boxcar nuclei (heart muscle cells are ordinarily tetraploid; they may increase to 8-ploid or more). In congestive failure secondary to hypertensive disease, the blood pressure will return to normal, confusing the clinicians. Cor pulmonale: Right ventricular hypertrophy/dilatation/failure from lung disease (i.e., narrowed vessels and/or congenital malformations and/or pulmonary emboli). The strained right ventricle is very prone to develop rhythm disturbances, and I have no problem signing out a sudden death in such a person as due to cor pulmonale. 6-8 kids per 1000 have congenital heart disease. Down's: endocardial cushion defects (i.e., low-atrial and/or high-ventricular septal defect). Cyanosis: 5 gm/dL or more of unoxygenated hemoglobin in the arteries. Remember right-to-left shunts (i.e., cyanotic shunts) tend to produce polycythemia, with extra viscosity that doesn't help matters; bacteria can go straight to the brain without being filtered through the lungs, and paradoxical embolization is commonplace. Tetralogy: Overriding aorta, stenotic pulmonary artery and/or valve, hypertrophic right ventricle, ventricular septal defect. Shoe-shaped heart on x-ray. Infected pulmonic valves. The common right-to-left shunt at birth. Uncorrected transposition, the blood flow is: right atrium --> right ventricle --> aorta left atrium --> left ventricle --> pulmonary artery To survive the first minute of life, there must be an atrial and/or ventricular septal defect. Right-to-left shunt. CORRECTED TRANSPOSITION, the atria are rearranged, so that the blood flow is: right atrium --> left ventricle --> pulmonary artery left atrium --> right ventricle --> aorta The problem is that the mitral and tricuspid valves are malformed. The other causes of congenital right-to-left shunt are truncus arteriosus (i.e., aorta and pulmonary artery are the same vessel; this will eventually cause bad pulmonary hypertensive damage), total- anomalous pulmonary venous return (i.e., all to the right atrium), and tricuspid atresia. Half of VSD's ("Roger's disease") close by themselves. Otherwise, it's surgery time. Atrial septal defects: Most are ostium secundum (i.e., patent foramen ovale); some are sinus venosus defects near the superior vena cava; some are ostium primum defects at the crux of the heart (think of Down's). Lutembacher's: atrial septal defect plus mitral stenosis, i.e., left-to-right shunt is especially bad. Atrial septal defects are often trivial, and even the bad ones may not make much noise during childhood; beware fixed-splitting of the second heart sound. Patent ductus arteriosus: Fails to close (try using a prostaglandin antagonist). Machinery murmur, easy surgery. The three principal left-to-right shunts: (1) ventricular septal defect; (2) atrial septal defect, and (3) patent ductus arteriosus. Congenital bicuspid aortic valve is a common (maybe 1%) of folks. It tends to calcify in old age, producing stenosis. Congenital aortic stenosis: Valve is a fibrous ring, or there's a fibrous ring below the valve (subvalvular) or above it (supravalvular). Aortic stenosis from any cause, including septal hypertrophy (hypertrophic cardiomyopathy) is bad; one reason is the propensity to cause sudden death by coronary insufficiency (Bernoulli's principle sucks blood out of the coronaries; shortening of diastole limits time for coronary filling). Problem terms: (1) Anitschkow cell: cell of unknown nature, looks like a muscle cell, stains like a macrophage, bears a caterpillar pattern of heterochromatin in its long nucleus, typical of rheumatic fever; (2) Aschoff body: an inflamed area in rheumatic fever, rich in Anitschkow cells and fibrinoid; (3) antihyaluronidase: antibody against strep, marker for recent strep infection; (4) antistreptolysin O ("ASO"): antibody against strep, marker for recent strep infection; (5) Barlow's syndrome: extremely common sub-disease of the mitral valve, "floppy valve", "prolapsing valve"; (6) caterpillar cell: anitschkow cell of rheumatic fever; (7) dextrocardia with situs inversus: backwards organs, including a usually well-formed heart; (8) dextrocardia, isolated: heart positioned backwards, often with other malformations; (9) erythema marginatum: snake-like red wandering lesions of acute rheumatic fever; (10): friable: crumbly; (11): Kartagener's syndrome: immotile cilia producing sinusitis, bronchiectasis, and situs inversus; (12) lines of closure: where the valve leaflets bump up against each others, the site where rheumatic fever lesions begin; (13): McCallum's patches: white geographic patches on the left atrium; (14): mid-systolic click: the sound of the Barlow floppy-valve snapping tight like a sail; (15) regurgitation: same as insufficiency, backflow through a valve that did not close; (16) Roth spots: on the retina, where septic emboli have been caught in the branches of arteries; (17) situs inversus totalis: all organs backwards; (18): splinter hemorrhages: the familiar lines under the fingernails, seen in keyboard users, patients with endocarditis, or anybody else; (19); Sydenham's chorea / St. Vitus's dance: movement disorder when rheumatic fever involves basal ganglia; (20) tamponade: increased pressure in the pericardial sac prevents venous return; (21) valvular stenosis: the valve failed to open when it should; (22) vegetations: masses of fibrin plus perhaps something else, on the endocardium, usually of the heart; (23) opening snap: as in mitral or tricuspid insufficiency, with thickened valves making the snap. MITRAL STENOSIS Old rheumatic fever (All other causes are uncommon) MITRAL REGURGITATION Old rheumatic fever Bacterial endocarditis Barlow's syndrome Other birth defects at the crux Ruptured papillary muscle (MI) Ruptured chorda (bacterial endocarditis, Barlow's) Dilated annulus (left CHF) Calcified mitral annulus (maybe) AORTIC STENOSIS Old rheumatic fever Congenital bicuspid valve that calcified Normal valve that calcified Birth defects (valvular, sub-valvular) NOTE: Some of the biggest hearts in clinical medicine result from aortic stenosis. Obviously, the pulse pressure is narrowed, and systole is prolonged. This can have very bad consequences for myocardial perfusion. NOTE: As I trust you've figured out, "aortic stenosis" (by custom) refers to stenosis of the valve, not the aorta. If a portion of the aorta is stenotic, it's called "coarctation". If the entire aorta is stenotic, you didn't get born. AORTIC REGURGITATION Old rheumatic fever Bacterial endocarditis Syphilis Dissecting hematoma / steering wheel injury Marfan's The ring dilates Rheumatoid arthritis Ankylosing spondylitis / HLA-B27 family Syphilis NOTE: You'll learn about increased pulse pressure, "Corrigan's jumping pulse", pistol-shot sign, etc., etc. on rotations. TRICUSPID STENOSIS Old rheumatic fever Carcinoid heart disease TRICUSPID REGURGITATION Old rheumatic fever Carcinoid heart disease Bacterial endocarditis (ask about IV drug use!) Loeffler's Dilated annulus (right CHF) NOTE: Look for those jumping neck veins! PULMONIC STENOSIS Tetralogy of Fallot Carcinoid heart disease Congenital ("funnel") PULMONIC INSUFFICIENCY Dilated annulus (right CHF). Rare. Vegetations...... ACUTE RHEUMATIC FEVEER Small, warty, sterile, on the lines of closure Seldom embolize BACTERIAL ENDOCARDITIS Often large, loaded with bacteria Find them on any deformed intracardiac surface Very prone to embolize NON-BACTERIAL THROMBOTIDC ("MARANTIC") ENDOCARDITIS Small, sterile, on the lines of closure May embolize LIBMAN-SACKS ENDOCARDITIS OF LUPUS Any size, sterile, on either surface of the leaflet May embolize As with any intracardiac lesion involving turbulence, deformed valves are prone to develop bacterial endocarditis. Calcific aortic stenosis: While bicuspid valves are notorious for calcifying later in life, sometimes a normal, tricuspid valve accumulates calcium-rich excrescences in its cusps. These can interfere with the valve opening, and can block the coronary ostia. The latter is very serious. { 3560} calcified tricuspid aortic valve { 6461} calcified tricuspid aortic valve The four complications of "Barlow's" elongated posterior mitral valve leaflet sub-disease: (1) bacterial endocarditis; (2) mitral insufficiency (notably if that chorda ruptures); (3) rhythm disturbances (notably paroxysmal atrial tachycardia, nobody knows why); (4) cardiac neurosis. Marfans and marfanoids (Sticklers, xyy's, some Ehlers- Danlos, just-tall-and-slim, others) tend to have Barlow's. Rheumatic fever follows strep throat particularly in poor kids; note no bugs in the lesions. Molecular mimicry: the antibody against M-protein cross-reacts with tissue; of course this is not the whole story, but the rest is unknown. Rheumatic fever is an important disease, and a test- writer's favorite. Look for: Evidence of carditis (i.e., pericardial pain, enlarged heart, murmurs, failure); rheumatic fever features a pancarditis (all 3 layers). Polyarthritis Sydenham's chorea (St. Vitus's dance), from involvement of the basal ganglia. This is a big deal right now. Mediated by antibodies that cross-react with neurons (type II immune injury) Erythema marginatum, a snake-like red skin eruption Subcutaneous nodules, little masses of fibrinoid with granulomas around them, over the bony bumps on arms and legs. Fever Lab evidence of recent strep infection (i.e., a high anti- streptolysin O and/or anti-hyaluronidase and/or anti-DNAse titer, a culture result, or whatever) Here are the Jones criteria for making the diagnosis. You need one major and two minor, or two majors). Major: Polyarthritis; carditis; chorea; subcutaneous nodules; erythema marginatum. Minor: Arthralgia; fever; preceding group A strep infection; preceding bout of rheumatic fever; elevated sed rate; prolonged PR interval on EKG. When the verrucae spread and organize, they may cause regurgitation (i.e., the valve leaflets scar up, and scar contracts) and/or stenosis (i.e., the verrucae stick together, joining leaflets before they scar up.) Valves involved: mitral most often, aortic next, tricuspid next; pulmonic seldom. Bacterial endocarditis arises in several typical settings: (1) low- virulence (green viridans after the dentist, enterococcus after a trip to the urologist or proctologist) strep infecting a rheumatic valve or some other site of bad turbulence; (2) virulent strep involving a normal valve (bad luck, "acute bacterial endocarditis"); (3) something horrid on the right side of a drug-infecter's heart; (4) low-virulence staph or fungi on a prosthetic valve. Neutrophils aren't much use in cleaning up infected fibrin bits on the endocardium, since it's avascular and the blood is flowing too fast to allow margination. Once the infection is set up, the foul breakdown products of these bacteria are going to make a person systemically sick. Fever, arthritis, the acute phase reaction, anemic of chronic disease, diffuse proliferative glomerulonephritis, evidence of B-cell hyper-activation (rheumatoid factor, cryoglobulins, false-positive syphilis test), clubbing, etc., etc., are prone to supervene. Embolization / immune complex injury produces Osler's nodes (sore finger pulp), Janeway's flat red lesions on palms (painless), Roth spots, splinter hemorrhages (the latter at least in books; do you believe it?), as well as abscesses wherever they land. Nonbacterial thrombotic endocarditis ("marantic endocarditis") is little fibrin things on the valve leaflets of those with hypercoagulable blood and profound disability. Nobody understands it; it's almost the norm in fatal cancer of the pancreas. Carcinoid tumors release their foul products into the bloodstream, causing the familiar syndrome, and endocardial fibrosis of the right side of the heart only. (Neuropeptide K and substance P are the fibrogenic ones; serotonin and bradykinin get blamed for the wheezing, flushing, and diarrhea.) More words to remember: (1) adriamycin / daunorubicin / the anthracyclines: "the red death", a red-colored cancer chemotherapeutic agent that is a notable heart muscle poison; (2) cardiomyopathy: non- ischemic disease of the heart muscle itself; daunorubicin; (3) myocarditis: autoimmune (rheumatic fever, post-coxsackie) or infectious (i.e., Chagas, toxoplasmosis, coxsackie A & B, diphtheria toxin). Cardiomyopathies: (1) restrictive (stiff heart, i.e. amyloidosis); (2) muscle-bound heart (i.e., hypertrophic cardiomyopathy); (3) flabby heart (i.e., all the others; this includes really bad hemochromatosis and Pompe's glycogenesis in which the heart might also be sort of stiff). Dilated cardiomyopathy features a big, baggy, weak heart, typically with mural thrombi. Alcoholic cardiomyopathy: some effect from alcohol (i.e., in the alcoholic with other wasted muscles); beriberi and cobalt (only in Quebec, and only in the past, from cobalt added to make a better head). Reggie Lewis's disease: Hypertrophic cardiomyopathy features disarray of the myocardial fiber arrangement, irregular bulges of muscle in these areas, typically occluding the outflow tract, and some vascular intimal fibrosis. "Asymmetric septal hypertrophy" / "idiopathic hypertrophic subaortic stenosis" / "obstructive hypertrophic cardiomyopathy": the classic hypertrophic cardiomyopathy in which the septum is primarily involved. Don't build your heart up with aerobics if you've got this. The murmur becomes less upon maneuvers to increase left ventricular volume ("knee bends"), louder if decreased ("valsalva"), in contrast to other causes of aortic stenosis. Genes include the beta-myosin chain. Endomyocardial fibroelastosis: fibrosis of the endocardium, with stiffening. Common in kids in sub-Saharan Africa. Loeffler's endocarditis features fibrosis and eosinophils. Cocaine heart: (1) coronary vasospasm; (2) muscle fiber necrosis; (3) super-sensitized to the effects of catecholamines, thus prone to rhythm disturbances. Hemopericardium: ruptured MI, penetrating injury, and backwards rupture of an aortic dissection To get tamponade, you need about 150 mL of fluid accumulating almost instantaneously, or more if it's prolonged. Look for Kussmaul's sign (neck veins pop out when inspiration causes additional tightening of the pericardium), exaggerated inspiratory drop in blood pressure (ditto). Fibrinous pericarditis: myocardial infarction, uremia, radiation, lupus, rheumatic fever and trauma as the causes of fibrinous pericarditis. Autoimmune pericarditis after MI: Dressler's. Coxsackie B. Friction rub, bread-and-butter look (actually, a pulled-apart ketchup sandwich). Atrial myxomas ("wrecking balls"), the only common primary tumors of the heart. Left atrium, attached to septum. Cardiac rhabdomyoma: a hamartoma in tuberous sclerosis. Say "REE-nin", not "RENN-in", when talking about that important hormone from human physiology. Rennin is from a calf's stomach and you use it to make cheese. "It's not the cough That carries you off, It's the coffin They carry you off in." -- Ogden Nash Chest wall problems structural THE CHEST DEFORMITIES neuromuscular THE PARALYSIS & WEAKNESS SYNDROMES Obstructed upper airway structural QUINSY ("PERITONSILLAR ABSCESS") CROUP ("LTB"") functional THE SLEEP APNEAS Obstructed large bronchi all, subtotal CHRONIC BRONCHITIS one, total OBSTRUCTIVE ATELECTASIS ENDOGENOUS LIPID PNEUMONIA Constricted small bronchi mast-cell mediated THE ASTHMAS platelet-mediated PULMONARY EMBOLUS apudoma products CARCINOID SYNDROME Fibrotic respiratory bronchioles SILICOSIS Collapsed respiratory bronchioles EMPHYSEMA/"CHRONIC BRONCHITIS" Fluid-filled alveolar spaces transudate ALVEOLAR PULMONARY EDEMA exudate & pus THE PNEUMONIAS exudate, fibrin, debris THE RESPIRATORY DISTRESS SYNDROMES surfactant ALVEOLAR LIPOPROTEINOSIS ENDOGENOUS LIPID PNEUMONIAS other lipid EXOGENOUS LIPID PNEUMONIAS blood GOODPASTURE'S DISEASE WEGENER'S GRANULOMATOSIS OTHER PULMONARY BLEED SYNDROMES organisms alone PNEUMOCYSTOSIS, CRYPTOCOCCOSIS Fluid-filled alveolar septa transudate INTERSTITIAL PULMONARY EDEMA exudate THE PNEUMONITIS FAMILY (VIRUSES, MYCOPLASMA) Fibrosis around ulcerated bronchi BRONCHIECTASIS Fibrosis of alveolar septa slow THE INTERSTITIAL RESTRICTIVE LUNG DISEASES (Hamman-Rich, rheumatoid lung, sarcoid, asbestosis, many others) fast THE RESPIRATORY DISTRESS SYNDROMES Collapsed alveoli extrapulmonary disease COMPRESSIVE ATELECTASIS large-airway disease OBSTRUCTIVE ATELECTASIS alveolar disease THE RESPIRATORY DISTRESS SYNDROMES ischemia PULMONARY EMBOLUS, SEVERE SHOCK Necrotic lung ("cavities", etc.) infarction PULMONARY EMBOLUS (COMPLICATED) suppurative NECROTIZING PNEUMONIAS LUNG ABSCESS caseous TUBERCULOSIS, HISTOPLASMOSIS, BLASTOMYCOSIS, COCCIDIOIDOMYCOSIS weird immune WEGENER'S GRANULOMATOSIS malignant LUNG CANCER Pulmonary hypertension 2ø to low alveolar oxygen see above; also MOUNTAIN DWELLERS 2ø to alveolar fibrosis see above primary PULMONARY EMBOLUS VASCULITIS IDIOPATHIC High pCO2 all whole-lung ventilation problems Low PO2 all whole-lung ventilation problems perfusing non-ventilated lung fluid/fibrosis in alveolar septa MOUNTAIN DWELLERS Blood pCO2 is almost entirely a function of adequacy of ventilation. Blood pO2 is a function of adequacy of ventilation, ventilation- perfusion matching, inspired oxygen content, right-to-left shunting, nad the thickness of the alveolar wall (extra collagen, fibrin, edema, hyperplastic cells). Pulmonary edema is due to (1) increased pulmonary venous hydrostatic pressure, i.e., left CHF; (2) plugged lymphatics (i.e., cancer); (3) excess water on board (kidney failure, iatrogenic); (4) low serum albumin (i.e., nephrotic syndrome, cirrhosis, kwashiorkor); (5) inflamed alveolar septa (i.e., pneumonitis). Less well understood: (6) opiate overdose; (7) altitude sickness; (8) acute brain injury. Edema may be confined in the septa (interstitial edema, creating an alveolar-capillary oxygen block) or eventually spill out into the alveoli (alveolar edema, when you'll hear the rales). Pulmonary congestion results from increased venous hydrostatic pressure, i.e., left CHF. The little capillaries are prone to break from time to time, creating little accumulations of hemosiderin-laden macrophages, and perhaps eventually some fibrosis. Pulmonary thromboemboli need no description here; most come from leg veins and hence bear valve markings. They cause problems by (1) limiting the amount of effective lung tissue available for gas exchange; (2) sudden increases in pulmonary vascular resistance make the right ventricle unhappy; (3) platelets release serotonin, a bronchoconstrictor which makes folks wheezy; (4) if bronchial circulation is inadequate, i.e., you are in shock or heart failure, you may infarct some of your lung, get a pleural friction rub, and generally be miserable. Saddle embolus: Instant death. Any cause of increased resting blood flow through the lungs (i.e., left-to-right shunts), any cause of generalized alveolar hypoxia (i.e., via the hypoxic vascular response), and any cause of pulmonary alveolar fibrosis will eventually lead to the vicious cycle of damaged vessels, narrowed vessels (i.e., increased vascular resistance), and increased pulmonary blood pressure. Pulmonary vascular resistance is the factor that tends to be most limiting on quality of life. Adult respiratory distress syndrome (ARDS, diffuse alveolar damage, many other synonyms) means the small lung vessels have leaked fibrin. The fibrin coats the alveolar spaces ("hyaline membranes"), debris and dead junk accumulate, the dead type I pneumocytes are replaced by big type II pneumocytes which aren't very permeable to oxygen and which, while healing, aren't going to make surfactant, causing widespread atelectasis. The fibrin membranes are likely to turn into scar, and that's the end of the lung. Causes include sepsis (most common), aspiration, severe wounds elsewhere, radiation, burns, viruses, drug toxicity, and many others, including oxygen therapy itself. Silo- filler's disease: nitric oxide. Neonatal respiratory distress results mostly from damage caused by breathing, to immature lungs. Replacing the surfactant helps, but is not curative, and if the primary problem was lack of surfactant, then the problem would be most severe right after birth; in reality it takes several hours. Again, the hyaline membranes are made of fibrin. Surviving kids may have fibrosis ("bronchopulmonary dysplasia") and it may not be possible to get them off the ventilator. Atelectasis means collapsed alveoli, from airway obstruction (i.e., something in the big airway), compression (i.e., something filling the pleura, or you not taking a deep breath), and/or lack of surfactant (ischemia from pulmonary embolus, diffuse alveolar damage, hyaline membrane disease, etc.) "Sudden infant death syndrome", a mysterious process by which a child, age 1 month to 1 year, simply dies, probably exists. It's now clear that many of these result from the baby falling asleep face-down on the mattress and smothering. It's also painfully clear that many, if not most, of the rest are the result of negligence or worse by caregivers. Supporting this politically-incorrect conclusion are these facts: (1) SIDS is largely an underclass problem; (2) SIDS incidence increases tremendously if a parent is under the purview of the criminal justice system; (3) SIDS incidence increases dramatically between 5 PM on Friday and 8 AM on Monday; (4) when one identical twin dies of SIDS, it's almost the rule that the other one dies at the same time; (5) crime-scene examinations, if properly performed, eliminate the "mystery" in many cases; (6) Waneta E. Hoyte, the mother whose "tragic story" spawned the whole apnea monitor racket, confessed in 1994 that she smothered her five children because their crying made her feel helpless. To cover your butt, you still have to prescribe an apnea monitor even though evidence that they've ever saved any lives is very dubious. Before you sign out a "SIDS" death, be sure you've ruled out ectodermal dysplasia (i.e., no sweat glands), botulism (i.e., ate raw honey), seizures (got Arnold-Chiari by any chance?), and lots else. Emphysema and chronic bronchitis are only artificially separated. The fundamental problem in each is loss of elasticity of the alveoli, causing the respiratory bronchioles to collapse on expiration. Smoking inhibits alpha-1-antitrypsin, enhances elastase function, and draws neutrophils to the area to do damage. Emphysema from smoking tends to be centrilobular, since smoke accumulates where the wind slows down. If you are alpha-1-antitrypsin deficient, the emphysema tends to be panacinar. The pink puffer has a strong hypercarbic respiratory drive, and works hard to breathe; since he's also going to be keeping his airway clear, his "chronic bronchitis" will be less noticeable. Puffers have an attitude, stay slim from the work of breathing, and get diagnosed with "emphysema". The blue bloater has lost his hypercarbic respiratory drive, and is now mercifully on hypoxic drive. He coughs, but not effectively enough to clear his secretions, so the doctor hears his airway crud gurgling and diagnoses "chronic bronchitis". Since these folks aren't working hard to breathe, and can't do much physical, they get fat. Hypercarbia- acidosis makes them mellow. The classic definition of emphysema as "an abnormal, permanent dilatation of part of all of the acinus, with destruction of alveolar walls" reflects the rather advanced disease; eventually, anything that's going to kill off the elastic tissue kills the whole of the septa. They are hyperinflated because puffers and bloaters learn to keep their chest expanded to keep their respiratory bronchioles open. Other tricks include breathing against pursed lips. "Bullous emphysema" / "blebs" result from the lung collapsing under its own weight, leaving huge empty sacks which the surgeon can remove; blebs can rupture, causing pneumothorax. "Chronic bronchitis" is pretty much a synonym for smokers' cough or the equivalent from other processes. Reid Index is the percent of the thickness of the lamina propria occupied by glands. The process is often superinfected, especially by pneumococcus and H. flu. Bronchial asthma results from chronically inflamed small bronchi, which are rendered twitchy and prone to episodes of constriction. Extrinsic (allergic) asthma is typical in kids, who tend to outgrow it, and in workers exposed to allergens. There's likely to be lots of eosinophils. Intrinsic asthma is havoc played by leukotrienes, especially after taking aspirin; this is poorly understood, and patients tend to have nasal polyps. Curschmann's spirals in the sputum; mucus plugging as the principal autopsy finding. Charcot- Leyden crystals are eosinophil protein debris, long red lozenge-shapes. "All that wheezes is not asthma." Wheezing may also result from: -- foreign body or tumor in the upper airway -- pulmonary edema (especially left-sided congestive heart failure) -- pulmonary embolus -- chronic bronchitis -- carcinoid syndrome Bronchiectasis: non-healing ulcers of the bronchi; massive sputum production, bad breath, continuing expansion due to scar contraction; increased dead space. Think of cystic fibrosis, Kartagener's, neglected TB, or after whooping cough. Bronchopneumonia: inflammatory exudate in the alveolar spaces, distributed in patches usually in several loves. Think of relatively low-virulence bacteria. Why sick people get bronchopneumonia: -- Many of them don't cough and clear their lungs like they should because of medications, old age, physical weakness, pulmonary fibrosis, other disease, or whatever; -- Many of them have poor mucociliary elevator function from smoking, infection, other disease, or whatever; -- Many of them have poor alveolar macrophage function from smoking, oxygen therapy, alcoholism, or whatever; -- Pulmonary edema from whatever cause is a great culture medium; -- Glop in the lungs (cystic fibrosis, airway obstruction, "chronic bronchitis", etc., etc.) helps get the lungs infected. Special bronchopneumonias: -- Staphylococcus: Complicating influenza, may get toxic shock -- Streptococcus B: newborns -- Gram negative rods: nosocomial, or after GI tract surgery (remember that the meanest bugs are the ones that live in the hospital) -- Anaerobic pneumonia: alcoholics with bad (but still present) teeth Lobar pneumonia: Inflammatory exudate filling a single lobe, i.e., the germs are aggressive and will stop only at the interlobar fissues. Think pneumococcus, Friedlander's Klebsiella, others. Stages: (1) "Congestion" (i.e., edema); (2) red hepatization (i.e., bloody and fibrinous; (3) gray hepatization (i.e., the red cells have lysed but the fibrin is still there; (4) resolution (you hope). Pneumonitis: Inflammatory exudate confined to the interstitium. Think of a virus or mycoplasma. The pneumonias (bronchopneumonia, lobar pneumonia) kill by (1) taking up alveolar space, and (2) more importantly, diverting blood through unventilated areas. Lung abscess: Aspiration of bugs from a dirty mouth, necrotizing pneumonia (staph, klebsiella, pseudomonas, legionella), obstructed airway behind a cancer, infected cancer, septic embolus (infection, dope- shooter), infarcting a pneumonia. Lung abscess can seed systemically. Pulmonary fibrosis: A family of diseases with collagen laid down in the alveolar walls, leading to obliteration. Idiopathic form is "Hamman- Rich". Others worth remembering: Rheumatoid arthritis, scleroderma, asbestosis, berylliosis, bad farmer's lung, histiocytosis X, bleomycin, cyclophosphamide, amiodarone, busulfan, paraquat, sarcoidosis, "Restrictive lung disease": It's hard to get the air in, range is from the fibrosis family to pleural effusions to boa constrictors. "Obstructive lung disease": It's hard to get the air out, i.e., emphysema, asthma, maybe bronchiectasis. Sarcoidosis: Mysterious proliferation of non-caseating granulomas. Pulmonary alveolar obliteration, lupus pernio on the skin, anergy, increased angiotensin-converting enzyme, hypercalcemia from vitamin D overactivation. T4 cells leave blood and go to tissue, making for a peripheral blood picture like AIDS. Don't ask for a Kveim test. Goodpasture's: Autoantibody against basement membrane of lung and kidney, with hemoptysis and rapidly-progressive glomerulonephritis. Treat with plasmapheresis, removing the harmful antibody. Eosinophilic pneumonia may be idiopathic (Loeffler's), parasite larvae migrans. Aspergillus lung infections: Fungus balls, superinfecting asthma, others. Endogenous lipid pneumonia: Obstruction of an airway gives surfactant accumulation, typically in macrophages; common behind tumors. Exogenous lipid pneumonia: Oil down the airway, mineral oil can kill you, vegetable oil is worse, animal (cod-liver-oil) killed children in bygone eras; lipid-laden macrophages. Alveolar lipoproteinosis: idiopathic, or acute silicosis; the lung fills with surfactant-rich junk, patients cough up jello. Lung (i.e., bronchogenic) cancer is finally decreasing in incidence among men, still increasing among women, as smoking becomes a teenaged girl's vice. Other risk factors are asbestos exposure, nickel, chromates, coal tar; the radon-in-your-home story (thousands of dollars "to protect your family") doesn't square with the extremely low incidence of lung cancer in non-smokers. Oat cell carcinoma: Kulchitsky (APUD) cell of origin, tiny white fishflesh primaries near hilum with early and widespread metastases; 15 micron almost-no-cytoplasm cells, paraneoplastic syndromes include Eaton-Lambert, inappropriate ADH, Cushingism from ACTH, more; not hypercalcemia. Bombesin's the autocrine growth factor. Squamous cell carcinoma: Pearls, bridges (prickles, desmosomes), single-cell apoptosis (single-cell keratinization), tonofilaments; large central lesions with a tendency to cavitate; parathyroid-hormone- like activity raises serum calcium; men smoking non-filtered cigarettes. Adenocarcinoma: Glands, papillae, mucin, surfactant protein, lumens, microvilli; peripheral lesions; women smoking filtered cigarettes and so inhaling more deeply than men. Bronchioloalveolar carcinoma is cancer cells growing along the septa, causing fatal mucus accumulation. Large cell undifferentiated carcinoma: Massive lesions, horribly anaplastic large cells. Hundred-day tumor. Pancoast-tumor: any lung cancer which has invaded the brachial plexus and cervical sympathetic chain, i.e., arm pain, Horner's. Bronchial carcinoid: John Wayne's cancer, a low-grade APUDoma with little ability to kill. Choanal atresia: Can't breathe through nose, i.e., baby turns blue on feeding, pink when he/she stops and cries. Acute epiglottitis: Croup, inspiratory stridor, think H. flu. Laryngeal masses: HPV, overuse ("teacher's nodule"). The trachea almost never gets sick except in diphtheria. Common cancer is squamous cell, from smoking-drinking. Chinese nasopharyngeal cancer: Epstein-Barr. Mesothelioma: Cancer of mesothelium, usually pleura. Usually asbestos- exposed. Long spaghetti microvilli, biphasic pattern (adenocarcinoma plus spindle cell sarcoma). Chylothorax: Damaged thoracic duct; chylomicrons separate out on refrigeration. Pseudochylous (i.e., cholesterol and neutrophil debris) is more common. Anemias For Understanders.... TOO MANY RED CELLS BEING DESTROYED IN THE BODY (hemolysis)------------ Membrane defects  BILIRUBIN \ ³ SPHEROCYTES \  LDH 1 \<--  MCHC \<------ Hereditary spherocytosis  RETICULOCYTES\ (HYPERCHROMIA)\ Spur cell anemias cirrhosis abetalipoproteinemia + HAM TEST <--------- Paroxysmal nocturnal hemoglobinuria (ACID HEMOLYSIS) Enzyme deficiencies / G-6-PD deficiency HEINZ BODIES <-----/ Other deficiencies of HMP shunt enzymes Pyruvate kinase deficiency Other glycolytic pathway enzyme deficiencies Abnormal hemoglobin TARGET CELLS<-/ Unstable hemoglobin SICKLED CELLS <-------- Sickle cell disease HEMOGLOBIN C CRYSTALS<--Hemoglobin C disease HEMOGLOBIN SC CRYSTALS<-Hemoglobin SC disease /---- Immune hemolysis (antibodies against red cell antigens)  ³ Hemolytic disease of newborn (Rh, etc.) SPHEROCYTES ³ Autoimmune hemolytic anemias ³ Systemic lupus + DIRECT  Methyldopa ("Aldomet") COOMBS TEST Malignant lymphoma and other cancers "Idiopathic" warm antibody type Paroxysmal cold hemoglobinuria Drug haptens (high-dose penicillin) Mechanical injury "March hemoglobinuria" (pavement pounding) /Clostridial sepsis --------/ Burns  \ Prosthetic heart valves SCHISTOCYTES \Microangiopathic hemolysis (fibrin slices RBC's) AND OTHER \ Disseminated intravascular coagulation (DIC) FRAGMENTS \ Thrombotic thrombocytopenic purpura (TTP) \ Hemolytic-uremic syndrome Malaria "Hypersplenism" (big spleen from various causes) Cirrhosis Rheumatoid arthritis Gaucher's disease, etc. Normoblasts being destroyed (not principal mechanism) Megaloblastic anemia  Idiopathic myelofibrosis (no  reticulocytes) Thalassemias TOO MANY RED CELLS BEING LOST FROM THE BODY (acute hemorrhage) Trauma  GI tract bleeding  RETICULOCYTES Uterine bleeding, etc. ENOUGH HEMOGLOBIN NOT BEING MADE  MCV \ Not enough usable iron  SERUM IRON (MICROCYTES)³<--/ Actual iron deficiency (none stored)  MCHC / / \ (HYPOCHROMIA) / Diet (junk food, poverty) \ PENCIL CELLS\<---/ Pregnancy  TARGET CELLS/ ³  SERUM FERRITIN \ ZERO MARROW IRON STORES \ Chronic blood loss \ Heavy menstruation \ Frequent blood bank deposits \ Lots of blood tests (preemies, others) \Slow GI bleeding, etc. ³--"Anemia of chronic disease" (never severe)  (RE cells fail to get iron into normoblasts)  SERUM FERRITIN Rheumatoid arthritis, systemic lupus  Chronic infections (TB, osteomyelitis, etc.) ³ Advanced cancer DIMORPHIC <--------"Sideroblastic anemias" RBC POPULATIONS (iron stays in normoblast organelles) Alcoholism Drugs (isoniazid, etc) Lead poisoning (inhibits ferrochelatase) *Pyridoxine responsive anemia Preleukemia ("myelodysplasia"), etc. Not enough heme rings Erythropoietic porphyria ---------- Lead poisoning (inhibits porphyrin synthesis) BASOPHILIC Not enough globin chains STIPPLING <-------- Thalassemias -----------------------> PANCAKE CELLS ENOUGH NORMOBLASTS NOT BEING MADE --------------->  RETICULOCYTES Renal disease (not enough erythropoietin) Hypothyroidism  MCV <------- Not enough nucleic acid (megaloblastic anemias) (MACROCYTES)  Cancer chemotherapy HYPERSEGMENTED PMN's B12 deficiency  SERUM B12 <-----------/ Pernicious anemia ³ Weird diets ("vegans", all vegetables) SCHILLING TESTS <-------³ Malabsorption (gut diseases) WITH AND WITHOUT \ Fish tapeworm infestation INTRINSIC FACTOR Folic acid deficiency ---------->  RBC FOLATE Weird diets (junk food, alcoholics) Pregnancy Chronic severe hemolysis Phenytoin (blocks absorption by gut) Folic acid antagonists (methotrexate) Zidovudine and other AIDS drugs /Infiltrative disease of bone marrow ³ "Myelophthisic anemia"  Cancer TEARDROP RBC'S Tuberculosis Fibrosis ("myelofibrosis") "Myeloid metaplasia" Polycythemia vera rubra (end-stage) "Idiopathic" "Primary" failure of normoblast production "Pure" red cell aplasia/hypoplasia Hereditary (Blackfan-Diamond) Thymoma / thymic hyperplasia Chloramphenicol "Aplastic anemia" ( granulocytes, plts also) Radiation Benzene Drugs (phenylbutazone, gold, many others) Aplastic crises (Hgb SS, other hemolyzers) Do you remember all those hemoglobins? Hemoglobin is four globin chains plus four heme units (porphyrin plus iron): 2à + 2á = Hgb A (à2 á2A) 96% in normal adults 2à + 2ë = Hgb A2 (à2 ë2) 3% in normal adults 2à + 2 gamma = Hgb F (à2 gamma2) 1% in nl. adults Hgb F is the main hemoglobin in the fetus, and remains abundant until the child is two years old. Do you remember the hemoglobins seen only in disease? Wrong ways of combining normal chains: 4á = Hgb H (á4) 4 gamma = Hgb Bart's (gamma4) Mutations: 2à + 2áS = Hgb S (à2ásS2) 2à + 2áC = Hgb C (à2ácC2) 2à + 2 á-ë Lepore = Hgb Lepore (à2 á-ë2) And about 300 other, less common, variants. (Some cause problems, some don't. Anemia: any reduction below normal limits of the total circulating red cell mass. All anemias except the anemia of acute blood loss are detected by your discovery of decreased hematocrit and/or decreased hemoglobin. Acute anemia (i.e., blood loss) produces shock. (Hemoglobin and hematocrit stay normal or near-normal until plasma volume is restored.) Chronic anemia requires increased cardiac output and eventually may produce hypoxia, weakness, malaise, easy fatiguability, koilonychia, fatty change in myocardium. Chronic blood loss: Anemia usually develops only when iron stores run out, i.e., iron deficiency anemia results. The bone marrow can increase erythropoiesis to eight times normal in the face of chronic bleeding or hemolysis. Hemorrhage is much commoner than hemolysis! Intravascular hemolysis: as in DIC, or when RBC's are sensitized to complement or mechanically injured) Extravascular hemolysis: Lysed in the RE system, as when RBC's are too stiff or fragile or are altered immunologically. Ongoing hemolysis will result in several pathophysiologic changes: Increased total body iron (gut overabsorbs), high reticulocyte count, zero haptoglobin, jaundice, bilirubin gallstones, expanded marrow space ("crewcut skull films" in kids) Hereditary spherocytosis: deficient spectrin, ankyrin, and/or protein 4.1; red cells are fragile and spherical. Increased osmotic fragility. Treatment is splenectomy. Hereditary deficiency of HMP shunt or glutathione systems cause oxidative damage to red cells. Masses of denatured hemoglobin are "Heinz bodies". Best-known is G6PD deficiency, common in Afro- Americans; must avoid fava beans, some antimalarials, some other drugs. Sickle hemoglobin features substitution of valine for glutamine at the sixth position of the beta chain (áS). Deoxygenation results in tactoid formation ("crystallization", "gelation") of HgbS. This forms sickle-shaped cells, and results in stasis (sludging), vaso-occlusive phenomena, and hemolysis. Made worse by high ionic strength and dehydration, better by hemoglobin F. Autosplenectomy and susceptibility to pneumococcal sepsis. Sickle cell disease is preventable by screening for carriers; sicklers have a pain problem commensurate with cancer patients. Hemoglobin C is another black hemoglobin, almost as common as Hgb S. Heterozygotes have mild hemolysis; homozygotes have moderate hemolysis. SC patients have a mild sickling problem. Hemoglobin E: Southeast asian, mild hemolysis in heterozygotes. Alpha-thal. Four alpha-chain genes in health. Africa, anywhere else. Lack one: Thal minima, no health problems, 3% hemoglobin Bart's at birth. Lack two: Alpha thal minor, smallish (82 fL or so) red cells, 5- 10% hemoglobin Bart's at birth, trace hemoglobin H as adult, anemia is rare. Lack three: Hemoglobin H disease; H has high affinity for oxygen, and tends to form Heinz bodies. Lack four: Hemoglobin Bart's disease, hydrops fetalis, i.e., congestive heart failure in the unborn child. Beta-thal. Two beta-chain genes in health. Mostly Mediterranean. (Alleles: á0 -- no chains produced; á+ -- some chains produced, but not enough) Lack one: Thal minor, basophilic stippling, small red cells (67 fL or so), pancake-shaped (leptocytes), mild intramedullary hemolysis (i.e., slight unconjugated hyperbilirubinemia). Lack two: Thal major, horrible anemia with intramedullary hemolysis, weird-shaped cells, need for transfusions, death from iron overload. Paroxysmal nocturnal hemoglobinuria: Abnormal sensitivity of RBC's to complement-mediated lysis, especially at low pH (i.e., while you're asleep). The cells have lost the gene (PIG-A) to make an inositol- based anchor for a group of surface proteins, including those that confer resistance to lysis by the body's own complement. Ham test. Coombs test (direct): Checks for antibody coating red cells in you. (Indirect is a laboratorian's test for the presence of antibodies, but not on your red cells). IgG (warm) autoimmune hemolytic anemia: lymphoma, lupus, methyldopa. IgG (cold) autoimmune hemolytic anemia: mycoplasma, infectious mono, lymphoma. Mechanical hemolysis: prosthetic valves, DIC, TTP, HUS, burns, malignant hypertension, scleroderma, lupus vasculitis. Look for helmet cells, burr cells, triangle cells, target cells, schistocytes. Infections of red cells: babesia, malaria, bartonella. In all megaloblastic anemias (i.e., the nuclei cannot keep up with the cytoplasm while developing), expect to see: -- anemia (and maybe neutropenia and maybe thrombocytopenia) -- increased mean corpuscular volume (why?) with normochromia and considerable anisocytosis (ask a pathologist to show you a "macro-ovalocyte") -- hyper-segmentation of the neutrophil and eosinophil nuclei (why?) -- shortened red cell survival time (often, much of the hemolysis takes place in the marrow; the marrow may appear hypercellular and serum LDH-1 levels, suggestive of hemolysis, can be extremely high) Pernicious anemia ("true pernicious anemia", "addisonian pernicious anemia", etc.): Lack of B12 due to lack of intrinsic factor. Dread neurologic syndrome of subacute combined degeneration of the cord. Diagnosis with Schilling test. This is a boards favorite. Understand why the physical findings: -- findings of anemia (pallor of all organs, big heart) -- slight icterus (why? ever hear of the "lemon yellow" pernicious anemia patient?) -- peripheral smear (from life) with macro-ovalocytes -- neutrophils on peripheral smear with 6-10 segments -- hypercellular, megaloblastic marrow; -- glossitis (can't replace those stratified squamous cells fast enough) -- autoimmune-style chronic gastritis ("fundic"; "type A"; achlorhydric) with some intestinal metaplasia -- immature, large nuclei in the remaining stomach epithelial cells -- loss of myelin in the posterior columns; NOTE: Often the lateral columns are affected, too. This is called "subacute combined degeneration of the cord", typical of B12 deficiency. Other causes of B12 deficiency: extreme vegetarians, whole stomach cut out by the surgeon, bad malabsorption, diphyllobothrium fish tapeworm, bad terminal ileum (B12 absorption site) from Crohn's. Folic acid deficiency (ever know someone who called it "vitamin P"? "folic" means "from (green) leaves"). Another megaloblastic anemia. Junk food, pregnancy, dilantin, birth control pills. A person may become iron-deficient by: -- heavy menstrual loss -- abnormal blood loss (GI bleeding -- remember hookworm --, GU bleeding, uterine bleeding) -- lousy diet (there's not much iron in twinkies, fries, or diet pepsi; heme iron is much better absorbed than iron from beans; poor diet is seldom the sole cause in U.S. adults, however U.S. kids can and do become iron deficient, despite "Big Robbins") -- malabsorption (sprue, those others) -- no HCl and/or no access of food to the duodenum (as after ulcer surgery) Doc: If you find iron deficiency, you MUST find the cause. The iron-deficient patient develops a hypochromic, microcytic (why?) anemia, which can be very severe. Tiny red cells with wide central pallor. Pencil cells. High total iron binding capacity, low serum iron, zero serum ferritin. Anemia of chronic disease: From prolonged interleukin 1 production. Osteomyelitis, rheumatoid arthritis, tuberculosis, leprosy, and generally the same diseases that cause amyloidosis A. Normoblasts have difficulty taking up iron. Iron stays in the marrow macrophages. Hemoglobin 8-10 g/dL, small red cells.. Sideroblastic anemia: Ferrochelatase cannot place iron into the heme ring. Alcoholics, preleukemia, isoniazid. Red cells stop being made: Aplastic crisis in sicklers and spherocytosis is likely mediated by parvovirus 19. Chloramphenicol suppresses erythropoiesis, and sometimes extremely well and permanently. Thymomas. Blackfan-Diamond (apoptosis unless loaded with erythropoietin). Renal failure benefit from erythropoietin injections. White cells: A tough chapter. Epstein-Barr virus: Burkitt's lymphoma in Africa; other B-cell lymphomas in the immunosuppressed HTLV-I: Adult T-cell leukemia-lymphoma; Caribbean spastic paralysis / leukemia HTLV-II: Hairy cell leukemia HIV: Immunosuppression allows Epstein-Barr lymphomas of brain; EBV and non-EBV lymphomas elsewhere Herpes 8 /KSHV newly-implicated in some, if not many, lymphomas Terms: (1) agranulocytosis: acquired lack of neutrophils, usually from a drug; (2) Auer rod: crystal of azurophilic granules stuff, proof of granulocyte origin; (3) Bence-Jones protein: free immunoglobulin light chains produced by plasma cell myeloma; (4) blast: baby white cell with all-euchromatin, some nucleoli, scanty cytoplasm; if easy to find, think of acute leukemia; (5) bcr/abl oncogene: the cancer gene produced by the Philadelphia translocation; (6) chloroma / granulocytic sarcoma: The solid phase of acute granulocytic leukemia; (7) cleaved (clefted) lymphocyte: a B-cell on its way to becoming an antibody producer; (8) convoluted lymphocyte: A T-cell in Sezary/mycosis fungoides; (9) cryoglobulin: marginally soluble plasma protein that precipitates in the cold; (10) D”hle body: rough ER masses in some turned-on white cells; (11) monoclonal gammopathy: extreme overproduction of exactly one particular antibody; (12) polyclonal gammopathy: too much of many antibodies being overproduced (lupus, AIDS, liver failure, rheumatoid arthritis, bad infections); (13) leukemia: cancer of the white cell precursors, cancer of the bone marrow; (14) aleukemic leukemia: no leukemia cells in the blood; (15) leukocyte alkaline phosphatase: marker high in leukemid reaction, low in chronic granulocytic leukemia; (16) leukocytosis: increased absolute total white count; (17) leukoerythroblastic smear: teardrops and nucleated reds, i.e. something's crowding the marrow; (18) leukopenia: decreased absolute white count; (19) lymphadenopathy: big lymph nodes for any reason; (20) lymphoma: solid cancer of the lymphocytes, not in the marrow; (21) M- protein: the particular antibody or chain overproduced in monoclonal gammopathy; (22) myeloid / myelogenous: derived from granulocytic precursors; (23) myeloma ("multiple myeloma", "plasma cell myeloma"): cancer of the plasma cells; (24) neutropenia: absolute lack of neutrophils; (25): paraprotein: consider this the same as M-protein; (26): Pautrier microabscess: clusters of convoluted lymphocytes in the epidermis in mycosis fungoides / Sezary's; (27) Philadelphia chromosome: the famous translocation in chronic granulocytic leukemia; (28) absolute polycythemia: too much red cell mass; (29) relative polycythemia: too little plasma, causing too high hematocrit; (30) primary polycythemia: absolute polycythemia due to overproduction of red blood cells bearing mutations; (31): secondary polycythemia: absolute polycythemia due to low oxygen tension or excess erythropoietin or taking gym steroids or high-affinity hemoglobin; (32) pseudolymphoma: ugly-looking chronic inflammation that fooled the other pathologist; (33) tingible body macrophage: a macrophage that has eaten debris in an inflamed lymph nodes; (34) toxic granulation: exaggerated granules in neutrophils during sepsis. T-cell zones: thymus, lymph node parafollicular cortex, splenic white pulp near arteriole B-cell zones: germinal centers and their mantles, splenic white pulp at its margins Among circulating lymphocytes, 80% are T-cells, and 20% are B-cells. Healthy absolute counts: Basophils: * few- 100/æL Eosinophils: few- 400 Lymphocytes: 1500-7000 (*3000-7000 for kids) T4 helper lymphocytes: >1000 Monocytes: few- 800 Neutrophils: 1800-7000 "95% lymphocytes" might mean either agranulocytosis (if the total white count is 2000) or chronic lymphocytic leukemia (if the total white count is 100,000). Somebody might actually have the crust to ask you about white cell markers. PAS+ chunks ("blocks"): immature lymphocytes or M6 leukemia TdT: immature lymphocytes E-rosettes: T-cells CD4, CD8, others: T-cells (various kinds) CD1 (T6) T-cells, Langerhans macrophages Surface Ig(M, etc): B-cells kappa, lambda: B-cell, plasma cells cytoplasmic Ig: plasma cells nonspecific esterase: monocytes Fc receptor: B-cells, monocytes TRAP: hairy-cell leukemia (tartrate resistant acid phosphatase) HLA-D/DR /Ia: Langerhans cells and other antigen- presenting macrophages; some other cells lysozyme: monocytes à1-antichymotrypsin: monocytes erythrophagocytosis: monocytes (myelo-)peroxidase: granulocytes Sudan black granulocytes chloroacetate esterase: neutrophils, basophils, mast cells platelet markers: megakaryocytes PAS+ diffusely: erythrocytes, megakaryocytes/platelets Even worse, someone might ask about the development of a B-cell: Resting small B-lymphocyte  Small cleaved ("clefted", i.e., folded-nucleus) B-lymphocyte  Large cleaved B-lymphocyte  Small non-cleaved B-lymphocyte [NOTE: This cell is as large as a large cleaved B-lymphocyte]  Large non-cleaved B-lymphocyte  B-immunoblast   Memory B-cell Plasma cell Neutropenia: The aplastic anemias, space-occupying lesions in marrow, the megaloblastic anemias, radiation, chemotherapy, typhoid, hypersplenism, phenylbutazone, other drugs. Agranulocytosis (extreme neutropenia) presents as mouth ulcers. Left-shift: Immature neutrophils appearing in the blood, usually from bad infection. Extreme case: Leukemoid reaction; distinguish from granulocytic leukemia. Leukemoid reaction Chronic granulocytic leukemia High leuk alk phos Low leuk alk phos Normal basophils High basophils No Philadelphia chr. Ph' or at least bcr/abl Chediak-Higashi: Problems with neutrophil membranes. Pelger-Huet: Poor segmentation of neutrophils, not a clinical problem. Alder-Reilley: Conspicuous neutrophil granules in mucopolysaccharidosis. Non-Hodgkin's lymphoma rules. All monoclonal lymphocyte proliferations are malignant. Most lymphomas are of unknown cause. The majority are of B-cell origin. Fever, weight loss, night sweats, hypogammaglobulinemia are from cytokine production by the tumor. Enlarged, non-tender nodes, less often gut or lung lymphoid tissue. Uniform overgrowth of cells, often not bizarre. Nodular (follicular) lymphoma means B-cell origin, better prognosis than diffuse counterpart. Pathologists diagnose lymphoma based on effaced architecture, cell uniformity, invasion, necrosis, monoclonality, chromosome rearrangements. Prognosis depends on subtype. High-grade ones are curable with chemotherapy. Low-grade ones are indolent but non-curable. Small lymphocytic lymphoma: indolent disease of older folks. Richter's: turns aggressive (Jackie Kennedy's disease). Plasmacytoid small lymphocytic lymphoma: Often Waldenstrom's, makes IgM, leading to hyperviscosity. T-lymphoblastic lymphoma: teenaged boys, in the thymus. Burkitt's: 8:14 translocation, Epstein-Barr virus, starry-sky (the white "stars" are macrophages devouring the lipid-rich debris); jaws of kids in Africa; sporadic cases in the U.S. are not Epstein-Barr related. Mycosis fungoides: T-cells with convoluted nuclei in the skin; disease progressively gets worse, from just red skin to horrible tumors ("toadstools"). Sezary's: mycosis fungoides-type cells circulating in the blood. Hodgkin's: Malignant cell is the Reed-Sternberg cell, cancerous counterpart of certain cells ordinarily found in excited nodes. You must recognize the classic Reed-Sternberg cell: -- 15-45 æ across -- multilobed nucleus (often appears "binucleate"), with lobes appearing as mirror images of one another -- large, red owl-eye nucleoli, surrounded by clear nuclear sap -- pink-to-lavender cytoplasm Reed-Sternberg variants appear in various subtypes. The elegant Rye classification is less prognostic than the stage of the disease. Staging simplified (they might ask): I: One group of nodes II: One side of the diaphragm III: Both sides of the diaphragm IV: Bone or 2 extra-nodal organs. A: No fever, weight loss, or night sweats B: Fever, weight loss, or night sweats Histologic types: Lymphocyte predominance: Only a few Reed-Sternberg cells, among many benign lymphocytes Nodular sclerosis: Lacunar Reed-Sternberg variants, mediastinum, mixed background Mixed cellularity: Lots of different cells, enough Reed-Sternberg cells Lymphocyte depletion: Horrible-looking cancer One type tends to become a worse type, with nodular sclerosis the most stable. Eosinophils tend to come out in large numbers in Hodgkin's. Acute leukemia: lots of blasts, presents abruptly as one of the cytopenias (anemia, neutropenia, and/or thrombocytopenia). Bone pain is likely to result from expansion of the marrow and infiltration of the periosteum. Chronic leukemia: few or no blasts, presents as cytopenia, or over- abundant white cells plugging vessels. Acute lymphoblastic leukemia: Kids' leukemia. Down's, radiation are the risk factors, otherwise strikes at random. Most are B-cell, some T-cell or null. Usually curable. Acute myeloblastic (granulocytic) leukemia: Down's, benzene, previous chemotherapy, preleukemia, "blast crisis" of chronic granulocytic leukemia / polycythemia vera / "aplastic anemia", "the fragile chromosome syndromes". I don't expect them to ask you the M1-M7 scheme, or about the myelodysplastic syndromes ("preleukemia"). Chronic granulocytic (myelogenous) leukemia: Benzene, previous radiation, most appear random. Huge spleens, Philadelphia chromosome. The disease smolders until blast crisis (i.e., more mutations, acute disease and death) supervenes. Chronic lymphocytic leukemia: Usually normal-appearing B-cells circulating. No risk factors, not even radiation. Anemia, thrombocytopenia, autoimmune hemolysis, Richter's. Hairy-cell leukemia: fuzzy lymphocytes, dry tap, positive stain for tartrate-resistant acid phosphatase, probably an infection, HTLV-II is one suspect, good response to anti-viral drugs. Polycythemia vera rubra: low-grade neoplasm of normoblasts, which (news) have their low-erythropoietin signals stuck "on". Actually a stem-cell problem; neutrophils and platelets are also up. Older- middle-age. Hyperviscous blood. Treatment is phlebotomy. Agnogenic myeloid metaplasia: Proliferative disease in marrow and spleen; marrow looks normal. Teardrops and red cell precursors. Later, marrow fibrosis. Plasma cell myeloma: Older folks, no known risk factors, minority have the punched-out lesions, but all have some bone rarification. Some make Bence-Jones protein, some make a complete antibody, a few make nothing. Bence-Jones protein eventually plugs kidney tubules. Patients have anemia and suppression of normal antibody production. IgG is most common paraprotein. Amyloidosis B. Hypercalcemia from some unknown bone-destroying hormone. Langerhans cell histiocytosis ("histiocytosis X"): Cancer of the dendritic macrophages. Archaic names: "Hans-Schuller-Christian; Letterer-Siwe, eosinophilic granuloma". Giveaway is CD1 / T6 stain, Birbeck granules (pentalaminar tennis rackets) on electron microscopy. Hypersplenism: Takes out neutrophils, red cells, and platelets. Think of cirrhosis, Felty's (rheumatoid arthritis), Gaucher's. All diseases of hemostasis have spontaneous bleeding (petechiae, purpura, mucous membranes, GI bleeding, hematuria, into joint spaces) and/or excessive bleeding after trauma or surgery. Testing hemostasis: Platelet count Bleeding time: tests number and function of platelets. Thrombin time: fibrinogen Prothrombin time: I, II, V, VII, X aPTT I, II, V, VIII, IX, X, XI, XII Clot retraction: fibrinogen, platelet count, and Glanzmann's factor Urea solubility: XIII (cross-linker) Fibrin split pr. DIC? D-dimer Better test for DIC Platelet aggreg. Not very useful clinically; exception is that von Willebrand's respond poor to ristocetin Increased vascular fragility: amyloidosis, scurvy, Cushing's, Osler- Weber-Rendu, Ehlers-Danlos, endothelial infections, rickettsia, viral hemorrhagic fevers, type III immune injuries Platelets <40,000: bleed after surgery. Platelets <20,000: bleed spontaneously. Platelets <10,000: bleed bad, spontaneously. Thrombopoietin was finally cloned in 1994. Thrombocytopenia of decreased production (few megakaryocytes): drugs, chemotherapy, marrow disease, megaloblastic anemia. Increased destruction (many megakaryocytes): autoimmune, isoimmune, hypersplenism, massive bleeding. Idiopathic thrombocytopenic purpura: Acute form in kids with virus- antivirus immune complexes adsorbed on the platelets; seen also in AIDS. Chronic ITP: real anti-platelet antibodies, adults. Thrombotic thrombocytopenic purpura (TTP): Fibrin-platelet microthrombi all over the vascular system. Mysterious. Confusion and CNS signs, fever, thrombocytopenia, kidney failure, red cell fragmentation, death. Administering fresh-frozen plasma controls it. Bernard-Soulier: Giant platelets that don't work. Von-Willebrand's: Lack of VIII-R, the stuff made in endothelium that keeps platelets working and VIII-C in the plasma. Very common, if you look. Glanzmann's tired-platelet thrombasthenia: Lack of a factor that makes platelets work, particularly in their role in clot retraction. Aspirin lesion stays for the 9-day life of the platelet. Thrombocytosis of seldom of interest, unless it's due to "essential thrombocythemia", in which the megakaryocytes have a mutation; this is preleukemic, and the platelets may not work well. Hereditary coagulation disorders: Classic hemophilic factor VIII. Christmas disease factor IX. Lack of vitamin K: malabsorption, little babies, coumadin, liver failure. Factors II, VII, IX, X. "Circulating anticoagulants" cannot be neutralized by adding the good factor; problem for hemophiliacs. Hypercoagulable blood: Factor C deficiency, factor S deficiency, lupus anticoagulant, protein C cofactor deficiency, antithrombin III deficiency (hereditary, birth control pills), hyperactive V (news), hyperhomocysteinemia (news). Memory work: Defects of the extrinsic pathway (normal aPTT, prolonged PT) usually indicate early liver disease or coumarin therapy (congenital factor VII deficiency is rare) Defects of the intrinsic pathway (normal PT, prolonged aPTT) include factor VIII and IX deficiencies or circulating anticoagulants (congenital factor XI and XII deficiencies are rare) Defects of both pathways (prolonged PT and aPTT): usually indicate heparin or coumadin therapy, advanced liver disease, or circulating anticoagulants (congenital factor II, V, and X deficiencies are rare) Defects of neither pathway (normal PT and aPTT): fragile vessels, platelet problem, or factor XIII deficiency (remember urea solubility test) Tooth decay: Dental caries, strep mutans hiding under a film (plaque) made of polymerized carbohydrates (sucrose is best), making acid, eroding teeth. Risk factors: high-sucrose diet, dry mouth from any cause. Fluoride in the drinking water protects. Eroded teeth may abscess, etc. Ludwig's angina: infection spreads to floor of mouth, neck structures. Periodontal disease: Plaque accumulates in the gingival sulcus, calcified is calculus, causes inflammation and resorption of the attachments of tooth to bone, tooth loss in older folks. Trench mouth (necrotizing gingivitis): Mixed borrelia and fusobacterium infection; severe cases (noma) destroys face. Leukoplakia: Any white lesion on the mucosa; may be nothing, or may be carcinoma in situ; smokeless tobacco. Squamous cell carcinoma of oral mucosa: tobacco, alcohol, herpes simplex. Lichen planus: White lines on oral mucosa. Aphthous stomatitis: White "canker sores" on the oral mucosa, nothing to do with herpes; local immune complex vasculitis probably strep antigens; rule out Crohn's, Bechet's (mouth and genital sores), agranulocytosis, lupus. (Erythema multiforme and pemphigus have their own looks.) Herpes stomatitis: First infection with type I. Herpes labialis: induced by stress, sunlight, hormonal chaos, fever, injury. Herpangina: Coxsackie A blisters on anterior tonsillar pillars. Salivary gland neoplasms: Pleomorphic adenoma is a cartilage-based mixed tumor. Warthin's tumor is benign. A variety of cancers occur here; only known risk factor is radiation. Ameloblastoma: the common semi-cancer of the jaws, simulates developing tooth, no tendency to metastasize. Gut words! (1) achalasia: failure of the gastroesophageal sphincter to relax, causing the esophagus to fill up with a few day's dinner; (2) hernia: gut (usually) pooching out where it doesn't belong; (3) polyp: a bump sticking up from the mucosa; (4) tenesmus: unpleasant spasms of the anal sphincter, continuous urge to defecate; any inflammation here can produce this. Tracheo-esophageal fistula: Kid chokes on feeding. Zenker's pulsion pseudodiverticulum: Esophagus pooches out next to cricophagyngeus muscle, traps yesterday's spaghetti. Mega-esophagus: Achalasia or Chagas's. Webs: little fibrous scars that may obstruct. Hiatus hernia: Stomach in the chest; sliding (common) from shortened esophagus (years of reflux; obesity; congenital), rolling (less common; think of obesity stretching the diaphragm wide) alongside esophagus of normal length. Reflux: familiar heartburn, damage from acid, lysolecithin, pepsin. Hyperplastic basal cells, eosinophils in the epithelium, tall papillae. Barrett's esophagus: Columnar metaplasia at the gastroesophageal junction, caused by healing of reflux in the setting of a mutation giving advantage to cells of glandular phenotype, hence the adenocarcinoma risk. Esophagitis: Candida, herpes, less often CMV. Lacerated esophagus: Bad vomiting. Mallory-Weiss: Several longitudinal tears in the distal esophagus from vomiting. Boerhaave's: Badly ruptured esophagus. Varices: from portal hypertension; prone to heavy bleeding. Esophageal angina: Popular new diagnosis to explain chest pain. The causes of portal hypertension.... Pre-hepatic Thrombosis of the portal vein Hypercoagulability Polycythemia vera, sickle cell, others Invasion by tumor (hepatocellular carcinoma) Tumor compressing the portal vein Intra-hepatic Cirrhosis from any cause Other obstructive disease Bad alcoholic liver disease without cirrhosis Schistosomiasis without cirrhosis Central hyaline sclerosis in alcoholism Post-hepatic Budd-Chiari (thrombosis of hepatic veins) Causes as for thrombosis of portal vein Squamous cell carcinoma of esophagus: Alcohol, tobacco, and herpes; old lye strictures, Red China (mystery). Adenocarcinomas arise in Barrett's. Diaphragmatic hernia: Stomach all the way up in the chest at birth. Pyloric stenosis (congenital): Boy has projectile vomiting at one month, surgeon feels an olive-like mass. Acute gastritis: Multifactorial, several mechanisms (ischemia, low pH, dead epithelial cells, compromised defenses). Causes include alcohol, aspirin, caffeine, chemotherapy, food allergy, helicobacter, radiation injury, lysolecithin refluxing from the duodenum, shock, spicy foods, staph food poisoning, tobacco, viruses, stress. Chronic gastritis: Type A: Autoimmune, fundic; stomach cancer common; pernicious anemia, intestinal metaplasia Type B: Hypersecretory, antral, lots of stomach acid, helicobacter Type AB: "Environmental", helicobacter, stomach cancer fairly common, but not as a bad as A; Japan, Chile, others. Menetrier's: Hypertrophy-hyperplasia of mucosa from helicobacter Zollinger-Ellison: Hyperplasia and worse from a gastrinoma. Stress ulcers: Common. In the burn unit, called "Curling's ulcers". In the neurosurgery unit, called "Cushing's ulcers". Peptic ulcer: Helicobacter is key; other risks are alcohol, aspirin, blood type O, smoking, cirrhosis, emphysema, gastrinoma. Gastric adenocarcinoma: dietary factors (smoked food, ethnic pickled stuff, lack of green vegetables, lack of animal fat), old ulcer surgery, chronic gastritis A or AB, blood groups A or AB (convenient). Epidemics now in Japan and Chile; helicobacter antibodies may be growth factor. Linitis plastica: Stomach cancer replacing the wall ("leather bottle"). Krukenberg tumor: Massive stomach cancer metastases to the ovaries. Meckel's diverticulum (persistent omphalomesenteric duct): 2% of folks have it, 2 feet proximal to the ileocecal valve, 2 types of ectopia are pancreas and stomach; ulcers, bleed, infection, volvulus. Mucosal infarcts ("hemorrhagic gastroenteropathy"): stress, shock, digitalis, long runs. Crohn's disease: mycobacterial origin now seems plausible; skip lesions, transmural involvement, string sign, fistulas, creeping fat, linear fissuring and cobblestone change of the mucosa, small cancer risk, aphthae, lesions anywhere from lips to anus, favored site is terminal ileum, B12 and folate malabsorption. Malabsorption has many causes. Cannot break down food to simple molecules ("mal-digestion") Exocrine pancreatic disease (duct obstruction by stone or cancer, damaged parenchyma in "chronic pancreatitis") Lack of bile salts (bile duct obstruction, liver failure; bacterial overgrowth in diverticula, stasis, after gastrectomy) Disaccharidase (lactase, etc.) deficiency Problems with the small bowel mucosa Sprue Tropical Non-tropical ("celiac disease" "gluten enteropathy") Crohn's Whipple's Acute infections Parasites Giardia (the usual cause of "malabsorption secondary to hypogammaglobulinemia") Less often, strongyloides, schistosomes Allergic gastroenteritis Kinks in the metabolism (abetalipoproteinemia, inability to absorb a particular molecule) Collagenous enteritis / scleroderma Amyloidosis Lymphomas Radiation sickness / B12 / folate deficiency (epithelium cannot replenish itself) Super-fast transit time Laxatives Mechanical problems Blocked lymphatics (cancer, TB) After re-routing surgery (gastrectomy, bypass) Celiac sprue: Gluten induces autoantibodies against reticulin, which somehow flattens the villi and microvilli. Skin manifestation is dermatitis herpetiformis; many get lymphoma of gut. Tropical sprue: Vicious cycle of malabsorption, folate deficiency, and bacterial overgrowth. Whipple's disease: Infection with Tropheryma whippli bacteria, which pack macrophages (see on PAS stain) in gut and anywhere else. Abetalipoproteinemia: no apolipoprotein B; acanthocytes, cannot absorb fat which stays in the intestinal epithelial cells. Intussusception: Telescoping of bowel into itself, as if it mistook a polyp or lymphoid mass for food. Volvulus: Twisted bowel. Adhesions: fibrous scarring, most often from surgery. Appendicitis: Pain migrating from crampy-around-navel to knife-at- Mcburney's-point. Cause is obstruction of appendix by fecalith or lymphoid tissue. Carcinoid tumors of the appendix are common, low- malignancy. Hirschsprung's aganglionic megacolon: Failure of Auerbach's and Meissner's plexi to develop over a segment of colon. Constipation is a problem. Diverticulosis: mucosa pooches out through the colonic wall where the arteries enter. Low-residue diet requires more force to push small, hard stools. Prone to bleed and/or get bacterial infections (diverticulitis). (Really pseudo-diverticula). Functional bowel syndrome (spastic colon): Uncoordinated peristalsis leads to ischemia and pain. Idiopathic ulcerative colitis: Rule out amebiasis, ischemia, shigella, bad E. coli. Inflammatory disease of the colonic mucosa, increasing distally without skip lesions. Bloody diarrhea. Pseudopolyps are surviving mucosa among coalescent ulcers. Large cancer risk after many years. Probable cause is some bacterial product. Here is the inevitable comparison: CROHN'S DISEASE ULCERATIVE COLITIS Etiology? Unknown / infect? Unknown / infect? Sex? > > Ethnic group?  among Jewish  among Jewish Hereditary? Contributes Contributes Exacerbate/remit? Yes Yes Stress exacerbates? Yes Yes Location? Variable Rectum and upwards Bowel? Small > Large Large only Terminal ileum? Favorite site "Backwash" Colon? Right>left, if any Left > right Bile ducts? May be damaged May be damaged Anal troubles? Common No Oral lesions? Maybe No Skip lesions? Yes No; continuous Layers? All three Mucosa only Ulcers? Linear fissures Broad / irregular Pseudopolyps? Yeah, sort of Yes unless very mild Fibrosis? Severe No Fistulas? Yes No Creeping fat? Yes No Granulomas? Often No Bleeding? Subtle Heavy-duty Pain? Wretched Not so much Malabsorption? Maybe No Bowel obstruction? Maybe No B-12 deficiency? Maybe No Lymphs/plasma cells? Yes Yes Arthritis, uveitis? Yes Yes Ankylosing spondylitis? if (+) for HLA-B27 if (+) for HLA-B27 Diagnosis? Tough Easy Surgery? Avoid Cures Carcinoma risk? Minor High Pseudomembranous colitis: Clostridium difficile overgrows normal flora at times of stress or antibiotic coverage; pseudomembrane is fibrin, and diarrhea may be followed by toxic megacolon. Necrotizing enterocolitis: Babies, especially bottle-fed preemies. Inflammation nad necrosis of gut. Hyperplastic colon polyps are harmless bumps. Peutz-Jegher's polyps are hamartomas in the small and large gut; look for freckles on the lips. True colonic adenomas are tubular or villous, depending on the shapes of their glands, may be mixed. Villous are more likely to be sessile, more likely to secrete potassium, more likely to turn malignant. Colorectal cancer: Major killer, almost always adenocarcinoma, except in Lynch's hereditary nonpolyposis colon caner syndrome the origin is almost always n a polyp. Diet is a risk factor but exactly how is unclear; the "red meat" hasn't held up recently; lack of roughage (i.e., complex carbohydrate that holds water) seems more plausible. News: an aspirin a day cuts colon cancer risk by about half. The majority of colon cancers, like polyps, arise in the rectosigmoid, present as narrowed stool. Those in the cecum present as iron deficiency anemia. Marker: CEA. * "You thing of no bowels!" -- Shakespearean insult Anal cancer: HPV-related, passive anal intercourse. Basaloid cancer: from the transitional zone. Hollow-organ pain is crampy-colicky and poorly-localized; patients tend to squirm. Peritoneal pain (remember it's the parietal peritoneum that feels it best) is knife-like and is exacerbated by movement (the patient lies still). Peritonitis can and does follow most intra- abdominal catastrophes. Most any bacterium can do it; fortunately, gas gangrene is rare. Spontaneous bacterial peritonitis: In cirrhotics, E. coli or enterococcus. Nephrotic syndrome: pneumococcus. Pseudocyst: A lesser sac or other cavity with its wall digested by lipase from a damaged pancreas. Retroperitoneal fibrosis ("sclerosing retroperitonitis"): idiopathic, ergot misuse. Pseudomyxoma peritonei: mucin-secreting, low-grade adenocarcinoma throughout the peritoneum. The primary is usually in the appendix, ovary, or pancreas. Sorting out food poisoning: A guide for future physicians and victims You ingested a bug that then made toxin E. coli Water, tacos from street vendors, anything else. Diarrhea in 24-72 hours. C. perfringens Ill-cooked food. Diarrhea in 8-14 hours. Vibrio cholerae Epidemic. Really bad diarrhea. This can kill anybody unless their fluids and electrolytes are managed. Vibrio parahemolyticus The raw oyster bug. Vomiting, diarrhea, fever in 8-96 hours. You ingested a bug that then invaded Salmonella Water, poultry, shellfish, most anything else. Fever, vomiting, diarrhea in 8-24 hours. E. coli Enteroinvasive type. Diarrhea in 8-96 hours. You ingested pre-formed toxin Staph. aureas Dairy products, custards. Impressive vomiting / diarrhea in 2-4 hours. Ever had it? Betcha you have. Beware, toxin is heat-stable. Bacillus cereus The fried-rice bug. Vomiting / diarrhea in 2-14 hours. Beware, toxin is heat-stable. C. perfringens as above. C. botulinum Sausage, ill-canned goods. Paralysis in 24-96 hours. This can kill you. Liver words: (1) Asterixis: liver flap of hepatic encephalopathy, probably from octopamine rather than ammonia; (2) bile acids / salts: cause the itching of cholestatic jaundice; (3) bridging necrosis: from the portal to the central areas; (4) chronic active hepatitis: inflammation plus piecemeal necrosis plus fibrosis, lasting six months or more; will lead to cirrhosis; (5) chronic persistent hepatitis: lymphocytes in the portal areas for more than six months, without necrosis or fibrosis; (6) Councilman body: apoptotic hepatocyte in hepatitis; (7) Giant mitochondria: alcoholism; (8) ground glass cell: homogeneous cytoplasm seen in hepatitis B infection; (9) limiting plate: the row of hepatocytes next to the portal area; it should be uniform and smooth; (10) lobular disarray: sign of acute hepatitis; the liver cords are indistinguishable; (11): Piecemeal necrosis: death of groups of cells in the limiting plate; (12): Cirrhosis: enough scarring of the liver to disrupt or scramble the normal blood circulation within the liver; there will be regenerative nodules of hepatocytes; (13) Peliosis: dilated veins, as in anabolic steroid use Hepatocytes regenerate, but disrupted stroma doesn't. Causes of jaundice: TOO MUCH BILIRUBIN BEING PRODUCED ("hemolytic jaundice") "Ineffective hematopoiesis", i.e., normoblasts dying in the bone marrow Thalassemias Megaloblastic anemias Intravascular hemolysis (many, many kinds) Extravascular hemolysis Big hematomas GI bleeding Red infarcts LIVER FAILS TO TAKE UP AND/OR CONJUGATE BILIRUBIN ("hepatocellular jaundice") Newborns Hypoperfusion Bad alcoholism Hepatitis (many causes) Cirrhosis (many causes) Gilbert's non-disease, the Crigler-Najjar syndromes LIVER DOESN'T SEND BILIRUBIN TO THE RIGHT PLACE ("cholestatic jaundice") Problems with the liver cells Drugs (estrogen, anabolic steroids) Dubin-Johnson (pigmented) non-disease Rotor (non-pigmented) non-disease "Benign familial recurrent cholestasis" Really bad cases of other liver diseases (hepatitis, cirrhosis, alcoholism; i.e., when the liver fails, the picture is likely to be mixed) Problems with the bile ducts in the liver Biliary cirrhosis Biliary atresia Problems with the bile ducts beyond the liver (call a surgeon) Gallstone in the common duct Cancer (i.e., biliary, pancreatic, ampullary) Iatrogenic (i.e., the surgeon nicked the common bile duct) In bile duct obstruction, expect clay-colored stools, smelly steatorrhea. Liver failure: Hypoalbuminemia, high ammonia, coagulopathy (VII goes first), fetor hepaticus smell, hepatorenal syndrome (kidney fails yet retains sodium), bad hypotension. Shock and heart failure from any cause produce central hepatic necrosis, raising enzymes ("ischemic hepatitis"); this regenerates upon recovery. "Cardiac sclerosis" is longstanding scarring, usually from tricuspid insufficiency. Hepatic necrosis: Central: Ischemia, carbon tetrachloride, chloroform, acetaminophen Mid-zonal: Yellow fever. Peripheral necrosis: Phosphorus, eclampsia Acute hepatitis histology: lobular disarray, lysis of liver cells individually or in small groups, Councilman bodies, some inflammatory cells, prominent Kupffer cells, regenerating hepatocytes. Massive necrosis ("acute yellow atrophy", unlucky hepatitis B, some poisonings): apoptosis of all hepatocytes. Cirrhosis: Problems include liver failure and portal hypertension (varices, caput medusae, hemorrhoids, ascites) because of the scrambled blood flow in the liver. Size of the regenerative nodules: <3 mm: Micronodular (cause involved all lobules uniformly, i.e., alcohol, hemochromatosis, primary biliary cirrhosis, other biliary tract disease; >1 cm: macronodular (hepatitis B or C, autoimmune lupoid hepatitis). Either pattern: Wilson's, galactosemia, antitrypsin deficiency. Post-necrotic cirrhosis: it's mostly scar. Hepatitis A: non-lethal, fecal-oral route, enterovirus; IgM is acute antibody, IgG means old infection; vaccine finally available. Hepatitis B: blood-borne, very infectious. You already have a chart; here's the antigens and antibodies.... HBsAg ("Australia antigen"): Surface antigen. Envelope protein. HBcAg: Core antigen. Nucleocapsid. Stays in liver nuclei, will not see in blood. HBeAg: Another nucleocapsid antigen, which means the virus is being replicated; marker for seriousness and infectivity. HBsAg first appears in the blood shortly before symptoms begin (if they are to begin). It remains in the blood for the duration of the infection, whether it is acutely symptomatic, slowly- progressive / subclinical, or merely the carrier state. HBeAg appears in the blood just after HBsAg, and before symptoms start. It remains as long as there is acute viral replication, marker for being very contagious, and disappears if (and only if) viral replication stops. The patient is still sick when HBeAg disappears, but can take comfort in the good news. Anti-HBeAg appears soon after viral replication and HBeAg production stop (if they stop). The patient can still be sick, but this is another piece of good news. Anti-HBcAg, in its IgM form, appears in the blood typically before symptoms begin, and generally remains present for years (IgG anti- HBcAg will eventually take over, maybe). If a person with clinical hepatitis has cleared his blood of HBsAg, but has not yet developed detectable anti-HBsAg, the presence of IgM anti-HBcAg confirms that the infection is, indeed, hepatitis B and is in the core window. Anti-HBsAg generally appears when the infection is pretty much over, and is a sure sign of recovery. Treat chronic persistent hepatitis B with masterful inactivity, chronic active hepatitis B with interferon. Hepatitis D: An incomplete virus only capable of causing disease in the presence of hepatitis B. Hepatitis C: Same routes of transmission as hepatitis B, not so catching. Antibody does not clear the infection; liver disease smolders for decades and may turn to cirrhosis. Hepatitis E: Water-borne, not much in the U.S. Autoimmune "lupoid" hepatitis: Chronic active hepatitis, perhaps triggered by virus or drugs; anti-smooth muscle autoantibodies. Primary biliary cirrhosis: Destruction of the small bile ducts, leading to scarring and cirrhosis; bad cholestasis causes itching from bile salts; anti-mitochondrial antibodies (i.e., anti pyruvate dehydrogenase). Cholangitis: Usually ascending, often E. coli; underlying cause is biliary obstruction. Polys in the bile ducts. May lead to liver abscess; do not confuse with (minimally-inflamed) amoebic abscesses. "Sir, I have known more old drunkards than old doctors." -- Dr. Rabelais Alcoholic liver disease: Fatty change after a case of beer, alcoholic hepatitis (Mallory bodies, neutrophils, giant mitochondria, necrosis, possible portal hypertension and/or liver failure) while on a drunk, cirrhosis (maybe) after many years of heavy abuse. Iron overload: Primary hemochromatosis is caused by too much iron being absorbed by the duodenum, autosomal dominant (one dose, mild) or recessive (two doses, severe), gene in HLA complex. Secondary hemochromatosis is from hyperabsorption of iron in hemolyzers, or in the over-transfused. Problems include liver cirrhosis, heart rhythm disturbances and cardiomyopathy, "bronze" diabetes, arthritis (knuckles), lost libido, skin pigment change, hepatocellular carcinoma. Porphyria cutanea tarda from inhibition of porphyrin synthesis in those carrying the gene. Treat primary hemochromatosis by phlebotomy. Wilson's: Autosomal recessive, cannot dispose of copper via the bile. Copper overload in liver and basal ganglia. Liver failure, mental changes, hemolysis. Other liver poisons: Toadstools, halothane, huge doses of acetaminophen (massive necrosis); old tetracycline (fatty change); isoniazid, methyldopa, many others (hepatitis). Reye' syndrome: poorly-understood syndrome, follows viral infection (especially if aspirin was given) in kids. Cerebral edema, extreme elevations of serum ammonia, hepatic fatty change and failure; evidence of generalized mitochondrial failure. Biliary atresia: Grim birth defect; these kids get transplants. Neonatal hepatitis: Many causes. Antitrypsin deficiency, CMV, bad cystic fibrosis, galactosemia, hepatitis A, hepatitis B, herpes simplex, syphilis, toxoplasmosis, total parenteral nutrition. Look for giant multinucleated hepatocyte formation. Liver cell adenomas: Sex hormones (oral contraceptive pill, gym steroids), prone to rupture. Hepatocellular carcinoma ("Mickey Mantle's disease"): risk factors are iron overload, hepatitis B and C, aflatoxin, old radioactive studies ("thorotrast"). Invades portal vein and obstructs it. Hepatocellular carcinoma is a dominant, non-umbilicated mass in a cirrhotic liver. Metastatic carcinoma is several umbilicated masses in a non-cirrhotic liver. Hepatic angiosarcoma: Vinyl chloride exposure in industry. Cholangiocarcinoma: cancer of biliary ducts, always a desmoplastic adenocarcinoma. Klatskin tumor plugs the junction of the hepatic ducts. Cholestasis. Gallstones: Don't trust the fat, fair-skinned, fertile, female, fortyish stereotype, anybody can have them. Cholesterol stones (yellow) are poorly understood. Bilirubinate stones (black) suggest ongoing hemolysis. Gallstones cause acute and chronic cholecystitis, may plug cystic or common bile duct, erode into duodenum ("gallstone ileus" or at least a fistula), cause gallbladder cancer. Courvoisier's law: Obstructive jaundice plus palpable gall bladder: cancer of the pancreas. Obstructive jaundice plus non-palpable gall bladder: common duct stone, because the scarred-up gallbladder cannot expand. Acute cholecystitis: probable cause is ischemic damage to the mucosa from gallstones (pressure, straining to push them out); lysolecithin compounds the damage, bacteria may supervene. Chronic cholecystitis: hypertrophied muscular wall, pseudodiverticula ("Rokitansky-Aschoff sinuses"). Acute pancreatitis: Alcohol (reflux of duodenal contents up pancreatic duct?), common duct stone, trauma; milder in mumps, hyperlipidemia I and V. Elevated amylase and lipase; fat necrosis, hypocalcemia (calcification of fat), hemorrhage (elastase). "Chronic pancreatitis": scarring after acute pancreatitis, pain syndrome from nerve involvement, pseudocyst formation. Cancer of the pancreas: Adenocarcinoma. Risk factors include cigarette smoking, maybe chemicals (garage mechanics). Back pain, jaundice, weight loss, depression, diabetes (amylin production by the tumor), Trousseau's migratory thrombophlebitis; Whipple procedure (your only chance for a cure) and death. Diabetes mellitus (MELL-uh-tuss, please): Systemic problems from glucose intolerance. Type I primary diabetes: autoimmune destruction of the islets by antibody-influenced T-cell mediated cytotoxicity; strikes at random. Type II primary diabetes: insulin resistance plus disordered insulin secretion; genetically programmed disease modifiable by lifestyle (known genetic synromes include maturity-onset diabetes of the young, which is mutant glucokinase, and some others). Secondary diabetes: from some other obvious disease, like Cushingism, cancer of the pancreas, hemochromatosis, acromegaly, severe pancreatitis damage. Gestational diabetes is a special case. The ultimate trivia question: eosinophils abound in the island of Langerhans in the children of diabetic mothers. Complications of diabetes: (1) ketoacidosis (mostly type I's), with osmotic diuresis from high glucose and ketone levels; (2) hyperosmolar nonketotic coma (mostly type II's, insulin reserve gives up and massive hyperglycemia causes diuresis); (3) accelerated atherosclerosis (stroke, gangrene, heart attack); (4) microvascular disease (hyaline arteriolar sclerosis, makes gangrene worse); (5) liability to bacterial infections (neutrophils slow down in hyperglycemia); (6) neuropathy: from accumulation of sorbitol, pain and dysautonomia; (7) retinopathy (microaneurysm, exudates, bleeds, later proliferation of vessels and blindness); (8) sorbitol cataract; (9) nephropathy ("glomerulosclerosis", thick glomerular basement membrane, nodular Kimmelstiel-Wilson disease, kidney infections); (10) reduced capillary lipoprotein lipase, which is insulin-dependent; this raises lipoproteins. Non-enzymatic glycosylation of proteins (as with HgbA1c) is important in most of these. Hypoglycemia: post-prandial "hypoglycemia" is really due to an overly brisk epinephrine response. Fasting hypoglycemia is suspicious for insulinoma; also consider addisonism, von Gierke's, secret insulin injection, some others. Glucagonoma: dermatitis, glossitis, diabetes. VIPoma (vasoactive intestinal peptide): Pancreatic cholera. Gastrinoma: Zollinger-Ellison ulcers. Kidney is my favorite area and I'll restrain myself. The seven renal syndromes: 1. NEPHRITIC SYNDROME. An inflamed glomerulus. Hematuria, oliguria, hypertension, mild edema, azotemia. Prototype is post- streptococcal glomerulonephritis, remember also lupus IV. 2. NEPHROTIC SYNDROME. A glomerulus leaking protein. Heavy proteinuria (selective for albumin, or not), hypoalbuminemia, high LDL, severe edema, fatty casts in urine. Causes are foot process disease (i.e., minimal change disease = nil disease = lipoid nephrosis, focal-segmental glomerulosclerosis), diabetes, amyloidosis, membranous glomerulopathy. 3. RAPIDLY-PROGRESSIVE GLOMERULONEPHRITIS. Severely injured glomeruli leaking fibrin, producing crescents. Nephritic syndrome becomes renal failure in a few weeks. Goodpasture's, bad immune- complex disease, Wegener's / polyarteritis. 4. FANCONI SYNDROMES. The proximal tubule is alive but incapable of reabsorbing some or all of the things it should. You lose things in the urine. Birth defects, cadmium poisoning, others. 5. LOOP FAILURE. The loop of Henle is damaged, urine cannot be concentrated, nocturia. 6. ACUTE TUBULAR NECROSIS: Dead tubules (mostly proximal tubule). Seen in shock, poisoning (drugs, remember the aminoglycosides and the NSAID family), pigment (hemoglobin or myoglobin free in bloodstream). Dead cells plug the tubules, glomerular filtrate leaks back. Oliguria, isosthenuria, azotemia. Recovery passes through a diuretic phase, with intact tubules (i.e., no backleak) unable to function (i.e., no reabsorption of glomerular filtrate). 7. RENOVASCULAR HYPERTENSION: Narrowed arteries cause ischemia of the glomeruli, leading to renin release and hypertension. A vicious cycle; all hypertension damages and narrows the small renal arteries. "Goldblatt hypertension". Azotemia: high BUN and creatinine. Uremia: symptomatic kidney failure. Volume overload, hypertension, heart failure, pulmonary edema, metabolic acidosis (sulfate, phosphate), calcium problems (cannot active vitamin D), phosphate retention, metastatic calcification, secondary hyperparathyroidism, osteomalacia, fibrinous pericarditis, platelet failure, mild anemia (no erythropoietin), nausea and vomiting, GI bleeds, pruritus, uremic frost (urea crystals), yellow color, peripheral neuropathy, amyloidosis H, general unhappiness. Cystic renal dysplasia: failure of drainage during intrauterine life, fibrous tissue, tubules, and cartilage. Autosomal recessive polycystic kidney: babies, cysts like daisy petals; uremia. Autosomal dominant polycystic kidney: football-sized kidneys, masses of cysts like grapes; hypertension progressing to renal failure in later life. Medullary sponge kidney: small cysts, place for kidney stones to form. End-stage kidney ("acquired dialysis cystic disease"): shrivelled kidney, breeding-ground for renal cell carcinoma. Hemolytic-uremic syndrome: When the cause is known, it's verocytotoxin from E. coli or Shigella ("Jack in the Box" undercooked hamburgers); endothelial cell damage with accumulation of platelet debris, plugging glomeruli and disrupting red cells. Acute pyelonephritis usually from E. coli swimming up from the bladder. Honeymoon cystitis, stones, diabetes, pregnancy, reflux. Chronic pyelonephritis: scar contraction, tubular atrophy, "thyroidization". Papillary necrosis: Phenacetin abuse, sicklers, diabetes. Urate nephropathy: Tubular failure in gout. Oxalate nephropathy: Tubular failure in vitamin C abuse or antifreeze drinking. Myeloma kidney: Bence-Jones protein plugs tubules. "Benign essential high blood pressure": variable mix of overworking heart, excess renal sodium retention, inappropriate vasoconstriction. Still mysterious, but causes encephalopathy (seizures, headache), heart failure, hyaline arteriolar sclerosis, intimal fibrosis, accelerated atherosclerosis, brain hemorrhages. "Malignant hypertension": hypertension from any cause leading to vascular necrosis, worse hypertension, and rapid death; heralded by papilledema. Endocrine secondary hypertension: Cushingism, Conn's, salt-retaining adrenal hyperplasia, pheochromocytoma, reninoma, hypercalcemia (constricts vessels), licorice abuse (inhibits 11-beta hydroxylase); diabetes contributes. Poorly-perfused kidney causing hypertension: most renal diseases, coarctation of the aorta, stenotic renal artery from atherosclerosis or other disease. Widened pulse pressure: Stiff aorta (atherosclerosis, Monckeberg's), aortic valve insufficiency, Hydronephrosis: dilated renal pelvis from any cause. Kidney stones: Most are calcium oxalate, i.e., somebody who absorbs too much calcium via the gut and/or drinks too little water. Cystine stones: hereditary inability of the proximal tubule to resorb cystine properly; hexagons in the urine. Magnesium ammonium phosphate stones: Proteus infection, coffin-lid crystals in the urine. Nephrogenic diabetes insipidus: Inability of the collecting duct to respond to hADH. Pseudohypoparathyroidism: inability of the proximal tubule to respond to parathyroid hormone. Casts are kidney boogers. Hyaline casts mean nothing. Red cell cast mean glomerulonephritis. White cell casts mean pyelonephritis. NOTE: Do not worry right now about changes in blood chemistry (blood urea nitrogen, creatinine, creatinine clearance, etc.). Except for glycosuria, hematuria, proteinuria, pyuria, and casts, do not worry at all about other abnormalities found on urinalysis. You will learn about these soon enough. Vocabulary One thing that makes kidney pathology so hard is that many of the words sound alike. Here are the most troublesome words: Collagenized glomeruli: These glomeruli have been obliterated by dense type I collagen. Most often, the collagen has been laid down concentrically on Bowman's capsule, as in longstanding arterial/arteriolar disease. Collagenized glomeruli are more often called hyalinized or obsolescent, despite the fact that these terms are less specific. Diffuse: As applied to glomerular disease, all the glomeruli are involved. Fibrosis: Dense, type I collagen deposited in the glomeruli and/or interstitium and/or vessels. Focal: As applied to glomerular disease, some glomeruli are involved and some are not. Global: As applied to glomerular disease, if a glomerulus is involved, all portions of it are involved. Glomerulonephritis: As usually used, this implies that the glomeruli are sufficiently inflamed to cause at least a few of them to lose blood into the tubules. ("Glomerulonephritis" without nephritic syndrome -- i.e., "membranous glomerulonephritis", "minimal-change glomerulonephritis", etc. -- is a less-common usage. Better to call these "glomerulopathy".) Glomerulopathy: Any primary problem with the glomeruli. Glomerulosclerosis, diffuse: Thickening of the basement membrane as a result of diabetes mellitus. Glomerulosclerosis, focal/segmental: A pattern of injury with foot process fusion and hyalinization of some lobules in some glomeruli. It has nothing to do with diabetes mellitus. Glomerulosclerosis, nodular: Diabetes mellitus with Kimmelstiel-Wilson disease. Always superimposed on diffuse glomerulosclerosis. *Hyalinosis: A distinctive, homogeneous pink blob seen in certain sick glomeruli, notably those damaged by FSGS, diabetes, or other causes of hyperfiltration. Hyalinized glomeruli: A term which can mean collagenized or sclerotic glomeruli. Hypernephroma: Obsolete term for renal cell carcinoma. Nephritis: Used by itself, this means "glomerulonephritis". Nephritis, interstitial: Inflammation of the kidney that spares the glomeruli. Includes cases formerly diagnosed as "chronic pyelonephritis". Causes U-shaped cortical scars. Nephroblastoma: The common childhood cancer of the kidney -- Wilms tumor. Nephrocalcinosis: Calcification of the basement membranes of the tubules in the medullae. It has nothing to do with calcium stones. A little calcification here is common, especially in older people. Extensive calcification suggests hypercalcemia ("metastatic calcification"). Nephrolithiasis: Stones (calculi) in the pelvis of a kidney Nephropathy: Anything wrong with the kidney -- glomeruli, tubules, or vessels. Nephrotic syndrome: The sequelae of heavy protein leakage at the glomerular capillaries. Nephrosclerosis: Disease of the renal arteries and/or arterioles. Nephrosclerosis, arterial: Multiple small infarcts destroying scattered groups of glomeruli. Causes V-shaped cortical scars. Usually caused by atheroembolization. Nephrosclerosis, arteriolar: Vascular disease that destroys scattered individual nephrons. Causes sandpaper-surface kidney. "Benign nephrosclerosis". Caused by high blood pressure and/or diabetes. Nephrosclerosis, benign: Arteriolar nephrosclerosis due to "benign essential hypertension". Obsolescent glomeruli: Another term which can mean collagenized or sclerotic glomeruli. Pyelonephritis: Inflammation of the interstitium of the kidney. Current usage mostly limits this to bacterial infection. Sclerosis: As applied to kidney, this means increased basement membrane/mesangial matrix material obliterating loops of a glomerulus. Sclerotic glomeruli: These glomeruli are fully replaced by basement membrane/mesangial matrix material, as in advanced diffuse, nodular, or focal-segmental glomerulosclerosis. They are also called hyalinized or obsolescent. Segmental: As applied to glomerular disease, some portions of some glomeruli are involved and some other portions of the same glomeruli are spared. Here is a list of the more important entities that are likely to be associated with a particular pattern; if you didn't learn them then... Subepithelial, large, irregularly-spaced ("coarse granules") Diffuse proliferative GN (especially post-streptococcal) Mesangiocapillary (membranoproliferative) GN type I (tramtracks) Lupus, class IV Subepithelial, uniform, evenly-spaced ("fine granules evenly spaced") Membranous glomerulopathy (any cause) Lupus, class V Anti-GBM diseases ("smooth linear" -- don't expect to see these on EM) Goodpasture's, others Subendothelial (various descriptions, you will only need to recognize on EM) Mesangiocapillary (membranoproliferative) GN type I (tramtracks) Lupus, especially class IV ("wire loops") Cryoglobulinemia Hemolytic-uremic syndrome ("fluff") Also look here for amyloid deposits. Intramembranous (various descriptions, depends on the disease) Dense deposit disease (mesangiocapillary GN type II) Late membranous glomerulopathy Late stages of any other progressive immune complex disease Mesangial ("mesangial pattern") IgA nephropathy IgM mesangial-proliferative glomerulopathy * Mesangiocapillary (membranoproliferative) GN type I Lupus, any class Also look here for amyloid deposits. Renal cell carcinoma: Common kidney cancer, "hypernephroma", "Grawitz tumor", 3p deletion, failed kidney, von Hippel Lindau and smoking are risk factors, yellow mass, cells rich in lipid and glycogen, invades renal vein and vena cava. Wilms tumor: Pediatric tumor of primitive kidney, mixed carcinoma- sarcoma histology is common, syndrome with aniridia and hemihypertrophy; good response to chemotherapy. Angiomyolipoma of the kidney is a tuberous sclerosis hamartoma; transitional cell carcinoma mirrors common bladder cancer. Exstrophy of the bladder: failure of the symphysis to close; runs with epispadias. Persistent urachus: urine out the navel. Cystocele: drooping bladder, as after childbirth. Hypertrophy of bladder wall: from obstruction, usually prostatism. Bladder diverticula: usually from mucosa going between bands of hypertrophied muscle. Bladder stones: usually magnesium ammonium phosphate, from proteus infection. Cystitis: Young women (short urethra, intercourse, etc.), older men (prostatism). Cyclophosphamide, Hunner's idiopathic interstitial ulcerative cystitis, and radiation are other causes of inflamed bladder. Squamous metaplasia: schistosoma hematobium. Hyperplasia of transitional epithelium: More than eight nuclear layers. Papillomas: benign seaweed-like tumors. Transitional cell carcinoma: the common bladder cancer; risks are smoking, aniline dye exposure, phenacetin abuse, cyclophosphamide exposure. Adenocarcinoma: from urachal remnants. Squamous cell carcinoma: schistosomiasis. I used to pray, "Lord, give me chastity, but not yet." -- St. Augustine, Confessions While you are away, movie stars are taking your women. Robert Redford is dating your girlfriend. Tom Selleck is kissing your lady. Bart Simpson is making love to your wife. -- "Baghdad Betty", Iraqui disk jockey, during the Gulf War Hypospadias: urethral opening somewhere short of the end of the glans. Epispadias: urethral opening on the dorsum of the penis, more serious. Phimosis: tight foreskin. Balanoposthitis: dirty infected glans from tight foreskin. Paraphimosis: foreskin is retracted, flips back and gets stuck. Priapism: persistent, non-pleasurable erection, usually from blockage of corpora veins, as in sicklers. Peyronie's: mysterious fibrosing process causing curved erection. Urethritis is gonococcal, chlamydial, mycoplasma, Mexican peppers. Lymphogranuloma venereum: wicked chlamydia producing watering-can perineum, ask about a Frei skin test. Gonorrhea's probably meaner because it produces an IgA- destroying enzyme. Reiter's: usually chlamydial urethritis which gives rise (somehow) to arthritis, conjunctivitis, horny rash on glans, palms and soles, low back pain in HLA-B27 men. Cancer of the penis: HPV- related, almost all are uncircumcised. Erythroplasia and Bowen's: premalignant. Cryptorchidism: nobody knows why they fail to descend; high rate of malignant change, risk of torsion, infertility. Torsion of testis: cremaster spasm leads to venous infarct. TB, gonorrhea, chlamydia: epididymitis; syphilis, mumps: orchitis. Hydrocele: fluid in the tunica vaginalis. Varicocele: varicose veins in the pampiniform plexus. Germ cell tumors are often mixed. Seminoma: fried egg cells, lymphocyte, excellent response to radiation or chemotherapy. Embryonal cell carcinoma: anaplastic carcinoma, alpha-fetoprotein. Choriocarcinoma: hCG, very malignant, mix of malignant cytotrophoblast and malignant syncytiotrophoblast. Prostatitis: gonorrhea, common bacteria, trichomonas, chlamydia. Prostatic hyperplasia ("benign prostate hypertrophy"): mysterious process that all intact, surviving men get sooner or later; heroic abstinence is a risk factor. Hyperplasia of glands and stroma especially periurethral; obstruction causes difficulty with urination, frequency, urgency, dysuria, residual volume, infection, renal shutdown. Every man is sitting on a time bomb #1. Prostate adenocarcinoma: Common prostate cancer. Risk factors include cadmium exposure. "Most commonly starts in posterior lobe", i.e., probably because that's where the doctor feels it first. Markers: prostatic acid phosphatase, prostate-specific antigen. Treatment includes hormonal manipulations. "If I were asked to what the singular prosperity and growing strength of [the Americans] ought mainly to be attributed, I should reply, "To the superiority of their women". -- Alexis de Tocqueville 1789 "Not from Adam's brain, to have the same mind as him, nor from Adam's foot, to be subordinate to him, but from the rib next to Adam's heart, to love and be loved by him." -- Anonymous Vulvar dystrophy includes lichen sclerosus (mysterious atrophy of the mucosa over dense collagen; male counterpart is balanitis xerotica) and squamous hyperplasia-dysplasia (mysterio