Primary sclerosing cholangitis (PSC) is an idiopathic, chronic hepatobiliary disorder characterized by inflammation with progressive obliterative fibrosis and focal dilatation of the intrahepatic and/or extrahepatic bile ducts which leads to biliary cirrhosis and end-stage liver disease. The clinical features of PSC in children and adolescents are summarized in Table 2. PSC is more common in Caucasian male patients and has a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis. In children, secondary causes of sclerosing cholangitis include Langerhans cell histiocytosis, immunodeficiencies, and cystic fibrosis. The incidence of PSC in children is 0.23 cases per 100,000 person-years compared with 1.11/100,000 in adults. The mean age at pediatric presentation ranges from 7.1 to 15.3 years. Presenting symptoms in children are similar to ones in adults and can include right upper quadrant discomfort, diarrhea, fatigue, jaundice, pruritus, weight loss, hepatomegaly, splenomegaly, and complications related to portal hypertension. Failure to thrive and delayed puberty are features unique to children. Episodes of cholangitis are rare at presentation. Up to 20% of patients may be asymptomatic and are diagnosed on routine screening that reveals abnormal liver enzymes.[3, 4]
Overlap autoimmune hepatitis and PSC is more common in children (up to 25%) than adults (1.5%-17%).[3, 5] Elevated immunoglobulin G4 in patients with PSC is associated with autoimmune pancreatitis and responds to corticosteroid therapy. A subset of patients with PSC will have positive autoimmune markers (elevated immunoglobulin G, positive anti-nuclear Ab and anti-smooth muscle Ab) but do not have any histological evidence of autoimmune hepatitis. Small duct PSC is defined as histologic evidence of PSC without cholangiographic abnormalities and has a slower progression rate.
The diagnosis of PSC is based on a combination of biochemical, histologic, and radiologic findings. Most children have biochemical evidence of biliary disease manifested in elevated gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP). GGT may be more sensitive in children, because growing children can have a wide spectrum of ALP originating from the bones. Magnetic resonance cholangiopancreatography is currently the most commonly used modality in the diagnosis of PSC, with 89% sensitivity in children (See Figure 1). Endoscopic retrograde cholangiopancreatography or ERCP, may be more challenging in small children than in adults or adolescents, yet yields similar results in all three groups, and enables therapeutic interventions such as biliary dilatation and stent placement (see Figure 2). In the presence of cholangiographic changes of PSC, a liver biopsy is not required for the diagnosis of PSC. A liver biopsy is warranted to rule out autoimmune overlap (high aminotransferases and positive autoimmune serologic markers) and small duct PSC (cholestasis in the setting of normal cholangiography). The histologic findings are shown in Figure 3. New modalities in the diagnosis of PSC include endoscopic ultrasound, computed tomography cholangiography, and a Spyglass direct visualization system through perioral cholangioscopy.
Most therapies are supportive and are directed at managing complications (portal hypertension, dominant stricture, pruritus, nutritional deficiencies, and cholangitis) rather than the underlying cause of PSC. Normalization of ALP has been associated with improved prognosis. Liver transplantation (LT) remains the only life-extending alternative for patients with PSC. Table 1 presents an overview of the different management approaches for PSC.
Table 1. Approaches to management of PSC in children and adolescents
Ursodeoxycholic acid (controversial, harmful in high doses in adults)
Oral (vancomycin, metronidazole)
Intravenous for acute ascending cholangitis
Oral prophylactic antibiotics for recurrent cholangitis
Fat-soluble vitamins (A, D, E, K)
Docosahexaenoic acid (pilot data)
Silymarin (nonrandomized study)
Immunosuppression for overlap autoimmune hepatitis (corticosteroids, MRL, azathioprine)
Ursodeoxycholic acid (UDCA) has demonstrated biochemical and histological improvements in some studies and may improve pruritus and reduce cholangiocarcinoma incidence. A pediatric study revealed improvements in serum bilirubin and liver enzymes with UDCA, but has not proven to prolong survival. Another pediatric study has shown rapid normalization of liver enzymes in children treated with UDCA. Recently, a double-blinded, controlled multicenter trial of high-dose USCA (30mg/kg.day) versus placebo in adults with PSC found significantly higher rates of death, LT, and other serious adverse events in the drug-treated group, despite biochemical improvement. At present, caution should be exercised in using UDCA at doses greater than 20 mg/kg/day, and full disclosure of adult experiences is recommended. UDCA may still be beneficial at certain doses and in a subset of PSC patients who tolerate it well and have normalization of ALP. Currently, a multicenter study of UDCA withdrawal is being conducted in children with PSC (ClinicalTrials.gov identifier: NCT01088607) to assess safety and efficacy in childhood.
In children with autoimmune overlap, corticosteroids are used, followed by other immunosuppressives, such as azathioprine, for maintenance. These children have a better prognosis than children with classic PSC. However, these agents may not control PSC in the long term.
Oral vancomycin has been shown to improve liver enzymes, erythrocyte sedimentation rate, and clinical symptoms in 14 children with noncirrhotic PSC and IBD and increase T regulatory cell levels in blood. There are ongoing clinical trials assessing the role of vancomycin in PSC (ClinicalTrials.gov identifiers: NCT01322386, NCT01085760). Other oral antibiotics were less effective and include minocycline, azithromycin, and metronidazole. Acute cholangitis warrants immediate antibiotic therapy, usually with third-generation cephalosporin with or without aminogylycosides in patients who appear to be sick. Recurrent cholangitis may respond to prophylactic antimicrobial therapy with cotrimoxazole or neomycin.
Docosahexaenoic acid has shown a significant decline in ALP in patients in a pilot study, and silymarin (milk of thistle) has shown >50% improvement in liver tests among 34% of adults with PSC. Other drugs, such as steroids, colchicine, methotrexate, etanercept, infliximab, pentoxifylline, tacrolimus, cyclosporine, azathioprine, mycophenolate mofetil, nicotine, and probiotics, were not found to be effective.[6, 9] Potential future therapies include non-UDCA bile acids (nor UDCA), other oral antibiotics, antiproliferative agents (sirolimus), biological therapy (vedolizumab), disruptors of the renin-angiotensin system, and nuclear receptor agonists.
Pruritus in PSC can be severe and may respond to UDCA, antihistamines, and resin-binding agents (i.e., cholestyramine) as first-line therapies. Colestipol and colesevelam are reported to be better tolerated. Rifampicin, phenobarbital, and opioid antagonists may be considered as second-line therapies. Future therapies for pruritus include selective serotonin reuptake inhibitors and leukotriene agonists.
Patients with advanced cholestasis need examination of fat-soluble vitamins (A, D, E, and K) and may require supplementation. Parenteral vitamin IM/SC K is recommended in PSC patients with jaundice and a prolonged INR. Metabolic bone disease was found in up to 10% of adults with PSC and does not correlate with the severity of liver disease. In children with cholestasis, periodic measurements of serum calcium, magnesium, phosphorus, 25-hydroxyvitamin D, and parathyroid hormone levels are warranted. Calcium and vitamin D supplementation should be instituted for documented deficiencies. Bisphosphonate therapy in children remains controversial.
Dominant strictures are less common in children than in adults. Endoscopic nasobiliary lavage, balloon dilatation, stent placement, sphincterotomy, or percutaneous transhepatic cholangiography with multiple sessions may be required. Biliary surgery has little influence on outcomes and is associated with increased morbidity and mortality; furthermore, it may adversely affect the outcome of liver transplantation.
The most recent American Association for the Study of Liver Diseases guidelines (2010) do not recommend screening for detection of cholangiocarcinoma in children due to the infrequency of this disease in this patient population.[1, 13] Patients with PSC have a high prevalence of IBD, and some may not manifest symptoms of colitis. Therefore, screening colonoscopy for children with new onset PSC is advised, and surveillance for adenocarcinoma should not be influenced by PSC diagnosis due to the rarity of this disease in children. Colonoscopy and an magnetic resonance cholangiopancreatography should be considered during evaluation for liver transplantation. Portal hypertension should be treated similarly to other cholestatic processes with considering screening for varices by endoscopy and prophylaxis.
LT is the only therapy that can reverse or correct end-stage liver disease due to PSC. In two series, LT was performed in 19%-21% of children with PSC at a mean of 6.6–7 years after the diagnosis of PSC.[3, 4] PSC was the indication for LT in 2.6% of children in the Studies of the Pediatric Liver Transplantation registry. Children transplanted for PSC were more likely to be male, Caucasian, and older with lower Pediatric End-Stage Liver Disease (PELD) scores; have a longer waiting time; and have more gastrointestinal bleeding compared with children listed for other etiologies. The PELD/Model for End-Stage Liver Disease score does not reflect intractable pruritus and recurrent bacterial cholangitis, and appeals or living donor LT have to be considered. Transplantation for PSC generally involves resection of the extrahepatic biliary tree and use of a Roux-en-Y loop. The 1-year patient and graft survival in children are superior in PSC compared with non-PSC (patient 96% versus 91% and graft 93% versus 86%). However, the 5-year outcome was not significantly different (patient 86.6% versus 86.5 and graft 76% versus 79%). Recurrence after LT was reported in 9.8% of children. Colitis may present after LT, with a cumulative rate of 6% at 1 year and 20% at 5 years after orthotopic liver transplantation. The effect of LT on IBD is controversial; most studies report reduced ulcerative colitis activity and need for colectomy, but flares that necessitate colectomy may occur. Special attention must be paid to adherence and preparation for transition to adult care.
PSC is a rare progressive cholangiopathy that presents more commonly in Caucasian males in association with colitis, mostly ulcerative colitis (see Table 1 for an overview). Diagnosis is based on a combination of biochemical (GGT is more sensitive than ALP in children), radiologic, and histologic (liver biopsy should be pursued when autoimmune overlap or small duct PSC is suspected) findings. Cholangiocarcinoma and dominant strictures are unusual in children. Therapy with UDCA may result in biochemical improvement; however, the effect on long-term outcome in children is unclear. Autoimmune overlap is more common in children, necessitating immunosuppression. Approximately 20% of PSC patients are likely to require liver transplantation during childhood. Studies directed toward exploring the etiology and treatment of PSC are essential so that appropriate therapies can be tailored and the prognosis of PSC can be improved.
Table 2. Overview of PSC in Children
Median age at presentation: 11 years
PSC is less common in children than in adults
May present as failure to thrive or delayed puberty
Since bone ALP is elevated by growth, GGT is a more reliable marker