Term
| how do salivary glycoproteins protect against bacterial colonization? |
|
Definition
| bind to cellular receptors for bacteria and inhibit bacterial attachment to the buccal epithelium |
|
|
Term
| how does lactoferrin in the saliva (and breast milk) protect against bacterial colonization? |
|
Definition
| sequesters iron, deprives bac of this essential nutrient |
|
|
Term
| how does lysozyme protect against bac colonization? |
|
Definition
| splits muramic acid, affects primarily gram+ bac. in conjunction with lactoferrin and bile salts also affects gram-. |
|
|
Term
| what is mucus made of and what protective factors does it have in it? |
|
Definition
| 95% water, glycoproteins (mucin), phospholipids; contains lysozyme, lactoferrin, sIgA, bicarb (forms pH gradient, 1-2 at luminal surface, 6-7 at epithelial cell surface) |
|
|
Term
| how do bile salts protect against bacterial colonization? |
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Definition
| UNconjugated bile salts inhibit the growth of anaerobes and some gram positive bacteria, but do not affect enteric AERobes. (conjugated bile salts lack this effect) |
|
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Term
| receptors or adherence factors for bacterial colonization. where are they expressed and what determines who gets what receptors? |
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Definition
| receptors expressed on surface of epithelial cells and in the glycocalyx covering the enterocytes. receptors are genetically determined |
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|
Term
|
Definition
| a cell surface glycoprotein that binds many gram+ bacteria, but not gram- as well |
|
|
Term
| what unique residue does the cholera toxin receptor have? |
|
Definition
| Neu5Ac sialic acid residue |
|
|
Term
| why do nonsecretors have a higher incidence of clinical illness? |
|
Definition
| bc blood group antigens in secretions (saliva, mucus) may neutralize intestinal receptors that bind bacteria since there are similarities b/w human blood group substances and antigens of gram- bacteria |
|
|
Term
| how do enterocytes avoid responding to commensal bacteria? |
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Definition
| do not have usual LPS receptor (CD14), but they do have TLR4 receptor |
|
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Term
| what antimicrobial peptides are found in the small intestine? |
|
Definition
| alpha defensins HD-5 and HD-6; produced in paneth cells, released into the intestinal lumen by exocytosis |
|
|
Term
| where can we find alpha defensins 1-4? |
|
Definition
| aka human neutrophil peptides 1-4, can be found in neutrophil granules. they are stored as preprodefensins --> prodefensins --> defensins --> released upon phagocytosis of pathogen |
|
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Term
| what do cryptidins 2 and 3 do? |
|
Definition
| (cryptidins = defensins in MICE, formed in germfree mice but upregulated after microbial stim) induce pore formation, membrane instability, and chloride secretion in eukaryotic cell membranes --> flushing of intestinal crypts and removal of bacteria |
|
|
Term
| what does cryptidin 3 do? |
|
Definition
| induces IL-8 secretion, first step in neutrophil recruitment into the mucosa. ultimately, formation of crypt abscesses |
|
|
Term
| what 2 non-bacterial pathogens are defensins protective against? |
|
Definition
|
|
Term
| which antimicrobial peptide is decreased in crohn's disease? |
|
Definition
| alpha defensin HD-5 --> lower capacity to kill E. coli and S. aureus |
|
|
Term
| paneth cells produce defensins, but what else? |
|
Definition
| lysozyme, phospholipase A2, lectin |
|
|
Term
| compare human B-defensins to a-defensins |
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Definition
| a-defensins produced by paneth cells (small int); b-defensins produced by enterocytes, expressed more widely in the GI tract |
|
|
Term
| when is human B-defensin 1 expressed? |
|
Definition
| constitutively (not affected by proinflammatory cytokines) |
|
|
Term
| when is human B-defensin 2 expressed? |
|
Definition
| only in resopnse to proinflammatory cytokines. also serves as a ligand for TLR4. |
|
|
Term
| what are trefoil factors? |
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Definition
| family of peptides, produced by goblet cells, no direct anti-microbial activity. confer resistance to acid, protease degradation --> maintain epithelial integrity. involved in the repair of the GI tract, production of these peptides increases after mucosal injury |
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Term
| TFF1 (trefoil factor1) located? TFF2? TFF3? |
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Definition
| TFF1 - gastric mucosa; TFF2 bile and pancreatic ducts; TFF3 - small and large intestine |
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|
Term
| where are peyers patches most concentrated? |
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Definition
|
|
Term
| what is GALT histologically characterized by? |
|
Definition
| lack of goblet cells and presence of M cells |
|
|
Term
| what do M cells require to differentiate from enterocytes? |
|
Definition
| factors released from lymphocytes |
|
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Term
| what is distinct about the M cell pathway across gut epithelium vs regular enterocyte pathway? |
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Definition
| M cell pathway - basolateral pockets of M cells contain APCs, B cells, T cells --> Ag transported by M cells are processed and presented by APCs to lys readily. in addition, dendritic cells in the lamina propria capture microbial ags or bac by extending processes b/w enterocytes into gut lumen |
|
|
Term
| describe the T cells of GALT |
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Definition
| mostly lack CD4 and CD8, but are CD3+ with gdT cell receptors. gdT cell receptors recognize MHC-like molecules (not MHC restricted) --> recognize injured enterocytes, kill via apoptosis. release keratinocyte growth factor --> promotes enterocyte growth and differentiation |
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Term
| describe germ free animals b and t cell population |
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Definition
| lack of diversity in B cell repertoire, but normal T cell repertoire; (germfree --> low levels of ICAM-1, low levels of interleukins) |
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|
Term
|
Definition
| (ie. cholera toxin) stimulates net secretion in ligated intestinal segments without evidence of histologic damage |
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|
Term
| describe cytotonic toxins |
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Definition
| (cytoskeleton altering) alter cell shape without inducing significant cell injury. mostly from rearrangement of filamentous actin (f-actin) (i.e. c.difficile toxin A) |
|
|
Term
|
Definition
| produce cell damage! (can be seen grossly) or produce cellular dysfunction (i.e. inhibition of protein synthesis) |
|
|
Term
| describe nerve or immune stimulating toxins |
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Definition
| induce release of neurotransmitters, alter smooth muscle activity, induce release of immune modulators (i.e. cytokines) by enterocytes or submucosal cells --> augment the biological activity of certain toxins (shiga, cdiff) |
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|
Term
| describe the general secretory pathway |
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Definition
| (main pathway for gram+ and gram- bacteria for protein secretion) periplasmic and outer membrane proteins are synthesized in the cytosol as precursor peptides --> guided by chaperones and ushers to the proper site --> exported into the periplasm where protein folding takes place --> translocation across the outer membrane uses type 2 secretion system |
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|
Term
| describe Type 2 secretion system |
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Definition
| proteins exported directly across cytoplasmic or inner membrane and outer membrane - bypasses periplasm. supports translocation of unfolded prtoeins does not depend on GSP |
|
|
Term
| describe type 2 secretion system |
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Definition
| 2 step process, involves GSP for peptide translocation across inner membrane into periplasm. uses a separate apparatus for translocation across periplasm and OM. proteins fold into translocation-competent conformation before their transport across the OM (req several geneproducts) |
|
|
Term
| describe type 3 secretion system |
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Definition
| contact dependent pathway, used exclusively by pathogenic bac to deliver virulence factors to host cells. single step. bypasses periplasm. supports translocation of unfolded proteins. does NOT depend on GSP. encoded by pathogenicity islands present in pathogens but absent in evolutionarily-related-non-pathogens |
|
|
Term
| describe type IV secretion system |
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Definition
| mobilization of DNA between bacteria (plasmids that spread antibiotic resistance); transport of h.pylori CagA also described. DNA-protein complexes transferred in single step (gsp independent); proteins transported via periplasmic space in 2 step GSP-dependent process |
|
|
Term
| describe type V secretion system |
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Definition
| autotransporter. GSP dependent. two step process, but the secreted protein mediates its own transport across the outer membrane, mayr emain attached to the bacterial cell or be released into the external milieu |
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|
Term
| what is primary biliary cirrhosis? |
|
Definition
| autoimmune disease affecting the medium sized intrahepatic bile ducts --> nonsuppurative, inflammaory destruction of the bile ducts --> portal inflammation, scarring, eventual dev of cirrhosis and liver failure (takes a while) |
|
|
Term
| who is mostly affected by primary biliary cirrhosis? |
|
Definition
| middle aged women. (6:1 female to male) peak incidence in 40-50 yo range; genetic factors, environmental factors; family members at increased risk for developing PBC |
|
|
Term
| how do we diagnose primary biliary cirrhosis? |
|
Definition
| elevated ALP and GGT (markers of cholestasis) elevated cholesterol, antimitochondrial antibodies, hyperbilirubinemia (late) |
|
|
Term
| what are the clinical features of primary biliary cirrhosis? |
|
Definition
| pruritis, fatigue, abdominal discomfort, skin pigmentation, xanthelasmas, steatorrhea, vit D malabsorption (osteomalacia, osteoporosis), juandice, portal HTN, extrahepatic manifestations of autoimmunity (dry eyes and mouth, sjogrens, RA, raynauds, celiac disease...) |
|
|
Term
| what are the 4 histological stages of primary biliary cirrhosis? |
|
Definition
| 1. florid duct lesion (dense portal infiltrate of lys, plasma cells, inflam cells, granulomas) 2. ductular proliferation (portal inflammation spills over into parenchyma) 3. fibrosis (fibrous septa interconnect portal areas and create nodules, inflammation down, bile ducts reduced) 4. cirrhosis (fibrous septa subdivide liver into overt micronodules) |
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|
Term
| what is primary sclerosing cholangitis? |
|
Definition
| inflammation and obliterative fibrosis of intra and extrahepatic bile ducts with dilation of preserved segments (beading!) d/t irregular strictures and dilations. |
|
|
Term
| primary sclerosing cholangitis has a close association with what disease? |
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Definition
|
|
Term
| what is the suggested pathogenesis of primary sclerosing cholangitis? |
|
Definition
| T cells activated in gut mucosa travel to liver, recognize bile duct antigen that cross-reacts with gut antigen. OR cross reaction of bile duct antigen with enteric bacteria or bacterial products |
|
|
Term
| how do we diagnose primary sclerosing cholangitis? |
|
Definition
| anti-smooth muscle antibodies, anti-nuclear antibodies, RF, ATYPICAL P-ANCA directed against nuclear envelope (80%)! |
|
|
Term
| what are the clinical sx of primary sclerosing cholangitis? |
|
Definition
| elevated ALP, progressive fatigue, pruritis, jaundice, weight loss, ascites, variceal bleeding, encephalopathy, risk for cholangiosarcoma (7%) |
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|
Term
| what is the characteristic pathologic feature of graft versus host disease? |
|
Definition
| endothelialitis - lymphocytes attach to and infiltrate the endothelium of the terminal hepatic vein and/or portal vein, lifting the endothelium off of the basement membrane |
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|
Term
| cholesterol gallstones are made up of? |
|
Definition
| cholesterol, calcium salts, bilirubin |
|
|
Term
| cholesterol gallstone formation involves four simultaneous conditions: |
|
Definition
| 1. bile must be supersaturated with cholesterol 2. hypomotility of the gallbladder promotes nucleation 3. cholesterol nucleation in the bile is accelerated 4. hypersecretion of mucus in the gallbladder traps the nucleated crystals, leading to their aggregation into stones |
|
|
Term
| what are some factors that contribute to cholesterol supersaturation of bile? |
|
Definition
| hypersecretion of biliary cholesterol by the liver. 1. fam hx 2. high BMI 3. parity 4. high serum trigs 5. low plasma cholesterol |
|
|
Term
| what causes gallbladder hypomotility? |
|
Definition
| toxicity of absorped cholesterol molecules --> decoupling of CCK-transduction at the level of the GB smooth muscle |
|
|
Term
| what causes hypersecretion of mucus in the gallbladder? |
|
Definition
| true hypersecretion (stimulated by cholesterol molecules being absorbed by the GB mucosa --> defense reaction, characterized by acute and chronic sterile inflammation of GB wall) + deficient mucin clearance d/t GB hypomotility |
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|
Term
| how is deoxycholate formed and what does it do? (pathology) |
|
Definition
| once the stone is formed, hepatic bile now bypasses the dysfunctional gallbladder to be exposed to colonic microbes --> increased conversion of primary bile salts to secondary species (deoxycholate) --> deoxycholate accumulates and is prolithogenic (promotes further hepatic cholesterol hypersecretion, accelerates solid phase separation in the GB, prolongs intestinal transit time |
|
|
Term
| describe briefly how black gallstones are formed |
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Definition
| unconjugated bilirubin supersaturation + accumulation of mucin gel (secondary to unconjugated bilirubin absorption by the GB mucosa) + GB hypomotility (bile is sterile!) |
|
|
Term
| characteristic features of brown stones |
|
Definition
| lots of mucin from bile duct wall, stone shape molded by biliary tree, soft feculent smelling stones, skeletons of dead bacteria within the stone structure |
|
|
Term
| describe the most prominent sx of gallstones |
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Definition
| biliary pain. sudden onset, RUQ. nocturnal, within 1-2 hrs of sleeping. unremitting, lasts >30 min. patient unable to lie still, little tenderness over the actual gallbladder. no lab changes. |
|
|
Term
| what are some of the more severe sx/complications of gallstones? |
|
Definition
| empyema (abscess of the gallbladder, can involve transmural inflammation, perforation), perforation, fistulae, ileus (intestinal obstruction), "porcelain" GB (severe degree of fibrosis and calcifications), hydrops, limy bile, cancer |
|
|
Term
| what is the primary complication of gallstones? |
|
Definition
|
|
Term
| what are the clinical sx of acute cholecystitis? |
|
Definition
| progressive RUQ pain, frequently associated with fever, anorexia, tachycardia, sweating, nausea, vomiting, leukocytosis, elevated ALP. |
|
|
Term
| what is acute cholecystitis? |
|
Definition
| sudden inflammation of the GB usually d/t obstruction of the cystic duct with a gallstone (can occur w/o gallstone "acalculus" d/t biliary sludge, hypomotility or vasculitis); inflammation is secondary to mechanical conditions and release of chemicals and later on may be exacerbated by bacterial infection |
|
|
Term
| what is acute cholangitis? |
|
Definition
| sudden inflammation of the common bile duct - occurs from a stone lodged in the duct system. |
|
|
Term
| what are the sx of acute cholangitis? |
|
Definition
| severe biliary pain, jaundice, fever, leukocytosis, lab evidence of cholestasis, rapid progression with systemic disturbances = medical emergency esp if invasion with pus-forming organisms occurs |
|
|
Term
| most important risk factor for gallbladder carcinoma? |
|
Definition
|
|
Term
| risk factors for cholangiosarcoma? |
|
Definition
| age, primary sclerosing cholangitis, ulcerative colitis, caroli disease |
|
|
Term
| hemochromatosis genetically linked to HLA type? |
|
Definition
|
|
Term
|
Definition
| autosomal recessive disorder, mutation of the ATP7B gene --> impaired copper excretion into bile and failure to incorporate copper into ceruloplasmin. marked by accumulation of toxic levels of copper in liver brain and eye |
|
|
Term
| how do we diagnose wilsons disease? |
|
Definition
| decreased serum ceruloplasmin, increased hepatic copper content, increased urinary excretion of copper, kayser-fleischer rings in the cornea |
|
|
Term
| describe the liver changes associated with wilsons disease |
|
Definition
| fatty change, hepatocyte necrosis, acute hepatitis with stainable copper, chronic active hepatitis, mallory bodies, cirrhosis (micro to macronodular), massive liver necrosis (rare) |
|
|
Term
| what is alpha-1 antitrypsin deficiency? |
|
Definition
| codominant condition. abnormally low serum levels of A1AT, which is a protease inhibitor --> proteolytic enzymes allowed to run amuck --> particular damage to the basilar lobes of the lung |
|
|
Term
| describe the pathology of A1AT deficiency |
|
Definition
| accumulation of the globular A1AT protein within hepatocytes (in ER) --> causes ER stress --> apoptosis/damage of hepatocyte |
|
|
Term
| how do we diagnose A1AT deficiency? |
|
Definition
| stainable by PAS and immunoperoxidase |
|
|
Term
| what clinical condition is A1AT deficiency associated with? |
|
Definition
| neonatal hepatitis (occurs in 10-20% of newborns with the deficiency); cirrhosis in children and adults |
|
|
Term
| what is the single most important tx for A1AT deficiency? |
|
Definition
| NO SMOKING! exacerbates the emphysema and destructive lung disease associated with the deficiency |
|
|
Term
| describe cavernous hemangioma |
|
Definition
| benign proliferation of the liver. beneath the liver capsule, discrete red-blue soft nodules made of cavernous endothelium-lined, blood-filled channels |
|
|
Term
| describe simple cysts of the liver |
|
Definition
| lined by flattened biliary epithelium, singly or in clusters |
|
|
Term
| what are congenital intrahepatic dilations? |
|
Definition
| occur in the biliary tree in carolis disease and polycystic liver disease |
|
|
Term
| describe choledochal cysts |
|
Definition
| extrahepatic biliary tree cysts |
|
|
Term
| describe focal nodular hyperplasia |
|
Definition
| well-demarcated but non-encapsulated nodules, marked by prominent central stellate scarring on cut section. normal appearing parenchyma b/w prominent fibrous septa containing proliferated bile ductules and intense lymphocytic infiltrate |
|
|
Term
| describe bile duct adenoma |
|
Definition
| hamartomas, incidental finding. firm, pale, discrete nodule, epithelium-lined channels or ducts separated by CT |
|
|
Term
| describe hepatocellular adenoma |
|
Definition
| well-demarcated, soft yellow nodule (1-30cm). looks like sheets or cords of normal hepatocytes (?more variation in cell and nuclear size), typically marked by abnormally arrayed blood vessels, no portal tracts or bile ducts. strong associatoin with oral contraceptive use, pregnancy, and anabolic steroids |
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|
Term
| what are features that we should look for if we want to prove a liver malignancy is hepatocellular in origin? |
|
Definition
| bile formation in canaliculi, cytoplasmic inclusions resembling mallory bodies, immunoperoxidase staining for alpha-fetoprotein (helps distinguish HCC from liver metastases from another tumor) |
|
|
Term
| what differentiates fibrolamellar HCC from HCC? |
|
Definition
| rises in absence of any identifiable risk factors or liver disease; occurs in children, adolescents, young adults; more indolent and more often resectable; hyaline globules and PAS+ inclusions, large eosinophilic polygonal hepatocytes; associated with use of anabolic steroids |
|
|
Term
| describe the important info about cholangiosarcomas |
|
Definition
| arise in the intrahepatic biliary tree; comes from exposure to thorotrast (contrast for xrays), infection of biliary tree with clonorchis/parasites; unifocal/multifocal/diffuse; dense fibrous stroma with vascular invasion, dismal prognosis (cannot resect) |
|
|
Term
| angiosarcoma - associated risk factors and latent period |
|
Definition
| exposure to vinyl chloride, arsenic, throtrast; latent period can range up to several decades |
|
|
Term
| what is a hepatoblastoma? |
|
Definition
| rare tumor; infancy; mimics development of the liver in utero, capable of met but sometimes resectable; can be epithelial or mixed type |
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