Another Bear Market Disappointment? Ursodiol for TPN Cholestasis

Tauroursodeoxycholic acid (TUDCA) in the prevention of total parenteral nutrition-associated liver disease. Heubi JE, Wiechmann DA, Creutzinger V, Setchell KDR, Squires R, Couser R, and Rhodes P. J Pediatr 2002;141:237-42.

Summary:

Ursodiol, extracted from the bear gall bladder, has been used for centuries in traditional Chinese medicine for treating liver disease and holds promise for treating a variety of hepatic disorders. This study examines its use in preventing parenteral nutrition-associated cholestasis in infants. The authors used ursodeoxycholic acid (UDCA) conjugated to taurine (TUDCA), in infants who were receiving total parenteral nutrition (TPN). Therapy was administered at a dose of 30 mg/kg/day. The study included infants expected to require TPN for more than two weeks who had conjugated bilirubin levels less than 2 mg/dL. No restrictions were placed on birth weight, gestational age, sex, or ethic origin. Children with biliary tract disease, cholestatic liver disease, or major cardiac and renal disease were excluded. The study was an open label trial rather then a placebo-controlled trial because of recruitment difficulties. Infants whose parents declined participation in the study were used as controls. The size of the control group was not specified. Patients were monitored weekly with laboratory studies. Biliary bile acids were measured in aspirated duodenal fluid after two weeks of therapy. Therapy with TUDCA was continued until children had conjugated bilirubin measurements of less then 1 mg/dL for two consecutive weeks.

The investigators found no significant differences between groups in any measured biochemical parameter throughout the study, including peak serum conjugated bilirubin, ALT, alkaline phosphatase, and serum bile acids. The mean duration of TPN was somewhat longer in the control patients (170 +/- 47 days) than the TUDCA treated patients (120 +/- 15 days). Despite the longer TPN duration of controls, there was no difference between controls and TUDCA-treated patients at any point in the 120-day study. UDCA enrichment of the duodenal aspirate was documented, but was relatively modest, perhaps due to underlying bowel disease in some patients.

Comment:

The more we study UDCA as therapy for liver diseases, the more confused we become. Previous studies suggest that UDCA has measurable benefits in TPN cholestasis (^1-4), primary sclerosing cholangitis (PSC) (^5,6), cholestasis of pregnancy (⁷), progressive familial intrahepatic cholestasis (⁸), chronic hepatitis B (^9,10), venoocclusive disease (¹¹), cystic fibrosis (¹²), acute hepatitis B (¹³), and autoimmune hepatitis (¹⁴). However, only a handful of these studies have been placebo-controlled and of sufficient duration to be convincing. Other weaknesses of published studies on UDCA therapy include the uncertainty over the proper dose and the tendency to measure outcomes that may have little relevance to prognosis. For example many studies evaluate serum transaminases, bilirubin, alkaline phosphatase, or GGT rather than such important outcome measures as survival, need for transplantation, or histologic progression.

Good examples of the outcome-measurement problem can be found in studies of primary biliary cirrhosis (PBC) and PSC. In patients with PBC, initial studies emphasized the improvement in biochemical measurements. However, long-term follow-up of these patients has shown that improved biochemical tests were not associated with improved survival (^15,16). Even higher-dose therapy has not proved beneficial to long-term outcome in PBC (¹⁷). A brighter picture has emerged from studies of PSC after initially discouraging reports. Although low-dose UDCA therapy had been found ineffective in improving major measures of outcome (¹⁸), a recent study of high-dose UDCA therapy appeared to slow the progression of pathologic cholangiographic findings (⁵). These studies raise the hope that children with PSC, in whom UDCA yields improved biochemical profiles, may benefit from long-term, high-dose UDCA (¹⁹).

Ursodeoxycholic acid has multiple modes of action-improved bile flow, cytoprotection of hepatocytes and cholangiocytes, decreased apoptosis, and immunomodulation (²⁰). Its efficacy ultimately depends on the nature of the underlying hepatic insult and whether the defect can be circumvented by UDCA. In liver diseases with established therapies, the most effective proven medicines should obviously remain the first-line therapy, with UDCA used as an adjunct. For conditions such as cystic fibrosis-associated liver disease, the choleretic and cytoprotective effects of UDCA may allow its use as single-agent therapy.

This study of TPN cholestasis by Heubi et al. must be interpreted cautiously. It was a short-term study of a long-term problem, and did not include adequate assessment of the major outcomes of children requiring truly prolonged TPN. The drug was given orally, and only limited enrichment of the bile with UDCA occurred. Oral administration was delayed in some of the infants because of underlying bowel disease. I agree with the authors' suggestion that intravenous administration should be studied in these infants. Future trials must be placebo-controlled, should measure clinically important primary outcomes such as development of cirrhosis, and must be of sufficient duration to draw firm conclusions. It is therefore too early to sell ursodiol short.

Warren P. Bishop

Associate Professor of Pediatrics

Director, Division of Gastroenterology

University of Iowa

Iowa City, Iowa, U.S.A.