Use of Ursodiol in Infants and Children

Marcia L. Buck, Pharm.D., FCCP

Pediatr Pharm. 2009;15(2) 

In This Article

Clinical Trials

Ursodiol has been used as adjunctive therapy in the management of infants and children with hepatic and biliary cholestasis since its introduction onto the U.S. market in 1987. There are now several dozen papers describing its use.[2] The earliest papers focused on the treatment of adolescents with hepatobiliary disease resulting from cystic fibrosis. In several publications, ursodiol in doses of 10-20 mg/kg/day resulted in improved biochemical markers of cholestasis, as well as increased fat absorption.[2,5,6] Ursodiol has also been used successfully in the management of hereditary conditions associated with hyperbilirubinemia and cholestasis, including Crigler-Najjar disease and Kabuki syndrome.[2,7,8]

Another long-standing use for ursodiol has been as an adjunct in the management of infants and children with biliary atresia. In 1987, Ullrich and colleagues treated two children with biliary atresia who failure to gain weight on maximal nutritional support had reduced their likelihood for successful liver transplantation.[9] Treatment with ursodiol, at a dose of 17 mg/kg/day given once daily at bedtime, resulted in clinically significant gains in both weight and length. One of the children also showed improvement in their hepatic function.

Since that publication, a number of other papers have further substantiated the benefit of ursodiol in pediatric patients with biliary atresia. Although it does not appear to alter the outcome of the disease, ursodiol may help to retard its progression and improve patient symptoms. In 2007, Stringer and colleagues at St. James's University Hospital published a series of 71 infants treated for biliary atresia.[10] Of the 60 who underwent a Kasai portoenterostomy, 50 received adjunctive therapy with oral dexamethasone for a 15 day period postoperatively, along with a regimen of ursodiol 5 mg/kg twice daily and phenobarbital 5 mg/kg once daily at bedtime for one year. Thirty-eight (76%) of the 50 infants who received the adjunctive therapy cleared their jaundice, defined as having a bilirubin level < 20 micromol/L, compared to only 4 (40%) of the 10 who were not treated (p=0.06). At the end of the study, cholangitis was significantly less common in the adjunctive therapy group compared to those who were not treated (36% versus 80%, p < 0.05). Of the 56 children from both groups surviving at the end of one year, 70% had not required liver transplantation at a median follow-up of 3.3 years. Based on their results, the authors concluded that their adjunctive regimen significantly improved clinical outcomes after a Kasai procedure.

These results were confirmed by a prospective study of 16 children with biliary atresia. In 2008, Willot and colleagues found that treatment with ursodiol after Kasai portoenterostomy improved liver function.[11] The authors evaluated patients who underwent a Kasai and were treated with ursodiol (mean dose 25 mg/kg/day, range 20-36 mg/kg/day) for at least a year after surgery. The decision to discontinue therapy was made by the attending physician. In 13 of the 16 patients, biochemical tests demonstrated significant worsening of hepatic function after discontinuation. Alanine aminotransferase (ALT) rose from 1.4 xN (the upper limit of the normal range) to 3.0 xN after discontinuation. Gama glutamyl transpeptidase (GGT) increased from 4.2 xN to 8.0 xN and aspartate aminotransferase (AST) rose from 1.3 xN to 1.7 xN. All of these patients responded to the resumption of therapy with improvement in their biochemical markers as well as a reduction in endogenous bile acid concentrations.

In contrast, Kotb found less favorable results in a review of 141 children who underwent a Kasai portoenterostomy at New Children's Hospital in Cairo between May 1985 and June 2005.[12] A total of 108 children were treated with ursodiol (mean dose 20 mg/kg/day) for an average duration of 252.6±544.9 days. More of the untreated patients were classified as having a successful outcome than the ursodiol-treated patients (8/33 or 24.2% versus 11/108 or 10.4%, p=0.043). There was no significant difference in the number of patients who failed therapy and required additional intervention (75.7% of the treated versus 77.7% of the untreated patients, p=0.489). The incidence of diarrhea was also significantly greater in the treated group (70.4% versus 6%, p=0.0001), leading the authors to conclude that ursodiol offered no significant benefit and could produce unnecessary complications.

Ursodiol has also been used in the treatment of parenteral nutrition-associated cholestasis (PNAC) in infants and children.[13,14] The incidence of PNAC ranges from 7 to 57%, with the highest percentages occurring in very-lowbirthweight infants requiring long-term parenteral nutrition. In 2004, Chen and colleagues reviewed their experience with ursodiol in 30 infants with PNAC (mean gestational age 28±0.44 weeks), including 12 who received ursodiol and 18 untreated patients who served as controls.[13] Ursodiol was initiated at the time cholestasis was diagnosed and patients were treated with 10 to 30 mg/kg/day, divided into three doses. The average duration of treatment was 51.5±8.5 days. The infants in the ursodiol group had a shorter duration of cholestasis compared to the controls (62.8 versus 92.4 days, p=0.006). Peak total bilirubin was also lower in the treatment group (8.8±1.6 versus 13.9±1.6 mg/dL, p=0.007). There were no significant differences in ALT, GGT, or AST. None of the patients in the study progressed to hepatic failure and there were no mortalities. There were no adverse effects reported with the use of ursodiol.

In 2006, De Marco and colleagues conducted a prospective evaluation of the effects of ursodiol in 12 children with short bowel and PNAC.[14] The patients were treated with an ursodiol dose of 30 mg/kg/day divided and given three times daily. At the 6-month evaluation period, 11 children had full remission or improvement in their cholestasis. The mean time to improvement was 2.1 months (range 1-4 months). Average values of ALT, GGT, and direct bilirubin improved significantly after treatment. Of the four children who were taken off ursodiol at the completion of the study, three had a return of their cholestasis. These three children were placed back on ursodiol with subsequent improvement. The authors reported no serious adverse effects related to treatment.

Based on the success of these investigations as well as others, Arslanoglu and colleagues recently published the results of a pilot study using ursodiol as preventative therapy for PNAC in premature infants.[15] The authors conducted their prospective, double-blind, placebocontrolled trial in 30 infants. Beginning on the third day of life, patients were randomized to receive ursodiol (5 mg/kg/day) or placebo. Once enteral feedings were initiated, the ursodiol dose was increased to 10 mg/kg/day and continued until the last day of parenteral nutrition. At that time, the ursodiol dose was increased to 20 mg/kg/day. There was no significant difference in fat absorption between the groups. Fecal fat excretion was slightly decreased in the ursodiol group, but the difference did not reach statistical significance. The treated group reached full enteral feeds two days earlier than the controls, but there were no differences in growth or nutritional status. Serum GGT levels declined throughout the treatment period in the ursodiol group, while increasing in the controls. Serum AST and ALT declined significantly with ursodiol, while AST increased and ALT remained unchanged in the controls (p < 0.05). There were no significant adverse effects associated with ursodiol administration. The authors concluded that the results of their pilot study support the need for additional research with ursodiol as preventative therapy in premature infants at risk for PNAC.

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