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Pathophysiology of Gallstone Formation and …

Of Gallstone Formation and PancreatitisRobert F. secretions and bile are required for digestion Bile: Emulsification of fat Pancreatic secretions: -Digestion of proteins, carbohydrates and fat-Neutralization of the acidic Secreted by hepatocytes- Transported through the biliary system- Stored and concentrated in the gallbladder- Released into duodenum after ingestionof food (mediated by CCK) compositionMiscellaneous (Pigment, Protein)CholesterolBile SaltsPhospholipids(Lecithin) salts are conjugated with glycine or taurine to increase their solubility at lower pHDehydroxylationDehydroxylationPrimary bile saltsSecondary bile functions of bile1. Emulsification of fats in the intestine2. Cholesterol excretiona. Bile salts are generated from cholesterol and their synthesis thus decreases the cholesterol poolb. Cholesterol is excreted into and secretion of bile acidsCholesterolBile acidsCyp7aABCG11 1.

1 S.N.S Pathophysiology of Gallstone Formation and Pancreatitis Robert F. Schwabe rfs2102@columbia.edu S.N.S Pancreatic secretions and bile are required for digestion

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1 Of Gallstone Formation and PancreatitisRobert F. secretions and bile are required for digestion Bile: Emulsification of fat Pancreatic secretions: -Digestion of proteins, carbohydrates and fat-Neutralization of the acidic Secreted by hepatocytes- Transported through the biliary system- Stored and concentrated in the gallbladder- Released into duodenum after ingestionof food (mediated by CCK) compositionMiscellaneous (Pigment, Protein)CholesterolBile SaltsPhospholipids(Lecithin) salts are conjugated with glycine or taurine to increase their solubility at lower pHDehydroxylationDehydroxylationPrimary bile saltsSecondary bile functions of bile1. Emulsification of fats in the intestine2. Cholesterol excretiona. Bile salts are generated from cholesterol and their synthesis thus decreases the cholesterol poolb. Cholesterol is excreted into and secretion of bile acidsCholesterolBile acidsCyp7aABCG11 1.

2 Synthesis ( )Fecal loss (equals hepatic synthesis)2. Enterohepatic circulation(5-10x daily)ABCG11 ABCG11 Pool =2-3gABC transportersVarious proteins located at the basolateral membrane that mediate transport of bile acids, cholesteroland phospholipidsinto do we have a mechanism for enterohepatic circulation of bile acids?Reabsorption and redelivery of bile acids allows to very quickly replenish the pool of bile acids in the liver/gallbladderThe digestive tract is prepared for the next mealwithin a relatively short is a sensor of bile acids and prevents bile acid toxicityCholesterolFXRCyp7aABCG11 Bile acidsHepatocyteSynthetic FXRA gonists(Moschetta et al, Nat Med 2004)The Nuclear receptors FXR plays an important role in bile salt metabolism increasing bile acid secretion into bile may prevent Gallstone formationFXR stimulation:1. Decreased bile salt synthesis2. Increased bile salt secretionLowers intracellular bile acid poolBile salts are hepatoxic at high of cholesterolCholesterolABCG5/8 SR-BIHDLLDLS ynthesisBileacidsExport intoPeriphery (VLDL) nuclear receptor LXR is a cholesterol sensor and lowers intracellular cholesterol levelsCholesterolABCG5/8 BileacidsBileacidsLXRABCG5/8 Cyp7aCholesterolLXR stimulation:1.

3 Increased bile salt synthesis decreases cholesterol2. Increased cholesterol requires bile salts for cholesterol precipitates to form cholesterol crystals and of Gallbladder BileComposition of Gallbladder bileHealthy controlsPatients with ducts:-Constant flow-Bile is not concentratedGallbladder:-Stasis of bile-Bile is concentratedWhere do Gallstone develop?Very large stonesUnlikely to pass into the duct butmore likely to cause local problemsSludge (viscous aggregate of crystals and mucus)Can pass into the duct but is much less likely to cause problems as it can easier pass the papillaSmaller stonesCan pass into the duct andcause biliary colic/ influencing the prevalence of gallstonesAgeunder 30y1-6%50-60y9-30%Environmental and genetic factorsFemale Pima Indians >25y73%Low prevalence in Asia and AfricaPREGNANCY2. Trim 3. Trim 4-6w gender/ sex hormonesMen under 301-3%Women under 302-6%Men 50-60y9-22%Women 50-60y16-30% stones:- Great majority of all stones in the US (>80%)- either pure cholesterol stones or mixed stones(more than 50% cholesterol content)1 cmMain contributing factors:-Decreased bile acids-Increased biliary cholesterol-Gallbladder factors allowing for stasis/nucleation due to increased hemolyis- or due to decreased bilirubin conjugationPigment stones:- much less common in US than Cholesterol stones- contain pigment = bilirubin1 causesChronic Hemolysisexcess bilirubinDecreased bilirubin conjugationdecreased bilirubin solubility(cirrhosis, bacterial infections) = Cholesterol Stones73% = Pigment Stones83% = Cholesterol Stones17% = Pigment Stonesx-Ray Appearance of Favoring Cholesterol Gallstones Hepatic Production of Lithogenic BileA.

4 Excess cholesterol secretion1. Obesity2. Estrogens3. Crash diet4. Genetic factors/Ethnicity (Pimas) - Point Mutation in ABCA8 accounts probably for 10% of gallstones (Nat. Genetics 2007) Gallbladder Factors1. Stasis (TPN, fasting, progestins)2. Nucleation (increased mucoproteins) Hepatic Production of Lithogenic BileB. Decreased Secretion of Bile Acids1. Decreased bile salt synthesis despite diminished pool, Cyp7a mutations (rare) 2. Decreased bile acid return to liver (ileal resection)Factors Favoring Cholesterol 80% of all gallbladder stones will nevercause symptoms 1-4% of gallbladder stones/year cause symptoms ( colic, pancreatitis, cholecystitis)Natural History of GallstonesUltrasoundERCPD ilated DuctIntraductal stone(not always visible) if contraindications for surgery: Observation Ursodiol Possibly emergency surgeryLaparoscopicCholecystectomy+/-ERC PS ymptomaticComplicatedUncomplicatedSchema tic diagram for the management of Gallstone diseaseLaparoscopicCholecystectomy+/-ERC PU rsodiolGood success with small Cholesterol stonesVery high recurrence rate-Visualize biliary tree andpancreatic ducts-Extract stonesEndoscopic retrograde cholangio-pancreatography (ERCP) GALLSTONES1.

5 Over 80% of gallstones are CHOLESTEROL stones caused by a dysbalance between cholesterol and bile acids in bile2. FASTING (Gallbladder stasis), OBESITY (increased cholesterol secretion) and ESTROGEN (increased cholesterol secretion) promote Gallstone formation3. SMALLER Gallstone pass easier into the duct4. 80% of gallstones remain unsymptomatic5. Therapy of choice for symtopatic Gallstone disease is laparoscopic macro- and functional unitsACINUSD igestive enzyme secretion(Trypsin, Elastase, Amylase, Lipase )DUCTULEW ater, bicarbonate rate (ml/min)Ion (mEq/L) and pH increase with increased pancreatic secretionMeal-stimulated secretionThe increase in HC03serves to buffer the acidic pH of food after it passes into the secretion is regulated through hormonal and neural mechanismsIntestinal phaseduodenalpH< phaseDistentionVagal AfferentspH sensitiveSecretin-releasing factorSecretinS-cellsSecretinH20, NaHC03 Dorsal Vagal ComplexCephalic phaseFoodcuesAchVagal of Enzyme Secretion is mediated by Neural MechanismsIntestinal phaseM3-RCCK-RFCCK(I-cells)

6 Proteins,AA, FADorsal Vagal ComplexCCK-sensingVagal AfferentsGastric phaseDistentionCephalic phaseFoodcuesVagal EfferentsAch, VIP, of pancreatic enzymes in the intestineTrypsinogenTrypsinSPINK2 Mechanisms to prevent autodigestion:-Trypsinogen activation occurs outside of the pancreas-Pancreatic inhibitor prevents trypsinogen OF PANCREATITISA ctivation of pancreatic enzymes within the pancreas and the resulting autodigestion is the most important mechanism that triggers of pancreatitisFunctional andmorphologic changesTimeCHRONICEtOHOutcome:PainEndocr ine insufficiencyExocrine stone, EtOH Outcome:Recovery or deathACUTE sludge, SODO utcome:Recovery or Pancreatitis- Clinically severe- Typically starts with moderate to severe abdominal pain- Complications such as pancreatic necrosis,infection, shock and multi-organ failure develop in some of Acute PancreatitisEtiology of Acute PancreatitisOtherOther Autoimmune Drug-induced Iatrogenic IBD-related Infectious Inherited Metabolic Neoplastic Structural Toxic Traumatic Vascular Autoimmune Drug-induced Iatrogenic IBD-related Infectious Inherited Metabolic Neoplastic Structural Toxic Traumatic Injury through Activated EnzymesRERG olgiComplexLysosomeIncreased pressurePerturbed environment1.

7 Blockage of Secretion2. Activation of Zymogensin Lysosymes (Cathepsin B)3. Organelle Damage and CellInjury by Activated Play an Important Role in Pancreatic InjuryCytokine productionCytokine productionInflammationCell DeathInflammationCell DeathInsultMacrophageMacrophageNeutrophi lNeutrophilChemoattractionand activationChemoattractionand activationPancreaticAcinar CellPancreaticAcinar ICAM-1 PAFE ndothelinINOS ICAM-1 TNF IL-1 IL-61 TNF IL-1 IL-61 ICAM-1IL-1 TNF PAFICAM-1IL-1 TNF PAFL ungsLungsLiverLiverCytokines Mediate Systemic ComplicationsLiver failureShock, Organ Pancreatic and peripancreatic necrosis Fat necrosis Fluid loss into third spaceLocal effects of inflammation and pancreas Pancreatitis- Chronic disease- Pain and malabsorption are the main symptoms- Weight loss can also be due to food fibrosisHereditary pancreatitisHypertriglyceridemiaAutoimmu neFibrocalcific (Tropical)Cystic fibrosisHereditary pancreatitisHypertriglyceridemiaAutoimmu neFibrocalcific (Tropical)

8 Alcoholic IdiopathicOtherOtherEtiology of Chronic PancreatitisEtiology of Chronic lymphocytesCytotoxic lymphocytesFibrosisFibrosisDecreased blood flowDecreased blood flowAltered protein synthesisAltered protein synthesisDirect toxic effectsDirect toxic effectsEffects of Chronic Alcohol on the PancreasEffects of Chronic Alcohol on the Pancreas(unfavorable ratio of trypsinogen vs. inhibitors) PancreatitisHereditary CLINICAL parameters are crucial to establish the diagnosis of acute pancreatitisAmylase and Lipase are typically highly elevated in Acute PancreatitisParotitisParotitisOther causes of hyperamylasemia and hyperlipasemia:Lipase is more specific than Amylase and remains elevated for a longer pancreatitisNecrotizing pancreatitisIMAGING DIAGNOSIS is important to judgeseverity and clinical course of pancreatitisIf CT is performed within 24h of first symptoms, necrosis may not yet be presentHigher rate of complications (bacterial infection, organ failure)

9 And mortality OF ACUTE PANCREATITIS Age > 55 years WBC > 16,000 mm3 Glucose > 200 mg/dl LDH > 350 IU/L AST > 120 IU/L Age > 55 years WBC > 16,000 mm3 Glucose > 200 mg/dl LDH > 350 IU/L AST > 120 IU/L0020204040606080801001000 to 20 to 23 to 53 to 56 to 86 to 89 to 119 to 11%Mortality%MortalityScoreScoreMost patients with severe pancreatitis Hct decrease >10% BUN increase > 5 mg/dl Ca2+< 8 mg/dl PaO2< 60 mm Hg Base deficit > 4 mEq/L Negative fluid balance > 6L Hct decrease >10% BUN increase > 5 mg/dl Ca2+< 8 mg/dl PaO2< 60 mm Hg Base deficit > 4 mEq/L Negative fluid balance > 6 LDuring first 48hAdmissionRanson s severity score & mortalityFat necrosisSystemic Pancreatitis ComplicationsGrey-Turner signGrey-Turner signARDSO bstructing PseudocystObstructing PseudocystNo epithelial NecrosisAcute Pancreatitis ComplicationsAntibiotic+ and Lipase are often within the normal range!!Chronic Pancreatitis: Diagnostic relies on imaging and functional tests(EUS)(EUS)x-ray and fecal fat have a low sensitivity to detect CP!

10 X-raySecretin testFecal chymotrypsinSerum trypsinogenFecal fatBlood glucoseLeastChronic Pancreatitis: Diagnostic of Chronic PancreatitisAbdominal X-rayAbdominal UltrasoundCT Pain and Malabsorption/Malnutrition are the most common Symptoms of Chronic painCCK-RF cellCCK-RF cellExogenous Proteases degrading CCK-RFExogenous Proteases degrading CCK-RFFoodFoodCCKCCKE xogenous ProteaseExogenous ProteaseExogenous proteases may not only improve maldigestionbut also CCK release and pain in chronic PANCREATITIS1. ACUTE PANCREATITIS is a clinically severe disease mostly caused by EtOH and GALLSTONES2. CHRONIC PANCREATITIS causes pain and malabsorption and ist most commonly caused by EtOH3. The diagnosis of ACUTE PANCREATITIS (but not CHRONIC Pancreatitis) is best made by detection of elevated AMYLASE and LIPASE4. Imaging ( CT) can reveal severity of acute pancreatitis (interstitial vs. necrotic)5. CHRONIC PANCREATITIS is diagnosed by imaging (x-Ray, Ultrasound, CT, ERCP) or functional tests (secretin, fecal fat)


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