Use of Corticosteroids After Hepatoportoenterostomy for Bile Drainage in Infants With Biliary Atresia

Abstract

IMPORTANCE Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome. OBJECTIVE To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver. DESIGN, SETTING, AND PATIENTS The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013. INTERVENTIONS Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy. MAIN OUTCOMES AND MEASURES The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events. RESULTS The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, −10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P= .008). CONCLUSIONS AND RELEVANCE Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia.

Postoperative steroid therapy for biliary atresia: Systematic review and meta-analysis

“…Five studies were removed based on our exclusion criteria, leaving 2 RCT and 5 OCS for metaanalysis [3,[9][10][11][12][13][14] (Fig. 1; Table 1).…”

“…demonstrating clear benefits of steroid therapy in BA [1][2][3]. We performed a systematic review and meta-analysis to determine the effect of steroids on bile drainage posthepatoportoenterostomy, and included the recent RCT, which was not included in the 2 previous published meta-analyses.…”

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

“…The pathophysiology of BA is inflammation and obstruction of the extrahepatic bile ducts that results in fibrosis, subsequent cirrhosis and eventual liver failure. Surgical treatment via portoenterostomy results in only ~60% transplant-free survival 2 years after surgery (1). Since the exact cause of the disease is unknown and medical and surgical treatments remain suboptimal, clarification of the mechanisms involved in initial induction and progression of biliary inflammation and identification of potential targets for therapeutic intervention remain essential for new treatment strategies.…”

“…In our early studies using this model, we demonstrated increased mRNA expression of the matrix metalloproteinases (MMPs) in liver tissue samples of infected mice (4). We had initially suspected that these genes may be upregulated via the transforming growth factor (TGF)β pathway, as we had also seen perturbations in mRNA expression of tissue inhibitor of metalloproteinases (TIMP) Tatiana Iordanskaia, 1 Miroslav Malesevic,2 Gunter Fischer, 3 Tatiana Pushkarsky, 4 Michael Bukrinsky, 4 and Evan P Nadler 1 as well as plasminogen activator inhibitor-1 (PAI-1), which are all regulated by TGFβ. However, several experiments utilizing anti-TGF strategies, comprised mainly of antibody blockade of TGF and its pathway members, failed to demonstrate any effect in this animal model (data not shown).…”

Genetic Contributors and Modifiers of Biliary Atresia

“…Among those with restored biliary drainage, as evidenced by a total serum bilirubin 3 months after Kasai HPE <2 mg/dl (or <34 micromolar), the majority of patients are able to postpone or avoid liver transplantation, while children whose jaundice does not resolve typically develop stigmata of cirrhosis and require evaluation for liver transplantation in the first year of life [6,11,19,24,25,26,27]. Unfortunately, there is no medical therapy that has been shown to alter the outcome of the Kasai HPE, including a recent double-blind study evaluating a potential role for corticosteroids [28]. Overall, the stratification of patients into one group or the other is poorly understood.…”