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MIT HST 121 - BILE

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FUNCTIONS OF BILE • especially cholesterol elimination • Facilitates dietary lipid absorption, obligatory for fat-soluble vitamin absorption • Conduit for endobiotic and xenobiotic excretion • Distributes immunoglobins and antioxidants throughout the gut Promotes “exocrine” lipid secretion, Harvard-MIT Division of Health Sciences and Technology HST.121: Gastroenterology, Fall 2005 Instructors: Dr. Martin C. CareyBILE WATER PRODUCTION Figure removed due to copyright reasons. Please see: Carey M. C, and S. J. Robins. "Bile Production and Secretion." In Internal Medicine. Edited by J. H. Stein, et al. Boston, MA: Little, Brown and Company, 1983, pp. 25-30.Figure removed due to copyright reasons. Please see: . Carey.Figure 3e in "Imaging biliary lipid secretion in the rat: ultrastructural evidence for vesiculation of the hepatocyte canalicular membrane." J Lipid Res 36 (1995): 2147-2163. Crawford, J. M., G. M. Mockel, A. R. Crawford, S. J. Hagen, V. C. Hatch, S. Barnes, J. J. Godleski, and M. CCourtesy of Dr. Siewert-Jan Marrink. Used with permission.Courtesy of Dr. Siewert-Jan Marrink. Used with permission.CHOLESTEROL ENRICHMENT OF BILIARY VESICLES BY BILE SALTS Figure removed due to copyright reasons. Please see: Carey, M. C. New Trends in Hepatology . Edited by W. Gerok, Dordrecht, The Netherlands: Kluwer Academic Press, 1996, pp. 64-83. A. S. Loginov, and V. I. Pokrowskij.LIPID PARTICLES IN HUMAN BILES Image removed due to copyright reasons. Please see: Carey, M. C. New Trends in Hepatology. Edited by W. Gerok, A. S. Loginov, and V. I. Pokrowskij. Dordrecht, The Netherlands: Kluwer Academic Press, 1996, pp. 64-83.Membrane Transporter Defects in Hereditary Cholestatic DisordersContent removed due to copyright reasons.Membrane Transporter Defects in Acquired Cholestatic DisordersContent removed due to copyright reasons.Pathophysiology of Bile Secretory Failure (Cholestasis) • Bilirubin Conjugates (MRP1) → Icterus (Jaundice),Bilirubinuria • Biliary Phospholipids (MDR3) → vesicular LDL • Biliary Cholesterol → • Bile Salts (MRP3) → Cholemia, Choluria, Pruritus, Bradycardia Biliary Lipids in the Systemic Circulation: Lipoprotein X (LpX) – a LpX – HypercholesterolemiaPathophysiology of Bile Secretory Failure (Cholestasis) Deficit of Biliary Lipids in the Alimentary Tract • Fat Malabsorption, principally Lipovitamins,Cholesterol, Monoglycerides but not Fatty Acids • Delayed Chylomicron Formation and LargeParticles • • Changed Ecology of Gut Flora Acholic Stools – Delayed Peristalsis – ConstipationImage removed due to copyright reasons.Image removed due to copyright reasons. Please see: Sömjen, G., and T. Gilat. "Cholesterol-phospholipid vesicles in human bile: an ultrastructural study." Biochim Biophys Acta 879 (1986): 14-21.Principles of Cholesterol Solubilization and Supersaturation in Bile CH [BS + PL]Stability CH [BS + PL] Lithogenicity ____________________________Image removed due to copyright reasons. Please see: Carey, M. C. New Trends in Hepatology. Edited by W. Gerok, A. S. Loginov, and V. I. Pokrowskij. Dordrecht, The Netherlands: Kluwer Academic Press, 1996, pp. 64-83.Etiology of Cholesterol Cholelithiasis • Genetic predisposition • - Monogenic -Polygenic “Cholelithogenic” environment - Diet/ Drugs - Adiposity / Weight Loss - Gestation / Estrogens / ProgestogensThe Genetic Factor in Human Cholesterol Gallstone Disease • obesity, Type 2 diabetes) • Possible genetic drift during last glaciation: “The Stone That Came in from the Cold” • American Indian and Viking migrations • Strong family clustering: Pedigrees, twinstudies, etc. • Essentially absent in sub-Saharan populations Apparently due to “thrifty” genes (like62% Environmental (unique) 13% Environmental (shared) 25% Genetic Genetic and Environmental Influences on Symptomatic Gallstone Disease* *Katsika et al, Hepatology 2005; 41:1138-43. “A Swedish Study of 43,141 Twins” 62% Environmental (unique)13% Environmental (shared)25%GeneticEmergence of Helicobacter Taxa Causing Disease (to 2001*) • Gastric Helicobacter species ≈ 10 (Humans and other animals) • Enterohepatic Helicobacter species ≈ 18 (Humans, rodents, other mammals, and birds) * J.V. Solnick & D. B. Schauer, Clin Microbiol Rev 2001; 14:59-97Helicobacter hepaticus in LiverContent removed due to copyright reasons.C57L Murine Cholesterol Gallstone Model: Lithogenic Diet Feeding • With Helicobacter spp. infection Supersaturated Bile Liquid Crystals Solid Crystals Sandy Stones Cholesterol Gallstones • Without Helicobacter spp. infection Supersaturated Bile Liquid Crystals Solid Crystals . . .Proposed New Paradigm for Cholesterol Gallstone Formation and Perhaps Biliary Cancer Complex Genetics (Lith Genes) Helicobacter spp. Infection Cholesterol Gallstones Chronic Cholecystitis Gallbladder Cancer Environment: Diet, Medication, Hormones, etc.TYPICAL ANATOMIC LOCATIONS OF PIGMENT GALLSTONES Image removed due to copyright reasons. Please see: Cahalane, M. J., et al. "Physical-chemical pathogenesis of pigment gallstones." Semin Liver Dis 8 (1988): 317-28.CHEMICAL COMPOSITONS OF PIGMENT GALLSTONES Image removed due to copyright reasons. Please see: Cahalane, M. J., et al. "Physical-chemical pathogenesis of pigment gallstones." Semin Liver Dis 8 (1988): 317-28.FORMATION OF BILIRUBIN Ostrow, J. D., et al. In: "Hepatic Excretory Function." American Gastroenterological Association Teaching Project, Unit 1. Image removed due to copyright reasons. Please see: Timonian, MD: Miller-Fenwick, 1975.Image removed due to copyright reasons. Please see: Cahalane, M. J., et al. "Physical-chemical pathogenesis of pigment gallstones." Semin Liver Dis 8 (1988): 317-28.BROWN PIGMENT STONE FORMATION Image removed due to copyright reasons. Please see: Cahalane, M. J., et al. "Physical-chemical pathogenesis of pigment gallstones." Semin Liver Dis 8 (1988): 317-28.(Courtesy of Drs. Carlos Pelligrini and Lawrence Way. Used with permission.)(Courtesy of Professor Donald M. Small. Used with permission.)CHRONOBIOLOGY OF BILIARY PAIN (ITALY) Image removed due to copyright reasons. Please see: Minoli, G., et al. "Circadian periodicity and other clinical features of biliary pain." J Clin Gastroenterol 13 (1991): 546-8.Image removed due to copyright reasons. Please see: Paigen, B., and M. C. Carey. Genetic Basis of Common Diseases. Edited by R. A. King, J. I. Rotter, A.


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