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Pathology
Y2S1B1
| Genetic Disease | Features |
|---|---|
| Hereditary diseases | inherited via gametes from parents; all hereditary diseases are familial |
| Familial diseases | increased incidence above normal within a family; disease pattern is NOT predictable/Mendelian |
| Congenital diseases | onset of symptoms at birth or shortly thereafter; may not be genetic |
| Sporadic genetic diseases | mutation arises de novo; not familial, but there may be a familial predisposition to form a de novo mutation; not hereditary, but they are genetic |
| De novo mutation | arises in post-fertilization development and may present in gametes of affected individual (later to possess Mendelian patterns); ex: Achondroplasia |
| Familial hypercholesteremia | Auto Dom; >50% of gene product is required for normal function |
| Marfans and Type II Osteogenesis Imperfecta | Auto dom; protein product from abnormal allele interferes with function of normal protein |
| Huntington disease | Auto dom; protein product from abnormal allele is disruptive/toxic to normal protein |
| Forme Fruste | a partial, arrested or inapparent form of a disease (ex: Penetrance and Variable expressivity) |
| Penetrance (ex: reduced penetrance) | some auto. dom diseases are present in an individual, but manifest no clinical symptoms |
| Variable Expressivity | certain auto dom diseases ALWAYS manifest some symptoms (fully penetrant), but there are differences in phenotype |
| Autosomal recessive | disease expression may occur if the one mutated allele translates a functional protein or if the body needs the protein gene product (generally <50% production from the normal allele is enough for heterozygotes not to manifest disease symptoms) |
| Heterozygous Hemoglobin S | Sickle Cell Trait; a heterozygote can manifest disease symptoms when placed under severe physiological stress d/t hypoxia |
| Compound Heterozygote | individual has DIFFERENT mutations in each allele of a gene pair (ex: Sicke Cell Trait - hetero, and Sickle Cell Disease - homo; no normal Hb, and Hemoglobin S-C Disease - one allele has Hb-S other Hb-C) |
| X-Linked Recessive - manifestations in females | 1. female inherits a defective X chromosome from each parent (homozygote), 2. female undergoes unfavorable Lyonization/X-inactivation resulting in silencing of many normal X chromosmes |
| X-Linked Dominant Diseases | symptoms manifest in males and females; less severe in females d/t Lionization/X-inactivation |
| Tay-Sachs | Auto recessive; enzyme deficiency |
| Cystic Fibrosis | Auto recessive; transport protein deficiency |
| Marfan Syndrome | Auto dominant; structural protein deficiency |
| Achondroplasia | Auto dominant; developmental gene deficiency |
| Familial Hypercholesterolemia | Auto dominant; receptor deficiencies |
| Gene polymorphisms | genes can vary in base sequence w/o damaging the function of transcribed proteins; many are benign and can be subclinical or identifiable as diseases |
| Most Common Genetic Diseases in Ashkenazi Jews | 1. Gaucher Disease, 2. Niemann-Pick Disease, 3. Canavan Disease, 4. Tay-Sachs Disease |
| Most Common Genetic Diseases in Blacks | 1. Sickle Cell Trait, 2. Sickle Cell Anemia, 3. Glucose-6-DH deficiency |
| Most Common Genetic Diseases in Whites | 1. Cystic Fibrosis, 2. Hereditary Hemochromatosis |
| Most Common Lethal Genetic Diseases | 1. Neurodegenerative Diseases, 2. Storage Diseases, 3. Inborn Errors of Metabolism, 4. Inherited Hematologic Diseases |
| Trisomy 21 | most common chromosomopathy and genetic MR (1 in 40 births to women >39); translocations can occur leading to multiple Downs children in one family; abnormal facies, simian crease, congenital heart disease |
| Trisomy 21 clinical course/sequlae | immune deficiency = increased infection and malignancy (leukemias); Alzheimer's; atlantoaxial subluxation; autoimmune thyroiditis/ hypothyroidsm |
| Trisomy 21 mosaicism | d/t mitotic error in post-fertilization mitosis; phenotype is proportional to number of trisomic cells |
| Hereditary Trisomy 21 | d/t parental translocation; phenotype proportional to size of translocation; can occur in serial offspring |
| Trisomy 18 | Edward's Syndrome; inc incidence w/advanced maternal age |
| Trisomy 18 clinical features | severe MR; cong HD (VSD, valve abnormalities); growth/developmental delay; microcephaly; micro-ophthalmia; micrognatia (mandible); microstomia; clenched fists (2nd digit overriding 3rd and 3rd/5th over 4th) d/t camptodactyly; rocker-bottom feet |
| Trisomy 18 clinical course/sequelae | <1% survive into 2nd decade w/o social delays; mosaics and hereditary/translocations are possible |
| Trisomy 13 | Patau Syndrome; MR; poor feeding; developmental delay; holoprosencephaly w/median facial clefting; polydactyly (postaxial); rocker-bottom feet; congenital HD |
| Cri du Chat Syndrome | deletion of short arm of paternal 5p15.3-5.2 |
| Cri du Chat features | MR; microcephaly; abnormal facies; low birth weight; laryngeal hypoplasia-> characteristic cry; simian crease; congenital HD; ok survival w/ok social skills |
| Catch 22 Syndrome | C-cardiac defects, A-abnormal facies, T-thymic hypoplasia, C-cleft palate, H-hypocalcemia/hypoparathyroid, 22-microdeleted chromosome 22q11.2 |
| 22q11.2 microdeletion | Catch 22 syndrome, DiGeorge Syndrome, Velocardiofacial syndrome |
| Catch 22 features | altered migration of neural crest cells to pharyngeal pouches; defect proportional to size of deletion (can be subclinical) |
| Monogenetic Enzyme Defects (enzymopathies) | Rule: substrate/product ratio is 0.10 meaning that only 10% of normal enzyme activity is required for normal functioning...therefore hets are rarely symptomatic |
| Pathological consequence of enzymopathies | 1. accumulation of substrate (diverted down alternative met path making toxic mebabolite); 2. deficiency of product; 3. combo of both |
| Pathophysiologic Categories of Enzymopathies | 1. Substrate Accumulation (large - tissue of origin; small - whole body; co-factor - all enzymes requiring it); 2. Deficiency of End Product (associated w/substrate accum); 3. Failure of Function (toxic product causes cellular damage) |
| Phenylketonuria | deficiency of hydroxylase; elevated [Phe], deficiency of tyrosine; Phe turns toxic (Phenylalanine, phenylpyruvic acid, phenylacetic acid) |
| PKU features | nml at birth; progressive DD --> MR; seizures; incoordination; "musty" odor; light skin and iris (lack of tyr for melanin); Tx: restrict phenylalanine in diet |
| Alkaptonuria | defective homogenistic oxidase enzyme; elevated homogenistic acid; black colored urine/tissues; early arthritis |
| Maple Syrup Urine Disease | aka: branched chain ketonuria; onset days/wks after birth; enzyme defect in catabolism of Leu, Iso, Val; accumulation of ketoacids leads to NS damage and progressive neurodegeneration; Auto recessive and common in inbred (Meninites); Tx: branched AAs |
| Homocystinuria | deficiency of cystathione synthase elevates [homocysteine]; promotes LDL deposition in blood vessels |
| Homocystinuria features | symptoms present over time; Marfanoid habitus; pale skin (melanin); mild MR; decreased lifespan d/t thromboembolic complications, pancreatitis; elevated serum Met/homocysteine; positive urine cyanide-nitroprusside rxn (purple/red) |
| Organic Acidurias | defective mitochondrial enzyme in AA synth pathway leads to accumulation of organic-acids and keto-acids...metabolic acidosis; secondary immunodeficiency d/t toxicity to bone marrow |
| Urea Cycle Defects | obstruction of nitrogenous waste elimination elevates serum ammonia and low serum urea (BUN); alkalosis; neurological and feeding probs can present in late childhood; Tx: protein restriction/dietary supplementation |
| Disorders of Fatty Acid Oxidation | presents early in life; manifests in recurrent symptoms during physiological stress; body normally depends on beta-oxidation of fats for energy when glucose is low (btw meals) |
| (MCAD) Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency | no b-oxid of FAs; hypoglycemia; hypoketonemia; monocarboxylic FAs and dicarboxylic organic acids (toxic) accumulate; metabolic acidosis; elevated serum ammonia; altered gluconeogeneiss; liver steatosis; presents w/ fasting; seizures/CNS edema; death |
| Galactosemia | deficiency of GALT-1; neurotoxicity/hepatotoxicity due to toxins from unconverted galactose; neonatal onset w/milk exposure; Tx: restrict lactose |
| Lesch-Nyan Syndrome | X-linked rec; deficiency of HPRT prohibits hypoxanthine from being recycled inot purine synthesis; elevated uric acid levels; onset in infancy; choreoathetosis (writhing of extremities); SELF-MUTILATION; MR; muscle spasm; dec lifespan; Gout; pylonephritis |
| Adenosine Deaminase Deficiency | accumulation of deoxyadenosine impairs T and B cells causing SCID (severe combined immunodeficiency) |
| Lysosomal Storage Diseases | leads to accumulation of undigested macromolecules and large lysosomes that cause cellular dysfunction and symptomatic disease; classified based on substrate accumulation; hepatosplenomegaly common; neurons are often affected since they are permanent |
| Tay-Sachs Disease | Ashkenazi Jews; auto recessive; GM2 ganglioside grp leading to rapid and progressive neurological degeneration; def of hexosaminidase A; ganglioside accumulates in neurons of CNS, myocardial, liver and spleen cells |
| Gaucher's Disease | Ashkenazi Jews; auto recessive; defective glucocerebrosidase enzyme; accumulation of glucocerebroside in macrophages, bone marrow, spleen, liver; anemia; thrombocytopenia; nose bleeds; bone pain; SERUM CHITOTRIOSIDASE; arthropathies/fx |
| Muscular Dystrophy | X-linked; DYSTROPHIN cytoskeleton/cell membrane component in all muscle and brain (bridges F-actin and basal lamina); rapid degeneration of skeletal myoblasts; progressive weakness (prox-distal); pseudohypertrophy (calves) due to edema |
| Duchenne MD | non-functional dystrophin protein; Dx when child starts sitting; "little Hercules" paradoxical muscle hypertrophy; mild MR; elevated CK (muscle damage); death by 20-30 (cardiomyopathy/scoliotic pulmonary effects) |
| Becker MD | limited function of dystrophin protein; longer lifespan than Duchenne |
| Marfan Syndrome | auto dom; fibrillin mutation (FBN1); tall aortic dilation/rupture/prolapse/valve sclerosis; pectoris excavatum; scoliosis; ligamentous laxity/joint hypermobility |
| Ehlers-Danlos Syndrome | familial CT disorders w/dec tensile strength and integrity of skin, joints, soft tissues; poor wound healing; Vascular Type (IV) -- MOST SERIOUS, type III collagen can rupture vessels in pregnancy, aorta or bowel |
| Osteogenesis Imperfecta | auto dom; mc=TYPE II COLLAGEN mutation (bone/fibrous tissue); thin trabecular bone w/frequent fx even at birth |
| Osteogenesis Imperfecta Type II | example of Dominant Negative Allele affect where the mutated product negatively affects the normal allele |
| Familial Hypercholesterolemia | auto dom; LDL receptor gene; liver cannot take up LDL, so serum levels are elevated and hepatocytes continue to produce cholesterol; it accumulates as XANTHOMAS in the skin and arteries; Predisposed to AMI: Heteros by 40/Homos in youth |
| Achondroplasia | de novo FGFR3 point mutation; most common cause of dwarfism; decreased endochondral ossification in growth plates; STENOSIS - foramen magnum (hydrocephalous, brainstem compression, ataxia, incontinence, apnea), and spinal canal |
| Neurofibromatosis Type I | auto dom disorder of neural crest; mutant NF-1 tumor suppressor gene can't stop ras oncogene from proliferating melanocytes/nerve, schwann cells; CHILDHOOD onset; cafe au lait; scoliosis; ADD, MALIGNANCY --> neurosarcoma |
| Neurofibromatosis Type II | auto dom; NF2 mutation allows Schwann cells to proliferate; intracranial neoplasms (acoustic, ependyomas, gliomas, meningiomas) NOT NEUROFIBROMAS; ADULT onet; NO MALIGNANCY, no cafe au lait |
| Hereditary Retinoblastoma | mutant RB cell cycle inhibition gene; related to other malignant neoplasms; BILAT RETINOBLASTOMA; inc risk for other malignancy |
| Cystic Fibrosis | auto rec; CFTR mutation; altered Cl- transport; alters Na and bicarb ions so secretions are viscous in airways, pancreas and biliary tract; recurrent bronchitis; PSEUDOMONAS - pneumonia and lung abscess; gallstones; infertility |
| Common multifactorial diseases | D/T Gen + Environ: atherosclerosis, cancer, cerebrovascular accident, diabetes mellitus, alcohol/drug addiction, suicide, schizophrenia, autism, congenital abnormalities (clefting, congenital heart def, pyloric stenosis), talipes equivarus, hip dysplasia |
| Causes of orofacial clefting | genetics, maternal alcoholism or smoking, intrauterine infection; failure of neural crest migration; inc risk if familial |
| Cleft lip | 6th week; lateral to philtrum on one or both sides; if uncorrected causes speech and social problems |
| Cleft palate | 8-9th week; soft palate (mucosa) or posteior palatine (secondary) palate; if uncorrected causes sinus infxs, aspiration pneumonia and meningitis |
| Fragile X Syndrome | X-linked reduced penetrance FMR1 triplet expansion disease; most common Male and inherited MR; normal pop has up to 50 CGG repeats; full mutation is >200 |
| Fragile X Syndrome: Inheritance Pattern | expansion occurs in oogenesis of female NOT in spermatogenesis of male; therefore, females can have a normal X turn into a premutation OR a premutation turn into a full mutation; males with premutation will ONLY pass on the premutation; it cannot expand! |
| Fragile X Syndrome Features | Males - large testes (macroorchidism); MR/DD; abnormally large facial features and stretched out CT (hyperestensibility of joints; flat feet; scoliosis; mitral valve prolapse); |
| Fragile X Tremor-Ataxia | occurs in males with premutation |
| Female Fragile X Syndrome | premutation can become fully expanded in female; one X is inactivated so her body is a mosaic; if she has UNFAVORABLE LYONIZATION she will have more symptoms//can also occur if both mother and father pass on premutations makinge her homozygous |
| Huntington Disease | triplet expan; onset 30-50; altered HD ptn binds abnormally to other ptns; complexes cannot be tagged/degrated by ubiquitin-proteosome system and accumulate as inclusions; prodrome: psychosis/spasmotic movements; die via malnutrition/hypostatic pneumonia |
| Defects of Mitochondrial Genome | mothers transmit mitochondrial genome to kids; mutations manifest in brain, heart, liver, kidney and skeletal tissue slowness d/t oxid-phosphorylation and ATP production problems |
| Genomic Imprinting | some genes (if from mother) are automatically silenced by methylation process; if the father's gene is normal, there is no problem; if it is mutated, the child lacks a normal allele |
| Prader-Willi Syndrome | d/t paternal mutation and genomic imprinting; mutation on long arm of 15q11.2-13 |
| Angelman's Syndrome | "Happy Puppet" d/t maternal mutation and genomic imprinting; mutation on long arm of 15q11.2-13 |
| Uniparental Disomy PW Syndrome | no deletion on chromosome 15; after fertilization the reshuffling of chromosomes resulting in 2 maternally derived chromosomes that are imprinted; leaving no functional gene |
| Uniparental Disomy AS Syndrome | having 2 imprinted paternal chromosomes and no functional gene |
| Klinefelter Syndrome | XXY (presence of barr body); atrophic testes, infertile, gynecomastia, low testosterone - tall, sparse body hair, small penis, high voice; MR inc w/each extra X |
| XYY Syndrome | d/t parental meiotic nondisjunction; tall, DD, acne congoblata, aggressive, FERTILE; children are normal |
| XO Syndrome | Turner Syndrome; only females; most pts have mosaicism (46, XX, 45, XO) lack barr body; missing either mat/paternal X; some have microdeletion-partial monosomy; ovarian dysgenesis d/t premature apoptosis of oocytes; variable phenotype |
| XO Syndrome continued | lymphedema in utero-webbed neck; short, hypogonadism (dec estrogen, inc pit. gonadotropins, amenorrhea, infertility, lack of 1*/2* sex charact.; Congenital heart defect (coarctation); severity relative to mosaicism; IDDM; autoimmune thyroiditis-atrophy |
| True Hermaphroditism | 46,XX mc; pheno-Male until puberty when breasts develop; ambiguous genitals; usually ovotestis combo |
| Pseudohermaphroditism | gonadal sex is discordant with genital sex; Femal pseudos-have ovaries and penis; Male pseudos-have testes and vagina; ALWAYS have normally developed internal singular sex organs BUT ambiguous external genitalia |
| Male Pseudohermaphrodite | 46, XY; Gonads - testes; Genitals - ambiguously female; d/t testosterone receptor defect causing tissue resistant to testosterone (Testicular Feminization/Androgen Insensitivity Syndrome); X-linked (Xq11-12)...OR mom given female hormones during pregnancy |
| Female Pseudohermaphrodite | Androgynism; 46, XX; Gonads - ovaries, Genitals - ambiguously male; d/t Congenital Adrenal Hyperplasia (mc) inc of circulating androgens; OR Androgen-secreting tumor (ovary/adrenal) in mom during pregnancy; OR male hormones administered during pregnancy |
| 50% of males with hypospadias have a disorder of sexual development | esp. true if cryptorchidism is present; DON'T circumcise a male with hypospadia b/c foreskin can be used to reconstruct penis |
| Most common causes of ambiguous genitalia | 1. Congenital Adrenal Hyperplasia (majority); 2. Gonadal dysgenesis; 3. pseudohermaphroditism; 4. true hermaphroditism |
| Any pt who genetically has a Y chromosome but streak/dysgenic gonads are at risk for: | malignant gonadal tumors (ex: gonadoblastoma) |
| Glucose-6-Dehydrogenase Deficiency | (pharmacogenic problem); lack of NADPH leads to reduced-glutathione; no glutathione to inactivate oxidative molecules, severe damage of erythrocytes and rapid hemolysis; Highly oxidative Drugs in these pts can cause hemolysis |
| Hepatic Arylamine N-acetyltransferase Deficiency - "Slow Acetylators" | def reduces metabolism/acetylation of drugs; causes higher circulating levels; Conversely, "fast acetylator" drug dose must be increased b/c recommended dose is insufficient to reach therapeutic level; w/carcinogens, acetylation inc carcinogenicity (dec?) |
| Pseudocholinesterase Deficiency | decreased function or complete lack of pseudocholinesterase enzymes (normally in blood and liver); inability to rapidly metabolize muscle relaxant drug succinylcholine; leads to marke prolonged half-life and Respiratory/Skeletal muscle PARALYSIS |
| Goals of inflammatory response | 1. inactivate/remove injurous agent; 2. remove infected/damaged tissue; 3. initiate tissue regeneration/repair; 4. restore tissues to natural fxn |
| Four Cardinal Signs of Acute Inflammation | 1. Rubor (redness d/t dilated vessels); 2. Dolor (pain); 3. Calor (heat d/t exotherm rxns of inflam); 4. Tumor (swelling/edema d/t extravascular fluid accum) |
| Common causes of acute inflammation | invasion by microorganism; traumatic injury; foreign bodies; immunopathological injury (autoAb, dysfxnl complement activ), malignancy, necrosis, thypothermia, radiation, toxins (chemical/metabolic) |
| Vascular dilation | d/t chemical mediators and nerve reflexes; Histamine (mast cells; acts on venules w/H1 receptors); Seratonin; Endothelial-produced NO; Inc blood flow w/in min and erythema/heat |
| Increased permeability of venules (vascular leakage) | gaps btw endothelial cells d/t retraction of cytoplasm via intracytoplasmic actin/myosin; allows circulating plasma ptns/Abs to enter extravascular space and increases lymph flow to eliminate pathogen; Histamine/leukotrienes/bradykinin/compl/IL1/TNF/INF |
| Chemotaxis mediators | bacterial ptn products, C5a, leukotrienes (arach acid deriv), kallikrein, fibrinogen, fibronectin, |
| Leukocyte activation | inc. cytoplasmic Ca; inc exp of adhesion molec/membrane receptors; inc activity of arach acid pathways/lysosomal enzymes; inc secretion of cytokines/inflam factors |
| Vascular transmigration (diapedesis) | neutorphils insert pseudopodia into endothelial gaps; facilitated by PECAM-1 (platelet-endothel cell adhesion molec); secrete collagenases to pass basement membrane and enter perivascular ECM |
| Movement and accumulation of neutrophils at site of injury | once in ECM, neutrophil cell adhesion molec permit movement thru the ECM |
| Acute inflammatory cellular response | #1: neutrophils arrive w/in 6hrs and die off; #2: macrophages arrive at 24hrs |
| Viral Invasion Resonse | #1: lymphocytes |
| Allergic Invasion Response | #1: eosinophils |
| Main functions of neutrophils at site of injury | 1. Phagocytosis (microbes, foreign mat, necrotic tissue); 2. Elaboration of proteolytic degradation (microbes/necrotic host tissue); 3. elab of cytokines to maintain inflam response until resolved; 4. source of arach acid for prostoglandin/leukotrienes |
| Neutrophils and Bacterial Infections | Greatest neutrophilic chemotractic repsonse!; Infx that attract many neutorphils = PYOGENIC (S.pyogenes, S.aureus, H.influenzae); Accumulation of PUS d/t # of neutrophils/high lysosomal liquifactive necrosis (expands if difficult to erradicate -> abscess) |
| Macrophages | can live for days at inflammatory site; phagocytic and intracellular killing properties; elaborate cytokines that help terminate acute infam and initiate regeneration/repair |
| Phagocytosis Opsonins | IgG, C3b, fibronectin, fibrinogen, CRP, mannose-binding lectin |
| Lysosomal contents | antibacterial ptns (cationic); enzymes producing oxygen free radicals (myeloperoxidase, catalase, superoxide dismutase); lysozyme (muramidase destroys cell wall) |
| Oxygen-dependent Microbial Killing | MOST EFFECTIVE method; hexose monophosphate shunt activated by phagocytosis (oxid rxns inc and generate e-s), NADPH oxidase in phagolysosome uses e-s to make free radicals (hydrogen peroxide, free hydorxyl radical) |
| Termination of Acute Inflammation | remove injurous agent; short half-life of inflam mediat/enzym; activated/degranulated leukocytes die; inc synth of anti-inflam substances (switch in arach acid path to make anti-inflam lipoxins; inc cortisol; inc macrophage TGF-b ); inhib macrophage-TNF |
| Anti-protease ptns | Alpha-1-antitrypsin/Alpha-1-antichymotripsin from liver; inhibit damage done by neutrophil/macrophage lysosomal proteases |
| Protein inhibitor: alpha-2-antiplasmin | from liver; helps regulate clotting cascade activated by acute inflam |
| Protein inhibitor: C1 esterase inhibitor | from liver; helps regulate/inhibit initiation of complement cascade |
| Proteins neutralize reactive oxygen radicals | metal-binding ptns; manganese superoxide dismutase |
| Acute inflam response increases pitutitary ACTH | via stimulation from IL-1 and IL-6; ACTH increases production of cortisol; cortisol has inhibitory affect on inflam cytokines; leads to dec levels of cytokines by inhibiting gene expression on inflam cells |
| Outcomes of acute inflammation | complete resolution; fibrosis; chronic inflammation |
| Classic Acute Inflammtion Histomorphology | manifests in cardinal signs of inflam; usu on skin/mucous membranes |
| Suppurative Inflammation Histomorphology | acute inflam w/pus (purulence) d/t predominance of neutrophils (pyogenic bacteria); may or may not form abscess |
| Fibrinous Inflammation Histomorphology | acute inflam dominated by formation of fibrin |
| Serous inflammation Histopathology | acute inflam dominated by fluid formation |
| Necrotizing Inflammation Histomorphology | acute inflam w/areas of necrosis |
| Inflammatory fistula | elongated ulcer forms pathologic communication/tract btw two hollow organs or a hollow organ and a surface (ex: colon to peri-anal or abdominal skin (Crohn's); rectosigmoid colon to vagina (traumatic childbirth); |
| Histamine | vasodilation, vascular permeability |
| Seratonin | vascular permeability |
| Phospholipase A2 | releases arachidonic acid and PAF from lipid membranes of cells |
| Interferon-gamma (INF-gamma) | macrophage activation, esp in relation to granuloma formation |
| Nitric Oxide | vasodilation, antimicrobial, anti-inflammatory (inhibits platelet aggregation, cell adhesion and leukocyte chemotaxis) |
| Complement system | produced by liver and macrophages; Classic/Alternate/Lectin binding pathways; both alternate and classical converge to activate C3 |
| Classical Complement Pathway | Initiated by IgM of IgG bound to antigens/epitopes on invader; generates anaphylaxotoxins, kinin system, histamine release, chemotatcis for phagocytes, membrane attack complex (MAC) to punch holes in target cell |
| Alternate Complement Pathway | DOESN'T require antibodies; more primitive; C3 directly activated by cell wall components of pathogen (zymosin-yeast; endotoxin-bacteria); Most useful when body is invaded by novel organisms; bypasses early classic complements |
| Lectin Binding Complement Pathway | Mannose-binding protein (MBP) binds to mannose of microbial CHOs; complex enzyme is similar to C1 of classic path..initiates complement; ALSO, MBP complex stimulates local macrophages to produce IL-1/IL-6 |
| Kinins | activated by Factor XII responding to bacteria, damaged collagen or basement memb; Factor XII initiates: Kinin system, complement cascade, hemostasis (coag), fibrinolysis |
| Effects of Bradykinin and Kallidin | relax venular smooth muscle (hypotension); inc vascular permeability; bronchial smooth muscle CONTraction; release of cytokines and eicosanoids (arach acid deriv: prostaglandins, leukotrienes, thromboxanes) |
| Coagulation System | intrinsicly initiated by Factor XII; bacteria, damaged collagen or basement membranes; |
| Factor XIIa | central component in inflammation; activates all other systems: intrinsic (direct) and extrinsic (indirect) coagulation; Kallikrein-kinin system directly; Plasmin fibrinolysis system directly; Complement system (indirectly via kallikrein/plasmin activ) |
| Arachidonic Acid System | complement C5a activates Phospholipase A2 to release arach acid from plasma membrane lipids; they enter either: 1. cyclo-oxygenase or 2. lipoxygenase pathway |
| Cyclo-oxygenase pathway | Cox-1 (platelets and stomach mucosa) and Cox-2 (located in many tissues; primarily responsible for thromboxane prostaglandin production in acute inflammation) |
| Arachidonic acid is converted by COX enzymes into | 1. Thromboxanes - vasoconstriction and thrombogenic (platelet aggreg); 2. Prostaglandins (diff effects on diff tissues; vasodilation, inhib platelet aggreg, stim hypothalamus to inc temp-pyrogen) |
| Lipoxygenase pathway | arach acid converted to 5-HPETE then to: 1. leukotrienes (LTB4 - chemotactant for neutrophils-stimulates adhesion); LTC4 - inc vascular permeability; 2. HETE - a powerful chemotactant |
| Lipoxins are generated in 2 steps | arach acid pathway in leukocytes generates LEUKOTRIENES; Platelets convert leukotrienes to LIPOXINS; They inhibit many inflammation processes |
| Clinical Signs of Acute Inflammation | hyperpyrexia (fever); chills; leukocytosis; inc acute phase reactants; inc ESR; inc gamma globulins; inc CRP; dec complement levels |
| Benefits of elevated core temp | denatures foreign ptns; debilitates pathogens; more efficient phagocytosis/killing of bacteria |
| Initiators of fever | exogenous (pyrogens - bacterial-related; LPS from G- bacteria); endogenous (cytokines IL-1, IL-6 induce hypothalamus via prostaglandins) |
| LPS-induced hyperpyrexia | LPS binds LBP (lipopolysac-bind ptn), which binds CD14 on macrophage; produces IL-1, IL-6, TNF; These cytokines bind to hypothalamus activating arach acid path for PROSTAGLANDIN E2; PGE2 goes to VMPO and PVH to elevate core temp |
| Chills (rigors) | systemic response to the difference btw the new core temp set-point and the actual body temp |
| Leukocytosis | in most bacterial infx; WBC elevates d/t cytokine accelerated release of leukocytes from bone marrow (left shift) |
| Leukopenia | charachteristic of viral and overwhelming bacterial infx (diptheria, salmonella?) |
| Toxic Granulation in Peripheral Blood neutrophils | indicative of systemic inflammation from bacterial infx |
| Dohle Bodies | basophilic body/super toxic granulation indicative of systemic inflam and inc levels of bone marrow granulopoiesis; cytoplasmic areas of condensed ribosomes |
| Elevated levels of acute phase proteins | CRP, complement, fibrinogen, von Willebrand Factor, alpha-1-antitrypsin |
| "negative acute phase reactants" | decrease in plasma level as liver makes actue phase reactants (albumin, transferin, etc) |
| Elevated ESR | physiological reason why erythrocytes clump together (rouleaux formation) is d/t increased circulating levels of acute phase proteins; especially fibrinogen |
| Complement factors | decreased levels of total complement; C3 and C4 b/c they are being used up by inflammatory process |
| Circulating Ig | frequently elevated esp if inflam response is d/t microbes; Elevated in Lupus (autoantibodies) |
| C-reactive protein | 100x increase during acute inflam; functions to: activate classic complement pathway, osponize microbes...these people can be predisposed to atherosclerosis |
| Causes of Systemic Inflammatory Response Syndrome (SIRS) | systemic infx/sepsis (septic shock); fulminant hepatic failure; pancreatitis; pneumonia; TSS; anaphylaxis; blood transfusion |
| SIRS Pathophysiology | represents a whole organism's immune response to a variety of immune challenges |
| Mediators of SIRS | TNF-alpha; IL-1, 5, 6, 8 11, 15 |
| TNF and SIRS | promotes systemic activation of clotting system leading to systemic microthrombi; multi-organ ischemia and generalized hypoxia |
| Features of SIRS | depressed liver fxn-hypoglycemia (no gluconeogenesis b/c of cytokine suppression); leaky capillaries in lungs (acute respiratory distress syndrome); systemic inflammation (general vasodil; hypotens; low blood flow; hypoxia) |
| Clinical Syndrome of SIRS | metabolic acidosis, hypotension, hyperpyrexia, tachycardia, tachypnea...many pts progress to Multiple Organ Dysfunction Syndrome |
| Causes of Chronic Inflammation | persistent infx; immunopathologic rxn; continual exposure to foreign bodies; autoimmunity; mostly predominated by mononuclear cells (macrophages, lymphocytes, plasma cells) |
| Pathophysiology of chronic inflammation - macrophages | continual activation leads to constant secretion of pro-inflammatory substances, degradative enzymes and repair substances (FGF and angiogen factors) leading to combo of injury and repair and fibrosis |
| Pathophysiology of chronic inflammaiton - lymphocytes/plasma cells | secrete cytokines and gamma globulins to stimulate neutrophils and macrophages leading to free radical regeneration and further destruction |
| Pathophysiology of chronic inflammation - mononuclear cells | secrete chemotactants to recruit more neutrophils and mononuclear cells; further amplifies destruction |
| Non-granulomatous chronic inflammation | lymphocytes, plasma cells, macrophages present, mixed with granulation tissue; NO Granulomas; (d/t repetitive trauma, chronic inf disese, autoimmune disease, chronic toxin exposure, allergies, chronic vascular ischemia) |
| Chronic Suppurative (pus) Inflammation | usu associated w/immune deficiency; common w/agent (bacteia/foreign body) cannot be eradicated and body switches to a strategy of containment (chronic osteomyelitis, lung or brain abscess) |
| Granulomatous Chronic Inflammation | Chronic macrophage activation causes macrophages to swell and take on an epithelioid cell appearance (INF-gamma transforms cells); the epithelioid macrophages can fuse together and form multi-nucleated GIANT CELLS; formation of GRANULOMAS |
| Granuloma features/causes | central area of enlarged macrophages w/lots of pale cytoplasm/indistinct membranes/indented nuclei; surrounded by collar of lymphocytes/plasma cells even if fibrous; Due to: #1 TUBERCULOSIS, leprosy, syphilis, fungus, foreign bodies (splinters) |
| Granuloma with caseous/central necrosis | high probability of TUBERCULOSIS |
| Primary Pulmonary Tuberculosis | most common alveolar infx is at apices/peripheray where O2 is low --> Assmann focus; if area is at periphery other than apices, it is called Ghon focus |
| TB-pathognomonic | acute reaction (neutrophils) becomes chronic dominated by macrophages/lymphocytes; granulomas w/central necrosis and Langhans giant cells-called TUBERCLES; organisms spread to enlarge hilar lymph nodes-GHON Complex = TB! |
| Prolonged TB | chronic inflam, scarification and calcification leads to resolution of infection, BUT the m. tuberculosis remains latent "walled off" in fibrosed lung and lymph nodes; this can reactivate if pt becomes immune compromised (old, malnourished, AIDS, CCstroid |
| Other mycobacterial infections | all form granulomatous inflammatory reactions, but others usually confined to skin or primary lymphadenitis |
| Defects/deficiency in Inflammation | recurrent infections; intractable infections; infections by opportunistic organisms; poor wound healing |
| Deficiencies in humoral immunity | lead to recurrent pyogenic bacterial infections |
| Deficiencies in cell-mediated immunity | lead to recurrent infections d/t viruses, fungi, mycobacteria, and parasites (toxoplasmosis) |
| Primary immune deficient pts are predisposed to: | autoimmune disease, malignant neoplasia (esp hematopoeitic); graft-versus-host disease; and usually accompanied by poor wound healing |
| Old Age - acquired immune deficiency | pathogenesis is multifactorial d/t dec function in many systems |
| Chronic liver disease - acquired immune deficiency | liver is major player in ptn metabolism; building blocks for Ig and other inflam-related molecules; synthesizes complement |
| Diabetes Mellitus - acquired immune deficiency | pts w/poorly controled DM can have many immune deficits |
| Chronic CCsteroid use - acquired immune deficiency | leukocyte adherance to endothelial cells is greatly reduced; CCsteroids inhibit activation and function of arachidonic acid system |
| Immunosuppressive drugs - acquried immune deficiency | post-transplant pts; chemotherapy for malignancy |
| other acquired immune deficiencies | generalized atherosclerosis, drug-induced neutropenia, HIV, malnutrition, chronic anemia, chronic alcoholism |
| Primary Diseases of Excessive Inflammation - aka: Immunopathologic Rxns | Autoimmune diseases; more common in women - SLE and RA |
| Hypoxic/Anoxic-Sensitive Tissues | 1. CNS 2-5min (Purkinje cells of cerebellum, neurons of hippocampus, pyramidal cells of neocortex); 2. Myocardium - 15-20min; 3. Renotubular epithelium |
| Tissues that are relatively insensitive to hypoxia/ischemia | 1. Skeletal muscle (up to 1hr); 2. Skin; 3. Fibrous tissue (can be viable up to 24hrs after death) |
| Pathophysiology of Hypoxia | Inhibition of oxphos; reduction in ATP and ATP-dependent processes (ie: selective permeability and function of cell membrane) |
| Disruption of Na-K pump | influx of Na swells intracellular organelles and entire cell |
| Influx of calcium | disrupts cellular processes by binding enzymes; b/c it's no longer sequestered in ER; uncontrolled Ca levels in cytoplasm lead to necrosis; disrupts oxphos and activation of lysosomal enzymes |
| Increase in anaerobic glycolysis | less ATP and more lactic acid produced; systemic metabolic acidosis |
| Disaggregation of ribosomes | decreased protein synthesis; pancellular metabolic dysfunction |
| Reactive oxygen radicals | disruption of normal anti-oxidant metabolic processes causes intracellular damage; peroxidation of lipid membrane, oxid inact of enzymes, mitoch membrane damage, DNA fragmentation, depletion of NADPH (required for ATP) |
| Structural cellular changes related to hypoxic injury | 1st sign - edema (d/t cell swelling); chromatin clumping; cellular shrinkage/distortion (d/t cytoskeletal damage); ==>necrosis |
| Clinical Course of Hypoxia/Anoxia | 1. Mild/short time: deprived tissues adapt by undergoing apoptosis leading to hypoplasia/atrophy; altered cytoplasmic environment = misfolded ptns and premature apoptosis; 2. Sudden/severe: tissue cannot adapt; it dies; necrosis |
| Reperfusion Injury | restoring O2/blood to hypoxic tissue; the quieted anti-oxidant defenses are not prepared for a rapid inc in free radicals (hydrogen peroxide, hydroxyl ion, superoxide); pancellular damage (ex:xanthine oxidase converts accumulated xanthine to radicals |
| Time frame for visual changes in damaged cells | Ultrastructural (electron microscope) - minutes to hrs; light microscopy - hrs to days; gross pathology - hours to days |
| Cellular swelling | (aka: hydropic change, vacuolar degeneration, oncosis, cloudy swelling); d/t hypoxia/ischemia, poisonings, vitamin deficiencies; reversible cell injury |
| Gross pathology of cellular swelling | inc organ weight, tissue consistency, and tissue/organ pallor |
| Fatty change | steoaosis; d/t disruption of normal metabolism...slower progression than swelling; occurs in FA-dependent organs (liver, myocardium, kidney) accumulation of TGs and other lipids |
| Free fatty acids | normally metab in liver from cholesterol to phospholipids, TGs; in liver and heart via b-oxid to ATP; chronic alcoholics have inc conversion of free FAs to TGs, but cannot leave liver d/t deficient hepatic synth/export of VLDL |
| Common causes of FA accumulation | chronic alcoholism, non-alcoholic fatty liver disease (diabetes, obesity, malnutrition); Grossly the liver has a yellow tint in the red/brown parenchyma |
| Abnormal protein accumulation - Nephrotic syndrome | hyaline granules, renotubular epithelium |
| Abormal protein accumulation - Multiple myeloma | russel bodies, plasma cells (neoplastic) |
| Abnormal protein accumulation - Alcoholic liver disease | mallory bodies in hepatocytes |
| Abnormal protein accumulation - Alzheimer's disease | neurofibrillary tangles |
| Abnormal protein accumulation - Alpha-1-antitrypsin deficiency | inability of hepatocytes to secrete the enzyme leads to toxic acummulation, cell injury and death (cirrhosis) |
| Urate accumulation | urate crystals cause severe inflammatory reaction as phagocytes try to break down the crystals in their lysosomes; chronic gout leads to permanent damage to joints and kidney |
| Hemosiderosis accumulation | Fe d/t cellular injury in alcoholics, chronic hemolytic anemias, mult blood transfusions, excessive Fe intake...but no real organ damage |
| Primary homochromatosis | Hereditary hemochromatosis is a genetic defect in HFE gene; leads to excessive Fe uptake and multisystem free radical damage, esp in liver, heart and pancreas; (HFE is a glycoprotein that interacts w/transferrin receptors to regulate ferritin uptake) |
| Calcium accumulation | d/t necrotic tissue injury or hypercalcemia; 3 types of abnormal calcification: 1. Dystrophic, Metastatic, Pathologic ossification (ectopic ossification) |
| Dystrophic calcification | always preceded by cellular injury; calcific aortic valve disease, atherosclerosis; infarction/inflammation/scarification/fibrosis; neoplasm-related Psamomma Bodies - foci |
| Metastatic Calcification | occurs in nml tissues w/o injury/necrosis; elev. serum phosphate/Ca: chronic renal failure, hyperparathyroidism, sarcoidosis, paraneoplastic syndromes, multuple myeloma, excessive Ca intake, hypervitaminosis D, metaststic osteolytic malig-breast/prostate |
| Metastatic calcification - continued | preferred sites of calcification: gastric mucosa, kidneys, interalveolar septi of lung, joint synovium; Reversible if underlying disease is ameliorated |
| Pathologic Ossification | aka: heterotropic bone formation; may occur at sites of old injury or metastatic calcification; can arise spontaneously in lung |
| Molecular "Cell Stress Response" | HSP - "heat shock proteins;" small molec weight HSPs protect ptns from denaturation; Ubiquitin binds and removes damaged ptns (ex: mallor bodies in liver or lewy bodies in CNS) |
| Necrosis Characteristics | d/t pathological injury; NEVER occurs spontaneously; does NOT need cellular energy; cellular autosysis elicits an inflammatory response |
| Serum findings in necrosis | 1. Pancreatic: amylase/lipase; 2. Hepatocellular - aminotransferases (AST/ALT); 3. Myocardial cells - creatine phosphpokinase (CK/CPK, troponin) |
| Coagulative Necrosis | FAST cellular death; denaturation d/t hypoxia/ischemia/intoxications; Visual changes in tissue seen as: Pus (6-8hrs) disintegration "ghost outline" (24hrs) |
| Liquifactive Necrosis | SLOW cell death; enzymatic disintegration/degradation; CNS (encephalomalacia), abscess central liquifaction; "wet" gangrene d/t bacteria; Tissues are soft/liquified and eventually dissolve, leaving a cystic space |
| Caseous Necrosis | combo of coagulative and liquifactive necrosis; "Dry cream cheese;" necrosis d/t cytokines/phagocytes/cytotoxic Tcells; repair is inhibited d/t inhibition of angiogenesis; d/t TB (other mycobacterial infx) or fungal infx |
| Gangrenous Necrosis - can only be detected at gross level | limbs/bowels; "wet" gangrene - ischemic injury/invasion by anaerobic bacteria (mostly liquefactive necrosis); "Dry" gangrene - mostly coagulative necrosis; inflam cell infiltrates that block bacteria (dessication/mumification); |
| The Viscious Cycle Effect | when systems are interdependent, pathological processes often generate other injurious causes; ie: Pneumonia - lungs invade by bug reduces O2 in blood = tissue hypoxia, tubular necrosis in kidney = oliguria = renal failure = fluid retention = pulm edema |
| Viscious Cycle of Myocardial Infarction | thrombosis in vessel of heart = immediate ischemia/hypoxia of that area of perfusion = dec cardiac output d/t left ventricular wall dysfxn = reduced CO = reduced circulation to coronary aa = exacerbation of ischemia to myocardium |
| Myocardial ischemia | pale to naked eye; dec ATP d/t anaerobic glycolysis; drop in intracellular ATP/creatinine-P; cardiac cells hydropically change; ejection fraction dec; electric instability (dysrrhythmias); contraction band necrosis; Serum inc LDH, CK-MB, and troponins |
| Acute Respiratory Distress Syndrome | d/t systemic hypotension/hypoxia, inflammatory response (accum of neutrophils in lung), or free radical endothelial damage; Loss of endothelial integrity = edema and serum ptn in alveolar space; Damage initiates diffuse inflamm response and more damage |
| Fatty Change in Liver | non-specific general indicator of liver cell injury and dysfxn (alcoholic liver dx, DM, viral hepatitis); damaged hepatocytes can't make lipoproteins and lipids accumulate in cytoplasm = steatosis lipid droplets; liver turns yellow color |
| Apoptosis | no inflammation!! internal contents of cell does not leak out |
| Biological Functions of Apoptosis | 1. embryogenesis; 2. eliminate cells w/irreparable DNA damage; 3. removal of cells after dec trophic (ie: prostate after castration); 4. Selective destruction of "self-reactive" lymphocytes; 6. cytotoxic Tcell-induced (viral/neoplastic cells) |
| Neoplasia | defect in normal fxn of apoptosis allows damaged cells to live; unregulated growth forms tumors; |
| Apoptosis ptns involved in tumorgenesis | bcl-2, p53 |
| Autoimmune disease | lymphocytes synthesizing antibodies against "self-antigens" are NOT being promptly eliminated d/t defect in apoptosis |
| Neurodegenerative Diseases | apoptosis is accelerated leading to premature neuronal death |
| Functional Deficits of Ageing | 1. reduced mitochondrial fxn and oxphos; 2. reduction in ptn synthesis (dec enzyme levels and receptors); 3. reduced nutrient uptake; 4. reduced ability to break down/recycle ptns leading to accumulation of indigestible ptn fragments (lipofuscin) |
| Disease of Premature Ageing - Werner Syndrome | aka: Adult Progeria; auto recessive; defect in DNA helicase; cannot repair damaged DNA; most common type; scleroderma-like disease; short, normal development until teens; death by 40s; inc malignancy |
| Disease of Premature Ageing - Cockayne Syndrome | aka: Pediatric Progeria; onset as young child of generalized premature ageing; defect in any of several DNA repair genes, including DNA helicase |
| Neoplasm | new growth; can be benign OR malignant (these can metastasize); uncontrolled proliferation; ignores negative growth regulation; induces angiogenesis; evades apoptosis |
| Dysplasia | abnormal growth and maturation not to extent of malignancy; reversible; developmenta (dysplastic kindneys); cervical dysplasia (disorderly growth, but no obvious malignancy) |
| Differentiation | the extent of parenchyma which resembles normal mature cells regarding morphology and function; well differentiated = very similar to normal tissue; moderately differentiated; Poorly Differentiated/anaplastic = unidentifiable cells/tissue |
| Metaplasia | a change in cell type usually d/t a stimulus (like smoking); often epithelial cells; may be reversible once stimulus stops; not all are neoplastic since they are replacing normal cells (ex: GERD) |
| Hamartoma | small bit of tissue in an organ that normally has that tissue (ex: nevus or foci of cartilage/mature bronchial epithelium in lung); angioma |
| Choristoma | ectopic; normal cells in abnormal locations |
| Epithelial cells | 1. Membranes; ext surface and lining of internal surface; sits on basement membrane separated from CT; 2. Glands - down growth and ingrowth to underlying CT |
| Mesenchymal cells | everything besides membranes and glands; CT (fibroblasts, adipoytes, osteocytes, etc) |
| Benign Epithelial Neoplasms - Adenoma | forms glands or is formed from a gland |
| Benign Epidermal Neoplasms - Papilloma | fingerlike projections from the surface |
| Benign Epidermal Neoplasms - Polyp | projection of mucosal surface; "sessile" - broad base of attachment or "pedunculated" stalk of attachment |
| Benign Mesenchymal Neoplasms | depends on cell of reference: fibroma; lipoma; leiomyoma (smooth muscle); rhabdomyoma (striated muscle; most common in peds) |
| Carcinoma | MALIGNANT tumor of epithelial origin |
| Sarcoma | MALIGNANT tumor of connective tissue/mesenchymal origin |
| Benign: ademoma, papillary cystadenoma, fibroma, lipoma, leiomyoma, rhabdomyoma | Malignant: adenocarcinoma, papillary cystadenocarcinoma, fibrosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma |
| Malignant tumors | clumped chromatin, poorly differentiated, invasive, not encapsulated, destroys tissue, invades vessels, metastasizes, significant effects on host, necrosis/hemorrhage, paraneoplastic syndromes |
| Teratomas | formed from all 3 germ layers; may be benign or malignant; teeth, hair, etc |
| Tumors of blood cells and lymphatics | ALL are MALIGNANT; lymphoma, leukemias, multiple myeloma, hodgkin's disease |
| Tumors of neural and glial cells | neuroblastoma, gliomas, meningiomas (cause probs d/t intracranial pressure) |
| Germ cell tumors | seminoma (malignant testicular cancer), teratoma (benign in F, malignant in M), teratocarcinoma, choriocarcinoma |
| Hodgkin's Disease | malignant lymphoma |
| Ewing Sarcoma | malignant bone tumor in kids |
| Wilms Tumor | malignant kidney tumor in kids (nephrobalstoma) |
| Kaposi Sarcoma | blood vessel tumor of skin and internal organs |
| Burkitt Lymphoma | malignant lymphoma |
| "-oma" exceptions...actually malignant tumors | seminoma, glioma, lymphoma, hepatoma, melanoma, insulinoma, gastrinoma, somatostatinoma, glucanoma |
| Metastasis via blood vessels | sarcomas (mesenchymal, CT); except synovial sarcoma |
| Metastasis via lymphatics | carcinomas (epithelial); except RCC and HCC |
| Why does metastasis occur? | neoangiogenesis, dec cell adhesion, inc migration, lytic enzymes, local invasion, penetration of blood vessels |
| Preferred sites of metastasis | breast to bone, prostate to bone, bone to lung; lymph nodes, liver, lung, brian, adrenal, bone |
| rare sites of metastasis | spleen, kidney, heart, muscle |
| Cancer epidemiology | #1/#2: prostate/breast and lung/bronchus...reverse order for cancer death |
| Genetic predisposition | 1. Autosomal dominant point mutation and 2nd hit ; 2. defective DNA repair; auto recessive; 3. familial cancers - no clearly defined pattern |
| Non-hereditary predisposing conditions for cancer | regenerative, hyperplastic, dysplastic proliferations (ex: endometrial hyperplasia, cervical dysplasia, bronchial metaplasia/dysplasia in smokers, cirrhotic livers) |
| Chronic inflammation | known association with occurance of canceer (ex: ulcerative colitis, Crohn's disease, H.pylori gastritis, viral hep, chronic pancreasitis) |
| Pre-cancerous conditions | chronic atrophic gastritis of pernicious anemia, solar keratosis, leukoplakia, villous adenoma |
| Principles of Carcinogenesis | Monoclonal: clonal expansion from single precursor cell; tumor progression w/excessive growth, invasion, metastasis |
| Targets for Damage | Genes for: growth factors, apoptosis regulation, tumor suppression, DNA repair enzymes |
| Protooncogenes | non-mutated form; the protein product of these are important for cellular growth and proliferation |
| Oncogenes | mutated genes that are responsible for the development of cancer |
| How protos become oncos | point mutation, gene amplification, chromosomal rearrangement, insertional mutagenesis |
| Growth Factor - SIS | encodes for PDGF; viral oncogene v-cis overproduces a PDGF-like molecule that binds to receptors to stimulate cell cycle |
| Growth Factor - RET | medullary thyroid carcinoma, adrenal and parathyroid tumors |
| Signal Transducing Protein - RAS family | encodes GTP binding proteins; v-ras binds and doesn't let go; causes uncontrolled proliferation |
| Translocations - Philadelphia Chromosome | chromosome 22; chronic milogenous leukemia |
| Tumor Suppressor Genes | RB - 2-hit theory (genetic and sporadic); p53 - 50% of human tumors contain p53 mutations |
| Li-Fraumeni syndrome | inheritance of one mutated p53 allele; 25x greater chance of developing cancer by age 50 than general population |
| Tumor adverse effects | based on location due to obstruction and mass effect; cachexia, hormone production, bleeding, secondary infections |
| Paraneoplastic Syndromes | grp of symptoms in cancer pts that cannot be explained by local spread of tumor OR elaboration of hormones d/t tissue from which tumor arose; present in 10% of cancer pts |
| Cushings | inc ACTH, 50% have small cell carcinoma of lung |
| Hypercalcemia | Most common paraneoplastic syndrome!! synth of PTHrP; squamous cell carcinoma of lung |
| Acanthosis Nigrans | verrucous hyperkeratosis of skin; often preceeds discovery of cancer |
| Hypertrophic osteoarthropathy | seen in up to 10% of lung cancers; new bone on distal ends; arthritis; clubbing of fingers |
| Lab diagnosis | morphologic, biochemical, immunohistochemistry, molecular, flow cytometry |
| Grading and Staging | Staging is more clinically appicable - size of primary lesion; extent of spread to lymph nodes, and presence of metastasis (T, N, M) |
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bscaryp