A Prospective Trial of Withdrawal and Reinstitution of Ursodeoxycholic Acid in Pediatric Primary Sclerosing Cholangitis

Abstract

Ursodeoxycholic acid (UDCA) is commonly used to treat several liver disorders in adults and children, including primary sclerosing cholangitis (PSC) for which it is not U.S. Food and Drug Administration approved. UDCA treatment has an uncertain impact on disease outcomes and has been reported in high doses to be associated with worse outcome in adults with PSC. In this context, controlled withdrawal and reintroduction of UDCA in children with PSC were studied. Prior to study initiation, participants were required to have alanine aminotransferase (ALT) and gamma‐glutamyl transpeptidase (GGT) <2 times the upper limit of normal on stable UDCA dosing. The study included four phases: I (stable dosing), II (50% UDCA reduction), III (UDCA discontinuation), IV (UDCA reintroduction), with a primary endpoint of change in ALT and GGT between phases I and III. We enrolled 27 participants (22 completed) between March 2011 and June 2016. Changes in mean ALT and GGT between phases I and III were ALT, +29.5 IU/L (P = 0.105) and GGT, +60.4 IU/L (P = 0.003). In 7 participants, ALT and GGT ≤29 IU/L did not rise above 29 IU/L (null response group). Eight participants had increases of ALT or GGT >100 IU/L (flare group). None developed elevated bilirubin. All flares responded to UDCA reinstitution. Serum GGT, interleukin‐8, and tumor necrosis factor α levels were higher in the flare group at baseline. Liver biochemistries increased in children with PSC during controlled UDCA withdrawal; one third increased above 100 IU/L and one third remained normal during UDCA withdrawal. Conclusion: The impact of prolonged UDCA use in childhood PSC and the significance of a biochemical flare are unclear. Further studies of the natural history and treatment of pediatric PSC and UDCA use are needed.

Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis

“…Notably, it took 6 years at 12 large centers to enroll 22 children to complete a 12‐week study protocol, in large part because of unwillingness of families to stop UDCA. ( 23 ) Here, we show the lack of effectiveness of the two major therapies used in pediatric PSC, which were comparable to observation. The clinical equipoise of existing strategies for PSC justifies the safety of placebo‐controlled trials, and the high rates of spontaneous biochemical normalization demands them.…”

“…Controlled withdrawal of UDCA from children on chronic therapy with normal biochemistry showed that most did not experience a biochemical flare. ( 23 ) One‐third of patients in the study maintained a completely normal GGT, raising the question of whether they were receiving any therapeutic benefit from UDCA or whether they would have initially normalized biochemistry spontaneously.…”

Pediatric Cholestatic Liver Disease: Review of Bile Acid Metabolism and Discussion of Current and Emerging Therapies

“…which showed approximately 1/3 of patients had no significant change in labs with withdrawal of UDCA, while 1/3 of patients met criteria for a disease flare with withdrawal of UDCA, though long term differences in these 2 subsets were not reported (103). This suggests that there may be a subset of patients who have biochemical evidence of UDCA response, and that those patients may have improved outcomes arguing for continuation of UDCA in these patients.…”

iTRAQ‑based quantitative proteomics analysis of the hepatoprotective effect of melatonin on ANIT‑induced cholestasis in rats

“…Cholestasis may be caused by either intrahepatic or extrahepatic dysfunction ( 1 ), and may lead to a range of clinical hepatobiliary diseases, such as liver failure, hepatobiliary malignancy and bile fibrosis, cirrhosis ( 2 ). Ursodeoxycholic acid (UDCA) is currently the only treatment approved by the US Food and Drug Administration for the treatment of patients with cholestasis ( 3 ). However, according to the Primary Biliary Cholangitis Treatment and Management Guidelines from the British Society of Gastroenterology from 2018, oral UDCA is not an ideal therapeutic option as it may aggravate liver injury and one-third of patients are unresponsive to it ( 4 , 5 ).…”