Our patient had normal ceruloplasmin levels serology and viral hepatitis was negative. Autoimmune evaluation did not reveal elevated autoantibodies. Her complete blood count did not show any evidence of underlying malignancy. Liver biopsy and MRCP findings led to the diagnosis of primary sclerosing cholangitis (PSC).
PSC is a chronic cholestatic disorder of unknown etiology, characterized by inflammation and progressive obliterative fibrosis of the intra- and/or extrahepatic bile ducts. It progresses slowly and often asymptomatically to biliary cirrhosis, liver failure, and sometimes cholangiocarcinoma.
The overall incidence of PSC is unknown in children, with the highest number reported from northern Europe. A recent study conducted at University of Calgary showed an incidence rate of 0.23 per 100,000 person-years in children.1 Most cases of PSC show strong association with male gender (62%), white ancestry, and inflammatory bowel disease (IBD). Lifelong risk of PSC increases in first-degree relatives of children and adults with PSC to 0.5%. The genetics of PSC are complex; different human leukocyte antigen (HLA) complexes have been associated with PSC, including HLA-B8 and HLA-DR3.
Pathophysiology of PSC is not well defined; the best described current theory about pathogenesis of PSC is an immune-related destruction of the biliary tree triggered by an infectious agent in a genetically susceptible host, with or without bowel involvement.
The usual age of presentation in children is 7 to 15 years. Most patients have no symptoms and are found incidentally, as was the case in our patient. The classic presentation of jaundice, fatigue, pruritus, and anorexia with concurrent IBD is distinctly uncommon in children. Presenting symptoms and signs may include abdominal pain, diarrhea, fatigue, jaundice, pruritus, weight loss, fever, hepatomegaly, splenomegaly, and ascites. Occasionally, children may present with complications related to portal hypertension, in the form of isolated splenomegaly, variceal bleeding, or an obstructive cholangiopathy.
Sclerosing cholangitis in children can present in the following ways:2
PSC associated with IBD: up to 80% of children with PSC have or will have IBD (most have ulcerative colitis, some may have indeterminate colitis), whereas PSC is diagnosed in up to 4% of children with IBD.
Autoimmune sclerosing cholangitis: sclerosing chonlangitis with strong autoimmune features is referred to as ASC or autoimmune overlap syndrome. Patients present with florid auto-immune features such as elevated ANAs, elevated smooth muscle antibodies (SMAs), and elevated IgG, along with histologic features of interface hepatitis and lymphoplasmacytic infiltration.
Small duct sclerosing cholangitis: this affects the small bile ducts and is often difficult to diagnose by imaging techniques. Diagnosis is made in the setting of biochemical and histologic features.
Neonatal sclerosing cholangitis: approximately 10% of cases present with conjugated hyperbilirubinemia with pale stools in early infancy, then later develop recurrent jaundice and/or hepatosplenomegaly with biochemical, imaging, and histologic findings of PSC.
The diagnosis of PSC is based on a combination of biochemical evidence of biliary disease, with radiologic findings and characteristic histologic changes typical for PSC.3 Elevated serum GGT (which reflects intrahepatic bile duct involvement) with or without elevated alkaline phosphatase (ALP), is a more sensitive marker than alkaline phosphatase level in growing children and reflects intrahepatic bile duct involvement. Children with PSC may also present with elevated serum IgG levels, positive ANAs, and positive anti-SMAs (suggestive of autoimmune sclerosing cholangitis), whereas those with IBD may have positive ANCAs. Complete blood count may reflect hypersplenism, leukopenia, and thrombocytopenia. Most of the patients have intact hepatic function and normal bilirubin levels; however, AST/ALT levels may be raised, as in our patient.
Imaging of the biliary tree is the most important tool in the diagnosis of PSC. Endoscopic retrograde cholangiopancreatography (ERCP) is sensitive but the associated risk of pancreatitis, cholangitis, and hemorrhage is high. MRCP is the most commonly used modality in diagnosis of PSC, as it is noninvasive and does not expose the patient to radiation. MRCP is reported to be 84% sensitive in diagnosing PSC.4 Findings include narrowing and strictures of the CBD, biliary dilatations, and beading of the intrahepatic or extrahepatic biliary tree. Our patient had a kink in the CBD along with beaded appearance of the hepatic duct.
Characteristic histologic changes on liver biopsy include bile duct injury and “onion-skin” type of periductal fibrosis around the medium- and large-sized bile ducts; most children have bridging necrosis at the time of diagnosis. Liver biopsy of our patient (Figure 3) showed prominent proliferation of the bile duct in the portal tract with scattered neutrophils and plasma cells. Bridging fibrosis was noted between portal tracts. Periductal onion-skin fibrosis was seen around small- and medium-sized bile ducts.
Treatment is mainly supportive and directed at managing complications (dominant stricture, pruritus, nutritional deficiencies, and cholangitis) rather than the underlying PSC. Administration of ursodeoxycholic acid (UDCA), the hydrophilic dihydroxy bile acid, results in improvements in serum bilirubin and transaminase levels but has not been proven to prolong overall survival in children. It produces improvement in the symptoms of pruritus. Current recommendations are to start UDCA therapy at a dose of 20 mg/kg per day. In patients with autoimmune overlap, corticosteroids are used along with other immunosuppressant treatment for long-term management. UDCA, antihistamines, rifampin, and cholestyramine have been used to control symptoms of pruritus. Surgical treatment is mainly to manage dominant strictures and to relieve biliary obstruction by utilizing endoscopic techniques such as balloon dilatation and stent placement.
Orthotopic liver transplantation is the only therapy that can reverse or correct end-stage liver disease caused by PSC. The most common indications for transplantation are recurrent cholangitis, cirrhosis with impaired liver function, intractable ascites, variceal bleeding, hepatic encephalopathy, and growth failure. Our patient was started on UDCA, and following that her liver enzymes levels returned to the baseline. She underwent colonoscopy to rule out IBD and biopsy results were normal. She was referred to a pediatric hepatic transplant center for further evaluation regarding liver transplant. PSC is a progressive liver disease that often presents in association with IBD colitis. Serum GGT should be tested in children with chronic hepatitis or whenever PSC is suspected. MRCP is an excellent screening imaging modality for PSC, being noninvasive and without risk of radiation. PSC cannot be ruled out without a liver biopsy. Biochemical improvement is noted with UDCA, but the effect on long-term outcome in children is unclear. Given the natural history of evolution to biliary cirrhosis and cholangiocarcinoma, orthotopic liver transplantation is ultimately required in the majority of patients diagnosed with PSC.