Hepatic bile

Classically the liver has been divided into hexagonal lobules centred around the terminal hepatic venules. Blood enters the liver through the portal tracts that are situated at the corners of the hexagon. The portal tracts are triads of a portal vein, an hepatic artery, and a common hepatic bile duct. The vast expanse of hepatic tissue, mostly consisting of parenchymal cells (PC) or hepatocytes, is serviced via terminal branches of the portal vein and hepatic artery, which enters the tissue at intervals. The hepatocytes are organized into cords of cells radially disposed about the central hepatic venule. Between these cords are vascular sinusoids that transport the blood to the central hepatic venules. The blood is collected through the hepatic venules into the hepatic vein which exits the liver into the inferior vena cava (Figure 4.1). 

LIVER Use of isolated perfused liver in studies of biological transport processes, 192, 485 measurement of unidirectional calcium ion fluxes in liver, 192, 495 preparation and specific applications of isolated hepatocyte couplets, 192, 501 characterizing mechanisms of hepatic bile acid transport utilizing isolated membrane vesicles, 192, 517 preparation of basolateral (sinusoidal) and canalicular plasma membrane vesicles for the study of hepatic transport processes, 192, 534. 

P. J. Meier, Molecular mechanisms of hepatic bile salt transport from sinusoidal blood into bile, Aw. J. Physiol. 269 0801-812 (1995). 

Verschure et al. (VI) have demonstrated by paper electrophoresis that in gall bladder bile the pigments form part of a lipoprotein complex to which cholesterol and bile acids are also bound. In hepatic bile this complex is not found in appreciable amounts, and the bile pigments are bound to two separate proteins. 

Boyer JL, Meier PJ. Characterizing mechanisms of hepatic bile acid transport utilizing isolated membrane vesicles. Methods Enzymol 1990 192 517-533. 

Wagner M, Halilbasic E, Marschall HU, et al. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology 2005 42 420-430. 

Bohme M, Muller M, Leier I et al. (1994) Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver. Gastroenterology 107 255-265 Boyer JL, Meier PJ (1990) Characterizing mechanisms of hepatic bile acid transport utilizing isolated membrane vesicles. Methods Enzymol 192 517-533... 

Malabsorption has many causes. Some malabsorptive disorders, for example coeliac sprue, impair the absorption of most nutrients, vitamins and trace minerals (global malabsorption) others, for example pernicious anaemia, are more selective. Pancreatic insufficiency causes malabsorption if >90% of function is lost. Increased lumen acidity (e.g. Zollinger-Ellison syndrome) inhibits lipase and fat digestion. Cirrhosis and cholestasis reduce hepatic bile synthesis or delivery of bile salts to the duodenum, causing malabsorption. Some causes are summarised in Table 4.2. 

Canaliculi enter canals of Hering in the portal triad and lead to intrahepatic bile ducts which coalesce to form the hepatic bile duct. The bile duct empties the bile into the gaU bladder which then is released into the duodenum. Bile that is excreted into the small intestine enhances nutrient uptake, protects enterocytes from oxidation, and facilitates excretion of xenobiotics and endogenous waste in the feces (Treinen-Moslen, 2001). 

About 80% of patients show both intrahepatic and extrahepatic changes in 20% of cases, only the extra-hepatic bile-duct system is affected. The severest changes are found in the area of the hepatic bifurcation (differential diagnosis Klatkin s tumour). Distal bile-... 

Tajima, T., Honda, H., Kuroiwa, T., Yoshimitsu, K., Irie, H., Aibe, H., Taguchi, K., Shimada, M., Masuda, K. Radiologic features of intra-hepatic bile duct adenoma a look at the surface of the liver. X. Corn-put. Assist. Tomogr. 1999 23 690—695... 

Bile, pH 7.8-8.6, is produced continuously in humans. Hepatic bile is concentrated and stored in the gall bladder between meals. It is ejected from the gall bladder and flows into the duodenum when food enters the intestine. The main constituents of bile are bile salts, bilirubin, end products of hemoglobin breakdown, the electrolytes sodium, chloride, and bicarbonate, cholesterol, phospholipids, and lecithin. The gall bladder contracts within 30 min after eating due to liberation of cholecystokinin. The most effective stimulus to this is food high in fat. 

The regulation of bile acid metabolism is a major function of the liver. Alterations in bile acid metabolism are usually a reflection of liver dysfunction. Cholesterol homeostasis is in large part maintained by the conversion of cholesterol to bile acids and subsequent regulation of bile add metabolism. Bile acids themselves provide surface-active detergent molecules that facilitate both hepatic excretion of cholesterol and solubilization of lipids for intestinal absorption. Bile acid homeostasis requires normal terminal ileum function to absorb bile adds for recirculation (enterohepatic circulation). Alterations in hepatic bile acid synthesis, intracellular metabolism, excretion, intestinal absorption, or plasma extraction are reflected in derangements in bile add metabolism. 

Hepatic Bile Formation. Carrier-mediated active transport of bile acids across the canalicular surface generates osmotic water flow that is a major factor regulating bile formation and secretion. Transport of these organic anions also influences secretion of the remainder of the major components of bile, such as bilirubin, cholesterol, and phospholipids. There is no secretion of the latter two compounds in the absence of bile acid secretion. The influence of bile acid... 

Bile formation occurs by processes that are not hilly defined. It takes place in canaliculi, minute passages lined by specialized modihcations of the hepatocyte membrane, that ultimately unite to form bile ductules. Hepatic bile contains 5% to 15% total solids, the major component of which is bile acids. The increase in biliary water and electrolyte excretion caused by this osmotic effect represents the bile acid-dependent fraction of bile flow. Even with severe depletion of the circulating bile acid pool, as is seen with bile duct diversion, some bile flow continues. The active transport of sodium and of glutathione and bicarbonate is mediated by Na-K-ATPase, which is responsible for the bile acid-independent flow of bile (up to 40% of total flow). Hormones such as secretin increase bile flow by stimulating secretion of sodium, bicarbonate, and chloride. Hormone-dependent flow accounts for 20% to 25% of the total. 

Schlaeger R, Hairs P, Kattermann R. Studies on the mechanism of the increase in serum alkaline phosphatase activity in cholestasis Significance of the hepatic bile acid concentration for the leakage of alkaline phosphatase from rat liver, En2yme 1982 28 3-13. 

Bile is formed and secreted continuously by polygonally shaped liver parenchymal cells called hepatocytes. An aqueous buffer component (e.g., HCOj") is added to the bile by the hepatic bile duct cells that carry the secretion toward the common bile duct. The membrane of the hepatocytes in contact with the blood has microvilli that facilitate the exchange of substances between plasma and the cells. Hepatocytes are rich in mitochondria and endoplasmic reticulum. Hepatic bile flows into the gallbladder, where it is concentrated, stored, and emptied into the duodenum when the partially digested contents of the stomach enter... 

Hepatic bile acid synthesis amounts to about 0.8-1 g/day. When loss of bile occurs owing to drainage... 

Active transport mechanisms for the intestinal absorption of amino acids, oligopeptides, monosaccharides, monocarboxylic acids, phosphate, bile acids, and a number of vitamins have been identified and the review by Tsuji and Tamai provides an excellent summary of those mechanisms. The potential use of intestinal peptide and hepatic bile acid carriers to enhance drug absorption also has been reviewed. Structural and molecular modeling studies have postulated molecular structural features necessary for substrate recognition by the intestinal peptide carrier and the bile acid carrier. ... 

The exact contributions of these alternate pathways to total hepatic bile acid synthesis in normal subjects is not certain, although 26-hydroxylation is usually regarded as the major pathway. In addition, it should be pointed out that current views of hepatic cholic acid and chenodeoxycholic acid synthesis are based primarily oh studies carried out in the rat. More recent studies, which have involved the administration of labeled bile acid intermediates to patients, have suggested that bile acid biosynthesis is more complex than previously thought and that multiple pathways exist to convert cholesterol to bile acids (Vll). 

Until recently, it was considered that hepatic bile flow was still possible even if no bile acids were excreted. This portion of bile flow was termed bile acid independent and was estimated to account for around one-third of canalicular bile flow in man (B33, P15). More recent evidence suggests that the relationship between bile flow and bile acid excretion is curvilinear, so that bile flow decreases progressively more rapidly as bile acid excretion rates decrease to very low values (B2, B24). Bile-salt-independent bile flow may therefore be much lower than previously thought and represent only a very small fraction of total bile flow (B24). 

Hepatic bile As for gallbladder bile 4—60 mmol/liter Collected firom common bile duct C7... 

M22. Mazer, N. A., Schurtenberg, P., Carey, M. C., Preisig, R., Weigand, K., and Klanzig, W., Quasi-elastic light scattering studies of native hepatic bile from the dog Comparison with aggregative behaviour of model biliary lipid systems. Biochemistry 23, 1994-2005... 

TIO. Thureborn, E., Human hepatic bile. Composition changes due to altered enterohepatic circulation. Acta Chir. Scand, 303 (Suppl.) (1962). 

An early observation about endogenous functions of PXR and CAR has been their implication in hepatic bile acid metabolism [48,49]. Most of the more recent findings on this topic are summarized in a number of reviews [9,50-52]. Briefly, CAR and PXR have been shown to play overlapping but not identical roles in hepatic bile acid detoxification [53,54]. Recent work has also drawn attention to the importance of PXR in cholesterol detoxification in the liver, kidney and intestine [55-59]. Both CAR and PXR are involved in bilirubin metabolism and clearance [60] activation of these pathways is of potential therapeutic interest in jaundice and chronic arthritis [61]. 

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