Faculty Bibliography

Cholestatic syndromes present symptomatically with pruritus and biochemically either with elevated levels of serum bile acid as an early manifestation of hepatocellular disease or with elevated levels of serum alkaline phosphatase if the disease originates in the biliary tree. Slow progression to cirrhosis occurs, with recurrent cholangitis and/or pancreatitis as the major problems if the obstruction is in the larger duct system. Maintenance of nutrition and relief of pruritus are important supportive measures. Colchicine and ursodeoxycholic acid administered orally have been proposed as useful therapies for delaying the progression to cirrhosis. Liver transplantation has proven successful in those patients in whom spontaneous remission does not occur

Intravenous administration of 26-hydroxycholesterol to the rabbit with a bile fistula yielded cholic acid in proportions (84 and 86%) not significantly different from that derived from cholesterol. By contrast, the naturally occurring C27 bile acid 3 beta-hydroxy-5-cholestenoic acid yielded not more than 8% cholic acid. Thus initial 26-hydroxylation of cholesterol followed by 7-alpha-hydroxylation can provide sufficient amounts of cholic acid to be considered a quantitatively significant pathway for bile acid synthesis, and in addition it is the only pathway that can be the source of the circulating levels of C24 and C27 monohydroxy bile acids

The regulation of bile acid synthesis was studied in rabbits after interruption of the enterohepatic circulation by choledochoureteral anastomosis. Total daily bile acid output was 772 +/- 130 (SD) mumol/24 h, of which greater than 95% was glycocholic acid. Administration of deoxycholic or cholic acid or their conjugates (300-800 mumol) or gall-bladder bile failed to down-regulate endogenous bile acid synthesis. In contrast, chenodeoxycholic acid administration did down-regulate bile acid synthesis, but this effect was related to the formation and excretion of lithocholic acid. This observation was confirmed by the finding that i.v. infusion of 10-20 mumol of either lithocholic acid or 3 beta-hydroxy-5-cholenoic acid significantly reduced cholic acid synthesis. Thus monohydroxy bile acids, derived from either hepatic or intestinal sources, participate in the down-regulation of bile acid synthesis

1. The effects of 26-aminocholesterol and 26-thiacholesterol on cholesterol synthesis and LDL (low-density lipoprotein)-receptor activity were compared with naturally occurring 26-hydroxycholesterol utilizing both human fibroblasts and hepatoma (Hep G2) cells. 2. At equimolar concentrations (0.625 microM), down-regulation of LDL-receptor activity and cholesterol synthesis was greater with human fibroblasts than with Hep G2 cells. 3. At much higher concentrations (5-20 microM) the 26-thia analogue had little effect on either cholesterol synthesis or LDL-receptor activity