Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

Abstract

Ursodeoxycholic acid (UDCA) has beneficial effects in cholestatic liver diseases. In primary sclerosing cholangitis (PSC), there is evidence that high doses (؎20 mg/kg) of UDCA may be more effective than average doses. Biliary enrichment of UDCA at such high doses may represent the decisive factor for its beneficial effect. Up to now it is not clear how high-dose UDCA correlates with its biliary enrichment and whether bacterial degradation of large amounts of UDCA may lead to an increased bacterial formation of more toxic hydrophobic bile acids. We determined the biliary bile acid composition in 56 patients with PSC including 30 patients with repeat bile samples treated with various doses of UDCA. At a UDCA dose of 10 -13 mg/kg/d (n ‫؍‬ 18) biliary UDCA represented 43.1% ؉ 0.3% (mean ؉ SD) of total bile acids; at a UDCA dose of 14 -17 mg/kg (n ‫؍‬ 14), its biliary content increased to 46.9% ؉ 0.3%, at 18 -21 mg/kg (n ‫؍‬ 34) to 55.9% ؉ 0.2%, at 22-25 mg/kg (n ‫؍‬ 12) to 58.6% ؉ 2.3%, and at 26 -32 mg/kg (n ‫؍‬ 8) to 57.7% ؉ 0.4%. During UDCA treatment, the biliary content of all other bile acids was unchanged or decreased. In conclusion, biliary enrichment of UDCA increases with increasing dose and reaches a plateau at 22-25 mg/kg. There was no increase of toxic hydrophobic bile acids. If biliary enrichment of UDCA represents the decisive factor for its clinical effect, it seems likely that UDCA doses of up to 22-25 mg/kg may be more effective than lower doses. (HEPATOLOGY 2004;40:693-698.)

In PSC with Colitis Treated with UDCA, Most Colonic Carcinomas Develop in the First Years After the Start of Treatment

“…During a dose-finding study, 20 patients received UDCA in doses of 22-32 mg/kg/day for 3 months and, during this relatively short time period, no side effects have been observed [26]. After UDCA, in patients with and without IBD, the laboratory parameters AP, GGT and ALT decreased as was expected [19][20][21][22][23].…”

“…Under the assumption that higher doses may be more effective [20][21][22][23][24][25][26], since 1995 the patients were treated with an increased dose of 750-1,250 mg/day (14-17 mg/kg per day), and starting from 2001 with 1,000-1,750 mg/day (18-21 mg/kg per day) in three divided doses. Intermittently, 56 patients participated in a dosefinding study and 20 patients received doses of 22-32 mg/kg per day [26]. There was no adjustment of UDCA doses on the basis of clinical disease activity, and unwanted effects of UDCA were not observed.…”

Effect of Colitis and Ileoanal Pouch on Biliary Enrichment of Ursodeoxycholic Acid in Primary Sclerosing Cholangitis

“…In PSC, the optimal dose of UDCA is unknown but there is evidence that high doses are more effective (7). At 22-25 mg/kg UDCA, the biliary enrichment curve reaches a plateau (21).…”

“…The selection criteria for enrolling patients were described previously (21) and included typical endoscopic retrograde cholangiographic findings, serum alkaline phosphatase activity of at least twice the normal range, negative antimitochondrial antibody, and a liver biopsy compatible with the diagnosis of PSC. Criteria for exclusion were decompensation of cirrhosis, liver transplantation being foreseen, and a history of neoplastic disease and/or coexisting hepatic disease.…”

Primary Sclerosing Cholangitis

“…Although the standard dosages of UDCA (10 to 15 mg/kg) have been used in most studies, if biliary enrichment of UDCA represents the decisive factor for its clinical effect, it seems likely that UDCA doses of up to 22 to 25 mg/kg may be more effective than lower doses [164]. UDCA may have an immunologic effect by decreasing the expression of Class 1 antigens, and a choleretic effect by increasing bile flow [165].…”