Adjuvant therapy in biliary atresia: hopelessly optimistic or potential for change?

Abstract

Given that the aetiology of biliary atresia (BA) is complex and that there is a multiplicity of possible pathogenic mechanisms then it is perhaps not surprising that the evidence for effect of a number of different agents is contradictory. Post-operative cholangitis for instance is common, bacterial in origin and various antibiotic regimens have been tested (although none in a randomized trial) but continuation beyond the early post-operative period does not appear to offer any greater protection. There is an inflammatory reaction in about 25-35% of cases of BA illustrated by abnormal expression of class II antigen and upregulation of ICAM, VCAM and E-selectin with an infiltrate of immune-activated T cells (predominantly CD4 + Th1 and Th17) and NK cells and a systemic surge in inflammatory cytokines (e.g. TNF-α, IL-2, IL-12). This has potential as a therapeutic target and is the main hypothesis behind the rationale use of steroids. The first report of steroids was published in 1985 by Karrer and Lilly as "blast" therapy to treat recalcitrant cholangitis, followed by a multiplicity of small-scale uncontrolled studies suggesting benefit. To date there has been one randomized placebo-controlled study with a low-dose (prednisolone 2mg/kg/day) regimen (2007); one with a high-dose (IV prednisolone 4mg/kg/day regimen) (2014); two prospective high-dose open-label studies (2013); a prospective comparison of low- and high-dose regimen and a large (380 infants) retrospective comparison. The most recent meta-analysis (2016) identified a significant difference in clearance of jaundice at 6months (OR 1.59, 95% CI 1.03-2.45, P = 0.04), in patients treated with high-dose steroids, particularly if < 70days at surgery. Ursodeoxycholic acid (UDCA) may increase choleresis or change the ratio of endogenous bile acids to a less hydrophobic and, therefore, less toxic millieu. UDCA may protect cholangiocyte membranes against damage and perhaps reduce the tendency to fibrogenesis. Biochemical benefit has been shown in a single crossover trial in older BA children who had cleared their jaundice. Other potential adjuvant therapies include immunoglobulin therapy, anti-viral agents and Chinese herbs although real evidence of benefit is lacking.