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Authors: W. Volwiler, R.A. Willson, A.M. Larson, and J.D. Ostrow
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L. Hepatobiliary Defects in Bile Salt Metabolism & Secretion

1. Primary Defects in Bile Salt Synthesis

Rare genetic defects


Accumulation of sterol precursors may account for many symptoms 		  Rare genetic defects in bile salt synthesis may lead to severe deficiency of bile salts in the bile and intestine, leading, respectively, to secondary decreases in biliary phospholipid and cholesterol secretion and to fat malabsorption. The deficient conversion of cholesterol to bile salts leads to high serum cholesterol levels and accumulation in the plasma and tissues of the sterol precursor(s) proximal to the block in bile salt synthesis.

2. Cholestasis

Mechanisms of cholestasis




Impaired secretion of all bile components 		  In cholestasis, there is impaired secretion of all components of bile. Stasis of bile flow may result from three processes: a) failure to secrete bile into the canaliculi, due to injury to the hepatocytes and/or the canalicular membrane, or altered function of the canalicular bile salt transporter; b) increased permeability of the canaliculi, cholangiocytes and/or their tight junctions; and c) mechanical obstruction of the biliary tree at any level. Diffuse injury to canalicular membranes causes loss of microvilli and dilatation of canaliculi which can be plugged by inspissated bile. In cholestasis, there is impaired secretion of all components of bile.

Impaired secretion plus regurgitation across the biliary tract increases plasma levels of all bile components



Early increase in alk. phosphatase & bile salts in plasma
Itching common in cholestasis 		  The retained bile salts secondarily damage the hepatocytes, canaliculi, cholangiocytes and tight junctions, aggravating any primary injury to these structures. Increased intrabiliary pressure proximal to a mechanical obstruction contributes to the increased permeability of the ducts and canaliculi. This increased permeability allows all components of bile to regurgitate into the blood via the peribiliary plexus, adding to the elevated plasma levels of bile salts, lecithin, cholesterol, conjugated bilirubins and alkaline phosphatase. The retained bile salts also induce synthesis of alkaline phosphatase in the affected hepatocytes and cholangiocytes. Thus, plasma levels of this enzyme, as well as bile salts, are earliest and most strikingly elevated, often in the absence of elevated plasma bilirubin levels. Retention of other cholephiles, possibly opioids, causes pruritus (itching) that accompanies 75% of cases of cholestasis.

Compensatory mechanisms in cholestasis   When cholestasis occurs, several compensatory mechanisms partially mitigate the retention of bile salts: a) bile salts retained in hepatocytes inhibit their synthesis from cholesterol; b) upregulation of MRP 1, 3 & 4 in the basolateral membrane of hepatocytes facilitates export of retained organic anions into plasma; c) decreased delivery of bile to the intestine diminishes the enterohepatic circulation of bile salts; and d) sulfation of the hydroxyl groups of bile salts is up-regulated in the liver and kidney, which, along with upregulation of OAT3 and MRP2 in the renal tubular epithelium, enhances the renal excretion of bile salts.

  a. Canalicular cholestasis

Canalicular cholestasis is most often due to drugs, estrogens, and infections   Canalicular cholestasis results from impaired function of the export pumps for bile salts (BSEP) and other organic anions (MRP2) in the canalicular membrane. Although most often caused by steroid hormones, such as estrogens, it also may occur in acute viral, or alcoholic hepatitis, in sepsis and during total parenteral nutrition. Some degree of canalicular cholestasis is a common feature of most diffuse intrahepatic inflammations and many drug reactions, due to injury to the secretory functions of the canalicular membranes.

  1. In drug-induced cholestasis, (phenothiazines, sulfonylureas) some degree of inflammation and hepatocellular necrosis can be present.


  2. In steroid-induced cholestasis (normal pregnancy, or treatment with synthetic estrogens, or with 17-a-alkyl anabolic steroids), maximum hepatic secretory capacity is impaired for organic anion cholephiles in almost all subjects, but a full-blown cholestatic syndrome ensues unpredictably in a small proportion of patients.


  3. Postoperative cholestasis. Mild to severe cholestasis may occur after long, difficult surgical procedures with multiple blood transfusions.


  4. Other causes of canalicular cholestasis. A similar syndrome may occur during severe infections with endotoxemia and/or septicemia, total parenteral nutrition, and sickle cell anemia crises.
  b. Obstructive cholestasis

  Obstructive cholestasis can result in the same functional changes as in canalicular cholestasis. If any portion of the biliary tree is obstructed, from ductules to sphincter of Oddi, flow of bile is retarded, excretion of all components of bile is decreased and regurgitation of all bile components occurs proximal to the block.

Classification of obstructive cholestasis by site of obstruction and etiology   Obstructive cholestasis can result in the same functional changes as in canalicular cholestasis. Flow of bile is retarded, and excretion of all components of bile is decreased if any portion of the biliary tree, from ductules to sphincter of Oddi is obstructed. Obstructive cholestasis is classified according to the site of damage to the biliary tree, and to the putative etiology.

  1. Obstructive intrahepatic cholestasis. Primary biliary cirrhosis, an autoimmune disease, affects the small bile ductules and intralobular ducts in the portal triads. Interlobular and larger intrahepatic bile ducts can be obstructed by multifocal lesions of the liver (granulomas, lymphomas, metastatic nodules). In sclerosing cholangitis and intrahepatic lithiasis, irregulary distributed fibro-inflammatory lesions lead to strictures and the formation of multiple, small calculi in the intrahepatic ductal system. These syndromes may cause a prolonged, marked elevation of the serum alkaline phosphatase without jaundice.


  2. Obstructive extrahepatic cholestasis is most often caused by local lesions such as carcinoma of the head of the pancreas, or by common bile duct stones or structures. Rarer cholangiocarcinomas of the common duct or right or left hepatic ducts often cause a slowly progressive cholestasis with marked elevation of the alkaline phosphatase long before jaundice develops. Strictures or primary carcinomas of the Papilla of Vater are other less common causes.
3. Hepatocellular Diseases

  a. Acute hepatocellular diseases (hepatitis)

Hepatocellular diseases may cause multiple defects including features of cholestasis   Acute hepatocellular diseases (hepatitis) may impair the basolateral uptake, synthesis, intracellular transport, and biliary secretion of bile salts as well as hepatic synthesis of cholesterol.

  b. Chronic hepatocellular diseases (cirrhosis)

  In chronic hepatocellular diseases (cirrhosis), in addition, bile salts absorbed from the intestine are partially diverted through the porto-systemic shunts into the systemic circulation, contributing to increased plasma bile salt levels.

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