Biliary atresia: will blocking inflammation tame the disease?

Abstract

Biliary atresia is the most common cholangiopathy of childhood. With complete obstruction of segments or the entire length of extrahepatic bile ducts, the timely pursuit of hepatoportoenterostomy is the best strategy to restore bile drainage. However, even with prompt surgical intervention, ongoing injury of intrahepatic bile ducts and progressive cholangiopathy lead to end-stage cirrhosis. The pace of disease progression is not uniform; it may relate to clinical forms of disease and/or staging of liver pathology at diagnosis. Although the etiology of disease is not yet defined, several biological processes have been linked to pathogenic mechanisms of bile duct injury. Among them, there is increasing evidence that the immune system targets the duct epithelium and disrupts bile flow. We discuss how careful clinical phenotyping, staging of disease, and basic mechanistic research are providing insights into clinical trial designs and directions for development of new therapies to block progression of disease.

Figures

FIGURE 1. Relationship between stages of liver disease and potential treatments

(A) Diagram depicting the liver acinus with expanded portal spaces containing inflammatory cells (left panel) and advanced fibrosis (right panel); the center panel shows mixed histological features with both inflammation and fibrosis. (B) Example of gene expression cluster analyses with a distinct expression signature for inflammation or fibrosis. Levels of gene expression are shown as a color variation from red (high) to blue (low); yellow denotes baseline levels; columns represent patients and rows represent genes (based on reference 15).

FIGURE 2. Tissue population by mononuclear cells after RRV challenge

Graphs depict the changes in the number of mononuclear cells of Balb/c mice at early phases (3 days) following RRV challenge in the first day of life, at the time of inflammatory obstruction of extrahepatic bile ducts (7 days), and at the time of atresia (14 days) (based on reference 55)

FIGURE 3. Mechanisms of epithelial injury in experimental biliary atresia

Triggering events on the left show RRV infection of cholangiocytes and macrophages (M), and the release of Mip2 and other chemokines to attract neutrophils (N). Soon after infection, plasmacytoid and conventional dendritic cells (pDC and cDC, respectively) activate NK lymphocytes, which injure cholangiocytes by direct engagement and release of Ifnγ and other cytokines. Progression of injury is promoted by pDC and cDC-driven activation and expansion of CD4+ and CD8+ T cells and formation of an inflammatory “plug,” to be followed by disruption of bile flow and collagen deposition. Based on references , -, , .