Bile Acid Changes After High-Dose Ursodeoxycholic Acid Treatment in Primary Sclerosing Cholangitis: Relation to Disease Progression

Abstract

High-dose (28-30 mg/kg/day) ursodeoxycholic acid (UDCA) treatment improves serum liver tests in patients with primary sclerosing cholangitis (PSC) but does not improve survival and is associated with increased rates of serious adverse events. The mechanism for the latter undesired effect remains unclear. High-dose UDCA could result in the production of hepatotoxic bile acids, such as lithocholic acid (LCA), because of limited small bowel absorption of UDCA and conversion of UDCA by bacteria in the colon. We determined the serum bile acid composition in 56 patients with PSC previously enrolled in a randomized, double-blind controlled trial of high-dose UDCA versus placebo. Samples for analysis were obtained at the baseline and at the end of treatment. The mean changes in the UDCA level (16.86 versus 0.05 lmol/L) and total bile acid level (17.21 versus 20.55 lmol/L) were significantly higher in the UDCA group (n 5 29) versus the placebo group (n 5 27) when pretreatment levels were compared (P < 0.0001). LCA was also markedly increased (0.22 versus 0.01 lmol/L) in the UDCA group compared to the placebo group (P 5 0.001). No significant changes were detected for cholic acid, deoxycholic acid, or chenodeoxycholic acid. Patients (n 5 9) in the UDCA group who reached clinical endpoints of disease progression (the development of cirrhosis, varices, liver transplantation, or death) tended to have greater increases in their posttreatment total bile acid levels (34.99 versus 9.21 lmol/L, P < 0.08) in comparison with those who did not. Conclusion: High-dose UDCA treatment in PSC patients results in marked UDCA enrichment and significant expansion of the total serum bile acid pool, including LCA. (HEPATOLOGY 2010;52:197-203)

The Mucosa-associated Microbiota of PSC Patients is Characterized by Low Diversity and Low Abundance of Uncultured Clostridiales II

“…Several studies have been published on the effect of UDCA on clinical symptoms, liver function tests, and serum bile acid levels in PSC. 26,27 However, bile acid composition in the gut of PSC patients remains uninvestigated, as does the effect of UDCA on fecal and mucosal bile acid composition. Regarding the effect of bile acid on the microbiota, it has been recently reported that increased bile production (as a result of a high-fat diet) has a significant impact on the composition and activity of the intestinal microbiota.…”

Current research on the treatment of primary sclerosing cholangitis

“…Sinakos et al investigated the serum bile acid composition in patients in the high-dose UDCA arm and compared that with serum bile acids in patients in the control group (49). They found a significant expansion of the total serum bile acid pool and increased UDCA and LCA enrichment in the UDCA-treated patients versus the placebo group when compared to pretreatment levels (49). In addition, they found that the increase in total serum bile acid pool correlated with worse outcomes in patients with PSC (49).…”

“…They found a significant expansion of the total serum bile acid pool and increased UDCA and LCA enrichment in the UDCA-treated patients versus the placebo group when compared to pretreatment levels (49). In addition, they found that the increase in total serum bile acid pool correlated with worse outcomes in patients with PSC (49). Together, these observations suggest that changes in the bile acid pool could be deleterious in patients with PSC, and alteration of the bile acid pool may be of therapeutic benefit in PSC.…”

Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in theabcb11−/−mouse: transport and gene expression studies

“…The use of UDCA in patients without BSEP function may be contraindicated. Notably, when UDCA was used at a high dose, in a clinical trial for primary sclerosing cholangitis, patients displayed significantly higher mortality, leading to premature termination of the trial (21,31).…”