The Riddle of Juvenile Sclerosing Cholangitis
Authors: Giorgina Mieli‐Vergani, Diego Vergani
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Article On Page 518 In this issue of Hepatology, Deneau et al. report on the 5‐ and 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.1 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 PSC+IBD 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.2 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 small‐duct SC in both children and adults.3 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.,1 cholangiographic studies were prompted by biochemical and/or histological features of cholestatic disease. Boys are more affected than girls, 20%‐40% having only intrahepatic cholangiopathy. There is a strong IBD association (60%‐90% of cases), over two thirds of patients having ulcerative colitis, the others Crohn's disease or indeterminate colitis. IBD can precede the diagnosis of liver disease by many years, be diagnosed at the same time, or develop during follow‐up. All retrospective studies recognize a form of SC with strong autoimmune features, but while in some this condition is reported to respond favourably to immunosuppression, having a better prognosis than PSC,4 in others the prognosis of AIH/PSC overlap is reported to be severe and not ameliorated by immunosuppressive treatment7 or similar to that of PSC irrespective of treatment.1 In agreement with the current study by Deneau et al., small‐duct SC is reported to have a more favorable prognosis.9 Major limitations of retrospective studies are uneven diagnostic protocols and lack of accurate information on IBD treatment before the diagnosis of SC, given that immunosuppression for IBD might have an effect also on the course of the liver disease. Only one study was conducted prospectively with the aim of establishing the relative incidence of AIH and autoimmune SC (ASC) among children with liver disease and positive autoimmune serology, by performing cholangiograms at disease onset, irrespective of biochemical or histological evidence of cholestatic disease. Patients were recruited over 16 years11 and are being followed up to date. Approximately 50% of the patients enrolled had alterations of the bile ducts characteristic of SC at presentation and were diagnosed as having ASC. One quarter of them, despite abnormal cholangiograms, had no histological features suggesting bile duct involvement, and the diagnosis was only possible because of cholangiographic studies. Serologically, ASC patients were indistinguishable from AIH type 1 (AIH‐1), being anti‐nuclear and/or anti‐smooth muscle antibody positive and having elevated immunoglobulin G levels. Perinuclear anti‐neutrophil antibodies were present in 74%. In contrast to AIH, which had a clear female preponderance, ASC affected a similar proportion of boys and girls. Surveillance enteroscopy to investigate possible IBD was performed in all cases, independently of symptoms, showing IBD in 45% of ASC and 20% of AIH‐1. At presentation, immunological and biochemical indices did not help in discriminating between AIH and ASC, although the alkaline phosphatase/AST ratio was significantly higher in ASC. Biochemical response to prednisolone ± azathioprine was similarly satisfactory in AIH‐1 and ASC, but bile duct damage progressed over the years in half of the ASC cases.11 It is noteworthy that neither the original nor the simplified International Autoimmune Hepatitis Group scoring systems, devised for the diagnosis of AIH,12 discriminate between AIH and ASC, because they do not include cholangiographic studies at disease onset, ASC being therefore frequently diagnosed as AIH‐1. As shown by the prospective study, often cited negatively to support a worse prognosis for ASC compared to AIH, immunosuppressive treatment is effective in controlling both parenchymal and biliary disease in 50% of ASC cases, suggesting that the real prognosis of ASC compared to PSC cannot be adequately established in retrospective cohorts with variable diagnostic approaches and treatment protocols. Thus, in the series by Deneau et al.,1 it would be interesting to know to which immunosuppressive drugs the PSC+IBD patients, who have a lower proportion of AIH overlap compared to PSC with no IBD, had been exposed before the hepatic presentation, given that immunosuppression might have modified their disease phenotype. It would be also interesting to search for possible exposure to vancomycin treatment, recently reported to have a beneficial effect in patients with PSC and IBD.14 In conclusion, in the largest cohort of patients investigated retrospectively to date, Deneau et al.1 confirm that juvenile SC is the result of different pathologies, with a high proportion of patients having associated IBD and/or autoimmune features. Multicenter prospective studies are needed for defining SC phenotype and diagnostic criteria and for exploring pathogenic mechanisms with the aim of devising more effective treatment for this unrelenting condition.