Abnormal hepatic sinusoidal bile acid transport in an Amish kindred is notlinked to FIC1 and is improved by ursodiol

Background & Aims: The mechanism for abnormal hepatic bile acid transport w as investigated in an 18-month-old Amish boy who presented with pruritus, p oor growth, and severe bleeding episodes. Serum bilirubin, gamma-glutamyltr anspeptidase, and cholesterol levels were normal, but prothrombin time and partial thromboplastin time were prolonged and bone alkaline phosphatase le vel was elevated. Methods and Results: Cholic acid plus chenodeoxycholic ac id levels measured by capillary gas-chromatography were 32 times higher tha n control in serum (34.7 vs. 1.1 +/- 0.4 mu g/dL) but were not detected in liver and were reduced in gallbladder bile. Treatment with ursodiol, a more hydrophilic bile acid, improved pruritus, produced 37% weight gain, and af ter 2 years reduced serum primary bile acid concentrations about 85%, while accounting for 71% of serum and 24% of biliary bile acid conjugates. On ur sodiol therapy, hepatic bile acid synthesis was enhanced 2-fold compared wi th controls, and microscopy revealed chronic hepatitis without cholestasis. Three younger sisters with elevated serum bile acids responded positively to ursodiol. Microsatellite markers for the FIC1 (gene for Byler's disease) region in these 4 children were inconsistent with linkage to FIC1. Conclus ions: Conjugated cholic acid and chenodeoxycholic acid were synthesized in the liver and secreted into bile but could not reenter the liver from porta l blood and accumulated in serum. In contrast, unconjugated ursodiol entere d the liver and was conjugated and secreted into bile. Thus, the enterohepa tic circulation of all conjugated bile acids was interrupted at the hepatic sinusoidal basolateral membrane. Unconjugated ursodiol bypassed the hepati c uptake block to enlarge the biliary and intestinal bile acid pools. A mut ation in FIC1 recognized among the Amish and linkage of the disorder to FIC 1 were excluded.