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PATHOLOGY MELTDOWN up and down

General Pathology



Cytopathic virus: Causes morphologic change when it hijacks the genome.

Cytolytic virus: Destroys the cell. Inclusion body: Any new kind of

intracellular structure, visible by light microscopy, that results from

disease. Viral inclusions are masses of viruses getting made.



Herpes simplex & zoster swollen nuclei (often several in one

cell) with a single, large intracellular

inclusion.



Cytomegalovirus huge cells with one enormous intranuclear

inclusion and often several small

intracytoplasmic inclusions.



Rabies eosinophilic intracytoplasmic Negri

bodies



Measles multinucleated epithelial giant cells

with herpes-like inclusions in the nuclei

(Warthin-Finkeldey cells)



Free radical: Has an unpaired electron, capable of setting off a chain

reaction which damages many molecules. They cross-link unsaturated

fat, mutate genes, cross-link sulfhydryls. Hydroxyl radicals result

from ultraviolet rays hitting water. Iron turns H2O2 into two hydroxyl

radicals. White cells generate free radicals to kill bacteria. Our

own drug-metabolizing systems turn some molecules (acetaminophen,

carbon tetrachloride) into free radicals. Too high an oxygen

concentration damages the lungs using superoxide. Endogenous

antioxidants include melatonin, vitamins C and E, glutathione,

glutathione peroxidase, selenium, ceruloplasmin, transferrin, and the

enzyme superoxide dismutase.



Apoptosis: \"Shrinkage necrosis\"; \"individual cell necrosis\"; \"cell

suicide.\" A cell activates a program that slices-and-dices its DNA

(\"endonuclease\"), cross-links its proteins (\"transglutaminase\"), and

dissolves its cytoskeleton (\"calpain\"). Embryogenesis, skin-cell and

gut-epithelium shedding, a woman\'s monthly cycle, elimination of

autoreactive or no-longer-useful immune cells, all forms of atrophy,

suicide on a T-cell\'s instructions (hepatitis, graft-vs.-host, many

others), suicide of a cell with an injured genome (p53-mediated),

hypoxia or cell injury insufficient to produce frank necrosis of a

large group of cells. This is the only kind of necrosis in which there

is no inflammation. \"Apoptotic bodies\" are eaten by macrophages (in

liver these are \"Councilman bodies\"). The fas receptor in cell

surfaces, when stimulated, activates the suicide program. This is the

only kind of necrosis where there\'s not going to be any inflammation.



Poison: Some of the less-subtle ones include mercury and arsenic (bind

sulfhydryl groups), cyanide (binds cytochromes, instant hypoxia),

carbon monoxide (binds hemoglobin so oxygen cannot be carried by it),

and molecules which are turned into free radicals by the body

(acetaminophen overdose, carbon tetrachloride). First law of

pharmacology: \"All drugs are poisons, all poisons are drugs.\"



Necrosis is visible evidence of cell death. In hypoxic injury, the

cell is dead long before necrosis is visible. The nucleus shrivels and

darkens until there is no more euchromatin (pyknosis), then fragments

(karyorrhexis), then vanishes (karyolysis).



Coagulation necrosis: The usual pattern of necrosis in poisoning or

hypoxia. Cytoplasm becomes hyper-eosinophilic, and the nuclear changes

appear. The cells persist as cell ghosts.



Liquefaction necrosis: The cytoplasm liquefies, at least in a few days.

(1) Hypoxia of the brain, provided it\'s been severe enough to kill the

glia as well as the neurons; (2) gas gangrene, i.e., clostridial

infection with bacterial enzymes hydrolyzing the tissues; (3) bacterial

infections that bring so many neutrophils to an area that their enzymes

hydrolyze the tissue. Situation (3) is called \"suppuration\" and the

result is \"pus\".



Caseous necrosis: Dead cells crumble into a pasty powder (\"cheesy\").

Effected by tumor necrosis factor on the body\'s tissues, in the

presence of waxes from certain micro-organisms, notably the

tuberculosis bacillus and some fungi (histoplasmosis, blastomycosis).



Enzymatic fat necrosis: Lipase from damaged pancreas digests

triglycerides; freed fatty acids precipitate with calcium as hard-water

soap (like in my bathtub ring).



Traumatic fat necrosis: misnomer for what happens after a blow disrupts

a group of fat cells; likely to scar up and calcify.



Fibrin: The body\'s sealant. Fibrinoid: A mix of fibrin and other

proteins, typically immunoglobulin and complement, pushed into the

walls of injured arteries when the endothelium is perforated.

Fibrinous: made mostly of fibrin. Fibrous: Made of collagen. \"Fibrin

is a scab. Collagen is a scar.\"



Collagen types to know:

I: Dense collagen

II: Cartilage

III: Reticulin

IV: Basement membrane



Gangrene: Necrosis that somebody can see grossly and that looks ugly.

Wet gangrene: It\'s infected by clostridia that are hydrolyzing, phew.

Dry gangrene: It\'s dried up and cannot be hydrolyzed. Autolysis:

Tissues self-destruct because of no blood flow, i.e., after death.

Heterolysis: Tissues get digested by another cell, usually neutrophils.

Putrefaction: Bacteria digest dead tissue.



Aplasia / agenesis: Never grew at all. Hypoplasia: Never grew to its

normal size. Local gigantism: Self-explanatory, but usually

mysterious. Syn-: Fused. Holo-: Never divided. Atresia: The hole

never formed. Stenosis: The hole is too narrow. Occlusion: Something

is blocking the hole. Ectopia: Good stuff, but in the wrong place.

Choristoma: An ectopia that actually forms a visible mass. Hamartoma:

The right tissue components, but scrambled (birthmarks, cartilage

hunks, etc.) Fistula: An abnormal, epithelialized communication

between two surfaces. Sinus: An (abnormal) opening onto a surface.

The Law of Epithelium: It does not tolerate a free edge. Diverticulum:

All three layers of the wall of a hollow organ are outpouched.

Pseudodiverticulum: The mucosa outpouches through a weak spot in the

muscular wall (\"diverticula\" of the colon and upper esophagus,

Rokitansky-Aschoff \"sinuses\" of the chronically inflamed gallbladder).

Cyst: abnormal, fluid-filled, epithelially-lined, and closed. Spasm:

Inappropriate, prolonged contraction of any muscle.



Atrophy: The organ shrank, because (1) the cells shrank (typical of

endocrine-sensitive or work-responsive tissue like gland and skeletal

muscle) and/or (2) the cells died off (apoptotic, typical of brain);

lack of blood supply can cause either kind of atrophy. Aplastic

anemia: A bad term for marrow cells dying off. Cachexia: Wasting of

body tissues, muscle more than fat, typically as a result of cancer or

any disease with overproduction of certain cytokines. Hyperplasia: An

organ became larger because of increase in the number of normal cells;

many examples. Hypertrophy: An organ became larger because its cells

became larger; only a few examples (athletes\' hearts, hypertensive

folks\' hearts, aortic valve stenosis, weight-lifters). Hypertrophy and

hyperplasia together: The pregnant uterus, an overstimulated endocrine

gland. Metaplasia: Transformation of one good cell type into another.

Dysplasia (\"intra-epithelial neoplasia\"): Replacement of a normal type

of tissue (usually epithelium) with bizarre cells which are not

invading. Carcinoma-in-situ: Bad dysplasia. Anaplasia: Bizarre cells,

typically lying topsy-turvy, with dark nuclei, frequent mitoses, and

high nuclear-cytoplasmic ratio; whether or not they are invading

(cancer) or not invading (dysplasia, \"carcinoma in situ\"). Neoplasia =

tumor: A new, worthless organ, i.e., a clone of abnormal cells has

figured out how to induce its own connective tissue stroma and blood

supply. Benign tumor: It will stay localized. Malignant tumor: It has

the ability, now, to spread to another site, and set up a metastasis.

A pathologist distinguishes benign from malignant tumors by several

means, including the presence of anaplasia in, and only in, the latter.



Anaplastic? A mass?

Dysplasia yes no

Cancer yes yes

Benign tumor no yes



Nowell\'s law / \"tumor progression\" / clonal evolution: Tumors arise

from selection of mutated clones with a tendency to overgrow their

neighbors. This happens again and again, so a tumor is a clone derived

from a clone derived from a clone derived... The genes that mutate are

the proto-oncogenes (mutated=\"activated\" into oncogenes, one copy being

sufficient to turn a cell bad), and the antioncogenes = \"tumor

suppressor genes\", both copies of which must be destroyed=\"inactivated\"

to turn a cell bad. Hypertrophy, hyperplasia, and atrophy typically

are mediated by these genes, functioning as they should. Metaplasia

can result either from these genes reacting properly to stimuli

(hormones, tobacco smoke), or being mutated, or having their products

inactivated by viruses (human-papilloma virus effect, for example).

Dysplasia indicates some serious genetic damage.





Hematoxylin stains nucleic acid (nuclei, abundant rough endoplasmic

reticulum), bacteria, and calcium blue. Eosin stains protein (arginine

and lysine) molecules pink. PAS stains insoluble carbohydrates

(glycogen, cartilage, fungi, mucin, basement membrane, alpha-1 protease

inhibitor, a few others not-so-strong) magenta; d-PAS stain is used to

prove something PAS-positive is, or is not, glycogen. Acid-fast stains

selectively stain mycobacteria. Sudan and oil-red stains demonstrate

lipid phases. Mucicarmine is for epithelial mucin. Trichrome stains

dense collagen blue. Immunostains turn a particular protein brown

(immunoperoxidase) or fluorescent (immunofluorescence).



Glycogen accumulates in various organ in glycogen storage disease, in

the nuclei of hepatocytes of those with hyperglycemia, and in the renal

tubules of those with heavy-duty glycosuria.



Fatty change is too much fat in business cells which shouldn\'t

ordinarily accumulate it; it\'s a sign that the cell is sick. The liver

in alcoholism, ischemia, and a variety of poisonings. The heart in

diphtheria (homogeneously yellow; toxin ties up carnitine) and severe

anemia (tiger-stripe). Fatty ingrowth is extra fat cells in an organ

where they don\'t usually belong. Cholesterol needles (really, plates)

are frequent findings; in semi-living tissue, think of atherosclerosis.



Hemosiderin is iron storage pigment. You diagnose it using the

Prussian Blue stain. Hemosiderosis is excess hemosiderin, at sites of

repetitive minor trauma, on the ankles of folks with varicose veins,

and so forth. Hemochromatosis is enough iron on board to make you

sick. Primary hemochromatosis usually results from a combination of

genetics (duodenum absorbs iron too well), diet (remember Bantu beer),

and being male (i.e., no menstruation, no pregnancy). Secondary

hemochromatosis results from some other disease, or from needing lots

of red cell transfusions. Ferruginous body: asbestos fiber coated with

iron. Hemozoin: malaria pigment, made by the bug to protect itself

from free radicals. Hematin: another iron-rich pigment in the spleen,

from hemolysis of any origin.



Alkapton: homogentisic acid polymer, typical of alkaptonuria

(ochronosis), premature-arthritis with the stuff in cartilage, which is

blackened.



Melanin is the familiar skin pigment. You diagnose it because it loses

its color on being exposed to hair bleach. Melanin is a tyrosine-based

polymer designed to keep you from getting skin cancer and vitamin D

toxicosis. Melanosis coli pigment usually results from heavy use of

cascara laxatives. Albinism is lack of melanin.



Bilirubin pigment generally occurs with bile plugs or bile lakes in the

liver. Jaundice: Excess bilirubin in the blood. Kernicterus: Brain

damage from high bilirubin; only babies seem to get it, and the

bilirubin must rise to maybe 20 mg/dL. Unconjugated (\"indirect\")

bilirubin is elevated in hemolysis and in conjugation defects.

Conjugated (\"direct\") bilirubin is elevated when most of the biliary

tree has become obstructed. Both are elevated in liver cell disease.

Gilbert\'s non-disease is a forme-fruste of Crigler-Najjar which affects

5% of folks and gives mildly-increased unconjugated bilirubin. The

yellow patient with jaundice has elevated blood bilirubin; if it\'s

uremia, the history and physical exam will tell you; if it\'s hyper-

carotenemia (i.e., eats carrots), palms and soles are most yellow.



Lipofuscin is an inert, wear-and-tear pigment. You diagnose it by its

location, or by process of elimination. Lots of lipofuscin in an organ

means brown atrophy.



Dystrophic calcification results from disease at the site of

calcification, i.e., in scars, in caseous necrosis, in psammoma bodies

of tumors, in scleroderma-CREST, in atherosclerotic plaques, and so

forth. Some stuff calcifies as you age (costal arches, pineal,

respiratory cartilages). Nowadays calcium gets electroplated onto

collagen during torture, a key finding in investigating human-rights

abuses. A lithopedion is a dead unborn child who calcified.

Metastatic calcification results from disease remote from the site of

calcification that has caused elevated blood calcium or phosphate;

calcium deposits in the lung alveoli, on the far-side of gastric

parietal cell, around the renal tubules, and perhaps in the elastica of

blood vessels.



Hyaline is a generic term for masses of acellular, amorphous protein.

It includes most viral inclusions, amyloid, fibrinoid, Russell bodies

(constipated plasma cells), fibrin, Mallory bodies, giant mitochondria

(alcoholism), super-dense collagen (keloids), excess basement membrane

(diabetes).



Mallory\'s hyaline is a mix of keratin and ubiquitin, usually in liver

cells, usually in response to lots of alcohol in a short time (marker

for \"alcoholic hepatitis\"). It\'s very chemotactic for neutrophils



Amyloid is beta-pleated anything. You diagnose it using Congo Red

staining, which stains it intense brick-brown; polarization shows

apple-green flashes.



Myxoid change: extra ground substance. Myxedema: generalized myxoid

change, usually from hypothyroidism. Barlow\'s syndrome, a common banal

problem, features myxoid change in the mitral valve posterior leaflet.



Mitochondrial abnormalities:

All very swollen: Reye\'s

Parking-lot crystals Mitochondrial myopathy (AZT, genetic)

Too many Hurthle cell (oncocyte)

Giant alcoholic\'s liver



Hereditary cytoskeleton problems:



Spherocytosis fragile red blood cells; lack spectrin,

ankyrin, or protein 4.1

Chediak-Higashi phagocytes show poor chemotaxis, giant

lysosomes



Storage diseases which will produce huge cells....



Gaucher\'s: glucocerebroside

Tay-Sachs\': ganglioside

Niemann-Pick\'s: sphingomyelin

Hunter\'s: \\ mucopolysaccharide

Hurler\'s: /

Fabry\'s: ceramide trihexose



The crumpled-kleenex (\"watered silk\") cells of Gaucher\'s are worth

being able to recognize.



Inflammation is the body\'s way of making war, and the analogies are

obvious. It\'s a stereotyped response of vascularized tissue to injury,

with specialized combat units, bystander casualties, and general misery

and havoc. Immunity nowadays means the activity of B-cells (\"humoral

immunity\") and T-cells (\"cellular immunity\"). Don\'t confuse

inflammation with infection, i.e., invasion by harmful bugs. -itis:

inflammation of. -osis: \"full of\" (in spite of what anyone else may

tell you).



Edema: Extra fluid outside the vessels. Unqualified, it means among

the cells. Effusion: Edema fluid in a body cavity. Transudate: Low-

protein edema, due to (1) plugged lymphatics (cancer, surgical,

filaria) and/or (2) too much total-body water (kidney failure, sodium

retention, iatrogenic) and/or (3) low plasma oncotic pressure (i.e.,

low protein as in liver failure, nephrotic syndrome, kwashiorkor,

others) and/or (4) increased venous hydrostatic pressure (varicose

veins, heart failure, occluded veins, others). Exudate: High-protein

edema, due almost always to inflammation (less often, to leaky vessels

in a cancer). Empyema: pus filling a body cavity. Hyperemia:

increased blood flow through an area because the vessels dilated, i.e.,

the reason things turn red and throb. Congestion: Increased blood in

an area because the veins aren\'t emptying, i.e., the reason things turn

blue and swell up. Nutmeg liver: Congested; liver is almost always

congested if the heart has suffered a few weak beats prior to death.

Anasarca: Horribly bad total-body edema.



Scratch yourself, and after the initial few seconds of reflex

vasoconstriction (\"Have I been deeply gashed? I guess not...\"), you

can observe the triple response of Lewis. (1) A red scratch, from

histamine. (2) A flare around the scratch, from a nerve reflex. (3)

Edema in the area, from histamine. This is how we discovered locally-

acting tissue molecules.



Acute inflammation: Vasodilatation and increased vascular permeability

to protein, plus invasion by neutrophils. Almost entirely stereotyped.

How much vessels leak depends how badly they are hurt. Mild injuries

release only albumin, producing edema which washes nasty things away.

Moderate injuries release immunoglobulin antibodies for more chemical

warfare. The worst injuries release fibrinogen, which seals damaged

vessels as fibrin.



Three ways of making vessels leak in inflammation.... Immediate-

transient response: Leaky vessels, due to histamine and prostaglandins

and leukotrienes and bradykinin and stuff. Starts right away, done in

about 30 minutes after the injurious situation is gone; immediate-

sustained-prolonged: Leaky vessels because they\'ve been damaged, lasts

until thrombosis or healing occurs; delayed-prolonged: Leaky vessels

because the cells have undergone apoptosis (sunburn, x-rays, thermal

burn).



Rubor (red) from the hyperemia. Dolor (pain) from the damage and

mediators. Calor (heat) from the hyperemia (heart\'s blood is warm).

Tumor (swelling) from edema.



Neutrophils (\"polys\") marginate, adhere (\"adhesion molecules\";

\"integrins\") to endothelium, and emigrate. Chemokinesis is increased

neutrophil random movement. Chemotaxis is directed movement.



We can\'t review bacterial killing by neutrophils here; you might want

to do this on your own. Same for the prostaglandins and leukotrienes,

both products of cyclo-oxygenase, and therefore suppressible by aspirin

and NSAID\'s.



Leaky vessels: histamine, bradykinin, leukotrienes, PGE2

Chemotaxis: Leukotriene B4; C5a; kallikrein, bugs

Opsonization: Ig, C3b

Histamine release: C3a, C5a (\"anaphylatoxins\")

Membrane attack: C5-9



Thromboxane A2, from platelets, is for when you need hemostasis. It

constricts vessels, makes platelets stick. Prostacyclin (PGI2), from

endothelium, is for when you do not need hemostasis. It dilates

vessels and makes the platelets not stick.



Prostaglandin E2: Dilates vessels, mediates fever in the hypothalamus,

mediates the ability of bradykinin to cause pain.



Memory: The following all both dilate vessels, and make them leak...

histamine, serotonin, prostaglandin E2, C3a, C5a, and bradykinin.

Warning: You\'ll go nuts if you try to memorize every inflammatory

mediator.



Neutrophil granule contents worth remembering:

Specific granules collagenase, alkaline phosphatase

Azurophil granules elastase, myeloperoxidase, acid hydrolases

Both kinds lysozyme



The collagenase and elastase are there, of course, to digest your own

tissues in pursuit of bacteria. They will form pus. In a confined

space that the polys made, this is an abscess; in a normal hollow

cavity, it\'s an empyema. Hydrolysis of tissue in this situation leads

to tremendous osmotic power, hence the ripening and pressure buildup in

a pimple. A surgeon should drain pus.



Which white cell comes out for which bug?

Neutrophils Most bacteria, chlamydia, rickettsia

Lymphocytes Viruses, autoimmunity, whooping cough

Macrophages Typhoid, mycobacteria, fungi

Plasma cells Spirochetes (Lyme disease, syphilis)

Eosinophils Worms (their cationic proteins are our

strongest weapon against worms); lots of

different \"mysterious immune diseases\" with

rashes

Nothing Prions, gas gangrene, severe immunosuppression



In lymphogranuloma venereum, cat scratch fever, brucellosis, plague,

tularemia, glanders-melioidosis, and yersinia infection, there will be

a plentiful mix of neutrophils and epithelioid histiocytes.



Acute phase reaction: \"Just being sick\". Interleukin 1 and interleukin

6 are released from phagocytizing macrophages. Interleukin 1 goes to

the hypothalamus and tells it (via PGE2 supposedly) to raise the body

temperature (\"maybe we will have an advantage over the germs better at

a different temperature\"). Interleukin 6 changes the relative amounts

of protein produced by the liver, so in a few weeks there is



Less: Albumin, transferrin, and transthyretin, and

More: Fibrinogen, complement components, alpha-1 protease

inhibitor (antitrypsin), and (from plasma cells)

immune globulin.



The more-cationic plasma proteins mask the zeta potential on red cells,

so red cells stack (\"rouleaux\") and thus are more streamlined and

settle more rapidly (increased sedimentation rate).



Macrophages (monocytes in tissue, histiocytes), lymphocytes (B, T), and

plasma cells are the principal actors in most chronic inflammation.



Granulomas are angry macrophages (i.e., influenced by gamma-interferon)

that have stuck together (\"epithelioid cells\"), typically to wall

something off (i.e., foreign body) and/or just because they\'re angry

(mycobacteria, fungi, sarcoid, Crohn\'s, beryllium, less often the

syphilitic gumma). Spot granulomas by the purple rice-crispies on a

frayed pink tablecloth gestalt. The purple is the reticulated, long-

oval, indented nucleus. The pink is the abundant cytoplasm without

clear borders. While you\'re learning, look for the \"giant cells\" to

spot granulomas; they\'re macrophages that have tried to eat each other.

Langhans giant cells have nuclei arranged as a horseshoe; foreign-body

giant cells have nuclei evenly dispersed; the distinction means exactly

nothing. Chronic granulomatous disease results from neutrophils unable

to kill staphylococci, hence macrophages must do it.



Ulcer: A portion of epithelium, and at least a bit of its underlying

lamina propria, has died and been lost. Ulcers are always inflamed,

and the crater is, of course, fibrin. Pseudomembrane: A very broad,

very shallow ulcer; of course the strength of the \"membrane\" is fibrin.

Look for pseudomembranes in diphtheria (throat) and C. difficile

colitis.



Tissue injury is almost always accompanied by inflammation. There are

a few exceptions: some infections in the very immunodeficient, yellow

fever (generalized apoptosis of the liver cells), prion disease, and

some of the diseases in which neurons just die off. (If you want to

count getting your hair cut as \"tissue injury\"... but let us not be

silly.)



Inflammation may resolve, i.e., so trivial there was no loss of local

cells, or there may be a need for healing. The terminology is a bit

confusion and not altogether standard. Regeneration refers to the

replacement of local cells by division. Labile cell populations are

continuously turning-over (epidermis, gut epithelium, marrow,

lymphocytes). Stable cell populations can divide when their neighbors

vanish (liver epithelium, kidney tubules). Permanent cell populations

don\'t replace (striated muscle, neurons, glia).



Scarring is laying-down of dense collagen (type I), which you will

usually see in chronic inflammation (\"transforming growth factor beta\"

effect) and wound healing. \"Chronic -itis\" in kidney, pancreas, and

gall bladder can refer merely to scarring, an unfortunate misnomer. In

healing of a nasty injury, the fibrin meshwork is ingrown by baby

capillaries (angioblasts) and fibroblasts (attracted by \"fibroblast

growth factor\" from platelets); they\'re here to \"organize\" it.

Plasmin, of course, competes with the scar-formers to break down the

fibrin; this is sometimes good, sometimes bad. Unless the plasmin is

the total winner, the fibroblasts and angioblasts show as soft, mushy,

red granulation tissue, which gradually is transformed into mature scar

as the fibroblasts make collagen and ground substance. As they finish

up, the fibroblasts grow little sarcomeres (\"myofibroblasts\") and the

scar contracts. If a wound is nice and clean and the margins well-

approximated and it heals by primary intention. Otherwise, it heals by

secondary intention. Both are dumb names but the idea is important.

Adhesions mark the site of old fibrin-rich inflammation in body

cavities; bands of dense collagen now bind surfaces together.



Timetable for \"the best possible wound\" (i.e., a clean, protected one

with edges apposed, in a well-nourished patient with good blood

vessels):



minutes: Fibrinogen from the severed vessels is activated

via one or the other arms of the clotting cascade,

forms a meshwork, and stops the bleeding. The

meshwork also contains platelets.



24 hours: Polys have entered the fibrin meshwork

Epithelial cells are regenerating from the edges of

the wound surface, etc.



3 days: The fibrin meshwork is extensively invaded by

macrophages.

Granulation tissue is appearing at the edges of the

incisions.

A thin layer of epithelial cells now covers the

wound surface.



5 days: Granulation tissue fills the entire wound, and

there is abundant collagen.



2 weeks: Fibroblasts continue to multiply, and collagen

continues to accumulate.



4 weeks: The overlying epidermis is now normal, though it

will not re-grow adnexal structures.

Capillary involution and scar contraction is well

underway, and the red scar is turning white.

The wound is still growing stronger, though it will

never have the tensile strength of uninjured tissue

(sorry).



Exuberant granulation tissue: \"proud flesh\" on a good healer. Keloid:

heals so well that the collagen weaves as dense as osteoid; dark-

pigmented folks often have this happen.



Bad for healing: poor blood supply, lack of zinc (for collagen-

strengthening enzymes), lack of vitamin C, infection (dirt and foreign

bodies promote infection), glucocorticoid excess, weak connective

tissue (Ehlers-Danlos), anemia, too few polys, fibrin problem.



Names for surgical operations:



\"-tomy\": The surgeon cut something.

\"-ectomy\": The surgeon cut something out.

\"-ostomy\": The surgeon cut something to make a mouth. If one

organ is named, the mouth opened to the outside of

the patient. If two organs are named, the mouth

connected two organs.

\"-plasty\": The surgeon changed the shape of an organ.

\"-pexy\": The surgeon moved the organ to the right place.



Types of pain...



Aching pain: Probably periosteum, tooth, dura, or some circuit

inside your own brain is involved



Burning pain: Either (1) the integrity of a mucosal surface has

been breached, or (2) the nerve or its immediate environment has

been damaged (probably a depletion of substance P; \"causalgia\"

from nerve injury, thermal burns, sunburns, leprosy, epidermal

necrolysis, capsaicin.



Crampy pain (gas, labor, kidney stones): A hollow organ is being

distended



Stabbing (\"lancinating\") (pleuritis, pericarditis, peritonitis):

If you haven\'t really been stabbed, then one of your serosal

membranes is hurting.



Not really any of these: ischemia, common inflammation (everything

from bee-sting to plague)



Edema of systemic disease. Heart failure (purists: right-sided heart

failure) edema is most likely to start in the feet, since the primary

problem here is increased venous hydrostatic pressure, and venous

hydrostatic pressure is highest here due to gravity). Kidney failure

edema is most likely to start around the eyes, since there\'s excess

total-body water and often low plasma oncotic pressure, and the tissue

spaces are loosest around the eyes. Liver failure edema is typically

in the peritoneal cavity, since portal venous pressure is usually

greatly increased in liver disease.



Cerebral edema results from cloudy swelling of the neurons, which

they\'ll do on the slightest injury; it\'s bad because the expanding

brain has no place to go except out of the skull. Hydrocephalus: Too

much cerebrospinal fluid for any reason. Angioedema is a curious

result of C1-esterase deficiency, with sudden, grotesque swelling of

bodyparts (weird feedback). Lymphedema results from plugged lymphatics

(cancer, surgery, filaria) and tends to be denser and more \"woody\" if

longstanding; bad cases produces dermal and epidermal thickening

(elephantiasis). Ascites: Effusion in the peritoneal cavity.

Hydrocele: Effusion in a man\'s tunica vaginalis. Hydrosalpinx:

Effusion in an oviduct, usually from old gonorrhea or something

similar. Hydrothorax: Watery effusion in the pleural cavity.

Hemarthrosis: blood in a joint. Melena: Passing digested (black,

tarry) blood in the stool. Hematochezia: Bright red blood out the

rectum. Effusion: Edema fluid from any cause in a body cavity.

Loculated effusion: Fibrin in an exudate divides the effusion into

smaller compartments; eventually the fibrin is likely to be replaced by

scar. Ileus: The gut is filled with extra water, typically because it

isn\'t moving.



Hemorrhage: Blood outside the circulatory system. Hemoptysis: Coughing

up blood. Hematemesis: Vomiting blood. Petechia: A little bleed in

the tissues, under a millimeter maybe. Ecchymosis: Fancy word for a

bruise. Purpura: Purple blotches where you\'ve bled into tissue.



Clot: Solid blood, generally used loosely. Hematoma: Solid blood

outside the circulatory system but in the tissues. Thrombus: Blood has

turned solid inside the circulatory system; all thrombi are variable

mixes of red cell, platelets, and (the basic component) fibrin. Ante-

mortem thrombi are easy to recognize by their lamination, i.e., layers

telling the story of their formation, the lines of Zahn (fudge-ripple

ice cream). Post-mortem thrombi feature a layer of red-cell-poor clot

(\"chicken fat\") and a layer of red-cell-rich clot (\"current jelly\"),

since the red cells sediment before the blood clots. Thrombi propagate

because their surface itself causes blood to clot. Vegetation: A

thrombus, typically small, on the endocardium of the heart at a site of

disease. Mural thrombus: A big thrombus overlying damaged myocardium.

Thrombi recanalize by turning (\"organizing\") into granulation tissue,

growing new channels, then having these channels pulled open by scar

contraction. Less often, plasmin destroys a clot; nowadays, physicians

can destroy them using therapeutic agents.



\"Virchow\'s triad\" is the most important concept in general pathology.

Here are the causes of thrombosis:



Injured endothelium

Myocardial infarcts

Myocarditis sites

Cardiac jet lesions (abnormal flow)

Inflamed or prosthetic cardiac valves

Ruptured atherosclerotic plaques

Vasculitis syndromes

Radiation injury

High blood pressure itself (?)

Cigaret smoke (?)

Invasion of vessel by tumor

(think of renal cell, hepatocellular, or follicular

thyroid carcinomas)

Iatrogenic

Sclerotherapy for varicose veins

Indwelling lines, etc.

Altered blood flow (\"turbulence and stasis\")

Myocardial infarcts (dead wall balloons out)

Quivering (\"fibrillating\") cardiac atria

Over big ruptured atherosclerotic plaques

In dilated cardiac chambers (valve or muscle disease)

In weakened arteries which have ballooned (\"aneurysms\")

Over-viscous blood

Sickle cell disease

Polycythemia (too much red cell mass)

Cryoglobulins (proteins that tend to precipitate)

Macroglobulinemia (too much IgM)

Vascular malformations

Prolonged bed-rest or immobilization

Hypercoagulable blood

Congenital factor deficiencies

Lack of antithrombin III

Lack of protein S

Lack of protein C (even heterozygotes) or its curious

cofactor

High blood homocysteine

Pregnancy and after childbirth

Tissue damage

After severe trauma or burns

After surgery

Nephrotic syndrome

(glomerular leakage of protein; probably because small

anti-coagulant proteins such as protein S are

selectively lost)

Secretion of thrombogenic factors by tumors

(notably adenocarcinomas, notably of the pancreas;

\"Trousseau\'s other sign\")

Presence of \"lupus anticoagulant\" (paradoxical)



Arterial thrombi (i.e., formed in an artery) are usually less rich in

red cells (i.e., they flow past in the fast stream). Look for thrombi

atop cracked atherosclerotic plaques.



Disseminated intravascular coagulation means that the clotting cascade

is getting activated in your bloodstream. You can expect bleeding

(depleted clotting factors), reopening of recent fibrin scabs (i.e.,

your venipuncture, the effect of plasmin activation), thrombocytopenia,

fragmented red cells (schistocytes, etc.), little infarcts (maybe; the

glomeruli get it bad in DIC), and death unless the disease is treated.



Causes of DIC worth mentioning now....

Things that release thromboplastin into the blood

Large infarcts

Massive intravascular hemolysis (remember bad malaria)

Acute promyelocytic leukemia

Various obstetrical catastrophes

Disseminated cancers

Snakebite

Things that damage endothelium

Rickettsial diseases

Meningococcemia

Other infections

Vasculitis syndromes

Toxemia of pregnancy (fibrin thrombi in placenta)

Things that do both

Shock

Gram-negative sepsis (mystery)

Major surgery

Burns

Massive trauma

Heat stroke



Fibrinolysis fills your vessels up with fibrin split products.



Emboli are anything that moves in the circulation, from one place to

another, that shouldn\'t. Most emboli are thromboemboli (they do not

cease to be thrombi). Paradoxical emboli: A thrombus from a systemic

vein went through a patent foramen ovale (note that right atrial

pressure must exceed left atrial pressure to allow this), and then to

the systemic circulation. Pulmonary emboli typically arise from the

deep veins of the legs, less often the right atrium. Systemic emboli

usually arise in the left atrium or ventricle.



Amniotic fluid emboli result from abnormal communication between the

contents of the amnionic sac (fetal urine, fetal hair, fetal skin

debris, and more unsavory stuff) and the veins of the womb. This can

wipe out the pulmonary vasculature and produce DIC, and is bad.



Air emboli can result from iatrogenic mishaps, stab wounds, caisson

disease (decompression sickness of divers) or weird practices. Listen

for the waterwheel murmur. Talc emboli slowly kill drug-injectors.

Fat emboli are most often from a broken heelbone; nobody really knows

why fat embolization makes you so sick (\"fat binds platelets, damages

lung and brain endothelium, etc., etc.\"). Red marrow emboli are

typically found in the lungs after vigorous but futile CPR, from broken

ribs and breastbones. Atheroemboli are crud from plaques of

atherosclerosis. Tumor emboli are not unheard-of in cancer patients.

Therapeutic emboli are squirted into sick organs by radiologists, to

destroy them.



Infarcts result from death of an organ (while the rest of the body is

still alive) from loss of its blood supply. (\"Death is a total body

infarct.\") Arterial infarcts result from emboli (i.e., wipe out one

arterial bed) or generalized circulatory insufficiency (i.e., appear

between arterial beds). Venous infarcts result from obstructed veins

(twisting, clots, mechanical problems.) Infarcts are white (pale,

anemic) if (1) they are caused by arterial insufficiency and (2) there

is no collateral circulation or reperfusion to flow slowly into the

dead vessels afterwards. Infarcts are red (hemorrhagic, bloody) if (1)

they result from occluded veins or (2) collateral circulation or

reperfusion.



Kidney & spleen These organs have no collateral circulation

(WHY not?) Infarcts are usually arterial,

white, and pyramid (\"wedge\")-shaped.



Lung Difficult to infarct due to its dual blood

supply. Emboli cause infarcts when shock or

heart failure compromises the bronchial

arterial flow. Infarcts are always

hemorrhagic, and are pyramid-shaped.



Brain Variable, but never wedge-shaped. Watershed

infarcts appear in the expected locations.



Heart Variable, but never wedge-shaped. Watershed

infarcts are the familiar \"subendocardial

infarcts\".



Gut Red. Never wedge-shaped. Arterial infarcts

are likely to be due to dopamine or digitalis

diverting the blood from the gut, in a setting

of underlying shock.



Liver Difficult to infarct due to its dual blood

supply. Occluding a branch of the portal vein

produces a wedge-shaped area of atrophy (\"Zahn

infarct\").



Extremity \"Milk leg\" is a venous infarct from a deep

post-partum strep infection of the leg.



Septic infarcts: The bacteria found it and are having a heyday.



Shock: You cannot perfuse your body adequately. Eventually, this

develops into a vicious cycle. Causes of shock that you must

understand....



Cardiogenic shock (i.e., pump failure)

Massive myocardial infarct

Rupture (ventricle, valve)

Diphtheria

Bad rhythm disturbances (\"arrhythmias\", a misnomer)

Certain poisons (remember massive nicotine ingestion)

Extrinsic compression (i.e., tamponade)

Hypovolemic shock

Heavy bleeding (4 or more of your 10 pints]

Externally

Internally (remember GI bleeds, hemoperitoneum)

Other fluid loss

Sweating

Vomiting

Diarrhea

Burns

Third-space losses (i.e., into effusions or ileus)

Loss of vascular tone (i.e., all vessels opening)

Septic shock (i.e., from bacterial breakdown products)

Anaphylaxis (generalized mast-cell degranulation)

Neurogenic

Certain poisons (notably war gases)

Profound anaesthesia

Spinal cord injury

Vasovagal (i.e., extreme pain, emotion)

Pulmonary embolism



In shock, the liver enzymes go up (underperfused liver), anaerobiosis

causes lactic acidosis (which is bad), and a huge host of chemicals get

released which further interfere with physiologic function. Histamine,

serotonin, leukotrienes, cachectin, interleukin 1, C3a, C5a, and many

other substances dilate vessels, inviting blood to pool in venules

(rightly called \"congestion\"), and/or make small vessels permeable,

causing blood to leak out. Some people even blame endorphins. Damaged

cells can release thromboplastin, producing DIC. Ischemia of the heart

produces the familiar subendocardial infarcts, which doesn\'t help the

pump.



Compensated shock: Blood pressure is maintained in the arms, but you\'re

probably not perfusing your kidneys, gut (\"I have stress ulcers!\"),

skin (\"I\'m cold\"), or muscles. Progressive / decompensated shock:

You\'re dropping your pressure and getting lactic-acidotic. If the

cause of your shock is treatable, you will probably survive; your

kidneys may be \"off\" for a few weeks, and \"shock lung\" may or may not

supervene in a few days. Less-fortunate people may have brain damage

(if the brain was underperfused), subendocardial heart infarcts,

Irreversible shock means your body\'s been sufficiently damaged by low-

flow that you won\'t recover, period. If your brain\'s being perfused,

you will probably still be lucid, and can talk sensibly, which is a

good thing at such a time.



Septic shock (i.e., from bacteria getting a foothold and growing in

your bloodstream) is a major mystery of medicine. Nobody really

understands what\'s happening. Lipid A (\"endotoxin\") dilating vessels

and making them leak is part of the problem, but not all. The body\'s

own chemical defenses play some role too.



[ If you were hatched from a swan\'s egg, it doesn\'t

matter that you may have begun life in a chicken

coop.

--Hans Christian Anderson



When you see a person who has been given more

than you in money or beauty, then look to those who

have been given less.

-- Mohammed]



In talking about genetic disease, watch what you say, especially when

you make a prediction about behavior. Common sense and common humanity

is the order of the day. I got an E-mail once from desperate parents

who knew their unborn child was XYY -- I sent my congratulations....



Genetic disease is the price we pay for the ability of our genes to

mutate, which has been important in the history of our species. Yet

\"genetic disease\" is almost impossible to define. My best shot:

Disease that is determined, more or less, when sperm meets egg.

Congenital disease: Present at birth. (How is THIS different from

genetic disease?) Familial disease: Runs in families. (How is THIS

different from genetic disease? Think of the cycle of abuse affecting

an adopted child.) Polygenic inheritance: Several genes are operating.

Multifactorial: What isn\'t?



Hopefully you can explain genes, the genetic code, alleles, chromosomes

(autosomal and sex), mitosis and meiosis, haploid and diploid cells

(exact multiples of the haploid number are euploid; others are

aneuploid), mutations (and the environmental problems that cause them),

centromeres, and the basic biology of nucleic acids. You also

understand classic Mendelian and sex-linked inheritance, homozygosity,

heterozygosity, hemizygosity, and consanguineous mating. Also, sex-

linked, sex-limited and lyonization, as well as penetrance, variable

expressivity of a single allele, genetic heterogeneity (same effect,

different loci). If any of these terms are unfamiliar, please review.

If you don\'t know what restriction fragment length polymorphism is all

about, ask a molecular diagnostician -- it\'s important. Know classic

genetic research (sequence the protein and find the gene) and reverse

genetics (find the gene, then find the protein). Remember that germ

line mutations are present in the sperm or the egg, while somatic

mutations are acquired after fertilization. \"New mutations\" (i.e., two

normal parents gave birth to an achondroplastic dwarf) indicate a

somatic mutation or a gamete or early-conception mutation. A few

diseases (notably McCune-Albright) cannot be passed from parent to

child, and always result from a mutation in the early unborn child

(post-zygotic mutations), being lethal to the fertilized egg.



Imprinting: Genes from Mom and Dad are labelled differently, and have

slightly different effects. Triplet repeat mutations: Big topic, these

elongate with successive cell divisions, and make those diseases in

which they are etiologic more severe with each generation

(Huntington\'s, fragile-X, myotonic dystrophy); this is called genetic

anticipation.



Be sure you are absolutely confident about the meaning of each of these

categories:



Cytogenetic disorders

Autosomal disorders

Sex chromosome disorders

Parental imprinting problems

Single-gene disorders

Autosomal dominant disorders

Autosomal recessive disorders

Sex-linked disorders

Mitochondrial gene disorders

Polygenic disorders



Cytogenetic disorders: From nondisjunction or anaphase lag.



Rules:



(1) Autosomal monosomy or no \"X\" chromosome causes early loss of

the embryo.



(2) All trisomies except trisomy 21 produce infants who will

usually die during the first few months of life; around half

of early spontaneous abortions has a trisomy.



(3) Unless a parent carries a balanced translocation, or when

advanced parental age is a factor, there is no real tendency

for these problems to recur.



Trisomy 21: Down\'s. 1 kid in 700, more with advanced maternal age.

Flattened face. Open mouth, big tongue with no central crease.

Slanting palpebral fissures and epicanthic folds (\"mongolism\"). Mental

retardation (IQ 25-50). Lack of muscle tone at birth (\"floppy baby\").

Low-set or funny-looking ears. Single palmar crease (\"simian crease\").

Radiographic abnormalities (middle phalanges, pelvis). \"Brushfield\'s

spots\" on iris. Heart defects (40%, notably endocardial cushion

defects). Gentle, shy demeanor. Hypothyroidism (untreated, doesn\'t

help intellectual function). Conductive hearing loss (untreated,

doesn\'t help learning). Bad respiratory infections (we don\'t know

why). Various leukemias (very common in these children). Alzheimer\'s

disease (always develops in patients surviving to age 40 or so).



Trisomy 18 is Edward\'s syndrome. Remember tiny jaw (\"micrognathia\"),

prominent occiput, low-set ears, overlapping fingers, and rocker-bottom

feet.



Trisomy 13 is Patau\'s syndrome. Remember tiny head (\"microcephaly\"),

arhinencephaly (\"abnormal limbic system\"), tiny eyes

(\"microphthalmia\"), cleft palate, polydactyly, and scrambled viscera.

The worst cases are cyclopses.



Deletion of the short arm of chromosome 5 (i.e., 5p-) is cat-cry (\"cri

du chat\", \"Is there a cat in the nursery?\") syndrome. Children are

profoundly retarded, but some survive into adulthood.



Imprinting problems are a major topic of fascination right now.

Prader-Willi and Angelman syndromes are the prototype.



Prader-Willi: a little bit dull, crossed eyes and almond-shaped

epicanthic folds, floppy babies, small hands and feet, growth delay,

short stature, and hypogonadism.They overeat, incorrigibly stealing and

hiding food, and become very obese (\"the commonest known cause of

genetic obesity\"). Docile and cute, until they get really upset, when

they are likely to become extremely violent. (Remember the fat, jelly-

donut-hiding kid in \"Fill Metal Jacket\"? True story.) The cause is

lack of a normal gene at 15q11-13 from Dad, i.e. uniparental disomy or

a mutation in Dad\'s copy.



Angelman: \"happy (?) puppets\", severely retarded, microcephaly and huge

jaws. They have jerky, puppet-like movements, and laugh a lot. The

cause is lack of a normal gene at 15q11-13 from Mom, i.e., uniparental

disomy or a mutation in Mom\'s copy.



Microdeletion syndromes probably account for a variety of other cases

of severe dysmorphism; this is a hot topic.



Sex chromosomal disorders



Rules:



(1) A Y-chromosome is necessary and sufficient to make a

phenotypic male, provided the body can also make and use

testosterone.



(2) The more extraneous X-chromosomes, the more abnormal the

person.



(3) You will usually miss the diagnosis at birth, and may only

make it late in adult life.



Klinefelter (XXY or sometimes XXXY etc.) One man in about 850. Tall

(delayed epiphyseal closure), small penis, limited body-hair, sterile,

gynecomastia, high voice, smell better than most men, gentle demeanor,

sometimes kind-of-simple-minded, diminished economic striving.



XYY (supermale). One man in maybe 1000. Tall, acne, wiry (even

Marfanoid), uncoordinated, bad temper. \"Look for the guy with the most

pimples on the prison basketball team.\" Often pectus, squint, \"kinda

different\".... Your lecturer, who fits the actual phenotype nicely,

plans to get checked when insurance reform becomes a reality; anyway,

he\'s always known he\'s a bad man trying to be good.



Turner\'s: One X, no Y. About 1 woman in 2000. Webbed neck, short,

shield-shaped chest, cubitus valgus, primary amenorrhea, failure of

secondary sex characteristics. The eggs are gone by age 2, leaving

streak gonads. Lymphedema and/or coarctation of the aorta are

additional troubles. A person of either gender can have Noonan\'s, a

Turner phenotype without Turner\'s. A woman I know worked for five

years in a six-man OB-Gyn department before mentioning, \"I\'m 24, do you

think I\'ll ever get a period?\" Only then did they notice that this

tiny woman had a webbed neck and...



Multi-X: Superfemales. XXX (one woman in a thousand) is usually

normal, XXXX and more might be retarded.



Intersex! Your genetic sex (or should be) is whether or not you have

testis-determining factor (usually on the Y-chromosome, and not on the

X-chromosome; but there are exceptions, as in families where the men

are XX, or where the women include XY\'s). Chromosomal sex: Do you have

a Y-chromosome? Gonadal sex: Do you have ovary, testis, both (true

hermaphrodite), or neither? Streak gonads, i.e., scar tissue: Woman

with Turner\'s, some folks without testis determining factor or its

receptor. Ductal sex: Did the muellerian (woman) or wolffian (man)

ducts develop? Phenotypic sex: What he/she look like?

Pseudohermaphrodite: Only one type of gonadal tissue, that does not

match the body phenotype. Male pseudohermaphrodite: Looks like a woman

with groin testes, no uterus. Female pseudohermaphrodite: Women with

enlarged clitoris, maybe some labial fusion. Being a parent is the

ultimate proof of which gender you are.



XXY Klinefelter phenotype

XO Turner phenotype

No testis-determining factor Woman, may be sterile

Testis-determining factor on X Man, may be sterile

No testis-determining factor receptor Woman, may be sterile

XY that lost TDF on a clone true hermaphrodite (?)

XX with Y on an autosome true hermaphrodite (?)

XX /XXY mosaic true hermaphrodite (?)

No muellerian-regression factor gene male pseudohermaphrodite

No testosterone receptor male pseudohermaphrodite

No five-alpha reductase male pseudohermaphrodite

Too much testosterone for any reason female pseudohermaphrodite



Don\'t confuse any of these with gender-dysphoria (seems to be wired in

the hypothalamus, side of the \"bed\" nucleus....), cross-dressing, or

homosexuality / bisexuality; the genetic basis for these conditions

(they do NOT meet my definition of \"disease\", nor most others) remains

obscure.



Autosomal dominant disease



Rules:



When a person has only one good gene where most people have

two, the person can expect to make 50% as much of the good

protein as do most other people. Sometimes, that isn\'t

enough. Therefore, the known autosomal dominant diseases

fall into five categories.



(1) Problems with the quantity or arrangement of large

structural proteins



(2) Problems with regulator proteins and receptors, which

permit relatively good quality of life.



(3) Deficiency in proteins which are in short supply even in

health.



(4) Anti-oncogene deletion syndromes, in which a \"second

hit\" on the normal allele of a normal cell turns it to a

tumor cell. More about this last category later.



(5) The mutant gene makes a harmful protein. Today, the

best-understood of these are the prion-related diseases,

in which an altered protein begins a terrible chain

reaction that can even be transmitted to genetically

normal creatures, even across species lines.



The common autosomal dominant diseases do not kill or disable until the

patient has had a good chance of having a family. Why? Hint: Most

genetic diseases do not result from new mutations. The major

exceptions are Von Recklinghausen\'s neurofibromatosis and

achondroplastic dwarfism (both are genes with very high mutation

rates).



The autosomal dominant disorders are mostly of variable penetrance

and/or expressivity, since they are modulated by other genes and/or

environment. Two doses of a bad autosomal dominant gene produces some

severe exaggeration of the single-dose syndrome, or else death in the

womb. Obviously, consanguinity does not play a role in autosomal

dominant disease.



The major autosomal dominant disorders which you\'ll meet in this

course:

Structural proteins

-- Marfan\'s syndrome family

-- Many Ehlers-Danlos variants, and plain old familial double-

jointnedness

-- Hereditary spherocytosis

-- The not-so-bad kinds of epidermolysis bullosa (abnormal

keratin in intermediate fibers)

-- Familial hypertrophic cardiomyopathy (some; Reggie Lewis,

mutant beta-myosin chain)

-- Achondroplastic dwarfism (fibroblast growth factor receptors,

maybe others)

-- Hereditary hemorrhagic telangiectasia (presumptive)

-- Osteogenesis imperfecta (collagen)

-- Pelger-Huet\'s non-disease (presumptive)

Receptor problems:

-- Familial hypercholesterolemia

-- Benign familial tremor (presumptive)

-- Glucocorticoid-suppressible aldosteronism (ACTH turns on

aldosterone)

Short-supply protein deficiency syndromes

-- Von Willebrand\'s disease

-- Maturity onset diabetes of the young (glucokinase)

-- Acute intermittent porphyria

-- Familial amyotrophic lateral sclerosis (superoxide dismutase)

Anti-oncogene deletion syndromes

-- Retinoblastoma gene syndrome

-- Neurofibromatosis I & II

-- Familial polyposis coli

(including its variant Gardner\'s syndrome)

-- Lynch\'s hereditary non-polyposis colon cancer

-- Multiple endocrine neoplasia syndrome I, IIa & IIb

-- Li-Fraumeni cancer syndrome

-- Tuberous sclerosis (presumptive)

-- Von Hippel-Lindau disease (presumptive)

-- Familial dysplastic nevus syndrome (?)

-- Peutz-Jegher\'s syndrome (presumptive)

-- Adult polycystic kidney disease

-- BRCA-1 breast-and-ovary cancer syndrome

-- more

Harmful proteins

-- Prion diseases (more about these later!)

-- Hereditary amyloidosis C

-- Gilbert\'s (harmless unconjugated hyperbilirubinemia; the

mutant gene product ties up the good copy)

-- Familial dysplastic nevus syndrome (? the melanin generates,

rather than protects from, free radicals)

Molecular biology being worked out

-- Huntington\'s disease (\"Huntington\'s chorea\")

-- Friedreich\'s ataxia

-- Familial psoriasis

-- Treacher-Collins (variably malformed face, \"Johnny Handsome\")

-- Waardenburg\'s (deafness, different-colored eyes, white

forelock)

-- Stein-Leventhal (probably)

Semi-diseases, heterozygotes for bad diseases

-- beta-thal minor

-- sickle-cell trait

-- hemoglobin C trait

-- one-dose hemochromatosis

-- alpha-thal is special, since there are four loci.



Marfan\'s syndrome: A heterogeneous group of genetic disorders with

connective tissue problems. Marfan patients are tall, with very long

extremities, and long fingers (\"arachnodactyly\"). The arm span exceeds

the height. Joints are hyper-extensible. Double-jointed. Chest-

deformities. Funny-looking face. Bones slim, muscles wiry, body

habitus slender. \"Ectopia lentis\" of eye (lax suspensory ligaments).

Elongate globe, flat cornea (progressive myopia). Weak central area of

thoracic aortic media predispose to aortic dissection (\"cystic medial

necrosis\"). Barlow mitral valve. Lax ligament around aortic valve,

causes regurgitation later in life. One gene is fibrillin, a

connective tissue protein. Semi-Marfan\'s abound. Related to Marfan\'s:

(1) Lathyrism, from feeding sweet peas to turkeys and resulting in

fatal aortic dissection, results from -aminopropionitrile inhibiting

lysine oxidase, which cross-links collagen and elastin fibers.

(2) Menke\'s kinky hair disease, on the X-chromosome, which prevents

normal handling of copper, prevents function of lysine oxidase. (3)

Stickler\'s, a common Marfan variant, results from a premature

termination codon on the type II procollagen gene.



Ehlers-Danlos syndrome (\"rubber man\", \"human pretzels\") is a family of

variably-inherited diseases which leave a person with poorly-woven

collagen; easy to hurt, poor healers. Some have overly-extensible

(even \"cigaret-paper\") skin; most have overly-mobile joints which often

slip out of place. Type IV: various problems with type III collagen

(\"reticulin\"); colon and arteries often rupture. Type VI: reduced

lysyl hydroxylase (autosomal recessive), ruptured corneas, detached

retinas. Type VII: inability to turn type I procollagen into collagen.



Familial hypercholesterolemia: Very common. Most of these patients

lack enough good apoprotein B-100 (\"LDL\") receptors. Therefore, they

have trouble with (1) hepatic clearance of VLDL leftovers (\"IDL\'s\") for

recycling, leaving them in the plasma to turn into LDL\'s; (2) hepatic

clearance of LDL\'s from the plasma, leaving high plasma LDL levels;

(3) receptor-mediated uptake of LDL\'s by other cells (do you remember

\"coated pits\"?), leaving more around to be taken up by the mononuclear

phagocytes by their receptor-independent method (which doesn\'t burn

LDL\'s very well). Xanthomas. Precocious atherosclerosis.



Stein-Leventhal syndrome is a mysterious very common woman\'s problem.

The combination is (1) secondary amenorrhea; (2) hyperandrogenism.

Usually also (3) relative tissue resistance to insulin; (4) big ovaries

with thick fibrous capsules (\"polycystic ovaries\"; the cysts are

follicles that could not rupture). The male phenotype is the super-

hairy guy who goes bald very early.



Autosomal recessive disease



Rules:



Many body proteins are in such abundant supply that if a person

has only half as much of that protein (i.e., has one good gene

where most people have two), there is no obvious problem.

However, if a person has no good gene where most people have two,

the person is sick. Therefore, the known autosomal recessive

diseases are either



(1) deficiencies or defects in highly specialized proteins

(enzymes, transport proteins), or



(2) hemoglobinopathies requiring more than one dose of a gene



In contrast to autosomal dominant diseases, autosomal recessive

diseases:



-- often result from consanguineous matings.



-- are often apparent at, or shortly after, birth;



-- have unknown mutation rates;



-- generally show complete penetrance (if there are several

alleles, expressivity may vary; the most conspicuous

exception is 1-protease inhibitor deficiency);



Heterozygote advantage accounts for the success of these diseases in

Darwin\'s world in certain ethnic groups. Sickle cell and some of the

other hemoglobinopathies protect heterozygotes from malaria.

Hemochromatosis heterozygotes are protected from iron deficiency.

Cystic fibrosis protects from cholera and other bacterial diarrheas.

Tay-Sachs protects from TB.



The major autosomal recessive disorders which you\'ll meet:

Deficiencies or defects in highly specialized proteins

Known proteins

-- Cystic fibrosis (\"mucoviscidosis\")

-- Phenylketonuria

-- Galactosemia (two kinds)

-- Adenosine deaminase deficiency (immunodeficiency)

-- 1-protease inhibitor (\"antitrypsin\") deficiency

-- Common albinism

-- The lysosomal storage diseases (except Fabry\'s)

-- Most glycogen storage diseases

-- Alkaptonuria

-- Really bad von Willebrand\'s variants

-- Abetalipoproteinemia (missing apoprotein B; spiny red

cells, malabsorption):

-- The bad kind of epidermolysis bullosa (bad type VII

collagen, therefore bad anchoring fibers)

-- Chediak-Higashi

-- hereditary fructose intolerance (aldolase B)

-- homocystinuria (cystathione synthetase)

-- hereditary tyrosinemia (fumarylacetoacetate hydrolase)

-- Various inborn errors of hormone metabolism

-- metachromatic leukodystrophy (arylsulfatase A)

-- Krabbe\'s (galactosylceramidase)

Proteins awaiting discovery

-- Werdnig-Hoffman (\"floppy baby\") disease

-- Wilson\'s family of copper problems

-- Unusual albinism syndromes

-- Some Ehlers-Danlos variants

-- Around 16 different familial deafness syndromes

-- Hartnup (can\'t absorb tryptophan well from gut)

-- At least two malignant hyperthermia genes (neurochemists

and anesthesiologists take note)

Major hemoglobin problems

-- Sickle cell anemia

-- Hemoglobin C disease

-- -thalassemia major

-- Three and four-dose -thalassemia syndromes

-- Combinations of the above



Albinism: Can\'t make melanin. Twelve or so different loci. The best

understood is tyrosinase deficiency.



Alkaptonuria (\"ochronosis\"): lack of homogentisic acid oxidase.

Precocious osteoarthritis, black urine, black cartilage (check those

ears).



Lysosomal storage diseases, of course, result from failure of

catabolism of large molecules within lysosomes, which accumulate.



Tay-Sachs disease (\"amaurotic, i.e., blind, familial idiocy\"): lack of

hexosaminidase A, causing accumulation of GM2-ganglioside. Mostly

neurons. Born normal, become retarded, blind, floppy. Head becomes

huge. Cherry spot on macula is normal red seen amidst cloudy neurons.



Niemann-Pick disease: lack of any one of several proteins required to

break down sphingomyelin molecules. Many types. Lipid-laden, foamy-

looking affected cells. Electron microscopy shows lamellar lipid

masses (\"zebra bodies\", other forms).



Gaucher\'s disease: Lack of glucocerebrosidase. Several types. Type I

is a semi-disease with a big spleen and liver; pancytopenia

(hypersplenism) and bone fractures are a problem. Type II is the

kiddie form; replacement enzyme is $400,000 per year for life. In

either form, pathologists see \"Gaucher cells\", huge reticuloendothelial

cells bloated with glucocerebroside.



The mucopolysaccharidoses: Problems degrading glycosaminoglycans

(\"mucopolysaccharides\", such as heparan sulfate, dermatan sulfate,

keratan sulfate, chondroitin sulfate, and/or others). These include

the very severe Hurler\'s syndrome (\"gargoyle\" children with progressive

mental retardation) to the variable Sanfilippo (severely mental

deterioration, near normal-looking) and Morquio (dwarves with bad

aortic valves and normal intelligence) syndromes. Hunter\'s (MPS-II) is

sex-lined, but all the others are autosomal recessives. Expect mild to

severe accumulation of mucopolysaccharides in the spleen, liver, etc.

Pathologists see PAS-positive material in affected cells.



Metachromatic leukodystrophy: deficiency of arylsulfatase A; galactosyl

sulfatide accumulates; brain deteriorates after infancy.



Krabbe\'s globoid cell leukodystrophy: deficiency of galactocerebroside

B galactosidase; galactocerebroside accumulates; brain deteriorates in

infancy.



Adrenoleukodystrophy (\"Lorenzo\'s oil\", etc.): a family of diseases,

some X-linked, with problems breaking down long-chain fatty acids; both

white matter and adrenal cortical problems. \"Lorenzo\'s oil\" was a

heroic failure.



Glycogen storage diseases: The clinical application of a \"Biochemistry\"

unit. Type I (Von Gierke\'s disease, glucose-6-phosphatase deficiency):

Big livers, hypoglycemia. A mild disease. Type II (Pompe\'s disease,

lysosomal glucosidase deficiency, \"acid maltase\" deficiency): All

organs, and die young of heart disease. Type III (Cori\'s disease,

limit dextrin disease, de-branching enzyme deficiency); Rare, patients

have liver storage problems. Type IV (branching enzyme deficiency):

accumulation of abnormal glycogen in all organs, including the brain;

death in infancy. Type V (McArdle\'s disease, muscle glycogen

phosphorylase deficiency): Patients are poor athletes, and get bad

cramps and muscle damage when they try. Glycogen is deposited beneath

the sarcolemma. Type VI (liver glycogen phosphorylase deficiency): Big

liver, hypoglycemia, mild disease. There are others.



X-linked dominant diseases: The only well-known one is familial vitamin-

D resistant rickets, a renal phosphate-wasting syndrome. Manic-

depression (nowadays, \"bipolar disorder\") probably has a locus here.



X-linked recessives: Expressing the phenotype requires one dose for

hemizygous men, two for women.



Rules:



X-linked diseases:



-- affect all males with the gene



-- affect a woman only if (1) she had two affected X-

chromosomes, i.e., she had an affected father and a carrier

mother (possible if we\'re just dealing with color blindness,

most unlikely if we\'re dealing with Duchenne\'s muscular

dystrophy); (2) she suffers from really unfortunate

lyonization; (3) the disease is expressed when individually

lyonized cells are affected (i.e., G6PD deficiency, in which

half the red cells hemolyze and half don\'t; or some cases of

fragile X syndrome); (4) she has Turner\'s syndrome (XO) or

testicular feminization (XY).



-- generally produce many affected family members, once the new

mutation has been propagated.



The major X-linked disorders

Familiar proteins

-- Hemophilia A (factor VIII deficiency)

-- Hemophilia B (factor IX deficiency)

-- G6PD deficiency (\"favism\"; several alleles)

-- Lesch-Nyhan syndrome

-- Duchenne\'s muscular dystrophy (Jerry\'s kids)

-- Chronic granulomatous disease

-- Hunter\'s mucopolysaccharidosis

-- Fabry\'s disease

-- Common red-green color-blindness

-- Testicular feminization (common type)

-- Nephrogenic diabetes insipidus (hADH receptor in collecting

duct)

[ -- Unnamed allele for monoamine oxidase A that correlates

strikingly with horribly aggressive misbehavior; this new,

major discovery caused a political flap...]

Being worked-out

-- Bruton\'s agammaglobulinemia

-- \"David the Bubble Boy\"\'s immunodeficiency

-- Several other immunodeficiency syndromes

-- Some adrenoleukodystrophy genes

-- Some cases of agenesis of the corpus callosum (alexithymia)

-- Ehlers-Danlos type IX

-- Mencke\'s kinky hair (a real \"kink\" in copper metabolism)

Fragile X chromosome



Fabry\'s disease (\"angiokeratoma corporis diffusum universale\";

deficiency of the enzyme that breaks down ceramide trihexose).

Glomeruli, maybe brain; lamellar bodies on EM.



Fragile X syndrome: About half of cases of familial mental retardation.

One guy in 1500, mildly to moderately dim. Enormous testes.

Difficulty counting things. Maxilla gets longer as you hit the

teenaged years. Dr. Bell, the discoverer, was a famous lady astronomer

before turning to medicine.



Y-linked inheritance: Passed father-to-son. Two are known: Testis-

determining factor (i.e., being a man), and having hair grow on your

ears when you get old.



Mitochondrial inheritance: From Mom. All are progressive and affect

cells non-uniformly, i.e., there\'s a growth advantage for the defective

mitochondria. These diseases include Leber\'s hereditary optic atrophy,

(a cytochrome oxidase problem), Kearns-Sayre disease (progressive

external ophthalmoplegia, retinal pigmentation, heart block, cerebellar

ataxia) and its variants progressive external ophthalmoplegia,

myoclonus epilepsy with ragged red fibers, and some others. The

\"ragged red fibers\" of mitochondria look that way because of

proliferated, dysfunctional mitochondria packed around their edges.

Electron microscopy shows creatine kinase crystals looking like parking

lots.



Polygenic inheritance is operating when family and adoption studies

show a strong genetic tendency but you can\'t find a single gene. [Be

extremely skeptical when anybody gets doctrinaire about a particular

problem, especially when race or politics gets involved.]



[Genetic disease is extremely political. Reasonable people will differ

about the issues within limits; there are plenty of charlatans on both

the right and the left who are ready to make political capital off the

public\'s misunderstandings. It will fall to you, the physician, to

help your community sort this all out.]



Tumor means the same as neoplasm. These are mutant clones of cells

that have acquired the ability to grown their own blood supply and

connective tissue matrix. They do no good and often great harm.

Benign tumors do not invade or spread to remote sites, but can compress

healthy structures, make hormones, or cause mechanical or cosmetic

troubles. They are usually round like balls, and lack microscopic

anaplasia. Malignant tumors are the same as cancers. They invade the

surrounding tissue, and most (exceptions: gliomas, basal cell

carcinomas) can metastasize. They tend to look like cauliflowers

(\"exophytic growth\", the various bumps representing overgrowing clones

and areas between dieback), ulcers (the mass of the tumor has died

off), or diffusely replace their parent organ. Differentiation of a

malignant tumor tells how well, or how poorly, it resembles its cell of

origin. Well-differentiated tumors show little anaplasia and tend to

be non-aggressive. Poorly-differentiated tumors show much anaplasia,

and tend to grow and spread rapidly. Any cancer will ultimately kill

the patient if not treated.



Carcinomas are cancers of epithelial origin. They tend to metastasize

via lymphatic vessels to the regional lymph nodes. (Exceptions:

hepatocellular carcinoma, renal cell carcinoma, and follicular cancer

of the thyroid tend to spread by vein.) Sarcomas are of cancers of

connective tissue origin. They tend to metastasize by veins to the

lungs.



Under the microscope, recognize cancers by their anaplasia (bizarre

nuclei, cells helter-skelter, high nuclear-cytoplasmic ratio, dark

nuclei with bumps on the membranes, and so forth), by mitotic figures

(especially bizarre ones), and by hemorrhage and necrosis (\"invade,

rather than outgrow, their blood supply\"); you may also see genuine

invasion.



Squamous cell carcinoma features keratin pearls (attempts to make

hair), intercellular bridges (desmosomes), and/or single-cell apoptosis

(i.e., thinks it\'s an old surface cell falling off the skin), plus

tonofilaments on electron microscopy.



Adenocarcinomas feature bizarre glands, either as tubules or papillary

structures (fronds, inside-out glands, with the connective tissue

growing like the branches of a tree); look especially for glands-

within-glands, stainable secretory product, signet-ring cells (the

product forms one large vacuole), or just cohesive nests. (Of course,

adenomas feature non-anaplastic glands). Many sarcomas are spindle-

cell tumors. Leukemias and lymphomas feature non-cohesive cells that

resemble blood cells or precursors.



Immunostains to learn (sometime):



CEA: adenocarcinomas

CLA:CLA: tumors of white cells (\"common leukocyte

antigen\")

desmin: myosarcomas

EMA: adenocarcinomas (\"epithelial membrane

antigen\")

Factor VIII: endothelium

GFAP: glial tumors (\"glial fibril acid protein\")

NSE: oat cell CA, isletomas, APUDomas (\"neuron-

specific esterase\")

keratin family: most epithelial neoplasms

S-100 melanoma, schwannoma, brain, dendritic

macrophages, histiocytosis X

vimentin: mesenchymomas, melanomas, kidney tubule



Benign tumors can give you trouble by compressing normal structures,

making a hormone, or (not very often) turning malignant.



One American in five dies nowadays of cancer. Malignant tumors in the

U.S:



The most common cancers:

Males (in descending order): prostate, lung, colorectal

Females (in descending order): breast, lung, colorectal



The most commonly fatal cancers

Males (in descending order): lung, colorectal, prostate

Females (in descending order): lung, breast, colorectal



Worldwide, cancer of the cervix is the great killer of women,

especially young women. The other great third-world killer is

hepatocellular carcinoma, which is primarily a man\'s tumor (because of

hepatitis B carrier status and iron overload; the third risk factor,

aflatoxin exposure, happens to both sexes).



In order to metastasize, cancer cells need only develop the ability to

chew through basement membrane (like polys do), and stick someplace

else, and start the new stroma growing. There are four routes:



(1) Seeding of serosal surfaces (or, in the case of CNS tumors,

up and down the neuraxis in the CSF)



(2) Mechanical transplantation (rare, typically iatrogenic;



(3) Via lymphatics (traditional route for tumors of epithelial

origin, i.e., carcinomas)



(4) Via blood vessels (traditional route for tumors of

mesenchymal origin, i.e., sarcomas, because the tumor cells

are in direct contact with blood vessels from the beginning)



Most tumors prefer certain metastatic sites. The common sites for

metastatic spread for many common cancers include lymph nodes, lung,

liver, bone, and brain. Most cancers seldom metastasize to the

muscles, spleen or gonads. A tumor\'s stage is how far it seems to have

gotten, and is assigned by the clinician. A tumor\'s grade is how

anaplastic its worst area looks, and is assigned by the pathologist.

Both help tell the prognosis and best therapy. Most high-grade tumors

present at high-stage, and most low-grade tumors present at low-stage.



Tumor Nomenclature



I. To assign a name to a tumor which you have examined, begin by

writing the suffix -oma. Most tumor names end in this way.

(Unfortunately, the suffix simply means \"swelling\", and some

non-neoplasms also use the suffix, i.e., granuloma, hematoma, xanthoma,

traumatic neuroma).



II. If the tumor is malignant, write the root carcin- (\"crab\") if the

tumor is of epithelial origin, or sarc- (\"flesh\") if the tumor is of

mesenchymal origin, before -oma. If the tumor is benign, do not write

anything.



III. Now choose one or more roots to describe the cell of origin.



If the tumor originated in glandular epithelium, use the root

adeno-. (It probably makes little glands and/or mucin.)



If the tumor originated in squamous or transitional epithelium, is

benign, and protrudes above the epithelial surface, use the root

papillo-.



If the tumor originated in non-glandular epithelium and is

malignant, name it for the cell of origin.



Basal cell carcinoma (skin)

Renal cell carcinoma (proximal tubule)

Squamous cell carcinoma (squamous epithelium)

Cholangiocarcinoma (bile ducts)



If the tumor originated from a non-epithelial cell, look for a root

in the following list. (We do not consider endothelium and mesothelium

to be epithelium.)



fibro- fibroblasts

myxo- myxoid tissue (Wharton\'s jelly, etc.)



chondro- cartilage

osteo- osteoblasts

lipo- fat

chordo- notochord remnants



leiomyo- smooth muscle

rhabdomyo- striated muscle



schwanno- nerve sheath

(neurilemmo-)

(neurofibro-)



hemangio- blood vessels

lymphangio- lymphatics

glomangio- glomus



synovio- synovium

mesothelio- mesothelium

meningio- arachnoid



lympho- lymphocytes



There are a few epithelial roots you will have to learn. For

example:



chorio- placenta

pheochromocyto- adrenal medulla



If the neoplastic cell types are mixed, use a compound, for

example, fibroadenoma. Some tumors arise in \"totipotential cells\" and

contain a variety of different mature and/or immature tissues from

different germ layers, and these are given names with the root terato-

(\"monster\").



IV. If needed, add an adjective to further describe the tumor. Some

examples:



papillary well-differentiated

keratinizing moderately well-differentiated

mucin-producing poorly differentiated

follicular pleomorphic

signet-ring cell cystic (cysto-)

scirrhus desmoplastic

medullary comedo-



V. A handful of tumors that are thoroughly malignant have \"benign\"

names. You will just have to learn these.



lymphoma mesothelioma myeloma (\"multiple\", plasma cell)

astrocytoma carcinoid glioma (micro-, oligodendro-)

ependymoma seminoma hepatoma

melanoma dysgerminoma leukemia



VI. A hamartoma is \"not a tumor, but is a developmental anomaly\"

(?) which contains the same tissues as the organ in which it is found,

but in the wrong proportions.



A choristoma is a mass of normal tissue in an abnormal location.



A tumor which ends in blastoma is composed of cells that resemble

those seen in a developing organ. Most blastomas are malignant (but it

depends on the site).



A few tumors of uncertain histogenesis are named eponymously:

Ewing\'s sarcoma, Hodgkin\'s disease, Pindborg tumor, Wilms\' tumor,

Enzinger\'s sarcoma.



Carcinogenesis: A series of events leading up to expression of full

malignant potential. Transformation: this process as applied to cells

themselves. The Nowell multi-step clonal evolution model, [first

articulated Science 194: 23, 1976,] is one of the most successful

theories in modern science (explanatory power, predictive value) and

should now be called \"Nowell\'s Law\". Mutations accumulate in

overgrowing clones. If we\'re on our way to becoming cancer, non-

disjunction creates cells with extra chromosomes (the deprived cells,

we may think, die off), and many (but not all) cancers become

aneuploid. Tumor progression refers both to the growth and distant

spread of cancer, and to the way the front-line cells become more

aggressive and more resistant to therapy (i.e., by the emergence, and

selection for, nasty subclones; \"multiple-steps\"). It is wrong to

think of cancer just as \"cells growing more rapidly than other cells\".

Rather, they are less subject to normal controls, and are growing

faster than they are dying off. \"Growth fraction\" can be determined

using the monoclonal antibody Ki-67, or getting out the tritiated

thymidine and finding the \"labelling index.\" A bizarre mitotic figure

can perhaps stick around for weeks.



Cancers cells exhibit transplantability: i.e., they grow easily in

culture or syngenic hosts or athymic (\"nude\") mice; immortality: i.e.,

they don\'t Hayflick Out after 50 generations, loss of contact

inhibition: i.e., cultured cells continue dividing and actually pile

up, instead of stopping once they have formed a nice monolayer; loss of

serum and anchorage requirements, loss of density-dependent growth

inhibition, and so forth.



Every cancer probably has its own chromosomal fingerprint, though no

two are exactly alike in all their mutations. Worth knowing:



t(9;22): chronic myelogenous leukemia (Philadelphia

chromosome)

t(8,14): Burkitt\'s lymphoma

del 3p: renal cell and oat cell carcinoma

del 13q: retinoblastoma

del 11p: Wilms tumor

monosomy 22: meningioma



Antigenic changes, studied in cancer, has generated almost nothing of

value.



Rules:



1. All tumors evoked by a specific oncogenic retrovirus (in one

organ in one species) tend to have the same tumor-specific

antigens (Nowell\'s law; laboratory retroviruses carry

extremely potent oncogenes sufficient to transform by

themselves).



2. Tumors induced by a specific chemical are all pretty much

different antigenically (Nowell\'s law, the background of

other mutations is different in each case).



There is still no known antigen unique to any cancer. This probably

accounts for the disappointing results of chemotherapy (\"drugs that are

more toxic to cancer cells than normal cells\") for the most common

cancers. \"Cancer is not \'other\', it is \'us\'\". \"To fully understand

cancer, we will need to understand all of life.\"



Metabolic changes, much studied, with no useful results. The \"Warberg

hypothesis\", still occasionally described, is dead wrong; the

\"chymotrypsin deficiency / trophoblast theory\" was part of a cynical

fraud (laetrile).



Chemicals and cancer. The Delaney Clause forbids the presence of any

\"cancer-producing chemical\" in any concentration in U.S. food. Today

this is silly. Now is a good time to learn the following associations:



Soot Cancer of the scrotum (\"chimney sweep\'s

cancer\" -- discovered by Percival Pott)

Cancer chemoRx Acute leukemia (the bad ones include

cyclophosphamide, chlorambucil, busulfan,

melphalan, others -- the alkylating agents)

Cyclophosphamide Transitional epithelial (mostly bladder)

cancers

Other alkylaters Many cancers (remember nitrogen mustard,

bischloromethyl ether, benzyl chloride)

Polycyclic HC\'s Tobacco smoking-related cancers (lung, larynx,

mouth, throat, esophagus, pancreas, bladder,

kidney -- remember 3-methylcholanthrene,

benz(a)anthracene and benzo(a)pyrene).

Azo dyes Bladder cancer (dye factory workers, ?? red-

M&M eaters, etc., etc. -- remember \"butter

yellow\" in margarine, \"scarlet red\" in

maraschino cherries, and beta-naphthylamine)

Aflatoxin Eaters of moldy grain and peanuts

(hepatocellular carcinoma, endemic in Africa;

the mold is aspergillus species)

Betel nut Mouth and throat cancer (addictive substance

chewed in India)

Mat Uruguayan herbal concoction; with black

tobacco, takes blame for Uruguayan epidemic of

bladder cancer

Pickled fish Chinese nasopharyngeal cancer

Pickled vegetables Chinese esophageal cancer

Safrole Sassafras (stomach cancer? other cancers?; a

free-radical generator

Vinyl chloride Angiosarcoma of the liver (factory workers)

Chromium, nickel Lung cancer (factory workers -- scramble

chromosomes)

Cadmium Prostate cancer (battery factory workers)

Asbestos Lung cancer, mesothelioma (scrambles

chromosomes)

Arsenic Skin cancers (amplifies genes)

PCB\'s Polychlorinated biphenyls (pollutants,

suspected of causing human cancers)

Saccharin Bladder cancer (in huge doses given to

animals, but epidemiologically not a

significant risk to human users)

Cyclamates Ditto

Human feces Several known carcinogens, including those

derived from bile salts (try and ban that,

Senator Delaney!)

Benzene Leukemias and related problems

Phenacetin Transitional epithelial (mostly bladder)

cancers

Anabolic steroids Liver cancer (this particular risk is

relatively small, but there are many other,

worse risks from use of these substances by

athletes)

Estrogen Endometrial hyperplasias and carcinomas

Ferric ion Liver cancer (hemochromatosis patients);

perhaps many other cancers (\"free radical

generator\")

Herbicides Chlorphenoxy- and chlorophenyl herbicides seem

to be linked to soft tissue sarcomas; Well,

maybe.



Some environmental carcinogens are direct-acting (\"activation-

independent\"), and exert their effect directly. However, the majority

(procarcinogens) require metabolic conversion (activation, often by

hepatic cytochrome P450) to produce carcinogenic forms (ultimate

carcinogens). Famous direct-acting carcinogens include the alkylating

agents (cancer chemotherapeutic agents) and a few acylators. The heavy

metals actually depolymerize DNA. Probably all chemicals that really

induce cancer are mutagens. The non-mutagens are probably promoters,

i.e., promote cell division and/or activate protein kinase C in order

to allow the malignant cells actually to overgrow. A rule that works

most of the time is that the actual carcinogen either damages DNA

directly (the alkylating and acylating agents) or is a potent

electrophile (the epoxide ultimate carcinogens derived from polycyclic

hydrocarbons, vinyl chloride, and aflatoxins; the N-hydroxylated dye

metabolites; the alkyldiazonium ions derived from nitrosamines, etc.,

etc. etc.)



Selective memory (\"I\'ve been trying SO HARD to think what could have

given Little Johnny his leukemia!\") probably explains the ludicrous (to

be frank) \"statistical studies showing a relationship\" between familiar

things and cancer (magnetic fields, cellular telephones). Where the

link has proved genuine, the relationship has been striking, and it

makes sense biologically.



Two terms from classic studies of chemical carcinogenesis: (1)

Initiation: The result of exposure of a cell or cells to a carcinogen,

which permanently alters its genetic material but not its phenotype

(yet). As noted, these are mutagens. (2) Promotion: A substance that

causes initiated cells to turn into tumors. Tumors result when the

promoter is administered after, but not before, initiation. Promoters

tend to be inducers of rapid cell turnover and/or induces of protein

kinase C.



A complete carcinogen is a substance that is both initiator and

promoter, such as \"tobacco smoke\" or certain really awful chemicals.

The Ames test for mutagenicity (and presumably carcinogenicity) relies

on production of mutants in a culture of typhoid bacteria.



Radiation carcinogenesis. Gamma rays (including x-rays) and

ultraviolet light cause mutations. The bane of the Curie family, and

many of the other pioneers. Atomic bomb survivors have greatly

increased incidences of all the common leukemias (except CLL; the

incubation time is a few years), and minor increases in many (but not

most) solid tumors (remember thyroid, breast, salivary gland, lung).

Chernobyl\'s children are getting thyroid cancer from radioactive

iodine, and other problems. Your lecturer believes the \"radon in your

home\" stuff is a scam. Nobody\'s shown an increased risk from living

near nuclear power plants. Radium paint workers who put their brushes

in their mouths developed bone and nose cancers. Uranium miners have a

greatly increased incidence of lung cancer, even if they do not smoke.

People given high doses of radiation for ankylosing spondylitis (x-

rays) or polycythemia vera (radiophosphorus) have greatly increased

incidences of all the common leukemias. Newborns treated for mythical

\"enlarged thymus\" developed many thyroid cancers as young adults.

Ultraviolet radiation is the principal risk factor in most skin cancers

(basal cell, squamous cell, malignant melanoma). Suntanning will not

protect you from the wavelengths that cause cancer and elastosis

(\"aging of the skin\").



Viral carcinogenesis: Most cancers are not contagious, period.



Wart virus (\"human papilloma virus\", HPV) causes warts (\"benign

tumors\") in humans, and certain strains also cause cancer of the

uterine cervix, penis, and anal canal in humans. The cancer-producing

strains produce products which tie up Rb and p53 antioncogene products.



Epstein-Barr virus (\"herpes 4\") is necessary (but not sufficient) to

cause African Burkitt\'s lymphoma, and is etiologic in Chinese

nasopharyngeal cancer, immunoblastic lymphoma, and Eskimo endemic

salivary gland adenocarcinoma.



Hepatitis B virus and hepatitis C virus cause hepatocellular carcinoma

by acting as mitogens, encouraging selection of damaged cells.



HTLV-I causes epidemic leukemia in Japanese humans. HTLV-II seems to

cause hairy cell \"leukemia\" (which might simply be an infection).



Before you tell me that \"nobody would ask us about particular cancer

genes\", be advised that they already have. I\'ve chosen the most-

testworthy.



Oncogenes were originally discovered in transforming retroviruses (\"the

RNA tumor viruses\"). \"Viral oncogenes\" turned out to be cancer-

producing genes that the viruses had just happened to pick up

(\"transduced\") while growing in established tumors. A proto-oncogene

that has acquired the ability to cause cancer (i.e., has become an

oncogene) is said to be activated.



(1) Classic tyrosine kinase proto-oncogenes: signal-transducers,

across membranes. src, abl (from the bcr/abl translocation in the

Philadelphia translocation in chronic myelogenous leukemia), RET

(multiple endocrine neoplasia type II). Usually activate by

mutation.



(2) GTP-binding protein proto-oncogenes: tell cells to divide in

response to signals (or just divide, period, when they\'re

damaged). Includes the ras family, which takes mutations at

certain hot-spot codons (12, 13, 61), which code for the active

site.



(3) DNA-binding protein proto-oncogenes: the myc family, whose protein

products are intranuclear and bind to DNA itself. myc activation

is usually by amplification (excess copies of a gene) and/or

translocation rather than by mutation. In Burkitt\'s lymphoma of

B-cells, c-myc (chromosome 8) is moved next to the immunoglobulin

gene (chromosome 14), i.e., the cell decides to multiply like

crazy every time it is told to make antibodies. myc genes are

much amplified in neuroblastomas and oat cell lung carcinomas.



(4) Growth factor protein proto-oncogenes. c-sis codes for the beta

chain of platelet-derived growth factor (PDGF), the stuff that

tells fibroblasts to divide in wound healing. Probably sis-

induced cancers grow by autocrine self-stimulation by PDGF.



(5) Protein growth factor receptor proto-oncogenes. erbB, which codes

for a protein homologous to the epidermal growth factor receptor,

neu / HER2 and fms, which codes for macrophage colony-stimulating

factor. These work by the familiar inositol triphosphate .

diacylglycerol second-messenger systems.



(6) Enhancer binding protein proto-oncogenes; erbA codes for the human

thyroid hormone receptor. It is linked to a variety of animal

cancers.



(7) Master-switches: jun is the factor that initiates transcription of

DNA at a particular sequence. fos apparently turns short-term

stimulation into long-term differentiation and immortalize.



(8) int-2, the second site where the mouse mammary tumor virus

integrates, is the gene for fibroblast growth factor #3; flg is

FGF1 and bck is FGF2.



(9) bcl-2, activated in most B-cell lymphomas, and its relative bcl-X,

tell the cell not to undergo apoptosis, but to divide if told to

do so. Nobody knows how it works.



(10) p16, discovered in 1993 on 9p21, is one of a new family of cyclin-

dependent kinase inhibitors; Cyclin D1 itself (11q13, bcl1, the

PRAD locus) is another cancer gene.



(11) A subject that will probably soon be important is the activation

of genes that enable cancer cells to metastasize.



Anti-oncogenes keep cells benign, even when the oncogenes are

activated. To lose their anti-cancer effect, both copies must be

altered. (Contrast the proto-oncogenes which exert their effect when a

single copy is activated to an oncogene.)



Knudson\'s Law for anti-oncogenes

One hit: You have a cell with a much increased

propensity to turn malignant

Two hits: You have a cancer cell.



If you derive from a mutation-bearing sperm or egg, or

were hit at conception, you have one of the autosomal

dominant anti-oncogene deletion (\"tumor-susceptibility\")

syndromes. The malignant phenotype requires both copies

to be bad, so it is autosomal recessive.



Sporadic examples of cancers seen in these cancer-family

syndromes exhibit the same markers, i.e., sporadic (bad-

luck) retinoblastomas are homozygous for loss of Rb.



Rb: Deletion syndrome features retinoblastomas in childhood,

osteosarcoma and breast cancer in survivors.



p53: Deletion syndrome is LiFraumeni, with increased prevalence of

cancer in most organs. The gene tells cells to undergo apoptosis, or

at least not to divide, if their genome has been injured. Lose p53,

and your clone\'s genome has become profoundly unstable. Many, if not

most, cancers lose p53. Aflatoxin produces a trademark mutation in

both p53 and ras.



p16INK4 (no syndrome) is a cell-cycle gene which is very commonly

deleted in lots of cancers.



VHL: Deletion syndrome is von Hippel-Lindau, with hemangioblastomas of

the cerebellum, eye hemangiomas, and kidney cancers. All renal cell

carcinomas have lost VHL.



WT1 (was WAGR): Deletion is an aniridia syndrome with Wilms\' tumor.



NF-1: Deletion syndrome is common Von Recklinghausen\'s

neurofibromatosis. Gene product \"neurofibromin\" facilitates action of

normal ras. Von Recklinghausen\'s is common (1 person in 3000),

variably expressive but very penetrant. Nerve tumors (schwammomas,

neurofibromas) anywhere, and pigmented skin lesions (\"caf au lait\",

i.e., coffee with milk, spots with smooth borders; look around the

armpits). The \"elephant man\'s\" elephant skin was caused by epidermal

and dermal hyperplasia overlying neurofibromas.



NF-2: Deletion syndrome is neurofibromatosis type II, with acoustic

neuromas.



APC: Deletion syndrome is familial polyposis of the colon. All colon

cancers lose this. Gardner\'s, with colon and mesenchymal (soft tissue,

bone) tumors, is a different allele here.



MEN-I: Deletion syndrome is multiple endocrine neoplasia type I

(pituitary adenomas, parathyroid adenomas / hyperplasia, gastrinomas).



RET: Deletion syndrome is multiple endocrine neoplasia type II.



The Lynch genes: Deletion syndrome is non-polyposis colon cancer. Very

common. Genes repair DNA mismatches.



NOTE: Turcot\'s, with brain tumors and colon cancers, can be at the

APC or Lynch loci.



Peutz-Jegher\'s: Not yet cloned; black freckles on the lips, hamartomas

of the intestines.



BRCA-1: Deletion syndrome is familial breast and over cancer, early in

life. Made the cover of \"Time\". Very common.



Dysplastic nevus syndrome: Deletion syndrome causes a variant melanin

which generates, rather than quenches, free radicals. Lots of

melanomas.



CDKN2 and P16-1NK4: pancreatic cancer and melanoma; Cyclin inhibitors.



Tuberous sclerosis: We\'d love to know where the genes are... TS is

common (1 in 2000 folks is you look) with lots of hamartomas, and no

two cases alike. Notable \"tumors\" include \"adenoma sebaceum\"

(misnomer; fibromuscular bumps on the maxillary region, nose, and

chin); \"candle gutterings\" (benign glial nodules on the walls of the

cerebral ventricles); \"rhabdomyomas\" of the heart; \"angiomyolipomas\" of

the kidney; various brain tumors. Many have seizures, most are at

least a bit slow mentally. Ash-leaf spots are easiest to see with

ultraviolet.



Autosomal recessive cancer family syndromes may involve chromosomal

instability; for the first three, heterozygotes are mildly affected.



Ataxia-telangiectasia: immunodeficiency from breaks in the T-cell

receptor genes, extra tumor risk and radiosensitivity, chromosomal

instability; Purkinje cells tend to die off, rheumatoid arthritis

is common.



Fanconi\'s anemia (pancytopenia, multiple birth defects, white cell

tumors, chromosomal instability)



Bloom\'s syndrome (carcinomas, leukemias; DNA ligase I deficiency)



Xeroderma pigmentosum (skin cancers -- cannot repair DNA; actually

a family of 16 different loci)



Werner\'s syndrome (sarcomas; this is the famous \"accelerated

aging\" syndrome, where 40 year olds look like 80 year olds from a

distance)



Cancer problems: There\'s no need to explain the havoc wrought by

cancerous invasion of the brain, destruction of the bone, replacement

of the marrow, or necrosis with fistula formation.



Sex hormones can wreck havoc. They\'re usually from adrenal or gonad.



Low serum sodium from hypersecretion of hADH: oat cell carcinoma, some

others.



High serum calcium: Bone metastases, plasma cell myeloma osteoclastic

activation, parathormone-like substance produced by squamous cell lung

cancer.



Hypoglycemia from insulinomas. Feels bad, makes you fat, kills.



Carcinoid syndrome (paroxysms of flushing, wheezing, and diarrhea) from

production of serotonin and kinins by certain apudomas.



Erythrocytosis (excessively high red cell mass): renal cell carcinoma

produces excessive erythropoietin.



Autoimmune hemolytic anemia: think of malignant lymphoma.



Hyperviscosity syndrome results from cancers that elaborate IgM. The

very thick blood sludges in the brain and death results.



Brain syndromes are often autoimmune. Anti-Yo disease (cerebellum),

Anti-Ri disease (opsoclonus), anti-retina antibody disease (blinded by

oat-cell), Anti-Hu disease (protean, oat-cell); Eaton-Lambert syndrome

antibody against calcium channel in myoneural junction, seen with oat-

cell.



Acanthosis nigricans is an accumulation of black hyperkeratotic papules

in the armpits and groin. Think adenocarcinoma somewhere.



Dermatomyositis-polymyositis is often a marker of occult cancer.



Clubbing of the digits (\"Hippocratic change\"; \"hypertrophic

osteoarthropathy\") commonly results from lung cancer, but is

nonspecific (and seen in many non-cancerous diseases, notably those

which cause extensive lung damage or right-to-left cardiac shunts).



Venous thrombosis, not just in the legs, is a marker for pancreatic

cancer (\"Trousseau\'s other sign\")



Disseminated intravascular coagulation is common in advanced cancer,

especially when the blood vessels have been invaded



Marantic endocarditis is little fibrin vegetations on the heart valves

seen in patients with any wasting disorder. They are prone to

embolize.



Myasthenia gravis, immune destruction of normoblasts and suppression of

plasma cells are all common in thymomas.



Plugging of the renal tubules by immunoglobulin light chains is common

in cancer of the plasma cells.



Glomerular protein leakage (\"the nephrotic syndrome\") is a troublesome

remote effect of various cancers, nobody knows why.



Cancer pain: Invasion of bone with microfractures. Obstruction of a

hollow organ. Invasion of nerve plexus. After surgery (post-op

analgesia is a joke since surgeons are lawyer-shy.) Psychosocial

problems in our screwed-up health-care system range from trouble

getting a job (if you survive) to ridiculous laws that make it hard to

give drugs for pain \"for fear of causing addiction\".



Death from cancer: Pneumonia (neutropenia, airway obstruction, not

breathing deeply, too weak to cough, got stuff down the wrong throat).

Sepsis leading to shock, the portal of entry being the tumor, the

bladder, the constipated gut, or the bedsores. Hemorrhage (brain, gut,

elsewhere) from thrombocytopenia. Pulmonary emboli from being

hypercoagulable and bedridden. Kidney failure. Paraneoplastic

syndrome (above). Iatrogenic disease. Suicide and active euthanasia;

before you consider these, remember that almost all cancer pain is

controllable if (and only if) the government will let you.



Tumor immunity is a subject of perpetual interest, and I\'m sorry to

have to tell you that the immune surveillance theory, so popular with

quacks, is simply not true. Folks who are immune-crippled only get

cancers of cells that tend to be hyperplastic in them (i.e., B-cells)

and/or caused by viruses (Epstein-Barr, Kaposi\'s). Nude mice (no

transplant immunity) have no higher rate of spontaneous cancers.



Harvesting lymphocytes from tumors, growing them, and reinjecting them

occasionally helps, and there are magic-bullets against those rare

cancers (notably melanomas) that express antigens not usually expressed

by benign cells.



Cancer epidemiology: It\'s simply not true that cancer\'s becoming more

common, if you control for the fact that we\'re not dying of infections

and violence as kids. Lung cancer: Becoming more common in populations

that are taking up smoking, less common in populations that have been

giving it up. Stomach cancer used to be very common, and is now pretty

rare. Melanoma is getting more common because of sunbathing.



Geographic differences seem related to environment rather than genes,

as shown by immigrant studies. Breast cancer is less common in the

poor nations where a woman is usually pregnant or nursing. Colon

cancer is highest where there\'s a high-meat, high-saturated-fat, low-

roughage diet. Prostate cancer is very rare in Japan; Afro-Americans

have a very high incidence. Esophageal cancer is the scourge of China

and central Asia. Stomach cancer is very common in Japan and Chile,

possibly from bacteria. Burkitt\'s lymphoma is epidemic in, and only

in, the African virus belt; explanations range from malaria to eating

poinsettias. Hepatocellular carcinoma runs with aflatoxin (moldy

food), iron overload, and hepatitis B in sub-Saharan Africa. Cancer of

the cervix is lifestyle-related, and is a sexually-transmitted disease;

if the man is circumcised, he has less chance of transmitting HPV.

Choriocarcinoma is common in the Far East because of the high rate of

molar pregnancies. Squamous cell carcinoma of the bladder is caused by

schistosome eggs and is a scourge in Egypt. Transitional cell

carcinoma of the bladder was a horrible problem in Rumania, where the

communists declared barns illegal (ideology at work); the cause may be

a toxin or mouse hantavirus in the grain, which folks had to store in

their houses.



[The major cancer frauds of the century include laetrile (apricot pits,

pseudo-conservatives), krebiozen (creatine in mineral oil), New Age

stuff (pseudo-liberals) and macrobiotics (no relation to real

Buddhism). There are literally hundreds of others. Using stolen

stationery to get your articles published in the refereed scientific

literature: JAMA 266: 1471 & 1749, 1991 (\"We were told it was often

necessary to deceive the unenlightened to advance our guru\'s plan to

save the world.\") It\'s to your credit that you chose scientific

medicine instead. While we practice it, our best weapon against cancer

quackery is the quack\'s own: Take time with your patient, be kind and

considerate and use common sense, explain things, let the patient make

choices within reason, be tactile when it\'s right, and just generally

be nice (even when it\'s hard).]



I am resisting the temptation to review basic immunology here. If you

don\'t know about the various cytokines, clonal expansion (one

stimulated T-cell or B-cell becomes thousands, with the same

specificity), please brush up.



Type I immune injury. \"Anaphylactic\". \"Immediate-hypersensitivity\".

\"Reagin-mediated\". \"Atopy\" (strange). IgE on the mast cells /

basophils and all that. Starts in moments, ends within a few hours.

IgE / mast cells are worm protection.



Allergy freaks make IgE more readily and/or have a more hair-trigger

allele for the IgE receptor on the mast cell.



Allergy symptoms are the kinds of things that would expel a worm

(itchy-urticaria, sneezing, coughing, vomiting). In each case,

histamine from mast cells makes vessels leaky, causes bronchial smooth

muscle to constrict, and causes the gastric parietal cells to churn out

acid. Mast cells also release \"eosinophil chemotactic factor of

anaphylaxis\" and neutrophil chemotactic stuff. Leukotrienes (C4, D4,

E4) are \"secondary mediators\" synthesized special after the first round

of degranulation. Leukotrienes are responsible for some of the

allergic wheezing, etc., that does not respond to antihistamines.



Systemic anaphylaxis: Penicillin injections, insect stings, infamous

food allergies (eggs, peanuts, shellfish). The whole vascular bed

opens and leaks (\"anaphylactic shock\"), then bronchospasm occurs.



Type II immune injury. Antibodies attach to antigens on the surfaces

of a cell, and then something (complement, hungry phagocyte, special T-

cell) injures or destroys the cell.



Transfusion reactions: ABO you should know, usually involves

ready-made, complement-fixing IgM. Rh incompatibility usually involves

IgG which must be induced. If you are Rh (\"D\") negative, the second

time you encounter the Rh antigen, you may get a little sick when,

beginning a few days later, the transfused red cells are slowly

destroyed.



Hemolytic disease of the newborn (\"erythroblastosis fetalis\"), Mom is

sensitized to one of the father\'s red cell antigens which she does not

share (probably during the birth of a previous child, with mixing of

fetal-maternal blood). If the isoantibody is IgG, it can cross the

placenta and wreck havoc on the fetus\'s red cells, causing anemia,

normoblastic (\"erythroblastic\") hyperplasia, etc. And when the baby is

born, there\'s no placenta to carry all the breakdown products of

hemoglobin away, so the child becomes jaundiced.



Autoimmune hemolytic anemia (lupus, lymphoma), autoimmune neutropenia,

autoimmune thrombocytopenia. Penicillin-as-a-hapten hemolysis. In

paroxysmal cold hemoglobinuria, the antibody against the red cells is

an IgM active only in the cold.



Goodpasture\'s disease: Autoantibody against lung and glomerular

basement membrane. Cough up blood; rapidly progressive

glomerulonephritis. Treat with plasma exchange daily until recovery

supervenes.



Pemphigus: Antibodies against desmosomes. Pemphigoid: Antibodies

against hemidesmosomes.



Autoimmune gland problems tend to feature a mix of autoantibodies and

angry T-cells, working together to destroy the gland. This includes

juvenile-onset diabetes, Hashimoto\'s / lymphocytic thyroiditis,

pernicious anemia, autoimmune adrenalitis, Sjogren\'s, and a few

oddities.



Hyperacute rejection of an organ is mediated by already-present

antibodies (type II + type III).



Rheumatic fever features autoantibodies against streptococci which

cross-react with other tissues; nobody really understands it. In

Sydenham\'s chorea, a component of the syndrome, antibodies against

streptococci cross-react with basal ganglia.



Anti-neutrophil cytoplasmic antibody diseases includes Wegener\'s and

small-vessel polyarteritis.



The paraneoplastic encephalopathies (the antigen is a cancer, the

victim is the normal cell) have been considered above.



Lyme neuropathy: Antibodies against the bug crossreact with the axon.



HIV infection features destruction of uninfected T-cells by anti-HIV

antibodies directed against dead viruses, which stick to the surfaces

of the unfortunate T-cells.



Type III immune injury. Caused by antigen-antibody complexes

precipitating when they\'re mixed in just the wrong proportions. The

\"aches and pains of the viral illness\" is the most familiar, and least

deadly.



Serum sickness: You get an injection of horse serum, against which you

already have antibodies. Total-body vasculitis. Arthus reaction: You

get an intramuscular injection of something against which you have

antibodies already. (Ever get a sore arm after a booster shot?)



Glomerulonephritis includes many variants that are type III immune-

mediated, including all the ones that look interesting on electron

microscopy.



In Farmer\'s lung, there\'s a vasculitis from antibodies precipitating

with inhaled bacteria.



In lupus, type III immune injury is a major problem.



n drug reactions, systemic infections, carcinomatosis, etc., etc.,

hypersensitivity angiitis of small arteries and small veins may be due

to drugs allergy, systemic infections, carcinomatosis, or what-have-

you.



In AIDS and childhood immune thrombocytopenia, antigen-antibody

complexes coat platelets, causing their destruction.



Polyarteritis nodosa is a reaction pattern which in many cases is

caused by antigen-antibody complexes with hepatitis B surface antigen.



Rheumatoid factor is IgM antibodies again the Fc portion of IgG. These

tend to precipitate in the walls of vessels, producing a vasculitis.



I\'m surprised more folks don\'t get awful sick from allergy shots.



Classic delayed hypersensitivity (Type IV immune injury variant):

Special T-helper cells (TD) programmed to recognize a particular

\"altered self\" antigen with HLA Class II, are stimulated. They in turn

coordinate other lymphocytes, macrophages, and other tissue elements.

The object is to destroy every cell bearing the \"altered self\" antigen,

i.e., get rid of those pesky viruses, any cells sheltering TB, your

transplants, etc. The local macrophages get angry and do most of the

dirty-work. The tissue reaction can be very brisk and locally

destructive. Antibodies are not involved. Inability to mount this

particular response is called anergy.



Cell-mediated cytotoxicity (Type IV immune injury variant): Special T-

cell (T-CTL) are programmed to alter a particular altered-self antigen

in association with HLA Class I. The T-CTL cell assassinates its

target using its perforin, without harm to surrounding tissues.

Antibodies may or may not be involved, too.



NOTE: Some folks call cell-mediated cytotoxicity \"Type IV-B\" if

(and only if) it is antibody-dependent. Other call it \"Type V\";

still others put it under \"Type II\". Yeah, these are artificial.



The tuberculin skin test is the prototype of classic delayed

cytotoxicity. Hepatitis B (antibody-independent) and the autoimmune

endocrinopathies (antibody-dependent) are prototypes of cell-mediated

cytotoxicity.



You\'ve also known these processes if you\'ve ever had poison ivy,

allergy to jewelry, or neomycin rash. It\'s also the basis of cell

damage in hepatitis B and the viral skin rashes.



Type V immune injury (as I number them) is said to be present when

antibodies bind to cells and cause them to malfunction instead of being

destroyed.



Circulating anticoagulants are antibodies against a coagulation factor

(usually VIII or prothrombin activator).



Classic pernicious anemia is due to an auto-antibody which binds to

intrinsic factor, rendering it unable to carry vitamin B12 through the

ileal mucosa.



A few cases of insulin-resistant diabetes mellitus are caused by

autoantibodies that tie up insulin receptors.



Antibodies against animal insulin were the bane of diabetics in past

years.



Graves\' disease: Stimulatory autoantibodies against the TSH receptor.



Celiac sprue / dermatitis herpetiformis features antibodies against

reticulin, induced by exposure to gluten in wheat.



Stiff-man syndrome: autoantibody against glutamic acid decarboxylase,

which synthesizes the neurotransmitter gamma-amino butyric acid. There

are LOTS more type V\'s known.



Hyperacute transplant rejection happens when the patient gets a

allograft and already has antibodies against it (oops!). There is a

pattern of type II + type III immune injury. Nasty.



Acute rejection is mediated by T-cells and is basically done by

cell-mediated immunity, mostly T-CTL. Can happen suddenly, years after

the transplant. Look for onion-skinning (i.e., subacute vasculitis).



Chronic rejection is still rather mysterious, and is usual in old

allografts. Mostly you will see fibrosis of the organ and dense

fibrous narrowing of the arterial lumens.



Graft vs. host disease: Marrow or other T-cell-bearing material given

to an immune-disabled host attack the \"foreign\" recipient. Skin

(dermatitis), intestine (diarrhea, malabsorption), and liver (biliary

epithelium -- jaundice, elevated serum alkaline phosphatase, portal

fibrosis) in the acute disease. Chronic graft-vs.-host is more

widespread and looks like scleroderma.



Mechanisms of autoimmunity: Still mysterious. Molecular mimicry: Well-

established in rheumatic fever (antibodies against M-protein in

streptococcus cross-reacts with heart and brain). Lyme spirochetes

mimic axons, thymoma mimics myoneural junction, oat cell carcinoma

mimics various neural antigens. Less clear: Coxsackie-B virus and

heart (Barney Clark), measles and T-cells (measles anergy), Klebsiella

and HLA-B27, Yersinia and the TSH-receptor, Escherichia and primary

biliary cirrhosis antigen, cow\'s milk and type I diabetes autoantigen,

Epstein-Barr virus and myelin. Autoimmune diseases exacerbate and

remit since the immune system is feedback-loops within feedback-loops,

both positive and negative. Autoimmune diseases tend to occur together

in the same person. You\'ll learn the familiar combinations later. In

the autoimmune endocrinopathies, the process seems to involve

expression, inappropriately, of HLA-II antigens on the surfaces of

attacked cells.



Women have a stronger immune system than men. [That\'s not politics;

it\'s the truth.] Which gender gets more of a particular disease (if

both genders can get that disease)? If a disease is autoimmune, women

get it more often than men. If a disease is not autoimmune, men get it

more than women. This almost always works. Exceptions: Men get more

of the HLA-B linked diseases (i.e., the ankylosing spondylitis family),

women get more osteoporosis, and autoimmune diabetes is sexes-equal.



Systemic lupus: Autoantibodies against ubiquitous little antigens;

usually anti-double stranded DNA. rim pattern on fluorescent ANA.

Anti-Sm, if present, is diagnostic. LE-cell is a phagocyte that\'s

eaten a stripped, homogenized nucleus. A \"hematoxylin body\" is a

stripped, homogenized nucleus. Butterfly rash. Discoid rash

(different, may occur alone). Non-mutilating arthritis (synovitis).

Insanity (anti-ribosomal antibody). Autoimmune hemolysis. \"Lupus

anticoagulant\" (anti-phospholipid antibody) makes blood hypercoagulable

(sic.), produces abortions, makes a false-positive syphilis screening

test; it\'s common enough in non-lupus patients. Immune-complex

glomerulonephritis. Libman-Sacks endocarditis features sterile

vegetations on all heart surfaces. Vasculitis with type III immune

injury. \"Lupus band test\" shows immune complexes in the dermal-

epidermal junction, as granules. Aphthae in the mouth are infarcts

(\"canker sores\"). Serositis (pleuritis, peritonitis). Neonatal lupus:

anti-Ro crosses the placenta and causes a rash and heart block.

Single-organ autoimmune disease (endocrinopathy, myasthenia) doesn\'t

usually appear in lupus. Lupus patients feel terrible, look healthy.



Drug-induced lupus: Anti-histone, homogeneous pattern on ANA.

Hydralazine, procainamide, less often isoniazid. Are you a slow-

acetylator?



Sjogren\'s: Autoimmune destruction of the salivary and lacrimal glands.

Common. Most have anti-Ro and anti-La. B-cell lymphomas tend to arise

here.



Scleroderma: Fibrous thickening of selected body parts (always the

fingers, often the rest of the dermis). Fibrous proliferation (onion-

skinning) of little arteries causes the Raynaud\'s that always precedes

scleroderma. Esophagus (garden hose, trouble swallowing), skin

(linoleum), lungs (pulmonary fibrosis, deadly), gut (malabsorption),

renal vessels (hypertensive crisis). Anti-topoisomerase (anti-Scl70)

is common. Anti-nucleolar antibodies; nucleolar pattern on ANA.



CREST: calcification of the fingerpads, Raynaud\'s, esophageal fibrosis,

sclerodactyly (linoleum fingers), telangiectasias (dilated vessels from

scars contracting). Defined by antibodies against centromeres.



Morphea: Localized scleroderma. Saber-cut scleroderma, etc.

Eosinophilic fasciitis, a scleroderma variant with eosinophils, is

idiopathic, and resembles the horrible eosinophilia-myalgia syndrome

from tainted \"health food\" tryptophan.



Polymyositis-dermatomyositis: Polymyositis features T-cells attacking

skeletal muscle, especially hips and shoulders, with pain and weakness.

Many patients have anti-Jo, antibodies against transfer-RNA synthetase,

and so forth. \"Dermatomyositis\" is polymyositis plus a distinctive

rash, with purple (\"heliotrope\") eyelids, purple bumps on the knuckles,

and so forth. Work these folks up for underlying cancer.



Mixed connective tissue disease: Antibodies against U1-

ribonucleoprotein (U1-RNP). Speckled pattern on ANA. Raynaud\'s,

arthritis, maybe more.



Polyarteritis nodosa: All-three-layer vasculitis with lots of little

aneurysms, i.e., the process is a vicious cycle locally. A great

imitator, and easy to miss, with fatal results. Small-vessel

polyarteritis is anti-myeloperoxidase disease (anti-neutrophil

cytoplasmic antibody with peripheral staining, p-ANCA disease). Gets

any body-part except lung; thrombosis in the little aneurysms is

devastating. Cyclophosphamide is the mainstay of treatment. Other

patients have type III immune injury with hepatitis B surface antigen

and antibody. Kawasaki disease features the histopathology of

polyarteritis, with a rash (face, palm, soles), sore throat, big lymph

nodes, and maybe coronary vasculitis; often in kids of Japanese

ancestry after any of several viruses. Henoch-Schonlein purpura:

Polyarteritis-like disease, without the aneurysms, and with lots of IgA

in the vessels; IgA glomerulopathy, arthritis, GI-bleed, skin rash;

kids get better by themselves.



Wegener\'s granulomatosis: Another great imitator, caused by c-ANCA

(anti-proteinase 3), with features of type III and classic type IV

activity, i.e., polyarteritis plus granulomas. Ears-eyes-nose-throat

involvement (\"saddle nose\"), lung-involvement, and/or necrotizing

glomerulonephritis. Fatal if untreated; cyclophosphamide is the

mainstay of therapy. Nobody knows how ANCA really cause disease;

probably we\'re expressing the antigens on the surfaces of other cells,

too.



Know your amyloids:



Amyloid A (AA) Serum amyloid-associated protein; those with

longstanding chronic inflammation (lepers, familial

mediterranean fever, osteomyelitis, TB, rheumatoid

arthritis); roughest on the kidneys



Amyloid B (AL) Immunoglobulin light chains; plasma cell myeloma or

other clonal overgrowths of B-cells; roughest on

the heart



Amyloid C (AF) Transthyretin; hereditary substituted forms are the

most amyloidogenic; peripheral neuropathy with

chronic pain



Amyloid H HLA light chains (\"beta-2 microglobulin\");

hemodialysis patients, since the kidney normally

clears these chains; worst on the joints and carpal

tunnels



Amyloid E Protein hormones, in the stroma of endocrine tumors

and the islands of some type II diabetics (in the

latter, it\'s beta-pleated amylin)



Amyloid beta / A4 Alzheimer\'s.



Kuru plaques Prions. This is the basis of the \"mad cow\" flap in

England; at present, I believe the index series is

a selection artifact.



There are others. Amyloid\'s effects... Heart: heart block, restrictive

cardiomyopathy (stiff heart). Vessels: brittle. Gut: Stiff,

malabsorption, diarrhea, constipation. Liver: Huge but normally

functioning, do not biopsy it. Wrist: Carpal tunnel syndrome. Kidney:

nephrotic syndrome progressing to uremia. Sago spleen: amyloid in the

white pulp (like the granules in tapioca). Lard spleen: amyloid in the

red pulp (like lard, with little air pockets). Make the diagnosis on

biopsy.



Immunodeficiency: Hereditary, retroviral, iatrogenic (cancer

chemotherapy, transplants), or secondary (Cushingism, alcoholism,

malnutrition, uremia, diabetes). B-cell problems / complement problems

/ neutrophil problems: Infections with the common bacteria. T-cell

problems: candida, later pneumocystis and the intracellular, non-

bacterial pathogens.



Bruton\'s X-linked hypogammaglobulinemia: Lack of a tyrosine kinase

essential to B-cell multiplication. Treat with gamma globulin

injections.



Isolated IgA deficiency: Not much of a problem, unless you get allergic

to IgA in a blood transfusion, then get another transfusion.



DiGeorge\'s thymic dysembryogenesis: No thymus, other midline defects;

often no parathyroids either.



Severe combined immunodeficiency: Lack of B-cells and T-cells. Most

familiar is adenosine deaminase deficiency (dATP builds up and is toxic

to lymphocytes), the first disease cured by gene therapy. In one X-

linked SCID, the interleukin 2 receptor is absent; another form

affected \"David the Bubble Boy\". There are others.



Wiscott-Aldrich syndrome: Lack of CD43, on the X-chromosome. Boys have

eczema, scanty platelets, poorly-understood immune deficiency.



There\'s another, poorly-understood X-linked immunodeficiency called

sex-linked lymphoproliferative syndrome in which affected boys develop

lethal lymphomas when they meet the Epstein-Barr virus.



T-cell membrane defects: For example, lack of a CD3 subunit.



Common variable immunodeficiency: Poorly-understood syndromes that

appear later in life, perhaps from clonal overgrowth; problems making

enough of the right kinds of antibodies.



Complement component deficiencies will confuse you. Remember that C2

deficiency presents an ANA-negative lupus picture, while the higher-

numbered deficiencies have problems with meningococcemia.



HIV disease: Retroviral immunodeficiency. HIV-1 (East Africa) is

probably a chimp zoonosis that\'s become established among humans; HIV-2

(West Africa) is probably a sooty mangabee zoonosis. Don\'t even ask me

about Duesberg; you should be able to see through his stuff yourself.



HIV infection wipes out T-helper cells (T4, CD4; counts and function);

there\'s a major dip during the acute infection (a mononucleosis-like

syndrome), then counts return to near-normal, then wane over the

following years until the opportunistic infections appear; T-cells are

lost/inactivated because of viral lysis, coating of the CD4 receptor by

gp120; B-cell hyperplasia creates a compensatory hypergammaglobulinemia

which handles most bacterial infections okay. Note that gp120 also

binds to, and HIV infects, the less-study-able dendritic macrophage

system. You know the opportunistic infections, which include \"Kaposi\'s

sarcoma\" (herpes 8 infection), \"lymphoma\" (Epstein-Barr infections),

pneumocystosis (lung), CMV (retina or anywhere else), TB, atypical

mycobacteria, histoplasmosis, coccidioidomycosis, giardiasis,

candidiasis, rochalimaea, herpes simplex, herpes zoster, toxoplasmosis,

cryptosporidiosis, campylobacter, herpes 6 (\"roseola bug\"), progressive

multifocal leukoencephalopathy (JC papovavirus), skin fungi (dandruff,

jock itch, more), etc., etc., etc..



HIV is neurotoxic; look for neuronal dropout, granuloma-style giant

cells in the brain (microglia eating each other because of the gp120 on

their surfaces; HIV \"giant cell encephalitis\").



Other problems: Thrombocytopenia from platelets getting coated with

antigen-antibody complexes. Cachexia: nobody knows why, maybe muscle

cell apoptosis. AIDS nephropathy is severe foot-process disease.



Good to know: HIV probably can\'t infect a white cell that isn\'t already

upset about something. The virus is passed cell-to-cell, avoiding

antibodies. The most efficient route of transfer is receptive anal

intercourse; there\'s lots of good recipient cells here. A man having

unprotected regular intercourse with his wife has maybe a 20% chance of

transmitting the infection over 70 years; a hygienic, lesion-free man

is very unlikely to catch it from a woman during regular intercourse.

Childbirth places the baby at risk, and so does breast-feeding. HIV in

babies usually progresses faster than in adults. Oral sex isn\'t very

efficient for HIV transmission, and kissing and necking are safe.

Missionaries in HIV-infested parts of the world (mosquitoes, etc.) just

aren\'t getting infected. Needle-sticks with HIV-positive blood have

about a 0.3% chance of transmitting the infection. Sharing dirty

needles is riskier. A blood transfusion with HIV-positive blood is 90%

likely to infect you. The ELISA is a good screening test; the Western

blot is definitive. AZT works by inhibiting reverse transcriptase.

Non-progressive HIV: About 5% of cases. Some are defective viruses,

some are mysterious. This is THE topic in AIDS work right now. [I

prefer understanding to rhetoric, and science to ideology and

prejudice; my saddest AIDS story is a gym acquaintance who told me, in

early 1996, \"There was only one man, I didn\'t like how it felt, but I

did it because I wanted a friend.\"]



[ \"A hungry man is not a free man.\"

-- Adlai E. Stevenson



\"It is better to know some of the questions than all of the

answers.\"

-- James Thurber



Each day, 50,000 people die directly or indirectly from undernutrition.

Most of the suffering is borne by children, and survivors are often

brain-damaged. Yet the world currently produces more than enough food.

Right now, all hunger is political. The problems are complex; my

prescription, like Virchow\'s, is democracy.]



Marasmus (\"wasting\"): Total-calorie malnutrition. Wasting, ravenous

appetite.



Kwashiorkor (African term): Protein malnutrition, as when the child is

displaced at the breast by a younger sibling. Hypoalbuminemia, fatty

liver, edema, sluggish mind, depigmentation (\"flag sign\" in the hair),

pellagra-like paint-chip rash.



Vitamin deficiencies: Hard to find nowadays in their pure forms, except

vitamin A deficiency. Usually seen as features of mixed malnutrition.

Folic acid is relatively deficient in the U.S. \"twinkies and diet

pepsi\" diet; iron less so. I am not aware of any good study confirming

the popular claim of \"widespread subclinical vitamin deficiencies\".

Fat-soluble vitamins (A, D, E, K) may get depleted in those with fat

malabsorption (steatorrhea, or any generalized malabsorption).



Vitamin A deficiency: Major world health problem. Metaplasia of

columnar epithelium into stratified squamous epithelium; over-

keratinization of existing stratified squamous epithelium

(xerophthalmia, Bitot\'s spots, acne). Bad respiratory infections (no

cilia), measles is likely to be fatal. Loss of visual pigments (rods

first, night-blindness). Several million people are blinded yearly

from vitamin A deficiency; the problem is worst in General Khadaffi\'s

Libya.



Vitamin A excess: Vitamin faddists, polar-bear liver eaters; you can\'t

do it with carrots) get increased intracranial pressure (\"pseudotumor

cerebri\") with headache and nausea-vomiting, a special kind of fatty

liver (vitamin A clogging the \"Ito cells\"), and desquamation of the

skin (as seen in those taking Accutane, but worse). Remember

retinoids, but not carotenoids, are teratogens.



Vitamin D deficiency: Rare in the developed nations unless you \"tea-

and-toast\" for all your meals. \"Rickets\" in kids, \"osteomalacia\" in

adults; problem is failure of the bone to mineralize. \"Rickets\"

features Harrison\'s groove, the \"rachitic rosary\", bow-legs,

\"craniotabes\", \"frontal bossing\", \"pigeon breast\", \"square head\",

pelvic deformities (die in childbirth).



Vitamin D excess: Vitamin faddists get hypercalcemia and kidney stones.



Vitamin E deficiency: Malabsorption or total-parental-nutrition.

Ceroid in the gut, damaged sensory pathways in the cord. Animals get

hyposexuality and infertility. Vitamin E therapy helps preemies with

their eye problems and hemolytic anemia.



Vitamin K deficiency: Vitamin K is the cofactor required to add a

gamma-carboxyl group to clotting factors II, VII, IX, X, S, Z, and C.

Required for clotting; your gut bacteria may or may not give you enough

vitamin K. Deficiencies, usually in preemies, are preventable with an

injection of vitamin K; you may want to inject your cirrhotic patients

too.



Vitamin B1 deficiency (thiamine): Polished rice eaters (historical),

alcoholics, women with hyperemesis of pregnancy. Beriberi may be dry

(neuropathy) or wet (congestive heart failure; heart is flabby, yet

vessels are dilated for \"high-output failure\"). Wernicke\'s (ataxia,

eye movement problems, damaged mammillary bodies; why you give

drunkards a shot of thiamine before starting the glucose) and

Korsakoff\'s (can\'t tell real from imagined memories, damaged

dorsomedian nucleus of thalamus).



Vitamin B2 deficiency (riboflavin): FAD precursor. I doubt its

existence as a distinct disease; the books describe \"cheilitis\"

(cracked angles of mouth), seborrheic-type dermatitis on the nose,

cheeks, and hands (\"glove dermatitis\"), and purple tongue.



Vitamin B3 deficiency (niacin, nicotinic acid): NAD precursor.

Deficiency is pellagra, with dermatitis (paint-flakes, especially on

the shins and wherever the sun shines), dementia (schizophrenia-like),

diarrhea, and death (the \"D\"\'s). Maize-eaters (lack of tryptophan, a

niacin precursor, and something that binds niacin).



Vitamin B6 deficiency (pyridoxine): Amino group shuttle. Best way to

get \"deficient\" is to poison your pathways with isoniazid. Neuropathy.



Folic acid deficiency (Vitamin P): In vegetables. Methyl-group

shuttle. Deficient in many alcoholics, pregnant women, folks with

malabsorption (especially disease of the terminal ileum), bacterial

overgrowth of the gut (including \"tropical sprue\", vicious cycle) folks

taking phenytoin \"Dilantin\". Macrocytic anemia, mental changes, neural

tube defects in babies.



Vitamin B12 deficiency (cobalamin, cyanocobalamin): In all foods of

animal origin. Deficiencies in the strictest vegetarians, those with

fish tapeworm, those with resected ileum or Crohn\'s disease here, or

antibodies again / lack of intrinsic factor (\"pernicious anemia\").

Macrocytic anemia, demyelinized posterior columns (\"subacute combined

degeneration of the cord\"), later brain dysfunction.



Biotin deficiency: Remember that \"avidin\" in raw eggs is very effective

at blocking absorption of biotin (\"Rocky Balboa\" take note).



Vitamin C deficiency (ascorbic acid): Redox cofactor, required for

making and maintaining collagen and for other stuff. Deficiency is

\"scurvy\". In kids, osteoid is deficient, mimicking rickets.

Regardless of age, capillaries weaken, with bleeds and general misery

(the worst is bleeds under the periosteum), old wounds reopen, bleeding

gums.



Vitamin C megadosing: Surprisingly safe; uremics die of oxalic acid

poisoning, normals get increased iron absorption and false-negative

blood and glucose tests in urine. The Linus Pauling story, if you care

to learn it, is sad.



Iron deficiency: From diet (\"twinkies and diet pepsi\", milk-only),

disease of duodenum (where it\'s absorbed), kooky diets

(\"macrobiotics\"), rapidly-growing youngsters, heavy blood loss (heavy

periods, GI bleeders notably those with ulcers, cancer, or hookworm;

hematuria, overzealous blood donors), starch-eaters. Rampant in our

world. Anemia (hypochromic, microcytic) appears late. The story about

\"esophageal webs\" just isn\'t true -- these are problem-drinkers with

scars from ripping their esophagus during the dry-heaves. Serum

ferritin tells your iron stores (\"zero\" in symptomatic deficiency);

other techniques include looking at zinc protoporphyrin (porphyrin

molecules building up waiting in line for iron) and transferring

saturation (Fe/TIBC).



Zinc deficiency: Malabsorption, breast-milk-only, etc. \"Acrodermatitis

enteropathica\" and loss of senses of smell and taste.



Copper deficiency: Preemies, starvation. Copper oxidizes iron, cross-

links lysine side-chains, oxidizes melanin.



Selenium deficiency: \"Keshan disease\", a deadly heart-failure syndrome

in Red China (a bureaucrat forget to add selenium to the fertilizer).

You need selenium for glutathione reduction.



Iodine deficiency: A world scandal. Hypothyroidism, goiter (extra

TSH), several million kids permanently brain-damaged each year.



Manganese poisoning: Simulates Parkinsonism.



Fat: In the U.S., even the beggars (\"Will work for food\") are often

fat. Those who are genuinely hungry are mostly the children of

substance abusers. Yet our women, on the average, are leaner and far

more physically fit than women, on the average, in many of the poor

nations. Your bodyfat is calories-in (food, alcohol) vs. calories-out

(malabsorption, work of living, work of carrying-your-body-weight,

exercise, heat given off from your skin, vomiting, tumor burden,

uncoupled mitochondria). Hunger (\"I\'m hungry\") vs. appetite (\"Mmmm,

that looks good!\"). Appetite uppers: Hypothalamus (brain injury,

Froehlich\'s, peptides), anabolic steroids, marijuana. The Ob gene

product (discovered 1995), leptin, suppresses appetite in the presence

of adequate or excess bodyfat. [The \"ideal weight charts\" are

subscience at it stupidest (the whole track team is \"underweight\", the

steroid-free weightlifters are \"obese\"); your best weight is what looks

and feels right for you, and which enables you to be athletic. Despite

all the sub-scientific chatter, I am not aware of any reason to believe

that a man needs any measurable bodyfat; women do best with a few

pounds, helps with the estrogen. \"Measuring bodyfat\" by dipping you in

water is also bunk (a bit of gas in your intestines will....)]



Obesity: Causes problems, but how serious? Think: (1) un-aesthetic,

(2) bad back; (3) sore knees; (4) sore hips; (5) exacerbates

hypertension maybe; (6) exacerbates type II diabetes somehow; (7) helps

form gallstones somehow; (8) makes surgeon\'s job harder; (9) airway

problems during sleep; (10) uterus cancer by making extra estrogens;

(11) slight fatty change in the liver but nothing serious; (12) slight

elevation of uric acid; (13) hard to keep your skinfold area clean

(crotchrot, etc.), (14) varicose veins.... Beyond this, it\'s probably

not an independent risk factor for anything. Are you thinking what I\'m

thinking, i.e., that obesity is over-rated as a health problem? Fun to

know: fat cells divide if you\'re overfed before age 1; they only

hypertrophy afterwards.



Malnutrition in America: malabsorption, don\'t feel like eating, child

abuse. Alcoholics: folate and thiamine deficiency, protein-calorie

malnutrition, later scurvy.



Tobacco: \"The American Indian\'s Revenge\". More physically addictive

than heroin, cocaine, or alcohol. (1) Lung cancer; (2) Emphysema; (3)

atherosclerosis; (4) mouth cancer; (5) esophageal cancer; (6) larynx

cancer; (7) bladder cancer; (8) kidney cancer; (9) pancreatic cancer;

(10) gastric ulcers; (11) Buerger\'s; (12) brain-damage to the fetus

(stay tuned, this is probably true); (13) household fires; (14) gum

disease; (15) stained teeth; (16) bad breath; (17) earlier wrinkling of

the skin. Quitting is always good. Emphysema is irreversible, but the

risk of cancer drops to baseline after some years, i.e., away from

smoke, there\'s selection against the bad clones.



Pneumoconiosis: Dust-disease of the lung. Particles 1-3 microns are

most likely to get deposited, and they\'ll be most abundant in the

respiratory bronchioles, where the wind speed drops.



Black lung: Coal miners. A mix of anthracosis (coal dust,

nonfibrogenic, mild, \"coal macules\" made of carbon-laden macrophages

can be washed out), silicosis (fibrogenic, nasty), TB, damage from

pollution, and/or tobacco effect. Weird immune responses to coal occur

in a few percent of coal workers (Caplan\'s is rheumatoid nodules in the

lung with lupus, rheumatoid arthritis, scleroderma, and/or

polymyositis-dermatomyositis; progressive massive fibrosis is a

gruesome, tumor-like mass).



Silicosis: Rock dust, sandblasters. Fibrogenic (when eaten by

macrophages, they produce interleukin 1). Nodules grow concentrically

around respiratory bronchioles, never stopping. Eggshell

calcifications. Increased TB risk, sometimes Caplan\'s.



Asbestosis: Fibrous silicate forms needles which move around in the

lung. Coated with iron (\"ferruginous bodies\"). Shipyard workers,

insulation workers, asbestos-abatement workers. Greatly increase your

risk for lung cancer if you smoke (trick question: the most common

asbestos-related cancer is common bronchogenic carcinoma). You need

asbestos to get mesothelioma, i.e. cancer of the pleura. Pulmonary

interstitial fibrosis, pleural fibrosis.



Berylliosis: Rocket workers (formerly), fluorescent bulbs (formerly);

Rocky Flats plant. Some folks have their T-helper cells excited by

beryllium, and these people get an exuberant growth of non-caseating

granulomas. Zirconium can do the same thing; it was big in deodorants

in past years (\"armpit sarcoid\").



Organic pneumoconioses: Spores from bacteria and/or mold. Farmers,

dirty air-conditioners. Type I, III, and/or IV immune injury.

Bagassosis: mold in sugarcane. Byssinosis: sensitized to cotton dust;

a dubious entity.



[ Violence is the antithesis of creativity and

wholeness. It destroys community and makes brotherhood

impossible.

-- Martin Luther King 1967



Go not in and out at the courts of law, that thy name

may not stink.

-- Egyptian papyrus, c. 900 B.C.



Confucius said, \"In hearing litigation, I am no

different from any other judge. But if you insist on a

difference, it is, perhaps, that I try to get the

parties not to resort to litigation in the first place.\"

-- Analects XII.13.



I have no easy solution to the world\'s violence. You already know the

right-wing and left-wing crackpot solutions; these would be funny if

only.... As before, my best prescription is Dr. Virchow\'s: reduce the

hurting and confusion through real democracy, honest science,

reasonable security of person and property, and access to education and

rewarding work.]



[Whose body is it? Distraught relatives are notoriously unreliable.

Time of death: Not an exact science. Filling out a death

certificate... The cause of death is your best opinion, as a

physician, with or without an autopsy. You list this on the death

certificate.



CAUSE OF DEATH: Thromboembolus in right main

pulmonary artery (circa 1 minute)

SECONDARY TO: Thrombophlebitis of leg vein (circa

5 days)

SECONDARY TO: Adenocarcinoma of the pancreas

(circa 6 months)



Please don\'t write \"cardiopulmonary arrest\" as the cause of death. We

already knew that....]



The mechanism of death is your story. \"The Trousseau pulmonary embolus

strained the right ventricle and a rhythm disturbance developed.\" Once

again, this is your best opinion.



The manner of death is for the lawyers: natural, accidental, suicide,

homicide, undetermined. This generates much weirdness.



All drugs are poisons, and all poisons are drugs.



Predictable toxicities:



Bleomycin Pulmonary fibrosis (high doses)

Cyclophosphamide Bladder inflammation

Adriamycin Cardiomyopathy, soft tissue necrosis

Vincristine Dysautonomia, painful neuropathy

Reserpine Sadness

Phenytoin Gum hyperplasia, teratogen

Cyclophosphamide Teratogen, kidney poison, gum hyperplasia

Coumadin Teratogen

Accutane (isotretinoin) Teratogen

Aspirin Rough on stomach and platelets

Benzodiazepines Amnesia

Scopolamine Amnesia

Caffeine Mild withdrawal syndrome (headache,

crabby)

Amphotericin B acute renal tubular necrosis

Opiates constipation, impotence

Methyldopa impotence

Serotonin happy pills delayed ejaculation

Thioridazine retrograde ejaculation

Anabolic steroids cholestasis, weird man stuff

Penicillin, high dose non-immune hemolysis

Methotrexate cirrhosis (be careful with doses)



\"The perfect crime\". I bet I\'d still catch you if you poisoned someone

with digitalis, succinylcholine, sodium fluoride, or insulin.



Unpredictable drug effects: The dose doesn\'t much matter



Penicillin anaphylaxis, rash

Quinidine class sudden death

Clozapine agranulocytosis

Phenylbutazone agranulocytosis

Gold nephrotic syndrome

Penicillamine nephrotic syndrome

Nitrofurantoin ARDS

Cyclophosphamide ARDS

Bleomycin ARDS

Busulfan ARDS

Azathioprine ARDS

Amiodarone ARDS, hepatitis

Griseofulvin hepatitis

Isoniazid hepatitis, lupus

NSAIDS renal shutdown

halothane liver necrosis

hydralazine lupus

procainamide lupus

methysergide retroperitoneal fibrosis

anti-malarials retinitis and blindness

anything rash



Cocaine: Major evil presence. Ischemic necrosis of nasal septum.

Cardiac muscle cell necrosis, vasospasm, sensitization to epinephrine.

Crack babies.



Opiates: The dangers of addiction itself have been greatly overrated;

it\'s constipating and bad for your sex drive, an overdose can kill you

(brain depression and/or pulmonary edema), and you\'ll make undesirable

friends. The bad health effects are from unhygienic practices.



[Cannabis (marijuana, pot, grass, hashish, etc.; \"I did not inhale\"):

Extremely political, but not really good for you. Probably makes you

lazy and stupid. Marijuana\'s been suggested as helpful for glaucoma,

AIDS wasting, and toxicity of chemotherapy; in the current political

climate, this isn\'t going to get acted-on.



The \"war on drugs\" needs no description. If our politicians (liberal,

conservative) actually WANTED to do something effective about our

godawful drug problem (rather than just making political capital off

it), we\'d have humane detoxification available on demand. We could,

and we don\'t.]



Elemental mercury: Work exposure, toxic encephalopathy, behavior

problems (\"mad hatter\"), clumsiness, sometimes ALS-like syndrome.

Inorganic mercury: Kidney tubule poison. Organic mercury:

Environmental contamination, particularly in high-on-the-food-chain

fishes. Minimata disease was a dread neurologic syndrome among

Japanese who ate fish caught near a mercury dump site.



Lead (\"plumbism\"): industrial exposure, moonshine, and children who eat

the sweet lead paint chips in slum housing. Stays in bone.

Hypochromic-microcytic anemia (inhibits delta-ALA synthetase and

ferrochelatase); also binds sulfhydryls. Basophilic stippling of red

cells. Renal Fanconi syndrome (proximal tubular dysfunction) with

acid-fast eosinophilic i intranuclear inclusions. \"Lead line\" in dirty

mouths. Encephalopathy, peripheral neuropathy (wrist drop).



Arsenic: Crime-fiction and crime-fact. (The guy in St. Louis who kept

his wife sick with arsenic \"wanted quality time with her\".) Disrupts

oxidative phosphorylation. Vomiting, blood diarrhea acutely, maybe

brain necrosis. Chronic cases (1) hyperkeratosis of the skin,

particularly the palms; these may turn into squamous cell carcinomas;

(2) \"Mee\'s lines\", white lines in the fingernails, where arsenic is

bound to keratin.



Paraquat: Drink it, and you\'ll die in a few weeks of ARDS.



Chlorinated hydrocarbon insecticides (DDT, dieldrin, others):

neurotoxins.



Organophosphate insecticides (malathion, parathion): Acute, or from

breakdown of bodyfat. Acetylcholinesterase inhibitors, i.e., first

you\'ll twitch, then go limp (why?).



Polychlorinated biphenyls (\"PCB\'s\"): Politicized; innumerable claims

that mostly can\'t be true. They do stay around in the environment

forever.



Dioxins: Agent orange, etc. Politicized, much bunk, but there\'s reason

to worry. A few weeks after heavy exposure, a human\'s sebaceous gland

basal cells undergo metaplasia into keratinocytes, pushing sebum out of

the follicle in huge horny blobs (\"chloracne\"). This gets better in a

few months or years.



Toadstools: Amanita phalloides, the \"death angel\" produces aminitin,

which inhibits RNA polymerase. Death results from hepatic necrosis.

Amanita muscaria produces muscarin(e), prototype of the

parasympathomimetic drugs. (\"SLUD\" strikes again.) Expect to survive.



[ \"When I put my arms around you and kiss you on your mouth,

Then I am happy even without beer!\"

-- Ancient Egyptian love song]



Alcohol: Your lecturer thinks he\'s being fair when he says that the

harm caused by alcohol exceeds, by an order of magnitude, the harm from

the illegal drugs. Yet most people who drink alcohol sensibly appear

to take no harm and perhaps even derive some healthy pleasure. Noah

needed a drink when... and made an \"ass\" of himself, the \"butt\" of his

son\'s joke. Proof: Double the percentage of ethanol. Nobody knows the

chemistry of drunkenness. The liver metabolizes alcohol first to

acetaldehyde (via alcohol dehydrogenase), then to acetic acid, and

ultimately to carbon dioxide and water. Problem drinkers lose their

dendritic spines; \"each drink kills x-number of brain cells\" is

rubbish. Each beer or shot raises a normal-size dude\'s blood alcohol

level by 20 mg/dL; \"legally drunk\" is maybe 100 mg/dL but you\'re

impaired below this. You metabolize alcohol at a rate of 15 mg/dL/hr,

using basically zero-order kinetics; faster if you\'re a practiced

drunkards.



Health problems of heavy drinkers: (1) alcoholic hepatitis and hepatic

cirrhosis; (2) brain damage (loss of dendritic spines, Wernicke,

Korsakoff, cerebellar atrophy); (3) pancreatitis (acute and the painful

chronic form); (4) cancer of esophagus, throat, and larynx; (5) GI

bleeding from ulcers, varices, gastritis; (6) fetal alcohol syndrome

(variable; look for flat philtrum, epicanthic folds, growth and mental

retardation); (7) neuropathy (numb fingers); (8) cardiomyopathy (rare);

(9) rhabdomyolysis (seldom dramatic, but probably contributes to long-

term wasting); (10) hangover, tremulousness, seizures, delirium tremens

on withdrawal (\"pink elephants on parade\", etc.); (11) losing job,

family, friends; (12) oh, and by the way, it probably has a slight

favorable effect on HDL and coronary atherosclerosis. Gee whiz.



[ \"I\'ve been asked if I ever get the

DT\'s. I don\'t know. It\'s hard to tell

where Hollywood ends and the DT\'s begin.\"



-- W.C. Fields]



Methanol (\"meth\", \"wood alcohol\", \"blind, vomiting, and drunk\") is

metabolized to formaldehyde and thence to formic acid (which gives the

famous high anion gap acidosis). The retina toxicity is infamous

(\"like stepping into a snowstorm\") and can be persistent. Part of the

treatment involves saturating alcohol dehydrogenase with ethanol.



Isopropanol (\"rubbing alcohol\", users are \"rubby-dubs\", etc.) is about

twice as potent an intoxicant as ethanol, but really nasty to the

gastric mucosa. Metabolized to acetone via alcohol dehydrogenase, and

produces an modest anion gap acidosis.



Ethylene glycol (anti-freeze) is metabolized to glycolaldehyde,

glyoxylic acid, and oxalic acid. Big anion gap acidosis, and little

crystals that carve up renal tubules, meninges, etc. Not a nice way to

die.



I\'m resisting the temptation to talk about guns.



Abrasions: Epidermis scraped off, dermis not much damaged, heal with no

scar. Lacerations: Splits and tears of skin and/or soft tissue, due to

stretching-shearing or crushing, on the body surface or deep inside.

Flail-chest: Broken ribs go in and out, making breathing relatively

ineffective. Tension pneumothorax: A rip in the pleural admits air to

the pleural cavity on inspiration, but does not allow it to exit; this

will push the mediastinal contents to the other side, obstructing

venous return.



Stab wounds (i.e., the track is deeper than the width of the skin

wound); incised wounds (cuts, i.e., the track is less deep than the

width of the skin wound); chop wounds (incised wounds plus an

underlying bone fracture or groove, made by heavy instruments). Sharp

trauma gives clean margins and no bridging in the depths. Blunt trauma

(i.e., lacerations) give bridging in the depths of the wound, frayed

and bruised margins.



Suffocation: Failure of oxygen to reach the uppermost airway. Too

little oxygen to breathe, and the hemoglobin refuses to bind it any

more. Smothering: suffocation by something pressing on the face.

Choking: Obstruction within the air passages. When \"natural\", the

cause is epiglottitis. Accidents include the cafe-coronary, popcorn,

vomit (Jimi Hendrix). Homicides: (1) stuffing a baby\'s mouth with

toilet paper to stop its crying, or (2) using a rag in the mouth in

conjunction with a gag. Mechanical asphyxia: Pressure outside the

body; large snakes, human piles, cars falling on mechanics. Each time

you breathe out, your chest is further constricted. When you try to

breathe back in, you cannot. At autopsy, you\'ll see bruises, petechiae

all over the conjunctiva and sclera, and impressive congestion of the

head. An important variation is positional asphyxia. Someone slips

into a confined space, and each exhalation causes the person to slip

deeper. Suffocating gases: Gases may displace oxygen in the

atmosphere. Methane (\"How\'s that canary doing?\") and carbon dioxide.



Strangulation: Occlusion of the blood flow and air passages in the neck

by external compression. Look for petechiae on the conjunctiva.

Hanging: Compression of neck structures secondary to a noose tightened

by body weight. (Humans are \"hanged\", inanimate objects are \"hung\"; a

man saying he\'s \"hung\" is bragging.) Death is due to a fractured spine

in a properly-done judicial hanging; more often, it\'s due to arterial

or venous compression. Ligature strangulation: Compression of neck

structures is secondary to a noose tightened by something other than

body weight. Manual strangulation: Compression of neck structures by

someone else\'s body part.



Chemical asphyxia. Cyanide: Blocks the cytochrome system. Painful,

and by no means instantaneous. At autopsy, look for (1) bright red

blood (i.e., cyanide prevents utilization of oxygen) (2) the \"bitter

almonds\" smell (around 1 person in 3 cannot smell it); (3) thiocyanate

in the blood (normal folks, especially smokers, will have some of this

on board already.) Carbon monoxide: Acts by tying up hemoglobin. Its

affinity for hemoglobin is 200 times that of oxygen. Smokers are

likely to have 10% saturation of hemoglobin. Saturation from 20-30%

will make you sick (it\'s at this point that cherry-red lividity may

appear). Saturation of 60% or more will probably kill you. In acute

toxicity, there is headache, drowsiness, and ultimately confusion and

coma. Necrosis of the basal ganglia, early or late, is common. Whole

family has a headache? How\'s that home heater working?



Surface burns.....



First-degree: The outer epidermis is damaged. The

dermal vessels probably dilate, but there

are no blisters.

Second-degree: Living cells are killed in the epidermis.

There will be a blister.

Third-degree: No more epidermis.

Fourth-degree: Charred through.



Complications of burns include:



-- hyperkalemia, from disruption of red cells and other cells by the

heat;

-- shock and hemoconcentration, from the tremendous amount of fluid

lost in the inflammatory exudate (this is the most serious problem

in the emergency department);

-- acute renal tubular necrosis;

-- disseminated intravascular coagulation, due to damaged vessel

walls and bad stuff getting into the bloodstream (distant

endothelium really is damaged);

-- Curling\'s ulcers of the gastric mucosa, with GI bleeding.

-- infection of the burn (pseudomonas, candida); this is the most

serious problem in today\'s burn unit.



[ \"What was the last thing the judge said to Ted

Bundy? More power to you!\"

-- Anonymous



\"What was Ted Bundy\'s last job? Conductor!\"

-- Anonymous]



High-voltage alternating current (i.e., 7680 volts, from the generator

plant) kills by generating heat.



Low-voltage alternating current (i.e., 110 volt household current)

kills by inducing ventricular fibrillation; or if the amperage is high,

the heart simply cannot re-polarize.



High-voltage direct current: Lightning; arborescent patterns.



Effect of current:



1 milliamp tingle, \"let-go\" current

10 milliamps \"can\'t-let-go\" current

30 milliamps respiratory paralysis

75-250 milliamps ventricular fibrillation is likely

4 amps asystole



Heat problems: Babies, the elderly, and those taking anticholinergic

agents and phenothiazine drugs are especially vulnerable to these

problems; so are those on cocaine, those doing forced labor in hot

quarters, and those training in the heat. Heat exhaustion, a person

over-exerts in a hot environment. Electrolyte problems, lactic

acidosis, maybe rhabdomyolysis. Heat stroke: Body gets so hot that its

thermoregulatory controls no longer work. Vicious cycle to death.



Cold: Below 31C / 86F, our enzymes don\'t work well. As a person dies

of hypothermia, the skin blanches (vasoconstriction, why?), then

reddens (loss of vasomotor control, with resultant rapid loss of heat.)

The latter effect probably explains why many people who are freezing to

death remove their clothes. Death probably results from brain and/or

heart dysfunction. Chilblains: Purple spots on the shins in cold

exposure; nobody understands it.



Ionizing radiation: Cells that normally divide a lot (i.e., epidermis

and its adnexa, GI mucosa, bronchi) are more vulnerable to radiation

than most other organs. Germ cells and lymphocytes also carry the

instruction: \"If you\'re hurt, then die, don\'t divide.\" (Why might that

be?) Bone, muscle, cartilage, and nerve are highly radioresistant.

Except as noted above, the susceptibility of a cancer to radiation has

little to do with the susceptibility of its parent cell. Pathologists

look for hyaline vascular sclerosis and big, hyperchromatic nuclei.



Radiation sickness



200- 500 rads Hemopoietic syndrome. Early nausea and vomiting on

the first day. Afterwards, blood cells disappear

from the body (lymphocytes first, since they are

the most vulnerable; afterwards, short-lived

neutrophils and platelets; ultimately, survivors

become anemic.) Victims receiving 200 rads will

probably survive; those receiving 500 rads will

probably die.



500-1000 rads Gastrointestinal syndrome. Severe nausea and

vomiting occur within a few hours, and are only the

most prominent symptom in a body in which many

cells have died in many places. Most victims will

die in a few days.



>5000 rads Cerebral syndrome. Brain necrosis and edema will

produce drowsiness, coma, and death in an hour or

two.



Lead me from death to life, from falsehood to truth.

Lead me from despair to hope, from fear to trust.

Lead me from hate to love, from war to peace.

Let peace fill our heart, our world, our universe.

-- Brihadaranyaka Upanishad

(Hindu scripture)



I think that people want peace so much that one of these days

governments had better get out of the way and let them have it.

-- Dwight D. Eisenhower, 8/31/1959



Embryo: An unborn child / product of conception with child parts for

the first eight weeks after the moment of conception. Fetus: An unborn

child / product of conception with child-parts (rather than just

placenta), between eight weeks after conception and the moment of live

birth (\"all-the-way-out with a beating heart\" for our lawyer friends).

Neonate: A child in the first four weeks of life after birth. Infant:

A child in the first year of life after birth. Infant mortality: For

a population, how many of its people per 1000 live births die before

their first birthday.



Pre-term: Born before 37-38 weeks. Born at 22 weeks: Will almost

surely die in first six months. Born at 23 weeks: Will probably never

be healthy. Born at 25 weeks: 50% chance of not having gross brain

damage. Post-term: Both after 42 weeks. Small for gestational age

(\"small for dates\"): Below 10th percentile on the charts. The child

did not grow properly in the uterus, and the organs will have extra

problems once the child is born.... Why SGA?



Problems with the unborn child itself

Chromosomal problems

Congenital infections (\"torch\")

Toxoplasmosis

Other (syphilis, etc.)

Rubella

Cytomegalovirus

Herpes (usually not an intra-uterine infection)

Other congenital anomalies

Problems with the placenta or uterus

Infarcts

Tumors

Etc., etc.

Problems with Mother

Cocaine (\"crack babies\")

Tobacco

Opiate abuse

Alcoholism

Toxemia and other hypertension



Large for gestational age: Above 90th percentile on the charts. Think

of maternal diabetes. Low birth weight: As it sounds; a mix of \"small

for gestational age\" and \"preterm\". By definition, <2500 gm. Very low

birth weight: <1500 gm.



Uterine constraint: begins around our 35th week of intrauterine life.

Worse with twins, oligohydramnios (no kidneys / leaky sac), fibroids,

bicornuate uterus. Deformation (as opposed to a \"malformation\"):

molded out of shape by uterine constraint. Two percent of kids get a

significant deformation. Most famous is oligohydramnios sequence, with

squashed (\"Potter\'s\") face and badly bent limbs.



Malformations result from chromosomal problems, genes of large effect,

deletions of chunks of a chromosome, polygenic problems, or \"just

happen\". Range from hypospadias to anencephaly.... Around 3% of kids

have a malformation that\'s at least of serious cosmetic importance

(i.e., \"a major malformation\").



Neonatal asphyxia is an important cause of death and brain damage in

babies.



Causes:

Placental problems

Placenta previa (i.e., a low-slung placenta overlying

the os)

Abruption (i.e., a big bleed between placenta and

uterine wall)

Cord problems

Compression (around neck, breech delivery, etc., etc.)

Other (poorly-understood)

Toxemia

Prolonged rupture of the membranes

Chorioamnionitis

Etc.



Birth injuries: Remember intracerebral hemorrhages from dural sinuses

or brain substance. The most important birth injury, devastating.

Upper extremity injuries: Fractured clavicle, brachial plexus injury

(Erb\'s palsy, etc., etc.), fractured humerus. Facial nerve injury:

Often from forceps (Silvester Stallone\'s syndrome).



Galactosemia: Two autosomal-recessive inborn errors. The not-so-bad

kind of galactosemia: lack of galactokinase. Galactolol cataracts.

The bad kind of galactosemia is caused by galactose-1-phosphate uridyl

transferase deficiency. Nobody really understands the pathophysiology.

Liver swelling, brain damage. You must eliminate milk from the diet.



Phenylketonuria should be familiar to you; inability to metabolize

phenylalanine properly results in brain damage, and a restricted diet

helps prevent this. Kids are typically fair-complected (not much

tyrosine to make melanin from).



Cystic fibrosis: homozygous lack of a membrane component (CFTR)

essential to proper chloride transport across membranes of the mucus-

producing exocrine glands and eccrine sweat glands in response to cAMP.

Name comes from the pancreatic and salivary gland changes resulting

from gooey plugs. Pancreatic insufficiency, causing malabsorption, is

easily corrected by supplementing enzymes. Sweat ducts fail to resorb

salt (hence \"salty skin\", positive sweat test). Goo fills the bronchi,

leading to bronchiectasis and repeated lung infections (staph,

pseudomonas). Good in the meconium causes meconium ileus. Males are

infertile (poor spermatogenesis, often the vas is lacking). Diabetes

and cirrhosis are rare; these kids usually die nowadays in young adult

life from lung problems.



\"God is great, God is good,

Get me through my childhood!\"

-- Bart Simpson



\"Ed tells it like it is.\" SIDS (the leading killer of normally-formed

kids age one month to one year) is far less mysterious than you\'ve been

led to believe. Known causes include (1) falling asleep face-down and

smothering on the mattress; (2) parent falling asleep (passing out from

alcohol or drugs, etc.) on top of the baby; (3) negligence on the part

of caretakers; (4) murder by smothering. Rule out (4) epilepsy; (5)

obstructive sleep apnea; (6) botulism from raw honey; (7) ectodermal

dysplasia with no sweat glands; (8) anomalous coronary arteries; (8)

carbon monoxide; (9) kinks in fatty acid metabolism. To be fair, some

cases probably are (10) \"mysterious\". To clinch what most pathologists

have known since the \"SIDS mystery\" nonsense began... Waneta E. Hoyte,

the mother whose \"tragic story\" led to the paper (Ped. 50, 646, 1972)

that spawned the apnea monitor racket confessed in 1994 to having

smothered her five children. (\"Their screaming made her feel useless\":

Ped. 93: 944, 1994). This is now common-knowledge, and the writers of

the USMLE surely know it; it would make a great test question.



[Children do not vote, and when politicians get involved (even to

\"protect our children\"), kids are almost always the big losers.

Tonight in the U.S., 100,000 kids will be sleeping on the streets;

almost all of them have run away / been discarded from intolerable home

situations. However, in the current political climate, you\'d better

not even try to be a real friend to the neglected, mistreated kids in

your own community. If you don\'t know this now, you will soon.]



[ Old people like to give good advice, as solace for no longer

being able to provide bad examples.

-- de la Rochefoucauld



Not so much to add years to life, as to add life to years.

-- Geriatrician\'s motto]



Our bodies are programmed to wear out. [The Darwinian advantage is

surely that this makes way for our children, who combine our genes with

those of others to make their long-term survival more likely.] The

Hayflick phenomenon results in the non-replication of baby\'s cells in

tissue culture after 50 divisions; it\'s unlikely that this has to do

with human aging, since there\'s no reason to think it applies to stem

cells, and the cells that bear the brunt of aging (i.e., brain) are

post-mitotic. Loss of telomeres with each cell cycle, and their re-

synthesis in germ cells, is interesting, but doesn\'t even account for

the Hayflick phenomenon, since a Hayflicked-out nucleus suppresses

division in a baby\'s nucleus. Stochastic theories (\"wear and tear\")

simply don\'t explain the stereotyped changes in aging, though \"wear and

tear\" does account for some of the degenerative changes. Attempts to

use free-radical acceptors to slow aging have been a total flop, though

they seem to control some wear-and-tear diseases.



Older folks have (1) more lipofuscin in their cells; (2) slower rates

of cell turnover; (3) greater vulnerability of mitochondria to hypoxia;

(4) extra cross-linking of connective-tissue molecules (why I\'m stiff);

(5) non-enzymatic glycosylation of proteins (why diabetics\' vessels

\"age faster\"); (6) more lymphoid tissue but less ability to make

antibodies appropriately, though this is mild; (7) more autoantibodies,

but less autoimmune disease (contrary to some texts); (8) less ability

to the T-cells to proliferate; (9) thinning of the dermis and

epidermis, and loss of some connective tissues (reversible with growth

hormone); (10) less sex hormone (we men will be getting replacement

when we get old, trust me); (11) some loss of neurons in brain and

ganglia, nobody knows why; (12) some loss of hearing, both conductive

and nerve; (13) some thickening of the intima of arteries, even without

atherosclerosis; (14) some decrease in glucose tolerance; (15)

substantially diminished nitric oxide synthesis in endothelium; (16)

loss of androgen receptors on erectile tissue, guys; (17) mild loss of

elasticity in the lungs and skin; the lungs get it much worse if you

smoke; (18) some loss of bone matrix (osteoporosis); (19) diminished

sense of smell, but not taste); (20) little bumps of various sorts on

your skin; (21) hair turns gray; (22) lens of the eye stiffens

(\"presbyopia\"), get those reading glasses.



You will surely die at, or soon after, age 100, even if you have no

diseases at all; and this hasn\'t changed since reliable record-keeping

became the norm. Every other vertebrate species has a maximum age,

too; it varies some among inbred strains.



Syndromes of accelerated aging aren\'t. Classic progeria, autosomal

recessive, features kids born looking old, with peachfuzz instead of

hair; this doesn\'t progress. Werner\'s features people that look older

than they are, and Werner\'s cells Hayflick-out at about 20-30 divisions

instead of 50. Both feature increased \"degenerative diseases\" as in

old folks,



[ \"Anything you can turn your hand to, do with whatever

power you have; for there will be no work, nor reason, nor

knowledge, nor wisdom in the grave where you are going.\"

-- Ecclesiastes 9:10]



Symbiont: The organism and its host have a mutually advantageous

arrangement (mitochondria producing ATP, E. coli producing vitamin K,

in exchange for room & board). Commensal: The organism does the host

no good and no harm (worthless bugs in the gut, hepatitis B carrier).

Parasite: The organism thrives by harming the host (i.e., the

pathogenic micro-organisms). Saprophyte: The organism lives off dead

stuff (i.e., fungi that thrive only in the hair, nails, or dead keratin

layer of the skin). Infection: The parasite or saprophyte is making

somebody sick. Infestation: A commensal, parasite, or saprophyte has

been detected, other than what most people carry, whether or not

somebody is sick. Superinfection: An infection which results because

tissues are made vulnerable by another infection. Hyperinfection:

Orders of magnitude more infectious agents than you \"should\" have,

because of a fundamental change in your relationship with your

parasite. (The prime example is strongyloidiasis, where the worm

changes its life cycle in the immunosuppressed). Vector: A

multicellular animal (usually an arthropod) which transmits an

infectious micro-organism. Fomites: Inanimate objects which carry

infectious organisms. Carrier: A clinically healthy person who is

shedding an infectious organism, and can make others sick. Nosocomial

infection: A hospital-acquired infection. Hospital pathogens are the

result of decades of selection for antibiotic-resistance and the

ability to infect the very-sick.... Epidemic: An outbreak of

infectious disease. Endemic: A never-ending epidemic. Pandemic: An

epidemic involving the whole world. Zoonosis: A disease contracted

from animals (ZOE-uh-NO-sis). Epizotic: An epidemic among animals

(EP-uh-zoe-OTT-ick). You already know Koch\'s postulates. Today, the

final \"fifth postulate\", which establishes the micro-organism as agent

of the disease, is the demonstration of a virulence gene.



Viruses:



Double-stranded DNA viruses

Adenovirus family

Hepadnavirus family

Hepatitis B

Herpes viruses

Cytomegalovirus

Epstein-Barr

Herpes simplex I

Herpes simplex II

Human herpes virus 6

Herpes zoster / chickenpox

Papovavirus family

Human papillomavirus

JC virus (PML, brain disease)

Poxvirus family

Molluscum contagiosum

Smallpox

Smallpox vaccine (\"vaccinia\")



RNA viruses

Reovirus family

Rotavirus (sporadic viral gastroenteritis)

Coronavirus family

Orthomyxovirus family

Influenza group

Picornavirus family

Calcivirus subfamily

Hepatitis E

Winter vomiting disease virus

Enterovirus subfamily

Coxsackie virus

Echovirus

Poliovirus

Many others

Hepatitis A

Hoof & mouth disease (animals, see above)

Rhinovirus subfamily

Paramyxovirus family

Hepatitis G (?)

Measles

Mumps

Parainfluenza

Respiratory syncytial virus

Retrovirus family

HIV-1 & 2 and their kin

HTLV I & II

Animal tumor viruses (many)

Togavirus family

Rubella

Hepatitis C (a flavivirus?)

\"Arboviruses\" (toga-, flavi-, arena-, bunya-, reo-, filo-)

Arbovirus encephalitis viruses

Colorado tick fever

Dengue family

Regional hemorrhagic fevers

Yellow fever

Hantavirus (\"Navajo pneumonia\", others)

Other

Norwalk agent (epidemic viral gastroenteritis)

Parvovirus

Rabies virus



Viral inclusions are aggregates of virus proteins, visible by light

microscopy. These assist greatly with the histologic diagnosis of

viral disease. Worth remembering:



Intranuclear (\"Cowdry A\" and \"Cowdry B\"; don\'t worry about the

distinction)

Adenovirus (\"smudge cells\")

Cytomegalovirus (one large, clearly-defined)

Herpes simplex I & II (1 large, clear, + multinucleate)

Herpes zoster (same as simplex)

Measles (in Warthin-Finkeldey cells, and SSPE)



Intracytoplasmic

Cytomegalovirus (many small)

Rabies (\"Negri bodies\" in neurons)

Molluscum contagiosum (\"molluscum bodies\" in skin)

Smallpox (\"Guarnieri bodies\" in skin)

Chlamydia (not really viruses....)



The common cold: Rhinovirus, coronavirus; bad ones are adenovirus.

Adenovirus produces the famous \"smudge cells\" in pneumonitis. \"Viral\"

chest colds may be mycoplasma.



[ \"Dost thou pray to thy god that thy

nose may not run? Nay, foolish one!

Thou blowest thy nose on the sleeve of

thy toga!\"

-- Epictetus]



Influenza A: Pandemic influenza. Influenza B: Epidemics; children

badly affected. Influenza C: Sporadic, upper respiratory infections.

Influenza in the lungs tends to get superinfected with staph.

Parainfluenza: Like influenza, causes \"croup\".



Coxsackie A: blisters on the back of the throat (\"herpangina\"), a

misnomer, and/or hand-foot-and-mouth disease. Coxsackie B: pleuritis,

myocarditis. Respiratory syncytial virus: Bronchiolitis in kids, fused

epithelial cells; now known to be common in debilitated adults.



Mumps: Salivary glands inflamed in kids, sometimes pancreas; orchitis

in grown men, if severe and bilateral, may sterilize but never

demasculinize; the cause is edema and ischemia because of the tight

capsule. Despite immunization, the virus is still around.



The GI \'flu: rotavirus (winter vomiting in kids), calicivirus (winter

vomiting), Norwalk agent (vomiting and diarrhea anytime), adenoviruses,

echoviruses; most sporadic \"GI \'flu\" is food poisoning.



HPV-2: The common wart. HPV 16 & 18: genital warts that tend to turn

into cancer. (\"Genital warts\" used to be called \"condyloma

acuminatum\").



Measles: Droplets. Incubation period 2 weeks. Koplik\'s spots are

blister-ulcers next to Stetson\'s duct. Rash, photophobia, anergy.

Dread complications include pneumonitis (\"measles giant-cell

pneumonia\", Warthin-Finkeldey epithelial giant cells), and/or

autoimmune brain damage. Slow-virus measles produces subacute

sclerosing panencephalitis. Measles is a morbillivirus, the other one

being the Australian horse-trainer-killer virus of 1995 fame.



Rubella: German measles, three-day measles. Arthritis, mild rash, and

teratogenicity (high IgM in cord, blindness, deafness, heart defects,

thrombocytopenia, big liver and spleen, skeletal deformities).



Smallpox: Do you think every rogue-nation has discarded its supply? I

doubt it, so someday we\'ll probably see it again. Droplet infection,

blisters on the skin, damage throughout the body of course.



Parvovirus 19: erythema infectiosum / \"fifth disease\", is now known to

be responsible for aplastic crisis in sicklers and spherocytosis folks.



Herpes 6: exanthem subitem / roseola, an AIDS opportunist which

probably speeds progression; lives in B-cells. Herpes 8 (KSHV): The

Kaposi\'s virus. Kaposi\'s \"sarcoma\" clearly is not, and never was,

cancer. It\'s epidemic in Africa (HIV or no HIV), arises multifocally,

usually shows no anaplasia, and gives a good therapeutic response to

antiviral agents.



Herpes simplex 1: fever blisters, from getting kissed as a baby

perhaps. Hides in the gasserian ganglion. Can be a major problem for

folks with eczema; \"Kaposi\'s varicelliform eruption\" is herpes simplex

pretending to be chickenpox in the immunosuppressed. Dendritic corneal

ulcers. Esophageal herpes is painful in the immunosuppressed, and the

presence of herpes is a risk for mouth, throat, and esophageal cancer

(synergistic with alcohol and tobacco). Sudden necrosis of the

temporal lobes (\"herpes encephalitis\") is a nightmare disease. Herpes

simplex 2: genital herpes, needs no description; don\'t let a mother

give vaginal birth while her lesions are active, or baby will get very

sick. Herpes zoster: chickenpox and recurrent one-dermatome

\"shingles\", the latter often with a pain syndrome. All blistering

herpes diseases are intraepithelial necrosis. Spot any of these with a

Tzanck smear, i.e., look for the herpes large epithelial cells with

swollen nuclei and maybe a prominent single intranuclear inclusion.



Cytomegalovirus: Another herpes virus. Met in the second trimester of

intrauterine life, this can produce a devastating infection (small for

gestational age, jaundiced, hemolytic anemia, thrombocytopenia,

\"blueberry muffin\" purpura, blind, deaf, retarded, and/or epileptic;

brain necrosis with calcifications around the ventricles is common).

Most intrauterine CMV produces none of this. Meet it in childhood,

nothing happens. Most of us meet it when we start kissing on dates.

CMV is a lung, gut, and/or retina opportunist in the very

immunosuppressed.



Epstein-Barr virus: Herpes 4. The acute infection immortalizes B-cells

and, in older folks, produces EBV infectious mononucleosis (blood is

full of big T-cells, called \"atypical lymphocytes\" or \"virocytes\",

pursuing the virus, which is hiding in B-cells). (Other mononucleosis

syndromes result from meeting CMV, toxoplasmosis, and HIV). In EBV

infectious mono, there\'s often cold agglutinins, mild thrombocytopenia,

or a rash (if you take ampicillin); you\'re already familiar with the

fever, malaise, and big nodes and spleen. For the lab diagnosis of

EBV, ask a microbiologist. Other EBV diseases: (1) Burkitt\'s lymphoma

(EBV scrambles chromosomes and probably promotes); (2) multiple

sclerosis (stay tuned); (3) Chinese nasopharyngeal cancer; (4) Eskimo

salivary gland cancer; (4) other cancers in the immunosuppressed,

including lymphomas and sarcomas.



Yellow fever: Apoptosis of hepatocytes, especially midzonally.

Reservoir is monkeys, vector is Aedes mosquito.



Dengue: Epidemic right now in Mexico. Painful, self-limited mosquito-

borne fever. DENGG-ee is the preferred pronunciation. Regional

hemorrhagic fevers are carried by ticks, or by mouse droppings. They

produce a platelet poison somehow. The worst is Lassa fever; the

closest we have is Colorado tick fever.



Marburg virus: hemorrhagic fever in people exposed to monkey blood;

explodes endothelium. Ebola virus, from Africa, is a severe,

moderately contagious hemorrhagic fever. It got into the U.S. in 1990

among some monkeys, but didn\'t stay. Hantaviruses, the cause of Korean

hemorrhagic fever and the agent now established as the cause of the

outbreak of fatal disease in the U.S. southwest in 1993, were once

popular candidates for biologic warfare agents.



Chronic fatigue syndrome is real and probably represents widespread

immune overactivation from any of a number of viruses.



Chlamydia: Little incomplete bacteria adapted for intracellular life.

Psittacosis (\"parrot fever\") is a chlamydia pneumonia. Trachoma is

low-virulence chlamydia in the eye in poor nations, especially with

vitamin A deficiency already there; we know it better in its even-more-

benign form as inclusion body conjunctivitis, one of the reasons we

chlorinate swimming pools. The same bug that produces swimming-pool

conjunctivitis gives genital chlamydia, giving a man a drop, and a

woman cervicitis/salpingitis, like gonorrhea but not quite so

impressive. Lymphogranuloma venereum is caused by aggressive

chlamydia, and is a festering, deep chlamydial infection of the

perineum (\"watering-can bottom\", etc.) TWAR chlamydia cause pneumonia,

especially in old folks.



Rickettsia: Little gram-negative bacteria that have adapted to live

inside endothelium, which they damage as they grow; they also release

noxious stuff into the bloodstream. Rocky mountain spotted fever (R.

rickettsii): tick-borne (the big spits into you), most common in

Appalachia (uh-huh), petechiae all over including the palms and soles.

Ehrlichiosis: Rocky Mountain Spotless Fever. Typhus (R. prowazekii) is

louse-born (the creature defecates while dining), less often flying

squirrel fleas; the bug hides between epidemics and re-emerges as

sporadic Brill-Zinsser disease, which can infect another louse. Murine

typhus (R. typhi) is rat-borne and mild. Scrub typhus (R.

tsutsugamushi), is a scourge of the Asian tropics. Q-fever (Coxiella

burnetti) is a pneumonia transmitted by ticks or sneezes, from humans

or animals. Bartonella (Rochalimaea) quintana is a rickettsia-like

creature that causes bacillary angiomatosis in AIDS and other immune-

compromised folks. Rochalimaea (formerly \"Afipia felis\") causes cat-

scratch fever.



Rash on the palms and soles: secondary syphilis, toxic shock, Rocky

mountain spotted fever, Kawasaki, and don\'t ever forget

meningococcemia.



Mycoplasma are more little incomplete bacteria. Mycoplasma pneumonia

(M. pneumoniae) is a common winter chest cold; most of these folks

respond to antibiotics and so forth. Other mycoplasma can cause

urethritis. There are rumors of a mycoplasma as the cause of Desert

Storm syndrome.



[Few \"issues\" are more one-sided than immunization; the fact that

people don\'t understand \"odds\" and \"risk-benefit\" keeps Las Vegas in

business. The extraordinary success and surprising safety of today\'s

vaccines has not stopped people (pseudo-liberals, pseudo-conservatives)

from making political capital by telling folks not to get immunized.

The 1980\'s saw devastating epidemics of rubella, measles, and whooping-

cough among the children of people who should have known better.]



Bacterial infections used to strike down people in their primes, and

still provide the pathway out of life for the sick and disabled. Some

bugs are very virulent (i.e., pneumonic plague), but most require some

weak spot for entry. If the weak spot is some already-existing

disease, the bacteria can produce a superinfection. The surface of a

foreign body is a great place for bacteria to grow, since neutrophils

cannot gobble them up.



Exactly how bacteria make us sick is still largely mysterious. The

ideas about depriving normally-perfused tissue of its buffers and

nutrients is ludicrous. Exotoxins (soluble molecules made by living

bugs) are rare; notable are the products of certain clostridia

(botulism, tetanus, perfringens) and other food-poisoners. Broken-down

walls may contain endotoxin. Phagocytes chasing bacteria will

predictably harm the body, at least to some extent.



Bacteremia: Bacteria in the blood, as after tooth-brushing. Sepsis /

septicemia / septic shock is currently getting sorted out and the

nomenclature standardized, but it means the bacteria have a foothold in

your bloodstream; your grandma called it \"blood poisoning\".



Staphylococci include the vicious \"coagulase positive\" / \"aureas\"=gold

strain, famous cause of hair-infections (big ones are \"furuncles\",

bigger ones are \"carbuncles\"); growing on magnesium-rich tampons, some

produced toxic-shock syndromes, and there are related skin-toxin

syndromes (\"scalded skin\"; epidermolytic toxin) too. Impetigo is

staph-strep infection of the upper-epidermis-only. Virulence factors

are coagulase, hemolysin, protein A (binds Fc of Ig), catalase

(neutralizes H2O2); food poisoning is from enterotoxin B (the warm-

milkshake and donut-creme-filling bug). Gold-staph\'s gimmick is

coagulase, which makes a fibrin cocoon to protect it from phagocytes,

hence the localized infections. Methicillin-resistant staph, a fad

problem, is best controlled by handwashing. White staph

(\"epidermidis\", coagulase-negative) are likely to infect heart valve

prostheses.



Strep A: Strep pyogenes, strep throat, rheumatic fever, skin infections

(impetigo), soft tissue infections (cellulitis, phlegmon, erysipelas,

lymphangitis streaks), post-streptococcal glomerulonephritis.

Virulence factors include the capsular polysaccharides, the M-proteins,

streptokinase, streptodornase (DNA wrecker), and streptolysin A.

Strep\'s gimmick is to dissolve ground substance and spread faster than

the polys can chase it. Strep throat needs no description; quinsy is

peritonsillar abscess, Ludwig\'s angina is cellulitis of the floor of

the mouth which can compromise the lower airway. Scarlet fever follows

strep throat when the bug contains the phage to produce erythrogenic

toxin. Puerperal sepsis: childbed fever, uterine infection post-

partum, was iatrogenic until handwashing was introduced. The flesh-

eater produces necrotizing soft-tissue infections and/or pneumonia; its

virulence factors are pyrogenic exotoxin A (activates huge numbers of

T-cells, which is unwholesome), and pyrogenic exotoxin B (cysteine

protease that actually dissolves tissue).



Strep B: New baby infections. Strep D: Enterococcus, now a drug-

resistance champion; others. Untyped: Green viridans strep which grow

on already-damaged heart valves; pneumococci; the latter are the

familiar encapsulated gram-positive diplococci so familiar from lobar

pneumonia; pneumococcal sepsis is a problem for those lacking a spleen

(surgery, sicklers), and pneumococci thrive in the ascites fluid of

cirrhotics and nephrotics.



Neisseria, the familiar gram-negative bean-shaped diplococci, include

the meningococcus, a nasal bug that from time to time mutates and

produces epidemics of meningitis and/or sepsis-DIC. Waterhouse-

Friderichsen syndrome is adrenal-cortex hemorrhage and necrosis in

meningococcemia or other sepsis. The gonococcus produces the familiar

urethritis, cervicitis, salpingitis, pharyngitis, proctitis, and

conjunctivitis problems; around the liver capsule, it\'s \"Fitz-Hugh-

Curtis\". Branhamella is similar to neisseria, and causes pneumonia in

older folks.



Escherichia coli is the most familiar of the enterics, most famous for

producing bladder infections when, for any reason, urine flow is

stagnant. Enteropathic E. coli actually sits and does a kind of dance

on the surface of an enterocyte, causing it to secrete fluid

(\"Montezuma\'s revenge\"); there are other strains that actually produce

a toxin which works like cholera toxin (toxigenic E. coli, more

\"Montezuma\'s revenge\"). Enteroinvasive E. coli flourish in America\'s

southwest, and invade like shigella, producing a bloody diarrhea

(dysentery) rich in neutrophils. Klebsiella pneumoniae

(\"Friedlander\'s\", relationship to your lecturer unknown) is a gooey-

encapsulated bug that causes its victims (usually drinkers) to cough up

red slime. Proteus gets its energy from splitting urea into ammonia

and carbon dioxide, hence its ability to lay down magnesium ammonium

phosphate crystals in kidney and bladder. Pseudomonas is the bane of

the burn unit, the cystic fibrosis unit, and anywhere in which

antibiotics get used a lot, since it\'s resistant; the bug smells like

grapes. \"Ecthyma gangrenosum\" is severe pseudomonas tissue infection.



Legionella are gram-negative rods that produce a vicious pneumonia

(\"Legionnaire\'s disease\") in smoker-drinkers and the unlucky; use the

Deiterle silver stain; Pontiac fever is the mild form.



Anaerobic infections are usually mixed, and the bugs are generally not

super-strict anaerobes, but the more familiar bacteroides,

fusobacteria, peptostreptococci, and so forth. They evoke lots of pus,

and worse smells.



Hemophilus influenza affects younger children, especially those under 5

who do not make the antibody well and tend to get meningitis. Older

kids get pink eye, croup (epiglottitis); the mean version is type \"B\".

Hemophilus ducreyi causes chancroid, a sexually-transmitted disease

that mostly affects the unwashed. Bordetella pertussis causes whooping

cough by binding to the epithelium of the large airways; it is still

around.



Diphtheria is caused by a gram-positive corynebacterium rod with a

toxin-producing phage. The toxin produces surface necrosis and

pseudomembrane formation, then ties up carnitine, causing the heart to

fail.



Salmonella typhi produces typhoid, which grows first in the Peyers\'

patches and then spread. Bugs will grow from the blood, but seldom

from stool, and patients tend to be constipated. Rose spots,

erythrophagocytosis, spiking fevers; monocyte-macrophage response

rather than neutrophils. Carriers have gallstones. Other salmonella

cause mild food poisoning (vomiting, diarrhea), or

osteomyelitis/arthritis in sickle cell patients. Stomach acid protects

you from salmonella, which are ubiquitous (they teem over uncooked

chicken; they caused the ban in pet turtles).



Shigella produces dysentery, and only a few ingested bugs is enough to

make you very sick. Cholera needs no description, and the action of

its toxin via cyclic AMP is well-known. Helicobacter thrives on

cleaving urea in the acid milieu of the upper gut, and causing ulcers

and gastritis; the link to gastric cancer is more tenuous. Yersinia

enterocolitica causes mesenteric adenitis or dysentery. Bacillus

cereus is the fried-rice food-poisoning bug. Staph and clostridial

food poisoning require ingestion of pre-formed toxin.



Tetanus is the result of tetanus clostridia germinating in the

anaerobic milieu of a deep, devitalized wound, especially with foreign

crud (rust from a nail is great). The toxin binds to the inhibitory

internuncials of the cord. Lockjaw, opisthotonos. Botulism requires

the ingestion of pre-formed toxin, usually from poorly-canned food, and

this is extremely powerful; this time, the result is paralysis, first

of the eyes. Gas gangrene is caused by aggressive clostridia that

dissolve tissue faster than the body can respond; lecithinase (alpha-

toxin) hemolyzes. Pseudomembranous enterocolitis results from

antibiotic administration which allows overgrowth of the relatively

resistant \"C. difficile\".



The zoonoses: Anthrax is a gram-positive zoonosis from sheep; its

produces dry necrosis (\"eschar\", \"black spot\") where it enters; inhaled

spores produce the lethal \"woolsorter\'s disease\". Listeriosis is a

zoonosis among the immunosuppressed. Erysipeloid (Erysipelothrix

rhusipathiae) is fish-handler\'s disease, a soft-tissue infection.

Plague results from Yersinia pestis, carried by fleas from the dead

rats; the \"buboes\" are suppurating lymph nodes, and later the disease

may mutate into an aggressive form transmissible by coughing.

Tularemia is why you\'re not advised to catch the slow bunnies.

Brucellosis is a major cause of chronic ill-health, a smoldering

infection among slaughterhouse workers and farmers. Glanders

(Pseudomonas mallei) affects donkeys and horses in the poor nations;

melioidosis (Pseudomonas pseudomallei) infests southeast Asia and can

linger in Vietnam vets (\"the bacterial time bomb\"); it produces hard-

to-treat infections. Leptospirosis produces hemolysis and/or jaundice

(\"Weil\'s disease\"), or just a mild meningitis. Relapsing fever

(Borrelia recurritens) mutates every week or so to produce a new

episode.



Actinomyces are filamentous bacteria (\"ray fungi\", a misnomer) that

grow in dense masses (\"sulfur granules\"), rendering them impervious to

phagocytosis. These infections begin on rotten teeth (\"lumpy jaw\") or

intrauterine contraceptive devices. The Whipple bacillus has not been

grown yet, but seems to be a relative. Nocardia is a weakly acid-fast

filamentous rod that causes jungle-foot infections and opportunistic

pneumonia, both hard to treat.



Syphilis: Treponema pallidum, \"the American Indians\' other revenge\"

against Columbus, whose men were the first European victims. In spite

of what you\'ve been told, the actual derivation of the name is

unrepeatable here. Primary syphilis is the familiar painless, firm,

ulcer (chancre) at the site of inoculation. Secondary syphilis is a

variable rash, weeks or months later; condyloma latum is the oozy form

seen in moist places. Both stages teem with spirochetes. The

histopathology of each stage is a vasculitis with lots of plasma cells.

Tertiary syphilis: (1) narrowed vasa vasora weaken the aorta, which

balloons where the pressure is highest, i.e., its ascending portion;

stretch-marks produce \"tree-barking\", and eventually the aneurysm

bursts; (2) gummas are granulomas of syphilis; under the periosteum,

they account for chronic severe pain, while necrosis caused the

familiar saddle-nose; (3) general paresis kills cells in the cerebral

(\"windswept\") cortex and makes victims crazy; (4) meningovascular

syphilis is an awful headache; (5) tabes dorsalis merely looks like

demyelinated posterior columns, but can hurt bad; eventually there\'s

loss of proprioception.



Congenital syphilis: Acquired during the second trimester; (1) \"saber

shins\" and other bony deformities; (2) \"mulberry molars\", \"Hutchinson\'s

teeth\", \"screwdriver incisors\", i.e., dental deformities; (3) gummas

destroying the bridge of the nose and/or the hard palate; (4) pulmonary

consolidation (\"pneumonia alba\", white pneumonia); (5) \"hepar lobatum\",

enlargement and severe distortion of liver architecture due to gummas,

and related splenomegaly; (6) rash resembling bad secondary syphilis,

often with sloughing of skin on palms and soles; (7) mental

retardation, nerve deafness, blindness, etc., etc.; (8) necrotizing

inflammation of the umbilical cord (\"necrotizing funisitis\"); (9)

and/or any other sign of secondary or tertiary syphilis. These babies

teem with spirochetes at birth.



Other spirochetes: \"Trench mouth\" (necrotizing gingivitis) is synergy

among mouth organisms; the most severe cases cause necrosis of the face

(noma). Yaws, bajel, and pinta are other spirochete diseases in the

syphilis family.



Lyme disease is caught from ixodes ticks that drank from infected deer

mice. Primary Lyme disease, which may not even be visible, occurs

around tick bite as the spirochetes spread outward in circles

(\"erythema chronicum migrans\"). The subsequent immune havoc (and maybe

other problems) produce \"arthritis\", cranial nerve palsies (Lyme

\"flagellin\" mimics an axon protein); non-suppurative meningitis;

demyelinating disease, and goodness-knows-what-else. \"When in doubt,

treat for Lyme disease\".



Granuloma inguinale: Calymmatobacterium donovani, a nasty mix of pus

and granulomas on the genitals.



Tuberculosis is enjoying a resurgence. The acid-fast mycobacterium

enters the lungs, where it gets notice by T-cells, induces a powerful

over-reaction by the body, with eventual caseous necrosis. The bug

wants this, since it is transmitted by riding coughed-up bits of the

powder. Initial exposure to the bug results in the infectious site

being walled off in a calcified granuloma (a \"Ghon focus\"; if some bugs

have made it to the lymph nodes, \"Ghon complex\"). The midlung is the

favorite site for a Ghon focus. TB may go on to wipe out your lungs;

contrary to what you\'ve read, primary progressive tuberculosis (the

bugs were never walled-off successfully) is probably more common than

secondary-reactivation tuberculosis. (I never knew why we taught the

other....) Risk factors include poverty, alcoholism, crowding,

immunosuppression (especially AIDS), silicosis, and glucocorticoid

administration. Miliary TB spreads like millet-seed (as millions, or

at least thousands, of little granulomas) through the oxygen-rich areas

of the body, and TB in the lung prefers the oxygen-rich apices, where

necrosis leads to cavity formation (the insides are coughed up).

Meningeal TB favors the high-oxygen areas around the circle of Willis.

Pott\'s disease is vertebral TB. Bovine TB abounds in cow\'s milk,

especially in the poor nations; it enters the body via the duodenal

lymphoid tissue.



Other mycobacteria include \"intracellulare\" and \"avium\", opportunists

which you must hope you do not catch; the scrofula bug (neck nodes),

and the leprosy bacillus. Immune-competent (paucibacillary,

tuberculoid) leprosy features neuropathy, granulomas, depigmentation,

and a positive lepromin test. Immune-poor (multibacullary,

lepromatous) leprosy features the leonine facies, globi (macrophages

packed with bacilli), and hideous mutilation.



Candida: Ubiquitous fungus, with pseudohyphae. Look like balloon

animals in smears and tissue. Most familiar as \"thrush\" in the mouth

and esophagus, or \"yeast infections\" in the vagina or groin (spot the

latter by its satellite lesions). The fungus thrives on parenteral

nutrition catheters (good stuff to eat) and anywhere in a diabetic

(lots of glucose); it\'s an early opportunist in anybody losing T-cell

function. \"The Yeast Connection\"; imaginary candidiasis was a fad

diagnosis some years back.



Mucormycosis: bread mold spores germinating in the body at low pH,

i.e., in ketoacidosis, or wherever there\'s a major break in defenses.

The favorite site is the deep faces, around the nasal sinuses. Once

they\'re germinated, you\'re in trouble. They invade vessels infarct

tissues. Wide-angle branching, no septa.



Aspergillosis: the familiar fruiting-body fungus. Likes to invade

vessels, and make its home in cavities in the lung (\"fungus balls\"); or

it can colonize the airway surfaces, or produce type I, type III,

and/or type IV injury. Narrow-angle branching, septa.



Cryptococcus: Pigeon-dropping bug, an encapsulated yeast that grows in

the lungs and/or spinal fluid of the immune-compromised. India-ink

test; single narrow-based bud. Fatal cases of meningeal cryptococcus

involve invasion of the Virchow-Robin spaces producing swiss-cheese

brain.



Blastomycosis: Midwest riverbank fungus. Yeast with a single broad-

based bud. Skin and/or lung infections, a mix of granulomas and pus,

hard to treat.



South-American blastomycosis (paracoccidioidomycosis): Amazon jungle

fungus, a devastating mouth or generalized disease. Yeast with

multiple buds (\"mariner\'s wheel\").



There\'s a popular tale that both variants of \"blastomycosis\", even on

the skin or in the mouth, always got there by way of the lungs; after

having investigated this claim, I found no reason to think it\'s true.



Coccidioidomycosis: San Joaquin valley fever, a large spherical yeast

full of endospores. Inhaling the spores may produce anything from a

mild chest-cold to a fatal systemic infection.



Histoplasmosis: A tiny (two micron) yeast, ubiquitous in the Midwest,

especially starling and bat guano. The pathology matches that of TB.



Sporotrichosis: Rose thorn or bayberry thorn prick; follows the

lymphatics up the arm.



The protozoans:



Luminal protozoa

Amebiasis

Amebic meningoencephalitis

Balantidium infestation

Cryptosporidiosis

Isosporidiosis

Sarcocystosis

Giardiasis

Trichomoniasis

Pneumocystosis

Blood and tissue protozoa

Malaria

Babesiasis

African trypanosomiasis

Intracellular protozoa

Chagas\'s disease

Leishmaniasis

Toxoplasmosis



Amebiasis: Entamoeba histolytica produces flask-shaped ulcers (the

bottoms lie along the muscularis mucosae; the bug uses perforins to

wreck havoc), where it engulfs and digests red cells (marker for

virulence). The bugs look like round Remington shavers. Bad cases

spread to the liver (\"anchovy paste\" abscesses, a misnomer since there

are few or no polys). Fecal-oral; ubiquitous in the poor nations, and

was (in the 1970\'s) very common among non-monogamous gay guys.



Acanthamoeba is the contact-lens amoeba, while Naegleria is the reason

not to swim in stagnant farm ponds (meningitis and worse).



Giardia: A sulfide-producing luminal parasite famous for producing

malabsorption, upset tummy, and mercaptans (\"phew!\" \"purple burps\").

Drink from a nice mountain stream in Colorado, and you\'ll probably get

giardiasis; it\'s easy to catch from the drinking water where the

politics is especially bad, most famously in Leningrad.



Cryptosporidiosis (\"Milwaukee diarrhea\"): a protozoan that lives in the

brush-border. Once considered a \"non-pathogen\", then a \"zoonosis\",

then \"only causes disease in the immune-compromised\", we now know that

cryptosporidiosis is one of the most common causes of diarrhea

worldwide, as the city of Milwaukee found out recently when its water

supply was contaminated. The bugs are acid-fast and easy enough to

spot in the stool.



Trichomonas: A sexually-transmitted disease which typically hides out

in his prostate (slight or no discomfort) and creates a frothy,

malodorous \"strawberry vaginitis\" in her. On wet mounts (which you\'ll

do), these loathsome creatures look like pears doing the hoochie-

koochie dance.



Pneumocystis: Once known as the cause of \"plasma cell pneumonia\" in

preemies, this is now familiar as a lung infestation (lower lobes,

\"ground glass opacities\") in the T-cell deficient (AIDS, chemotherapy

patients). The organisms pack exudate-filled alveoli, typically (in

immunosuppression) with no sign of an inflammatory response, creating a

foamy-like appearance.



Malaria: An extremely severe health problem worldwide. \"Falciparum\" is

worst, probably because of the type III immune injury superimposed on

the episodes of hemolysis. Worth remembering about malaria: (1) large

spleen; (2) hemoglobin can shut down kidneys (blackwater fever).



Toxoplasmosis: From eating undercooked beef, or from emptying kitty-

litter that\'s sat too long; the protozoan can only complete its life

cycle if you\'re devoured by a cat, lion, tiger, leopard, saber-tooth,

etc. Mild or no disease if you\'re healthy; brain damage (maybe) if

you\'re a second-trimester fetus; retinitis if you\'re unlucky; massive

necrosis of the brain if you have AIDS or are otherwise T-cell

compromised.



Babesiosis: \"Nantucket fever\", with tiny malaria-like parasites in the

red cells. Mostly a problem if you lack your spleen.



African trypanosomiasis: Tsetse flies carry these dread organisms;

population pressures have forced people back into these once-shunned

territories. No one knows how they effect their neurotoxicity, but

\"sleeping sickness\" is a grisly disease.



American trypanosomiasis: Chagas\' disease, acquired from the disgusting

reduvid bug (\"kissing bug\") in the Latin American mountains. Paralysis

of the esophagus (dysphagia, cancer risk), less often the colon;

dilated cardiomyopathy.



Leishmaniasis: \"Baghdad boil\", \"Kala-azar\", etc., etc. Acquired from

phlebotomus sandflies; these protozoans are about 2 microns across and

live inside phagocytes.



Ascariasis: Fecal-oral transmission. A large worm burden can kill you

by obstructing or perforating the bowel.



Whipworm (trichuris): Fecal-oral. Harmless unless the infestation is

massive.



Pinworm (enterobius): This charming parasite lays her eggs on the

anoderm, hoping you\'ll scratch and then put your fingers in somebody

else\'s mouth or food. Judging by the success of the creature, this

happens a lot. Scotch-tape test.



Hookworm (necator, ancylostoma): Acquired from walking barefoot on

larva-infested soil, the worms pass through the lungs, get swallowed,

settle in the duodenum, and tear at the mucosa with their fangs in

order to get blood to drink. Each hookworm costs you a teaspoon of

blood each day, and iron deficiency soon supervenes.



Strongyloides: Appalachia and elsewhere. Acquired from the soil, like

hookworm; in the immune-compromised, these worms can carry out their

life cycle without needing to leave your body (\"hyperinfection\", bad

news).



Dracunculosis: Guinea worm, acquired from wading in water bearing

infected cyclopses (little marine critters). The worm encysts under

the skin, then erupts when mature; the cure is still to wrap the

critter, day by day, around a stick (origin of the caduceus, most

likely; one snake is medicine, two snakes is commerce, diplomacy, and

thievery.)



Trichinosis: Undercooked pork. Worms coil and encyst in busy muscle,

preferring those of the eye and the diaphragm. Eosinophilia, sick as

heck, but usually self-limited.



Filariasis: Mosquito-borne worms plug lymphatics.



Onchocerciasis (\"river blindness\"): Worms spread by river-flies invade

the eyes. A grim West African disease.



Cysticercosis: Stray larvae of a pork tapeworm find their way to the

brain. The most common cause of seizures in many poor nations.



Echinococcus: A tapeworm that cycles between canines and herbivores

(wolves and caribou, sheepdogs and sheep, others) finds its way to a

human, typically via dog feces (a doggie puts its nose in another

doggie\'s behind, then licks your mouth). \"Hydatid cysts\" are full of

dozens of little worms, like masses of grapes, they can be several

centimeters across. Don\'t bust the cyst, anaphylaxis can result. Call

a surgeon with special tools.



Schistosomes: Blood flukes with a life cycle between humans and snails.

Ma and Pa schistosome live and love in the veins of the abdomen and/or

pelvis, laying their eggs and letting the razor-sharp spines cut their

way through the vital organs to the lumens of bowel and bladder.



Mansoni Big lateral spine

Hematobium Big terminal spine

Japonicum Small lateral spine



Other flukes worth remembering include the Chinese liver fluke,

memorable as a cause of biliary tree cancer, and paragonimiasis, a lung

fluke which causes tremendous suffering in Asia.

ED\'S PATHOLOGY MELTDOWN

Part II -- Systemic Pathology



\"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

2 to low alveolar oxygen see above; also MOUNTAIN DWELLERS

2 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 \\

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)

Hemolytic disease of newborn (Rh, etc.)

SPHEROCYTES Autoimmune hemolytic anemias

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)<--/ Actual iron deficiency (none stored)

MCHC / / \\

(HYPOCHROMIA) / Diet (junk food, poverty) \\

PENCIL CELLS\\<---/ Pregnancy

TARGET CELLS/ 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.

--\"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.)

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

Weird diets (\"vegans\", all vegetables)

SCHILLING TESTS <------- 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

\"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)







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 (S). 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: 0 -- no chains produced; + -- 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) Dhle 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.





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 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.





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 (mysterious, some malignant potential,

non-HPV-related); both are leukoplakias.



Bartholin duct abscess: think gonorrhea. Bartholin cyst: medial to

labia minora. Gartner\'s duct cyst (mesonephric cysts): Wolffian duct

remnants along anterolateral vagina.



Vulvar squamous carcinoma arises in HPV (strains 16, 18, 31), or

hyperplastic vulvar dystrophy. Vulvar adenocarcinoma may present as

extramammary Paget\'s, with adenocarcinoma cells invading the epidermis.

Melanoma.



Vaginal adenosis: from high estrogen exposure (i.e.,

diethylstilbestrol) before birth. A small percentage of these people

get clear-cell adenocarcinoma of the vagina.



Sarcoma botryoides: embryonal rhabdomyosarcoma of childrens\' vaginas.



Pap smear: parabasal cells indicate no estrogen or progesterone effect

(think post-menopausal woman); superficial squamous cells indicate

estrogen effect (if predominant, think of Stein-Leventhal, anovulatory

cycles, estrogen-secreting tumor), intermediate squamous cells indicate

progesterone effect (if predominant, think of prepubertal child,

pregnant woman). A normal, non-pregnant woman has a mix depending on

the stage of her cycle.



Cervicitis: gonorrhea, chlamydia, herpes, trauma, intrauterine device,

streptococcus B after childbirth.



Transformation zone of cervix, i.e., squamo-columnar junction, is site

where dysplasias and cancers arise. Finding HPV: colposcopy with

acetic acid (\"acetowhite\"), look for koilocytes (clear halo around

wrinkled-raisin nucleus) on pap smear. Most cancers here are squamous,

and most are caused by HPV. First symptoms: bleeding on intercourse.



I can\'t review the anatomy, histology, or physiology of menstruation

and pregnancy. Menorrhagia: periods too heavy (>80 mL) or too long,

metrorrhagia: bleeding at irregular intervals. Dysfunctional uterine

bleeding: abnormal bleeding with no anatomic cause; think of

anovulatory cycles (follicle never ruptures but keeps making estrogen),

persistent luteal phase (i.e., the corpus luteum fails to involute),

inadequate luteal phase (i.e., corpus luteum fails to form.)



Stein-Leventhal: secondary amenorrhea, hirsutism, insulin resistance,

often obesity); ovaries with thick capsules, high LH, low FSH.



Acute endometritis: post-partum, polys, from common bacteria. Chronic

endometritis: plasma cells in endometrium; think of chlamydia,

gonorrhea, TB, intrauterine device.



Endometrial polyps: mutant areas, may be hyperplasia (\"cystic\") and/or

responsive to estrogen but not progesterone; tend to slough

irregularly. Endocervical polyps: similar, hang out cervix and present

route of infection.



Cystic hyperplasia of endometrium: big, dilated, busy-looking glands

(swiss cheese). Adenomatous hyperplasia: folded, benign glands.

Atypical hyperplasia: anaplasia, crowding, cancer risk.



Asherman\'s syndrome: endometrial cavity scarred shut after dilatation

and curettage (diagnosis, legal abortion).



Adenomyosis: outpouching of endometrium into the myometrial wall.



Endometriosis: functioning endometrium outside the uterine cavity;

bleed during menstruation. Chocolate cst of the ovary, dyspareunia

from uterine ligament involvement, blood in the pouch of Douglas, low

back pain, pain on defection, bowel obstruction, infertility. To

diagnose, must see two of these: glands, stroma, hemosiderin.



Leiomyomas (\"fibroids\"): tough, white, watered-silk look; subserosals

cause bleeding and infertility, numerous or large make pregnancy and

delivery difficult.



Endometrial adenocarcinoma: risk factors are high unopposed estrogen

(thecoma, replacement, anovulatory cycles), obesity, diabetes,

hypertension, never pregnant, tamoxifen. More common in older woman.

Postmenopausal bleeding.



\"Pelvic inflammatory disease\": gonorrhea, chlamydia, sometimes other

infections involving and damaging the oviducts. Increased risk for

infertility, faulty implantation (i.e., ectopic pregnancy).



Placenta over the os during childbirth: placenta previa (bleeds).

Placenta detaches from the wall prematurely: abruption (catastrophe).



Ectopic pregnancy: becoming more common; the more prevalent gonorrhea

is, the more prevalent are ectopic pregnancies.



Ovarian cysts: non-neoplastic, poorly-understood, may arise from

follicles, corpus luteum, or who knows.



Ovarian tumors fall in three groups, and tend to be mixtures of the

types within one group.



Coelomic:

Serous (mostly malignant; papillary, cilia, psammoma bodies,

common ovary cancer, often bilateral, recapitulates oviduct)

Mucinous (mostly benign, usually unilateral, recapitulates

endocervix, can be huge)

Clear-cell (malignant, resembles kidney cancer)

Brenner (mostly benign, resembles transitional cells in balls in a

dense stroma)

Endometrioid (malignant, same risk factors and histology as

endometrial adenocarcinoma)



Coelomic cancers tend to spread over the peritoneal surface, and

be positive for CA-125 in blood.



Sex-cord / stromal:

Fibroma (twisted, with ascites and pleural effusion: Meig\'s)

Thecoma (mostly benign, often estrogen-producers)

Granulosa cell tumor (low-grade cancer, simulate the cells that

encase the egg, Call-Exner bodies, coffee-bean nuclei)

Arrhenoblastoma (Sertoli-Leydig tumor, often testosterone-

producing; Reinke crystalloids are marker for Leydig cells)



Germ cell:

Choriocarcinoma

Dysgerminoma (counterpart of male seminoma)

Teratoma (common, \"dermoid cyst\", teeth, 3 germ layers, etc.; may

have preponderance of thyroid, or carcinoid, or squamous cell

carcinoma)



Twins: if there is a single amnionic sac, or the amnionic sacs are

fused without a layer of chorion between, the twins must be identical.

If the placentas are separate, or if there is a layer of chorion

between the amniotic sacs, then you cannot tell.



Chorioamnionitis may cause, or result from, premature rupture of the

membranes. Strep B.



Pre-eclampsia and eclampsia (both \"toxemia of pregnancy\") are poorly-

understood; probably a vicious cycle between narrowing of the spiral

arteries of the uterus and production of vasoconstrictors / production

of endothelial poisons / non-production of vasodilators (nitric oxide,

prostaglandin G) by the placenta. Patients have hypertension, edema,

and proteinuria and eventually azotemia; eclampsia is the development

of seizures. Toxemia of pregnancy is more common in first pregnancies,

twins, hydatidiform mole.



Gestational trophoblastic disease: hydatidiform mole, invasive mole,

choriocarcinoma. All are baby\'s cells, i.e., some of dad\'s genes.

According to some, a complete mole is all Dad\'s chromosomes (usually

XX, sometimes XY, two sperms, and Mom\'s chromosomes are deleted); in

partial mole, there\'s trisomy.



Hydatidiform mole: very common in Asia (1/100), rare in the U.S.

(1/2000); edematous (\"hydropic\") villi look like grapes; excess hCG

production.



\"Invasive mole\" can invade and metastasize, but bears villi; officially

\"benign\", I\'ve never understood why; this entity is falling out of

fashion.



Choriocarcinoma: 1/2 arise from hydatidiform moles, 1/4 from abortions,

1/4 from normal pregnancies. No villi, but lots of syncytiotrophoblast

and cytotrophoblast. Lots of metastases, chemotherapy cure is usual.



\"Hirsutism\": terminal (big thick) hairs on androgen-sensitive areas,

more than most folks of your gender. \"Virilization\": a woman has an

enlarged clitoris, and perhaps also temporal balding (all men lose

their temple hair around age 20), muscles, deep voice, increased

libido. \"Hypertrichosis\": increased fine hair, as in porphyria,

anorexia nervosa, phenytoin therapy, diazoxide, minoxidil.



Breast development.... Estrogen: Ducts. Progesterone: Lobules. Milk

production: Prolactin / placental lactogen. Milk comes down: Oxytocin.



\"Fibrocystic disease\" affects all women if you look hard enough. Cysts

(\"blue dome\"), fibrosis, epithelial hyperplasia, papillae, sclerosing

adenosis; tenderness before periods; malignant potential only if

epithelial hyperplasia is \"atypical\".



Fibroadenomas: Common, banal, benign tumor of younger women. Phyllodes

tumor (\"cystosarcoma\") is a fibroadenoma with an atypical stroma and

some potential to metastasize as sarcoma.



Acute mastitis: staph abscess acquired during lactation.



(Non-enzymatic) fat necrosis: considered \"mysterious\", probably results

from wife-beating and girlfriend-beating. Tends to calcify.



Plasma cell mastitis: near nipple, cheesy material in ducts, benign.



Blood from the nipple: usually intraductal papilloma has twisted and

infarcted itself. Galactorrhea: prolactinoma, dopamine blockers

(phenothiazine, methyldopa).



Risk factors for breast cancer: Previous cancer in other breast, family

history (especially BRCA1, BCRA2, retinoblastoma family), radiation,

atypical ductal hyperplasia, atypical lobular hyperplasia. In the poor

nations, women who are pregnant much or most of their reproductive

lives do not get breast cancer; translating this effect to the U.S.

(early menarche, late menopause, nulliparity) has yielded conflicting

results. The \"legal abortion\" and \"high-fat low-fiber\" diet haven\'t

held up last time I did my reading.



Infiltrating ductal carcinoma (75% of breast cancers): scirrhous

(desmoplasia, Indian-files), medullary (many lymphocytes), colloid

(mucin lakes), tubular (well-differentiated, good prognosis),

inflammatory (plugged lymphatics, raging-red breast, terrible

prognosis).



Intraductal carcinoma: cribriform (swiss cheese), and squeeze-the-

blackheads (comedocarcinoma); better prognosis. Paget\'s of breast:

cancer cells growing from duct into epidermis of nipple, producing a

red \"eczematous\" rash.



Lobular carcinoma: more desmoplasia and Indian-files circling the

lobules, tends to be bilateral; \"lobular carcinoma-in-situ\" is cells

filling the lobules.



Prognostication: Most important is presence or absence of axillary

metastases; next is size of primary. After this, presence of c-erb2

(neu, HER-2) is bad, aneuploid is bad, no estrogen receptors is bad, no

progesterone receptors is bad.



Gynecomastia: breast duct development in a man. XXY, cirrhosis, guy at

puberty, malnutrition, testicular tumors (extra hCG from

choriocarcinoma or seminoma, estrogen from Leydigoma), spironolactone,

cimetidine, flutamide.



\"No one is born wise.\"

-- Ptahhotpe, c. 2350 B.C.



Hypopituitarism (\"Simmond\'s disease\"): loss of some of the anterior

pituitary hormones. Panhypopituitarism: loss of most or all of them.



Pituitary adenomas: Only known risk factor is MEN-I. Some feedback

control. Endocrine problems, visual problems (chiasm compression

causes bitemporal hemianopsia), enlarged sella on x-ray, less often

signs of increased intracranial pressure (headache, nausea, vomiting).



Acidophil adenomas: growth hormone, prolactin. Basophil adenomas:

ACTH, gonadotropin. Chromophobe adenomas: usually prolactin. These

distinctions are unreliable.



Prolactinoma: lost libido; galactorrhea-amenorrhea in women; obesity.



Growth hormone: gigantism before the epiphyses close, acromegaly after;

glucose intolerance. Acromegalics suffer joint problems, precocious

atherosclerosis, diabetes, neuropathy, myopathy; spot them by huge jaw

(prognathism), oily skin, deep voice, frontal bossing, spade fingers.



ACTH: Cushing\'s disease (definition).



Gonadotropin: usually silent (secret: most \"non-secreting pituitary

adenomas\" produce gonadotropins).



TSH: Secondary hyperthyroidism, rare.



Empty sella: infarcted pituitary gland, necrotic adenoma, post-surgery,

arachnoid herniated downward compressing the gland.



Panhypopituitarism: Loss of growth hormone makes kids short, adults

atrophy. Loss of gonadotropins remove sexual features. Loss of TSH

produces secondary hypothyroidism. Loss of ACTH produces secondary

adrenal insufficiency. If the posterior pituitary is lost, diabetes

insipidus.



Causes of hypopituitarism: Sheehan\'s (necrosis of pituitary during

post-partum shock), empty-sella syndromes, pituitary adenoma, surgery,

radiation, trauma, rarely autoimmunity.



Pituitary dwarfism (miniature adults): \"Idiopathic dwarfs\" often had

obstetrical mishaps with possible damage to pituitary stalk; Laron

dwarves have defective growth hormone receptors; pygmies have a

different kind of tissue resistance; other dwarfs lack somatomedin;

some just-plain-short folks have mild growth hormone receptor defects.



Craniopharyngioma: benign tumor in a bad place, Rathke\'s pouch

remnants, recapitulates tooth, machine-oil cysts, keratin, calcium.



Froehlich\'s syndrome: the fat, simple boy in gym class who didn\'t get

his pubic hair. Hypothalamic problem of some kind; several syndrome

are known.



McCune-Albright: polyostotic fibrous dysplasia of bone, cafe-au-lait

spots with rough edges, precocious puberty, other gland problems, no

two cases the same. Post-zygotic mutation causes growth signals (cGMP)

to be translated into make-hormone signals (cAMP).



Thyroglossal duct cysts mark the track of the gland\'s descent from the

back of the tongue. Goiter: any large thyroid, also \"struma\".



Hyperthyroidism: Hypermetabolism, excess heat production, increased

appetite, diarrhea, hyperdynamic heart, uncoupling of oxidative

phosphorylation, enhanced epinephrine effect, lid lag, atrial

fibrillation, cardiomyopathy, osteoporosis, low LDL, fine tremor.



Primary hyperthyroidism: Gland makes too much thyroxine and/or tri-

iodothyronine (Graves\', hot Hashimoto\'s, hot \"Plummer\'s\" adenoma, Jod-

Basedow; rarely thyroid follicular carcinoma, autonomous struma

ovarii). Secondary hyperthyroidism: TSH-oma of the pituitary, \"TSH\"-

production by choriocarcinoma, rare. Tertiary hyperparathyroidism:

TRH-producing tumor, rare. Remember factitious hyperthyroidism.



Jod-Basedow: hyperthyroidism from sudden administration of iodine to an

iodine-starved goiter.



Cretinism: Hypothyroidism affecting the unborn child or baby.

Inexcusable unless the cause is lack of thyroid receptors. Other

causes include maternal hypothyroidism (especially iodine deficiency,

epidemic in Communist boondocks and among most \"indigenous peoples\"

living away from the ocean), problems synthesizing thyroxine (chemical,

or failure of the gland to form; become symptomatic after birth, which

is why we screen by TSH levels). Cretins may be myxedematous, or just

remain childlike.



Hypothyroidism: Slowing of mind and body, constipation, cold skin,

obesity, coarse voice, myxedema (increased ground substance), insanity,

\"depression\", coarse facial features, big tongue, high LDL,

atherosclerosis, hypercarotenemia with yellow skin, cold intolerance,

delayed \"hung\" deep tendon reflexes, dry skin, coarse and brittle hair.



Primary hypothyroidism: Thyroid cannot make the hormone despite lots of

TSH (iodine deficient, gland never formed, biochemistry problems, gland

was removed, gland was radiated, Hashimoto\'s, occasional DeQuervain\'s,

TSH-receptor-blocking autoantibodies, goitrogens). Secondary

hypothyroidism: Pituitary failure. Tertiary hypothyroidism:

Hypothalamic failure.



Hashimoto\'s thyroiditis: Antibody-related T-cell-mediated havoc in the

thyroid. Goiter with lots of lymphocytes, germinal centers, epithelial

cells packed with mitochondria. Breeding-ground for thyroid lymphoma.

Commonest cause of acquired hypothyroidism in adults. Many have

concurrent autoimmune addisonism and/or type I diabetes and/or

pernicious anemia. A forme-fruste (?) is lymphocytic thyroiditis,

common in Down\'s and sporadically.



DeQuervain\'s subacute granulomatous thyroiditis: some virus attacks the

thyroid epithelium, and there\'s a brisk foreign-body reaction to the

thyroglobulin colloid. Common, passes in a few weeks; may render you

temporarily hyperthyroid or hyothyroid.



Riedel\'s struma: A fibrous \"woody\" proliferation mimicking sarcoma.



Graves\' disease (\"diffuse toxic goiter\"): Stimulatory autoantibodies

against the TSH receptor; nobody knows why extra ground substance

accumulates behind the eyes (\"ophthalmopathy\") or on the shins

(\"pretibial myxedema\").



\"Diffuse nontoxic goiter\": Common, usually idiopathic. Most patients

remain euthyroid though the gland may be huge and/or turn multinodular.

Mutations are present but there\'s little or no extra cancer-potential.



Thyroid adenomas: Most are non-functioning and \"just happen\". Hot ones

may produce hyperthyroidism (T4, T3).



Papillary adenocarcinoma of the thyroid: \"Orphan Annie\'s tumor\". Young

women, slow-grower, seldom kills, \"Orphan Annie eye\" nuclei, psammoma

bodies (sand-like, Orphan Annie\'s dog is named Sandy).



Follicular adenocarcinoma of the thyroid: More aggressive, tendency to

invade veins and metastasize to lungs; takes up iodine, thyroglobulin a

tumor marker.



Medullary carcinoma of the thyroid: from C-cells, produces calcitonin,

which is beta-pleated to amyloid in the stroma. Seldom lowers blood

calcium, but may produce ACTH or VIP.



Anaplastic carcinoma of the thyroid: arises in a papillary or

follicular carcinoma, dismal prognosis.



Adrenal cortex layers: Salt sugar and sex. The deeper you go, the

sweeter it gets.



Addisonism now means chronic primary hypoadrenocorticism regardless of

cause (Dr. Addison\'s had bovine TB, most common nowadays are iatrogenic

and autoimmune). Also remember leprosy, TB, CMV in AIDS, amyloid,

hemochromatosis, metastatic lung cancer, adrenal leukodystrophy

(\"Lorenzo\'s oil\").



Autoimmune addisonism (Jack Kennedy\'s disease) is antibody-related T-

cell attack on the adrenal cortex; antigen is 21-hydroxylase. Runs

with Hashimoto\'s, pernicious anemia, and type I diabetes.



Chronic hypoadrenocorticism: weakness, hyperkalemia, hypoglycemia,

nausea, weight loss, hypotension, sudden death. If the problems is

primary in the adrenal, excess ACTH will turn the skin brown.



Acute hypoadrenocorticism: meningococcemia, stressing an Addison\'s

patient, rapid withdrawal of glucocorticoids, Waterhouse-Friderichsen,

sudden death.



Cushing\'s syndrome: Iatrogenic (most common), Cushing\'s disease (ACTH-

oma), ACTH-producing cancer (oat cell, carcinoid, medullary carcinoma

of thyroid), autonomous cortisol-producing adrenal adenoma, a few

obscure entities.



Cushing\'s folks: truncal obesity, buffalo hump, increased appetite,

insomnia, mental changes, thinning of dermis, fragile vessels,

diabetes, red round face, hypertension, hypokalemia, osteoporosis,

acne, cellulitis, hirsutism, oligomenorrhea, muscle wasting, ringworm.



Nelson\'s syndrome: After removing the hyperplastic adrenals in someone

with an ACTH-producing pituitary adenoma, the adenoma becomes huge and

blinds the person in short order.



Primary hyperaldosteronism: Conn\'s, from an autonomous adenoma or

\"mysterious hyperplasia of the zona glomerulosa\". Hypertensives with

hypokalemia before you start a diuretic. Since atrial natriuretic

peptide overrides aldosterone in regulating total body water, these

patients do not have edema (for that matter, neither do patients with

syndrome of inappropriate ADH). Glucocorticoid-correctable Conn\'s

results from a chimeric gene that makes aldosterone in large quantities

when stimulated by ACTH.



Secondary hyperaldosteronism: Any time you have low effective

circulating volume. Seen in CHF, nephrotic syndrome, cirrhosis,

Goldblatt hypertension.



Congenital adrenal hyperplasia: Six enzyme deficiencies, any one of

which cause difficulty making cortisol, resulting in lots of ACTH, and

shunting of steroids into the male-hormone pathways. 21-hydroxylase

deficiency: excess male hormones, salt-waster. 11-hydroxylase

deficiency: excess male hormones, salt-retainer (deoxycorticosterone is

a potent mineralocorticoid). Ambiguous genitalia in girls, or

hirsutism in women, depending on severity. Infant Hercules in boys.



Adrenal cortical carcinoma: Usually makes a mix of unpleasant hormones,

bad prognosis.



Pheochromocytoma (\"chromaffinoma\"): 10% bilateral, 10% metastasize, 10%

familial (i.e., MEN-II, neurofibromatosis). Very vascular, produce

epinephrine, norepinephrine, or both. Headache, hypertension, \"panic

attacks\"; screening tests include vanillyl-mandelic acid (VMA),

metanephrines, more.



Neuroblastoma: pediatric tumor, present in one baby in 50; most regress

spontaneously. Tumor of small blue cells, look for rosettes (attempts

at neural tubes). Cures with chemotherapy in many, but not all, cases.

Likely to suddenly mature into ganglioneuromas. Older age, bone

involvement, myc-gene amplification are ominous. Marker: homovanillic

acid (HVA).



Parathyroids: Most folks have somewhere around four, somewhere around

the neck; anatomy books are idealized.



Primary hyperparathyroidism: usually an adenoma, except in familial

syndromes. Hypercalcemia, hypertension, depression, kidney stones,

pancreatitis, gastric ulcer, bone lesions (\"osteitis fibrosa cystica\"),

low serum phosphate, high urinary cAMP, high urinary 24-hour calcium

excretion.



To know you have an adenoma rather than hyperplasia, you must find a

normal parathyroid gland (if it were hyperplasia, all would be

hyperplastic).



Secondary hyperparathyroidism: parathyroid glands enlarge because of

phosphate retention by failing kidneys. Normal or low calcium, high

phosphate. Tertiary hyperparathyroidism: Autonomous hyperfunction in

the setting of secondary hyperparathyroidism.



Parathyroid carcinomas are rare and not very aggressive.



Hypoparathyroidism: usually iatrogenic (thyroidectomy mishap), less

often DiGeorge\'s or autoimmune; hypocalcemia and tetany.

Pseudohypoparathyroidism: defective adenyl cyclase renders proximal

tubule unresponsive to parathyroid hormone, also skeletal

abnormalities. Pseudopseudohypoparathyroidism: the skeletal

abnormalities without the calcium problem.



Thymic hyperplasia: germinal centers in the gland. Thymoma: tumor of

the epithelial cells of the thymus. Think of lupus (hyperplasia),

myasthenia gravis (either), \"pure red cell aplasia\" (thymoma, i.e.,

something is making normoblasts undergo apoptosis),

hypogammaglobulinemia (thymoma, mysterious).



Pineal: remember that testicular-type tumors are prone to occur here.



Multiple endocrine adenoma (neoplasia) syndromes:



MEA (MEN) I: PPP (Wermer\'s syndrome)



Parathyroid adenomas, often multiple (rarely hyperplasia)

Pituitary adenoma (anterior)

Pancreatic islet cell adenoma (gastrinoma)





MEA II: PAC (Sipple\'s syndrome); gene is RET

Parathyroid adenomas (some books still say \"hyperplasia\" too)

Adrenal medullary tumor (pheochromocytoma) or hyperplasia

Calcitonin-producing hyperplasia-carcinoma of thyroid





MEA III (was IIb):

Similar to MEA II; the patients have Marfanoid body habitus and

mucosal (ganglio)neuromas (bumps on the edges of their tongues and

elsewhere), and are less likely to have parathyroid problems.

Same locus, different allele.



It will be easy to recognize Ed\'s bleached bones in the desert, since

his are bright, fluorescent yellow from years on tetracycline (acne).



Bone words: (1) Diaphysis: The long shaft, remote from both growth

plates; (2) Epiphysis: Between the growth plate and the nearest joint;

(3) Metaphysis: Between the growth plate and the diaphysis. In kids,

this is where most of the bone growth is taking place, so this is where

most pediatric bone disease (infections, tumors) will occur; (4) woven

bone: crisscross fibers, never normal in an adult; (5) lamellar bone:

parallel fibers.



Osteogenesis imperfecta: problems making collagen. Fractures during

birth, or after; short statue, brittle bones.



Osteopetrosis (\"marble bones\"): osteoclast failure, bones become

brittle, marrow cavity obliteration leads to pancytopenia. Hereditary

forms with severe skull deformities.



Achondroplasia: Long bones fail to grow; common achondroplastic

dwarfism is caused by lack of fibroblast growth factor receptor 3.



Osteomyelitis: pus-producing infection in the marrow cavity. Bad,

since when the pressure rises, bone infarcts and acts like a foreign

body. Brodie\'s abscess: hiding place for bacteria after osteomyelitis

is supposedly cured. Pott\'s disease: TB osteomyelitis, typically of

the spine. Psoas abscess: Think TB.



Osteoporosis: Rarification of cortical and spongy bone, in old age, or

from disuse, cortisol, plasma cell myeloma, prolonged hyperthyroidism,

hypogonadism, anorexia nervosa, prolonged heparin therapy, or being

weightless for months in space. About 75% of the unexplained

variability in osteoporosis from person to person is now known to be

due to variations in the vitamin D receptor (big news).



Osteomalacia: failure of bone to mineralize in an adult.



Trivia... but it makes sense. Where do bone tumors arise?



Diaphysis: enchondromas

some chondrosarcomas, Ewing\'s, and

eosinophilic granulomas



Epiphysis: chondroblastomas

some giant cell tumors



Metaphysis: all other primary bone tumors



Osteomas arise from the cortical bone of the face. Plasma cell myeloma

produces its \"punched-out\" lesions throughout bone.



Paget\'s osteitis deformans: slow-virus infection, probably measles or

canine distemper, of osteoblasts and osteoclasts, which go crazy

remodeling bone. Soft woven bone with mosaic lines, thickening skull,

arteriovenous shunting, osteosarcoma risk. Pelvis, femurs, spine.

Beethoven\'s deafness, bulbous forehead, and heart failure.



Fibrous dysplasia: Woven bone in a fibrous stroma, a bone hamartoma.

Monostotic tends to be in the jaw; polyostotic means McCune-Albright.



For your patient histories on USMLE:



Metastatic neuroblastoma: infants and toddlers

Ewing\'s sarcoma: older children and adolescents

Osteosarcoma: adolescents and young adults

Giant cell tumors: young adults and middle age

Chondrosarcoma: middle age

Metastatic cancer: middle and old age



Osteoma: Bone bump on you skull somewhere.



Osteoid osteoma: Painful nidus of miniature bone, surrounded by a

sclerotic rim.



Osteosarcoma: Commonest primary bone cancer, malignant osteoblasts are

making osteoid. Teenagers\' knees or elsewhere, Paget folks.



Most bone tumors arise for no apparent reason; radiation (remember

strontium 90 and leukemia/osteosarcoma?), retinoblastoma family

(osteosarcoma). \"Codman\'s triangle\" is elevated periosteum near the

primary. Majority are cured nowadays.



Exostosis: A little ectopic epiphysis, a bony knob capped with

cartilage.



Enchondroma: A hunk of hyaline cartilage in the center of a bone shaft.



Chondrosarcoma: Typically in the pelvis of middle-aged men, slow-

grower.



Ewing\'s sarcoma: Teenager\'s tumor of small blue cells, glycogen-loaded,

very aggressive, liquid, simulates osteomyelitis.



Giant cell tumor / osteoclastoma: common in the knees.



Chordoma: benign tumor of notochord remnants, unfortunately it\'s

located on the clivus and is inoperable, destroys the cranial nerves

over years.



Prostate metastases to bone tend to be blastic, others tend to be

lytic, but there are many exceptions.



Malignant fibrous histiocytoma: the commonest soft-tissue sarcoma.







Bone alkaline phosphatase: elevated whenever osteoblasts are working

overtime. Urinary hydroxyproline reflects total-body collagen

synthesis.



Systemic diseases affecting joints: amyloidosis (especially

amyloidosis H of renal failure), gout (complement-fixing chemotactic

crystals), lupus, Lyme disease, hemochromatosis (osteoarthritis),

hemophilia (hemarthrosis, mutilation), scurvy (hemarthrosis),

ochronosis-alkaptonuria (osteoarthritis), rheumatic fever (synovitis),

scleroderma (synovitis), sickle cell disease (infection, infarcts),

syphilis (gummas), viremias (type III immune injury with synovitis),

peripheral neuropathies (nobody knows why, but joints without sensory

input tend to become deformed \"Charcot joints\", as in leprosy,

diabetes, syringomyelia).



Osteoarthritis: supposedly non-inflammatory (but ever see a red

Heberden\'s node?), limits movement, painful; wear-and-tear and

destruction of cartilage; worst in knees, hips, and first metacarpal

joint (so much for \"the cause of weight-bearing...\"). Fibrillation and

loss of cartilage, eburnation and \"cysts\" in underlying bone,

osteophyte formation, lipping, joint-mice (detached fragments).

Kashin-Beck in Central Asia is from fulvic acid toxicity and selenium

deficiency.



Rheumatoid arthritis: common, dread inflammatory synovitis.

Proliferated, inflamed synovium is \"pannus\". Rheumatoid factor is IgM

directed against Fc portions of IgG, usually but not always present.

Joint deformities include the familiar ulnar deviation, swan-neck and

variants. Mediators of the disease are probably macrophage products.

Complications include Felty\'s hypersplenism, rheumatoid fibrotic lung,

cryoglobulins, amyloidosis A, vasculitis (gangrene, heart attacks),

rheumatoid nodules (granulomas around injured collagen), Sjogren\'s,

pleuritis, others.



Juvenile rheumatoid arthritis (\"Still\'s\"): same histopathology,

different immunology, some are slow-virus infections with influenza A.



\"The reactive enthesopathies\" (HLA-B27 family): ankylosing spondylitis

(Marie-Strumpell, poker-back), Reiter\'s, arthropathy of inflammatory

bowel disease.



Pseudogout: calcium pyrophosphate crystals. Dupuytren\'s contracture:

palmar fibromatosis, locks one or more fingers in flexion. Osgood-

Schlatter\'s: repeated avulsions of the periosteum of the attachment of

the quadriceps tendon to the anterior tibia.



Ankylosis: Joint is fused and immobile. Pseudarthrosis: fracture that

healed with fibrous scar rather than bone.



Infectious arthritis: Think of gonorrhea in anyone, salmonella in

sicklers.



\"One slow red ox\". Type I fibers are slow-twitch, for posture, dark

meat, red muscle, oxidative phosphorylation for steady energy

expenditure. Type II fibers are fast-twitch, for sudden bursts of

hard work, white muscle, glycogen (why white meat on chickens is

sweeter), glycolytic enzymes abundant to burn lots of glucose fast.

Fiber type is determined by its current axons, and will change if

reinnervated; if only a few axons remain, type-grouping results.



Muscle atrophy: disuse, ischemia, damaged nerve, glucocorticoids. Lose

volume, keep nuclei. Angular fibers: denervation, other problems.

Target fibers mean denervation-reinnervation. Ring fibers: think of

myotonic dystrophy. Group atrophy: probably denervation.



Myasthenia gravis: antibodies and/or angry T-cells directed against the

NMJ. Tensilon test and thymic hyperplasia/thymoma.



Werdnig-Hoffman: apoptosis of the anterior horn cells, far-along at

birth, continues until death a few years later. Charcot-Marie-Tooth:

autosomal dominant (defects in myelin proteins) atrophy of lower legs.



Duchenne\'s muscular dystrophy: X-linked, pseudohypertrophy of calves,

lumbar lordosis, progression to severe disability and death. Variable

fiber size, fiber degeneration, fibrosis, fatty ingrowth. Muscles are

yellow (i.e. almost all fat and scar) at death. Lack of dystrophin, a

membrane protein. Milder alleles produce Becker\'s. Affected boys and

carrier Mom\'s have elevated creatine kinase.



Rhabdomyolysis: alcoholism, weekend athletes, heat stroke, seizures,

cocaine abuse, crush injury, malignant hyperthermia (hereditary

disease, anesthesiologist\'s nightmare), electrical injury.



Myositis ossificans: localized form is ectopic bone production at site

of injury. Generalized involves new bones bridging joints; rare and

miserable.



Muscle membrane diseases and semi-diseases: Myotonia congenita

(chloride channel disease) often features hypertrophied muscles in non-

exercisers, eventually cramps and atrophy become a problem. Periodic

paralysis: sodium channel problems, currently being sorted out.



Eosinophilia-myalgia: followed ingestion of tainted \"health food\"

tryptophan.



Vitiligo: autoimmunity against melanocytes; Michael Jackson\'s

depigmentation; runs with addisonism and pernicious anemia, but most

often alone.



Freckle: extra pigment, especially in response to tanning. Lentigo:

extra melanocytes with some acanthosis. Nevocellular nevi:

intradermal, junctional (dermal-epidermal), or mixed (compound). Blue

nevus: spindle-shaped, darkly-pigmented, in deep dermis. Halo nevus:

being cleared, along with nearby melanocytes, by immunity. Congenital

nevus: can be huge, follow dermatomes, some melanoma risk. Dysplastic

nevi: junctional nevi which are irregularly pigmented and with

irregular borders; often multiple and familial, melanoma risk.



Melanoma: risk factors are sunlight, fair skin, dysplastic nevus

syndrome, xeroderma pigmentosum. Look for irregular borders,

variegated pigmentation, bleeding, rapid growth. When in doubt, cut it

off.



Melanoma types: Hutchinson\'s lentigo-maligna freckle is in-situ,

single-cell growth, no invasion until late. Superficial spreading

melanoma: clusters of cells at dermal-epidermal junction, invades

(grows vertical) sooner or later. Nodular melanoma: vertical growth

from the onset. Clark\'s levels are replaced by Breslow\'s thickness

(less then 0.75 mm: safe).



Seborrheic keratosis: crusty keratotic lesions, old folks; sudden

eruption of dozens heralds colon cancer.



Keratoacanthoma: rapidly-growing volcano-shaped hyperkeratotic lesion;

benign.



Actinic keratosis: squamous cell carcinoma in situ. Sunlight, arsenic,

xeroderma pigmentosum. Bowen\'s disease: Very anaplastic carcinoma in

situ.



Squamous cell carcinoma: sunlight, osteomyelitis sinuses, arsenic,

xeroderma pigmentosum, coal tar, immune suppression for a long time

(the last are caused by KSHV, news). Metastasize late.



Basal cell carcinoma: pearly-bordered \"rodent ulcers\" on sun-exposed

skin, locally destructive but do not metastasize.



Dermatofibroma: fibrous nodule of histiocyte (?) origin; pinch it and

the overlying skin dimples since it is not attached to the epidermis.



Xanthomas: Masses of lipid-laden macrophages, including the familiar

xanthelasma.



Eczema: Acute inflammation of the epidermis, with edema in and between

cells, some cell loss, inflammatory cells, dried protein-rich exudate

(\"crusts\"). Includes contact dermatitis (allergic, irritant), atopic

eczema (cracks in creases of elbows and knees), many drug rashes

(haptens?)



Erythema multiforme: T-cells angry with the epidermis. Triggers

include drugs, herpes simplex, mycoplasma, lymphoma, lupus, or just

plain idiopathic. Target lesions, variable course, worst is Stevens-

Johnson syndrome.



Psoriasis: Hyperkeratosis, parakeratosis, long rete pegs, pustules in

epidermis and dermal papillae tips, thin epidermis over distended

dermal papillae (peel it off and the pinpoint bleeds are Auspitz\'s

sign), Koebner phenomenon (scratch anywhere and psoriasis appears

there). Silvery scales, pitted nails; arthritis; HLA-B27 types get

ankylosing spondylitis.



Lichen planus: purple polygonal pruritic papules. Hyperkeratosis,

apoptosis, band-like infiltrate.



Acne vulgaris: Propionibacterium thriving on free fatty acids in sebum

gets the process started. When your epidermis gets hyperkeratotic and

your sebaceous glands enlarge during puberty, the problem begins.

Basic lesion is the \"comedome\" keratin-and-sebum plug.



Pemphigus vulgaris: antibodies against desmosomes; tombstone basal

layer. Nikolsky\'s sign on rubbing the skin.



Pemphigoid: antibodies against hemidesmosomes, milder than pemphigus

vulgaris.



Dermatitis herpetiformis: IgA in the dermal papillae; symmetric itchy

blisters.



Pompholyx (\"dyshydrotic eczema\") is blisters on palms and soles, a

nuisance disease; ask about nickel allergy, offer low-zinc diet.



Epidermolysis bullosa: no type VII collagen in the basal lamina of the

skin (genetic defect, autoimmunity).



Molluscum contagiosum: acanthotic, itchy lesions with a central plug

made of poxvirus. Transmitted by touch.



Impetigo: infectious, often mixed staph-strep, of the horny layer of

the epidermis. Honey crusts.



Seborrhea: caused by pityrosporum yeast. Tinea versicolor: another

superficial yeast. Jock itch and athlete\'s foot require no

description. Itchy glans and finger webs suggest scabies.





\"It must be inconvenient to be made of flesh,\"

said the Scarecrow, thoughtfully, \"for you must

sleep, and eat and drink. However, you have

brains, and it is worth a lot of bother to be able

to think properly.\"

-- The Wizard of Oz



Selective vulnerability:

Purkinje cells Alcoholism, carbon monoxide

Mammilaries, Purkinje cells Wernicke\'s

DM of thalamus Korsakoff\'s

Hippocampus Alzheimer\'s, hypoxia, hypoglycemia

Cerebellar granular layer Mercury, radiation injury

Retina Methanol

Anterior horn cells Polio, bad cassava, lower-ALS

Globus pallidus Carbon monoxide, Wilson\'s,

kernicterus (baby jaundice)

Posterior columns B12 deficiency, syphilis (tabes)

Caudate Huntington\'s

Prefrontal, temporal Pick\'s

Deep brain Progressive supranuclear palsy

Intermediolateral cord Shy-Drager dysautonomia

Substantia nigra Idiopathic Parkinson\'s, von Economo

Left-center temporal cortex Schizophrenia

Upper motor neurons Upper-ALS





Neural tube defects: folic acid deficiency at conception. Arnold-

Chiari: long cerebellar tonsils out the foramen magnum, beak-shaped

tectum, platybasia, maybe hydrocephalus, maybe neural tube defects.



Dandy-Walker: No good cerebellar vermis; prominent occiput.



Syringomyelia: acquired tube-shaped deformity down center of cervical

spine; etiology is obscure, loss of spinothalamic tracts at this level.



Red neuron: ischemia, hypoglycemia; this is coagulation necrosis of

neurons.



Neurofibrillary tangles: Twisted filaments of tau protein inside cells;

stain with silver, think of Alzheimer\'s, post-influenzal parkinsonism

(\"Awakenings\"), progressive supranuclear palsy, boxers.



Lewy bodies: Pink spheroids inside cells; substantia nigra of

Parkinsonism, cortex in Lewy dementia, others.



Pick bodies: Big silver-staining barrel-shaped intraneuronal

inclusions. Pick\'s disease (easy).



Granulovacuolar degeneration: Silver-staining spheres of tau protein,

surrounded by a vacuole, inside neurons, in Alzheimer\'s.



Lafora bodies: sunflower-shaped masses of carbohydrate in neurons,

myoclonus epilepsy.



Negri bodies: eosinophilic inclusions in rabies.



Central chromatolysis (axonal reaction): neuron swells, endoplasmic

reticulum (\"Nissl substance\") moves to the periphery of the cell.



Axonal degeneration: Changes in the neuron cell body and other points

proximal to where an axon is cut. Wallerian degeneration: changes

distal to where an axon is cut. Axonal spheroids: retraction balls

typical of diffuse axonal injury.



Gliosis: astrocytes proliferate and heal injured brain. Sclerosis:

oligodendroglia die off, axons are preserved, and astrocytes replace

the lost volume. Spongiosis: reactive astrocytes plus edema.

Alzheimer type I glia: monstrously enlarged astrocytes in progressive

multifocal leukoencephalopathy (JC papovavirus) and subacute sclerosing

panencephalitis (slow measles virus). Alzheimer\'s type II glia:

astrocytes with swollen nuclei from hyperammonemia (liver failure,

Reye\'s).



Leukodystrophy: disease primarily affecting diffusely oligodendroglia,

usually hereditary.



Microglia: CNS macrophages. Giant-cell encephalitis: HIV. Rod cells:

elongated microglia in syphilis and rickettsial disease. Gitter cells:

microglia eating dead lipid. Microglial nodules: viruses and

rickettsia.



Increased intracranial pressure presents as headache, dullness, nausea

and vomiting.



Cingulate (subfalcine) gyrus herniation: under the falx; lose anterior

cerebral artery, weak leg on opposite side.



Uncal (hippocampal, transtentorial) herniation: under the tentorium,

lose III (dilated pupil), posterior cerebral artery (contralateral

homonymous hemianopsia).



Tonsillar herniation: out the foramen magnum, compress medulla,

autonomic death.



Duret hemorrhages: in brainstem following herniation, from damage to

arteries.



Vasogenic edema: hurt or leaky capillaries, as in infarcts, infection,

lead poisoning, trauma, \"ring enhancement\" around tumors or abscesses.

Cytotoxic edema: ischemia, acidosis, Reye\'s, Cerebral edema is bad

since the brain has nowhere to expand.



Interstitial edema: from obstructed flow of spinal fluid.



Hydrocephalus: any increase in volume of CSF. Hydrocephalus ex vacuo:

loss of cortex. Non-communicating hydrocephalus: blockage within the

brain. Communicating hydrocephalus: too much fluid produced, scarring

in the subarachnoid space, problems with arachnoid villi (i.e.,

sagittal sinus thrombosis).



Cerebral infarcts may be hemorrhagic or pale, depending on how much

reperfusion takes place.



Blood in the subarachnoid space is very painful. Bleeding in the brain

itself is toxic, but recovery is better than from ischemia. Blood in

the ventricles is a disaster.



Intracerebral bleeds: blamed on \"hypertension\", the common site is the

putamen (\"lenticulostriate artery of Charcot\"). Less often,

congophilic angiopathy, vascular malformations, others.



Subarachnoid hemorrhages: usual cause is berry aneurysms; risk factors

include polycystic kidneys; \"defects in the elastica\" are ubiquitous

even in folks who do not have berries; we don\'t understand how they

form. Most common site is anterior communicating artery, next is

middle cerebral, next is posterior communicating. (The other cause of

subarachnoid bleeds is AV malformations in the meninges.)



Germinal plate bleeds: Premature babies, especially with lung disease;

cor pulmonale raises the venous blood pressure, rupturing the fragile

baby-veins in the wall of the ventricles.



Subdural hematoma: from avulsion of the bridging veins. Acute subdural

hematoma: catastrophic injury. Chronic subdural hematoma: slow leaks,

especially in atrophic brains (stretched vessels); mass of granulation

tissue diverts blood from the underlying cortex.



Epidural hematoma: blow to the head fractures skull, nicking middle

meningeal artery. Upon regaining consciousness, the patient feels

okay, then drifts into coma, herniates, and dies. Why we monitor head

injury patients.



Concussion: blow to the head causing loss of consciousness. Contusion:

bruise to the brain, perhaps damaging it. Coup contusion: under the

impact. Contrecoup contusion: opposite the impact, typical when the

head strikes something bigger than itself, i.e., the ground. Typical

contrecoup sites are the occiput (fall on face), bottom of prefrontal

lobes (fall backwards off bar stool), temporal lobe above the petrous

ridge (hit on top of head).



Diffuse axonal injury is tearing of axons. Brain damage with no

radiologic correlates. At autopsy, we look for petechiae in the

reticular formation and the corpus callosum, axonal retraction

spheroids.



You will be quizzed frequently on the most common etiologic agents of

meningitis:



E. coli Newborns (strep B too)

H. \'flu 1 month to 3-5 year old kids

Meningococcus Older kids and younger adults (remember

epidemics, military recruits, Waterhouse-

Friderichsen syndrome)

Pneumococcus Oldsters and drinkers

Anything The immunosuppressed -- tough diagnosis



Disastrous effects of meningitis include brain damage, cranial nerve

loss, spinal nerve loss, hydrocephalus.



Acute lymphocytic meningitis: virus, leptospira; the familiar \"stiff

neck\", photophobia, and so forth. Recovery is the norm.



TB meningitis: around circle of Willis, where the oxygen is. Damage to

cranial nerves.



Cryptococcal meningitis: Bugs thrive in spinal fluid nad Virchow-Robin

spaces. India ink prep.



Brain abscess: after dirty wound, mastoiditis, lung abscess, right-to-

left shunts.



Von Economo\'s encephalitis: after influenza. Herpes simplex I:

necrosis of the temporal lobes, notably the hippocampus and amygdala;

herpes incisions in oligodendroglia. Herpes simplex II encephalitis:

why you deliver babies of a woman with active herpes by C-section.



Poliomyelitis: attacks anterior horn cells. Rabies: follows the axons

up to the brain. CMV: periventricular calcifications in the unborn.

HTLV-1: a spastic paralysis endemic in the Caribbean.



Spongiform encephalopathies: scrapie (sheep), mink encephalopathy and

mad cow disease (from eating scrapie sheep carcasses), kuru

(cannibals), Creutzfeldt-Jacob disease (sporadic, iatrogenic), and

Gerstmann-Straussler are the same disease. The cause is prions,

twisted PrP protein which catalyzes the transformation of normal PrP

into copies of itself, equally infectious, i.e., a chain reaction.

Gerstmann-Straussler is a hereditary disease with PrP prone to

transform spontaneously into prion, and this can happen to anyone who\'s

unlucky. Myoclonus, ataxia, dementia. Histopathology: neuronal

dropout with intracellular and extracellular water vacuoles

(\"spongiform encephalopathy\").



The most common causes of headache are probably caffeine withdrawal,

hangover, and eyestrain (needing glasses). Worry about the unusual

headache, i.e., the one that\'s not typical for that patient. Migraine

is a pain syndrome inside the brain; what you\'ve heard about vasospasm

and vasodilatation is simplistic.



Alzheimer\'s: \"Just plain senile\", or \"presenile dementia\".

Neurofibrillary tangles in the cortical neurons. Senile plaques

(masses of amyloid made of beta-A4 protein and apolipoprotein E)

surrounded by neurofilaments with altered tau protein in them.

Granulovacuolar degeneration. Amyloid in the vessels. Cortical

atrophy. Mutant beta-A4 for early-onset disease, mutant apolipoprotein

E4 is a risk factor for late-onset disease.



Pick\'s disease: Alzheimer-like dementia, only selectively involving the

prefrontal and temporal lobes (\"walnut atrophy\"). Pick bodies, swollen

cells.



Huntington\'s: degeneration of the caudate head, usually in young adult

life. Autosomal dominant with complete penetrance, shows genetic

anticipation. Dance-like (chorea) gait disturbance, dementia, a bad

way to die.



Parkinsonism: familiar movement disorder, difficulty initiating or

stopping movement, mask-like face, pill-rolling tremor. Lewy bodies,

or neurofibrillary tangles if post-influenzal. Shy-Drager: Parkinson\'s

plus dysautonomia, often including impressive orthostatic hypotension.

Progressive supranuclear palsy: Under-recognized degenerative disease

of basal ganglia and deep brain structures; eye movement disorders and

dementia.



Benign familial tremor: 1% of people, comes on around age 20, autosomal

dominant, a beer or a tiny dose of propranolol abolishes the intention

tremor.



Friedreich\'s ataxia: degeneration of spinal tracts and cerebellum, with

foot deformities and cardiomyopathy.



Amyotrophic lateral sclerosis: Lou Gehrig\'s, actually a family of

diseases in which upper and/or lower motor neurons die off.



Schizophrenia: Obviously a neurologic problem rather than \"your mother

looked and talked to you funny\"; old psychologist models are now

totally discredited. Loss of cells in the cortex, most notably the

center of the temporal lobe; hydrocephalus ex vacuo is usual. Autism

(\"rain man\": Also obviously a neurologic problem rather than \"bad

parenting\"; deformities of the vermis are usual.



Subclavian steal (\"Robin Hood\"): stenosis of the subclavian artery

proximal to the thyrocervical trunk results in diversion of blood from

the brain when you exercise the corresponding arm.



Vascular dementias: Severe atherosclerosis can and does produce

dementia. Binswanger\'s subcortical leukoencephalopathy: brain failure

from hyaline arteriolar sclerosis in hypertensives; under-recognized.



Most brain tumors in kids are infratentorial (medulloblastomas,

cerebellar astrocytomas). Most brain tumors in adults are

supratentorial. They present as personality changes, then headache,

nausea-vomiting, etc.



All gliomas are malignant. Astrocytomas may be hard to see, simply

extra astrocytes in an area. Oligodendrogliomas tend to calcify, and

exhibit fried-egg cells (lipid). Ependymomas sit on the walls of

ventricles and make little tubes, cilia, and so forth. All tend to

transform into glioblastoma multiforme, an extremely malignant tumor,

with necrosis, hemorrhage, vascular proliferation, palisading of

bizarre cells, and rapid death.



Medulloblastoma: small blue cells, arising in cerebellar vermis,

spreads up and down neuraxis.



Meningioma: arises from arachnoid cap cells, along sphenoid ridge or

sagittal sinus, sometimes elsewhere. Whorls, psammoma bodies; most are

benign, tend to recur, may result from trauma.



Brain lymphomas: usually from Epstein-Barr infection in the immune-

suppressed.



Metastatic cancer: the most common brain tumor. Usually at the gray-

white junction, where vessel size drops off.



Multiple sclerosis: the dread demyelinating disease of young adults.

T-cells go after the myelin. Most likely cause of Epstein-Barr virus

mimicking myelin. The farther away from the equator that you grew up,

the more likely you are to get multiple sclerosis. Hereditary Finnish

MS maps to the myelin gene. Plaques appear, especially near the

ventricles, then may partly heal, accounting for the exacerbations and

remissions; the ultimate course is downhill though the final degree of

disability is widely variable. Classic signs are optic neuritis,

dysconjugate eye movements. Devic\'s: optic neuritis and spinal cord

lesions.



Acute disseminated encephalomyelitis: after a virus or immunization,

the immune system tears up the brain\'s myelin, especially around

vessels. Recovery may be partial or complete. There is a necrotizing

version.



Central pontine myelinolysis: in the center of the basis pontis; takes

out the descending motor tracts, currently blamed (sometimes) on too-

rapid correction of hyponatremia (\"osmotic myelinolysis\").





Korsakoff\'s: nice fantasy life, damaged dorsomedian nucleus.

Wernicke\'s: damage mammillary bodies.





Guillain-Barr: autoimmunity against the spinal motor nerves, with

ascending paralysis lasting up to months.



Other peripheral neuropathies: alcoholism / thiamine deficiency;

diabetes; lead; Charcot-Marie-Tooth; paraneoplastic, more.



Neurilemmoma (schwannoma): Tumor of perineurium; sits on nerve with

fibers passing alongside the tumor. The familiar acoustic neuroma, or

anywhere else. Verocay bodies, Antony A (dense palisades) and Antoni B

(myxoid) areas.



Neurofibroma: Tumor of endoneurium. Fibers pass through it, with

ropelike transformation of nerves; those on the skin of

neurofibromatosis patients look like erasers.



[Mind and brain: Our brain is clearly our interface with the familiar

world, and handles the automatic stuff that our minds do for us. But

I\'ve seen and heard enough to hold, as a reasonable working hypothesis

(and probably the best available), that what makes us who we really are

is something fundamentally different from, and separable from, our

brains. I am not the only science-jock to reach this tentative

conclusion. I\'d add that we should probably try to be kind and decent

to each other, just for this reason.]





T3 resin uptake value is inversely proportional to the number of

unbound sites on the thyroid binding globulins.



What\'s in those vacuum-filled blood sample tubes? I could see them

asking....



Red-top: Nothing. The blood will clot, and we\'ll extract

the serum. Used for most routine chemistries.



Purple-top: EDTA (calcium-chelating anticoagulant). Best for

blood cell counting.



Blue-top: Citrate (calcium-chelating anticoagulant, readily

neutralized). Best for routine coagulation

studies.



Gray-top: Fluoride-oxalate. Inhibits glycolytic enzymes.

Best for glucose and routine toxicology.



Green-top: Heparin anticoagulant. Less popular than the

others.

The porphyrias: Acute intermittent and its variants feature

neurotoxicity from delta-amino levulininc acid and porphobilinogen;

somtach aches and insanity; exacerbate the enzyme deficicy by further

inhibiting it with barbiturates. Cutanea tarda and its worse relatives

feature photosensitivity, with scarring, extra hair, and blistering,

from buildup of porphyrins themselves.



LDH isoenzymes: 1 (1-2 flip) is heart, red cells, kidney; 3 is lung; 5

is liver and skeletal muscle.



SGOT (AST): Up in liver cell injury, heart cell injury, red cells,

skeletal muscle. SGPT (ALT): Liver only.



Creatine kinase (CK, CPK): MM is skeletal muscle, MB is heart (or fit-

person\'s skeletal muscle), BB is brain.



Alkaline phosphatase: bone, liver, placenta, less often intestine. If

of hepatic origin, 5\' nucleotidase, leucine aminopeptidase, and gamma-

glutamyl transpeptidase will be up as well.



Prerenal azotemia: BUN/creatinine ratio around 20, low urine sodium.

Renal shutdown: BUN/creatinig ratio around 10, urine soidum mEq/L.



\"RDW\" is red-cell distribution width, measure of size differences;

early detection of iron deficiency and most other stuff.



High LDH, high potassium: Hemolyzed specimen.



The titer of a substance measured in the serology lab is the maximum

dilution (of a series of dilutions) at which the substance can be

detected. Thus a titer of 1:2 or 1:10 is a \"low titer\" and indicates

that not very much of the substance is present. And a titer of

1:128000 is probably a \"high titer\". Depending on what you are

measuring, a titer of 1:100 might be \"high\" or \"low\".



\"A significant rise in titer\" suggests a recent infectious disease.

\"Significant\" is usually considered to be a \"fourfold rise\". If a

titer rises from 1:16 to 1:64 during an episode of acute illness, or

when a titer rises from 1:10000 to 1:80000, the patient probably had

the acute disease to match.



To screen for malabsorption, do a fecal fat stain. To distinguish

pancreatic malabsorption from intestinal malabsorption, do a d-xylose

test. To find the cause of intestinal malabsorption, do a biopsy.



Analytic sensitivity: how little of the substance you can detect.

Analytic specificity: how sure you can be that you\'re not looking at

something else instead. Accuracy: How close to a known true value.

Precision: How reproducable your results are, right or wrong.



DIAGNOSTIC SENSITIVITY (\"Bayesian sensitivity\") is the percentage of

positive results in patients with a particular disease.



True Positives

Diagnostic sensitivity = ________________________________ x 100

True Positives + False Negatives



DIAGNOSTIC SPECIFICITY (\"Bayesian specificity\") is the percentage of

negative results in patients without a particular disease.



True Negatives

Diagnostic specificity = ________________________________ x 100

True Negatives + False Positives



Sensitive tests are best for the diagnosis of treatable diseases:

bacterial infections, early cancer, phenylketonuria. You want a very

sensitive test when the benefits of detecting the disease are great

(curing it, preventing new cases, etc).



Specific tests are best for the diagnosis of non-treatable

diseases: chronic neurologic disease, disseminated cancer, etc. You

want a very specific test when the risks of a wrong diagnosis are great

(getting very upset, losing your insurance, getting cancer

chemotherapy, etc.)



These are appalling over-generalizations, but there is always a

tradeoff between sensitivity and specificity. If a new test is both

more sensitive and more specific than an old test (and not much more

expensive), it replaces it. Otherwise, whether we are a pathologist

setting a \"reference range\" or \"decision level\", or a clinician

ordering a lab test, we must remember that sensitive tests lack

specificity and specific tests lack sensitivity. Clinicians commonly

order the sensitive tests first, followed by the specific ones.



Predictive value: the percent chance that a result correctly

identifies the patient as diseased or non-diseased.



True Positives

Predictive Value of = ________________________________ x 100

a Positive Result True Positives + False Positives



True Negatives

Predictive Value of = ________________________________ x 100

a Negative Result True Negatives + False Negatives



Diagnostic accuracy (\"diagnostic efficiency\"): the percent of

patients correctly identified as diseased or non-diseased by the test.



True Positives + True Negatives

Diagnostic accuracy = _______________________________ x 100

All Results



Prevalence: the percent of those tested who actually have the

disease.



True Positives + False Negatives

Prevalence = ________________________________ x 100

All Results



Prevalence may be expressed in different units. Contrast

incidence: the fraction of new cases of the disease in a population

over a given time.



Prevalence = Incidence x Average Duration



Bayes\' Theorem



(Sensitivity)(Prevalence)

Predictive Value of=_____________________________________________

a Positive Result Sensit.)(Prev.)+(1-Specif.)(1-Prev.)


















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