CHAPTER 1 – CELLULAR INJURY
Main types of cell injury: ischemic, free radical, chemical
(In addition to hypertrophy, hypotrophy, atrophy, metaplasia, hyper/hypoplasia)
Ischemic Cell Injury
1. Causes: O-COPA: Obstr of arts (most common); CO poisoning; poor oxygenation; perfusion poor; anemia
2. Early Injury: mita are first to suffer (PRP: pump failure (swelling of vacuoles, ER, mita); Ribosomes disaggregate; PFK stimulated ( glycolysis, lactate and \ acidic)
3. Late Injury: membranes (Morph signs include Myelin figures = membrane; Cell blebs = cytoskeleton)
4. Cell Death: point of no return = suff damage to allow massive Ca influx; sometimes (eg heart) enzymes are release (AST, LDH, CPK); A morphologic hallmark of irrev cell dmg = nuclear changes
5. Death: 3-5 mins for neurons, 1-2 hours for myocardial cells, hepatocytes, days for skM
Free Radical Injury
· Generation: NastyO2 RADicals Create Ruin (normal metabolism; o2 poisoning; ionizing radiation; chemical damage; reperfusion injury)
- drugs & chemicals: induce p450 & prliferation of SER (eg SER sign of barbituate poisoning in hepatocytes)
· Degradation: I-S E A (Intracellular Enz’s: glut perox, catalase, SOD; Spont decay; Endog: ceruloplasmin, transferrin; Antioxidants: vit A, E, ascorbic acid)
Necrosis
Degredative reactions occuring after death
Types of necrosis: CLC,G,FAF (coag, liquef, caseous, gangr, fibrinoid, apop, fat)
ReversibleCellular Changes & Accumulations
1. Fatty change;
2. Hyaline change; caused by accums of proteinaceous material
3. Exogenous accums (APP: pul accums, plumbism, argyria);
4. Endogenous accums: “Moshe’s body looks hairy”; Melanin (made in melanocytes from tyrosine); Bilirubin (bkdown prod of Hgb; when it accumulates k/a Jaundice); Hemosiderin , lipofuscin);
5. Calcifications: a)Metastatic: caused by hypercalcemia b)Dystrophic: occurs in prev damaged tissue: trauma, TB, scarred heart valves, Ath lesions; not caused by hrcalcemia)
CHAPTER IV – GENETIC DISORDERS
Abnorm’s of Auosomal Chrs / Down’s; Cri du Chat; Edward’s; Patau’sAbN’s of Sex / Klein, Turner, XYY, XXX, Fragile X
Kleinfelter’s / Tall, Tits, Testes (atrophy); Male hypogonadism; pit gonadotrophins (¯ feedback)
Turner’s / Female hypogonadism
XYY / Tall, severe acne, (violent)
XXX / MM (mild retardation, menstrual irregularities)
Fragile X / Mental retardation (2nd in freq only to Down’s); ¯ x » Y » big balls
Down’s / Round drawing of face (p47); Complic’s: HAIL (ht dz, alz, inf, leuk)
Cri du Chat / Like Down’s (wide face, epicanth, low ears); h/e Like Cat (small head, svr retarded, wideset eyes, cry)
Edward’s / Picture of triangular face (prom occiput, low ears, rocking); overlapping fingers; (rare)
Patau’s / Pow!!, polydactyly; (rare)
Mendelian Aut Dom / A F/ Her, Her, Hu/ M N/ T V
Familial HyperChol / LDL Receptor anomalites à chol à atherosclerosis; xanthomas
HeredHem Telang / skin & mucous-membr telang’s; nosebleeds HHT aka OWR (Osler-Weber-Rendu); Mormon; fragile vessels
Hereditary Spherocy / Defects in RBC membrane (\ spheical eryths) à spleen à hemolytic anemia
Huntington’s / Choreiform mvmnts & Dementia; Chorea = Gr. ‘dance’; progressive destr of caudate nucleus; chrom 4 ( prodn of huntingtin protein); doesn’t manifest until 30-40
Marfan’s / A defect of CT (¯ fibrillin à CT is loose): A-E-I Defects: Eyes (ectopia lentis; myopia), CVS (esp aorta b/c it stretches; s/a aneur, dissec, valve), muscle, Infective Endocarditis; aka Arachnodactyly
Neurofibromatosis / No C L a S T (“no class”) ; aka Von Reckling..; Neurofibromas, Café au lait, Lisch nod, Skel disorders, Tumors (other)
Tuberous Sclerosis / A phacomatosis; Tubers (swellings- a phacomatosis); nerves/brain; seizures, facial hamartomas; white leaf birthmark (Kolten’s story); rare
VonHippel-Lindau / HARC: Hemangiomas of retina, cerebellum/SpC; Adenomas; incidence of renal cell carcenoma; Cysts (liv,kid, renal); chr #3
Autosomal Recessive Disorders / Lysosomal (TS, Gauch, NP, Hurler’s); Glycogen (VonGierke, Pompe, Cori, McArdle); Carb (galactosemia); AA (PKU, Alkapto)
Tay Sachs / ¯ hexosaminidase A = Gm2 ganglioside; CNS degen; blindness; cherry-red spot macula; death < 4yo
Gaucher’s / ¯ glucocerebrocidase = glucocerebroside; Gaucher’s cells
type I: liv, spl, bone (viscera) II: CNS degen; III both (3 = 1 + 2)
Niemann-Pick / ¯ sphingomyelinase = sphingomyelin; combo of TS (cherry-red; mental degen) & Gaucher’s (hepSplMeg & anemia); foamy histiocytes
Hurler’s / ¯ a iduronidase = mucopolysacchs (hep & derm so4) So ugly you want to hurl (dwarf, gargoyle, stubby, cloudy cornea, mental, dead at 10); svr than Hunter’s
Von Gierke’s (type I) / Aka hepatorenal; ¯ Gluc-6-Pho-ase = glycogen (liv and kid) \ hypoglycemia; Char by hepatomegaly and hypoglycemia
Pompe’s Dz (II) / Char: cardiomegaly, muscle hypotonia, splenomegaly; death by age 3; ¯ a 1,4 glucosidase = glycogen (liv, ht, skM);
Cori’s Dz (III) / Char: stunted growth hepatomegaly, hypoglycemia ; ¯ amyl-1,6-glucosidase = glycoten (liv, ht, skM);
McArdle’s (V) / painful muscle cramps and weakness following exercise ; ¯ muscle phosphorylase = glycogen (skM);
Galactosemia (Classic) / failure to thrive, infantile cataracts, mental retardation, cirrhosis; can be prevented by early removal of galactose from diet ; ¯ gal-1-phos-uridyl-transferase = gal-1-Phosphate;
Phenylkeotonuria / blond, blue eyed, but dumb (MR) and smelly (acid in urine, sweat); screen on 3-4 day of life ; ¯ Phe-hydroxylase = Phe;
Alkaptonuria / [Al Capone is dark]; incapacitating ocrhonic arthritis
¯ homogentisic oxidase = homogentisic acid; dark (urine & tissue)
Cystic Fibrosis / LIP (chronic pulm dz, meconeium ileus, pancr insuff); Faulty CFTR \ Cl in sweat and tears (sweat test);
X-Linked Rec / H F/ H L/ G D: Hunter’s, Fabry’s, Hemophil A, Lesch-Nyhan, G6PD Def, Duchenne’s MD
Hunter’s / Similar to Hurler’s; not as ugly, not as severe, retinal degen, joint stiffness
Fabry’s / angiokeratomas over lower trunk; febrile episodes; severe burning pain in extremities; early death from renal failure ; Aka angiokeratoma …; ¯ a galactosidase A = ceramide trihexoside;
Lesch-Nyhan / gout, self-mutilation; aggressive behavior ; ¯ HPGRT = ¯ purine metabolism and \ uric acid;
Brushfield’s spots / Down’s syndrome (light smudgy opacity in pupil)
Chap. 5: Immune Dysfunction
Immune Deficiency / AIDS-AIC (Adult polycyst kid dz, Isolated IgA Def, DiGeorge (thymic hypoplasia), SCID, AIDS, Immunodef w thrombocytopenia & eczema (aka Wiskott-Aldrich), Common variable immunodefAutoimmunity / CHAI (CT Dz’s, Hashimoto’s Thyroiditis, AHA, Idiopathic Adrenal Atrophy)
CT Diseases / SSS, PMP (SLE, Scleroderma aka PSS, Sjorgen’s, Polymyositis, PAN)
Amyloidosis / 1°, 2°, PAF, MDS (Portuguese type polyneuropathy, Alz Dz, Familial Mediterannean Fever, Medullary Carc of Thyroid, DM, Senile Amyloidosis)
Cells of Imm Sys / Lymps (Bs, Ts, NKs), Mo, Dendritic, Langerhans
Cytokines / · IL1-6, IFN a-g; TNF a and b
· Prolif (2), Grow (2), Mature (2), Antiviral (3), Prolif (2)
· IL1 similar to TNFs
· Ts: All exc IL1, IFN a, b; Alone in IL3-5, TNF b; With NKs otherwise
· Mo: IL1, IL2, IFN a, TNF a
· Bs and Ts: 2nd, 4th, 6th (IL2, IL4, IL6)
IFN g / Antiviral (as w. all IFNs); activates Mo; enhance MHC II expr
IL 4 / B&T growth; enhance MHC II expression (“B+T+II = 4”)
IL 1 / T prolif; IL2 prod’n
IL 2 / B&T prolif; activates Mono’s
IL 3 / Growth of Tiss mast cells and hematopoietic stem cells
IFN a & IFN b / Antiviral
TNF a & b / Just like IL1 (T prolif, IL2 prod’n) & cytotoxic to some tumors
HLA I / on all cells exc RBCs; type = A, B, C; involved in tissue graft rejection
HLA II / On immunocomptent cells (Mo, Dendr, Langer, Lymphs); DP, DQ, DR (ie: Ag presentation cells [?])
Type I Hypersensitivity / Ag causes B’s to make IgEs which then bind to mast cells and basophils. Subsequent exposure triggers degranulation s/a histamine. (k/a Anaphylactic H); includes Allergic/Atopic rxns
Type II Hypersensitivity / Type II had 3 types! ; k/a Cytotoxic Hrsens
1. Complement: Abs bind to integral parts of membrane; other end of Ab binds to complement (eg: autoImm Hem Anemia, hemol transfusion rxns, Hemol Dz of newborn (Eryth Fet), Goodpastures
2. ADCC: Ab binds to integral component; other end binds cytotoxic cell (eg NK, etc)
3. Graves Dz type reaction
Type III Hypersensitivity / The immune complexes do three things: bind complement, activate Hageman’s factor, aggregate platelets;
Compl: Neutrs à rel degrad enz’s; Hageman: coag, bradykinin; Platelets: microthrombi, degranulation
Type III Hypersensitivity Clinical Examples / Serum Sickness
Arthus reaction (introduce exog Ag when an excess of preformed Abs is present)
PAN (generalized Imm Compl Dz of small/med arts)
Imm Compl Glomerular Dz’s (membr glom, poststrepto glom, lupus neuropathy)
Type IV Hypersensitivity / Delayed: (exemplified by tuberculin rxn and contact derm); 1. Mo present MHC II/Ag to CD4 cell. CD4 is triggered to make specific T memory cells. ON subseq exposure, memory Ts both prolif and secr Cytokines s/a IL-1, IFN g (\ Mo \ phag)
CTL Mediated: tumors/virus; Mech: CD8 (Killer-T) recognizes Ag and kills it. [?]
Transplant Rejection Types / Hyperacute: localized Arthus rxn; marked by: Infl, fibrinoid necr, extensive thrombosis
Acute: char by infiltr of lymphocytes & Mo
Chronic: Ab-mediated vascular damage; Atherosclerosis & smal, scarred kidney
X-linked Aggamaglob / Failure of Ab due to block in maturation of preB’s to Bs
Isolated IgA def / Failure of IgA’s to mature; most common inherited B cell defect (1:700); Recurrent sinus & lung inf’s; recurr diarrhea
DiGeorge Syndrome / Di = “De”velopment; aka thymic hypoplasia \ lymphopenia
Dz due due faulty dev of 3rd and 4th branchial arches (mandible, ear, thymus, parathyroid)
Thymus = failure of T maturation; recurr viral & fungal infs
Parathyroid = tetany (hypocalcemia fr hypoparathyroidism)
SCID / Common = failure of both Bs and Ts
Fr a variety of genetic defects (X-linked and AutosRec): eg: ADA defic = accum of deoxyATP w. is toxic to L-cytes
MIT: malig, infections (viral, fungal, bact), failure to thrive
Immunodef w Thrombocytopenia & Eczema / Aka Wiskott-Aldrich; Death from svr hemorrhage and overwhelming infections; X-linked;
AIDS / · gp120: affinity for CD4 (T’s, other immunocomp cells w CD4)
· Path: ¯ CD4 Ts (helper)\ failure of humoral and cell-mediated; hypergammaglobulinemia(!)
· Clinical: Immunodef (PCM, CCC, GMT); Malig (Kaposi’s, NHL, Hodg Dz, Hepatocell C-oma); NS problems
· Stages: “ALAS”: Acute ilness (resembles mono); Lymphadenopathy; AIDS-related complex (fever, weight loss, diarrhea); Seropositivity (gag, pol, env)
Mechs that can cause autoimmunity / Ag, Ab, REG: Antigens, antibodies (auto); ImmunoREGulation disorder ( helper Ts, ¯ supressor Ts, B activ by EBV); Environmental (eg inf’s viruses); Genetic (eg HLA antigens) )
How Ags cause autoimm / MOCk: modification (infection, infl); Ordinarily isolated (lens protein, spermatozoa, thryoglobulin); Common structure
SLE Clinical / Ray JR’S Eye Got Nailed in PEI (Raynaud’s, Joints, Rash, Serosal Infl Eye, Glomerular (subendoth, wire-loop), Nervous, Pulm Fibrosis, Endocarditis (Libb-Sacks), Imm Complex Vasculitis(Spl: onion-skin around arterioles))
SLE Lab Findings / Anti dsDNA-ANA (“rim” pattern); anti-Sm; ¯¯ complement; BFPs for syphilis; Immune complexes at dermal-epidermal jctn