Year: 2017
Type: article
Abstract: Potential conflict of interest: Nothing to report. Primary sclerosing cholangitis (PSC) is a rare disorder of the hepatobiliary system characterized by a chronic diffuse inflammation and obliterative fibrosis of the intrahepatic and/or extrahepatic bile ducts that subsequently progresses to liver cirrhosis and end‐stage liver disease in the majority of patients. Unique aspects of pediatric PSC compared with adult PSC includes the use of gamma‐glutamyl transpeptidase (GGT) instead of alkaline phosphatase (ALP) as a biomarker of bile duct injury, higher levels of serum GGT, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at diagnosis, higher rates of autoimmune sclerosing cholangitis and small‐duct PSC, and the rarer occurrence of cholangiocarcinoma.1 Immunoglobulin G4‐related syndromes are rare in children with PSC, and there is only one case report of such an association.2 In the United States, the estimated incidence and prevalence of pediatric PSC is 0.2 and 1.5 cases per 100,000 children, respectively,3 compared with an incidence and prevalence of adult PSC at 0.4 and 4 cases per 100,000.4 The largest studied cohort of pediatric patients with PSC includes 781 children from throughout the world, revealing a median age of 12 years at diagnosis, 61% male predominance, 76% with inflammatory bowel disease (IBD), and 33% with autoimmune sclerosing cholangitis (autoimmune hepatitis [AIH]‐PSC overlap syndrome).5 AIH‐PSC overlap syndrome is defined based on elevated liver tests and imaging and/or biopsy results consistent with PSC along with positive autoantibodies and gold standard histopathology of AIH (interface hepatitis, plasma cell infiltrates, piecemeal necrosis). The majority of pediatric PSC is found in Caucasians.3 Small‐duct PSC is defined as biochemical cholestasis and liver histology consistent with PSC (i.e., “onion skin” periductal fibrosis) in the absence of bile duct abnormalities on standard biliary imaging (Fig. 1). In comparison, large‐duct PSC will have evidence of bile duct abnormalities on imaging. The occurrence of small‐duct PSC in children ranges from 13% to 42% of all pediatric PSC cases, a rate that is much higher than that found in adults.1 The reason as to why children with PSC have higher rates of autoimmune sclerosing cholangitis and small‐duct PSC is not known.Figure 1: Representative histology of small‐duct PSC. Shown is the classic “onion skin” fibrosis surrounding a small intrahepatic bile duct branch in PSC.Many cases of pediatric PSC have nonspecific symptoms at presentation, including fatigue, abdominal pain, and diarrhea.6 Asymptomatic patients are often diagnosed after routine screening of liver biochemistries in the setting of preexisting IBD. Children with PSC have significantly higher levels of serum GGTP, ALT, and AST compared with their adult counterparts.7 The use of serum ALP as a biomarker of biliary disease in pediatric PSC is not reliable, and GGT is considered to be a more specific marker of bile duct injury in children. The range of normal ALP levels substantially increases during times of rapid bone growth in children, making any single elevated ALP level difficult to interpret in children. In four large retrospective reviews of pediatric PSC, only 53% to 81% of patients had an elevated ALP at diagnosis compared with 94% to 100% of patients with elevated GGT.1 The most common symptoms of pediatric PSC are fatigue, abdominal pain, anorexia, and pruritus. Other signs include fever, jaundice, weight loss, delayed growth, and fat‐soluble vitamin deficiencies. Approximately 20% of pediatric patients with PSC have pruritus at presentation, of whom approximately 4% have extremely debilitating pruritus.1 A health‐related quality‐of‐life assessment on children with autoimmune liver diseases revealed that symptoms of abdominal pain, fatigue, and psychological distress were associated with impaired physical activity and school functioning.8 Children with symptoms suggestive of PSC should be assessed for secondary causes of sclerosing cholangitis that are more commonly seen in childhood (Table 1).9 Table 1 - Causes of Secondary Sclerosing Cholangitis in Children7 Mechanical Choledocholithiasis • Idiopathic • Sickle cell anemia • Parenteral nutrition associated Infection Recurrent bacterial cholangitis E. coli O157:H7 enterocolitis Cryptosporidium CMV Trichosporon Septic shock Recurrent bacterial cholangitis (including biliary atresia post‐Kasai portoenterostomy) Immunodeficiency X‐linked hyper‐IgM syndrome CD40 ligand deficiency (Cryptosporidium) Wiskott‐Aldrich syndrome Natural killer cell deficiency (Trichosporon) Agammaglobulinemia (Cryptosporidium) Combined variable immunodeficiency (Cryptosporidium) AIDS‐associated cholangiopathy (CMV, Cryptosporidium) Neoplastic Langerhans cell histiocytosis Hodgkin's lymphoma Ductal cancer, gallbladder cancer Reticulum cell sarcoma Congenital Cystic fibrosis Congenital hepatic fibrosis Ductal plate abnormalities Caroli disease Progressive familial intrahepatic cholestasis type 3 Injury Postsurgical stenosis Trauma Caustic injury Abbreviation: CMV, cytomegalovirus. The natural progression of pediatric PSC was assessed in the worldwide study noted earlier and included a rate of portal hypertensive complications (ascites, encephalopathy, varices) of 38% after 10 years of disease.5 Survival with the native liver at 10 years was ∼70%; however, once complications of portal hypertension arose, the survival with the native liver 5 years later was only 40%. The management of pediatric PSC is similar to that of adults. Acute worsening of jaundice, pruritus, or acute cholangitis may be signs of a dominant stricture and should be assessed with magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic retrograde cholangiopancreatography (ERCP). Acute cholangitis with strictures can be managed with antibiotics, and ERCP may be indicated if medical management fails. Medical treatment options for the pruritus include ursodiol, rifampin, or naltrexone, and medication‐refractory severe pruritus is an indication for liver transplant. Close monitoring of growth and serum fat‐soluble vitamin levels are necessary for pediatric PSC. Cholangiocarcinoma is rare (∼1%); however, it is reasonable to screen with CA19‐9 levels annually in the older children. Currently, no treatment is known to stop the progression of disease. There is a small, yet intriguing, body of literature pertaining to the use of oral vancomycin for the treatment of pediatric PSC. Cox et al.10 showed that vancomycin therapy in 14 pediatric patients with PSC was associated with significant improvement in GGT, ALT, erythrocyte sedimentation rate (ESR), and liver histology, with resolution of inflammation and fibrosis. When vancomycin was stopped, the liver biochemistries worsened, suggesting that vancomycin was directly responsible for decreased biliary injury.11 A subsequent study by the same group revealed vancomycin‐induced immunoregulatory effects in pediatric PSC, with increased levels of serum transforming growth factor‐β and circulating regulatory T cells.12 This study also showed subjective improvement in liver histology and MRCP findings in response to vancomycin. Collectively, these data suggest that vancomycin may be of therapeutic benefit in pediatric PSC. However, due to the small cohort of patients and the lack of a control population, future investigations entailing a multicentered placebo‐controlled trial on the efficacy of vancomycin in pediatric PSC are warranted. Liver transplantation is a viable option for end‐stage liver disease secondary to pediatric PSC and accounts for ∼2% of all pediatric liver transplants in the United States (https://www.unos.org). Calculated 10‐year transplant‐free survival rates in pediatric PSC and autoimmune sclerosing cholangitis range from 65% to 90%.1 The largest published series characterizing pediatric patients with PSC undergoing liver transplantation comes from the Studies of Pediatric Liver Transplantation registry, which characterized 79 pediatric patients with PSC who underwent liver transplant.13 At the time of transplant, 46% of patients had IBD and an additional 9.8% experienced development of IBD posttransplant. The pediatric PSC cohort had similar patient and graft survival rates compared with patients transplanted for indications other than PSC. Posttransplant recurrent PSC occurred in 9.8% of patients at a mean of 18 months posttransplant. In summary, pediatric PSC has many unique characteristics compared with adults, including more pronounced intrahepatic pathology, manifested as a higher rate of autoimmune sclerosing cholangitis/overlap syndrome and small‐duct PSC disease. However, pediatric PSC is similar to adult PSC in that the disease does progress in a steadfast fashion, resulting in significant morbidity and the need for liver transplantation. A greater understanding of the pathogenesis of disease will lead to better therapies aimed at halting progression of PSC.
Source: Clinical Liver Disease
DOI: 10.1002/cld.672
Authors: Jillian M. Cotter, Cara L. Mack
Institutions: Children's Hospital Colorado, University of Colorado Anschutz
Language: English
Topic: Liver Diseases and Immunity
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2774728453