Outcome after Portoenterostomy in Biliary Atresia: Pivotal Role of Degree of Liver Fibrosis and Intensity of Stellate Cell Activation

Abstract

Biliary atresia (BA), a congenital idiopathic obliterative cholangiopathy, rapidly leads to liver cirrhosis and liver failure if untreated. A timely Kasai portoenterostomy (KP) variably alters this natural history. We evaluated liver fibrogenesis by the intensity of alpha-smooth-muscle actin (SMA) expression, which is a marker for hepatic stellate cell activation. We hypothesized that liver fibrogenesis as determined by intensity of alpha-SMA is already progressing at the time of KP, is related to age and degree of fibrosis at KP, and predicts outcome after KP. BA patients at KP (n = 22, age 22-84 days, median 59) had wedge liver biopsies assessed by quantitative morphometry of immunohistochemistry for alpha-SMA expression. Fibrosis was scored by blinded pathologists. Outcome, reflected by conjugated bilirubin concentration 3 months after KP (CBili3m), survival of the native liver, need for liver transplant, or death, were assessed for 2 to 10 years after KP. At KP, age, fibrosis score, and alpha-SMA expression were significantly correlated. Moderate-severe fibrosis and intense alpha-SMA expression was observed in 15 of 22 (68%) patients. Severe fibrosis and high alpha-SMA expression were significantly associated with CBili3m greater than 2 g/dL and unfavorable liver survival (>90% of these ultimately underwent liver transplantation or died). Conversely, those with mild fibrosis and low alpha-SMA expression had normal CBili3m and favorable liver survival. Intense liver fibrogenesis is already established in many cases of BA at the time of KP. Fibrosis scores and intensity of alpha-SMA expression may be predictors of outcome after KP and may indicate those patients who might benefit from trials of potential antifibrotic agents early in the course of BA.