The Riddle of Juvenile Sclerosing Cholangitis

In this issue of HEPATOLOGY, Deneau et al. report on the 5and 10-year outcome of an impressive number of children diagnosed with primary sclerosing cholangitis (PSC) recruited in 36 transplant and nontransplant referral centers from Europe, North America, the Middle East, and Asia. The study shows the importance of multicenter collaboration and data collection in dedicated registries. Of 781 patients analyzed retrospectively, 33% had autoimmune hepatitis (AIH) features, 76% inflammatory bowel disease (IBD), and 13% small-duct PSC. Ten years after diagnosis, 38% had developed portal hypertension and 25% biliary complications, the median survival with native liver after the onset of these complications being 2.8 and 3.5 years, respectively. The overall event-free survival was 70% at 5 years and 53% at 10 years. Unsurprisingly, patients with the highest elevations of total bilirubin, gammaglutamyl transpeptidase levels, and aspartate aminotransferase (AST)/platelet ratio index at diagnosis had the worst outcomes. Patients with PSC1IBD or with small-duct disease had more favorable prognoses. Cholangiocarcinoma developed in 1% (median, 6 years after diagnosis), an incidence lower than that reported in adult PSC (6.8%) over similar follow-ups. Age, sex, and AIH overlap did not impact the long-term outcome. The researchers conclude that in children, PSC has a chronic, progressive course, with nearly half developing an adverse liver outcome 10 years after diagnosis. With growing use of noninvasive biliary imaging, sclerosing cholangitis (SC), hitherto considered rare in children, is diagnosed with increasing frequency in pediatric age. It is an important cause of morbidity and mortality, accounting for approximately 2% of the pediatric liver transplants in the United States between 1988 and 2008 (United Network for Organ Sharing Data Report, October 2009; http://www.unos.org/data/). There are important differences between adult PSC and juvenile SC. “Primary” denotes ignorance about etiology/pathogenesis, whereas in pediatrics there are well-defined forms of SC, including biliary atresia and autosomal-recessive neonatal SC. Other inherited conditions, for example, mild-to-moderate defects in the ABCB4 (MDR3) gene, are a possible cause of smallduct SC in both children and adults. SC also complicates a wide variety of disorders, including primary and secondary immunodeficiencies, Langerhans cell histiocytosis, cystic fibrosis, and sickle cell anemia. An overlap syndrome between AIH and SC (autoimmune SC; ASC) is more common in children than in adults. Only in those children/adolescents in whom SC occurs without any of the above defining features the name of primary would be appropriate. There is a limited number of published series of pediatric SC, most being retrospective, single-center, and including small patient numbers. In these reports, the incidence of the various clinical forms of SC differs depending upon year of publication and centers where the study was conducted, reflecting different study designs, patterns of referral, and diagnostic protocols. In the retrospective series, as in the one by Deneau et al., cholangiographic studies were prompted by biochemical and/or histological features of cholestatic disease. Boys are more affected than girls, 20%-40% Abbreviations: AIH, autoimmune hepatitis; AIH-1, AIH type 1; ASC, autoimmune SC; AST, aspartate aminotransferase; IBD, inflammatory bowel disease; PSC, primary sclerosing cholangitis; SC, sclerosing cholangitis.