The lack of relationship between hepatotoxicity and lithocholic-acid sulfation in biliary bile acids during chenodiol therapy in the National Cooperative Gallstone Study,

Abstract

To test whether hepatotoxicity occurring in National Cooperative Gallstone Study patients was caused by a toxic effect of chenodiol per se or of lithocholate caused by defective sulfation, bile samples were analyzed using a new high-performance liquid chromatography method that measures the proportions of the four individual lithocholate amidates (sulfated and unsulfated lithocholylglycine and lithocholyltaurine) and all common bile acid amidates. Samples were obtained from National Cooperative Gallstone Study patients (n = 17) with abnormal light microscopic liver biopsy results or major aminotransferase elevations and from a matched control group of patients (n = 14) who received similar chenodiol doses but had no evidence of liver injury. Bile samples from 45 healthy subjects were also analyzed. The analytical method was validated by showing that the percentage of chenodiol and cholic and deoxycholic acid obtained by high-performance liquid chromatography correlated highly (r greater than 0.94) with previous gas-liquid chromatography analyses of these samples by the National Cooperative Gallstone Study Reference Laboratory. No significant differences were seen between gallstone patients with and without evidence of liver injury for percent total lithocholate amidates, percent sulfated or unsulfated lithocholate amidates or percent chenodiol amidates. Lithocholate was partially sulfated in all bile samples (52% +/- 17% [mean +/- S.D., n = 50]), but the extent of sulfation varied widely between and within patients during the course of therapy. Mean values of healthy subjects were similar and also showed a wide range in the extent of lithocholate sulfation. It is concluded that (a) liver injury caused by these doses of chenodiol could not be attributed to the accumulation of unsulfated lithocholate per se in circulating bile acids; (b) liver injury appeared to be, directly or indirectly, caused by enrichment in circulating bile acids with chenodiol or chenodiol together with lithocholate, suggesting that the hepatocytes of those patients with hepatotoxicity were injured by the change induced in bile-acid metabolism by the feeding of chenodiol; and (c) about half of lithocholate amidates in bile samples were sulfated, but the extent of sulfation was highly variable both in gallstone patients and healthy subjects.

Biliary Bile Acids in Primary Biliary Cirrhosis: Effect of Ursodeoxycholic Acid

“…38 CDCA and DCA feeding to humans can induce liver injury, and toxicity has been attributed to the fed bile acid. 8,39,40 Little information is available about the effects of feeding CA to PBC patients. When Guldutuna et al 41 administered CA to their patients with PBC, worsening of liver test results was observed in the second and third months of treatment; but CA administration to PBC patients or healthy subjects causes biliary bile acids to become enriched in DCA, its 7-deoxy metabolite.…”

“…Bile acid composition was measured by a high-pressure liquid chromatography method, 7 which had been validated against gas chromatography. 8 For determination of the mode of conjugation of the four major biliary bile acids (cholic acid [CA], chenodeoxycholic acid [CDCA], deoxycholic acid [DCA], UDCA), chromatograms were selected that had excellent peak resolution of the corresponding glycine and taurine conjugates of those acids and in which unknown bile acids and non-bile acid components had distinctly different retention times. There were 61 such chromatograms: 12 from patients before treatment, 22 from patients who received placebo, and 27 from patients who had received UDCA.…”

A randomized double-blind, placebo-controlled trial ursodeoxycholic acid in primary biliary cirrhosis

“…Entry inclusion criteria consisted of (1) the presence of evidence of PBC with manifestations of cholestatic liver dis-HEPA~OLOGY September 1995 ease of a t least 6 months' duration; (2) a serum alkaline phosphatase level a t least one and a half times the upper limit of normal; (3) a positive antimitochondrial antibody test; (4) exclusion of biliary obstruction by ultrasonography, computed tomography, or by endoscopic cholangiography; and (5) a liver biopsy specimen within the previous 6 months judged compatible with the diagnosis of PBC. Exclusion criteria consisted of (1) treatment in the 3 months before entry with immunosuppressive, antiinflammatory agents such as azathioprine, colchicine, corticosteroids, cyclosporine, methotrexate, and d-penicillamine; or with ursodiol; (2) recurrent bleeds from esophagogastric varices, spontaneous encephalopathy, or diuretic-resistant ascites; (3) a serum bilirubin of 20 mg/dL or greater; (4) pregnancy; (5) age younger than 19 years; and (6) findings of other causes of liver disease. Patients with a negative antimitochondrial antibody were accepted if they met all other criteria for the diagnosis of PBC and had no evidence of extrahepatic obstruction.…”