Background
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology characterized by progressive inflammation of the intrahepatic and/or extrahepatic bile ducts that is increasingly recognized in children. The diagnosis is based on a combination of clinical features and cholestatic biochemical profile, along with typical cholangiographic abnormalities, and confirmed by liver histologic findings. In the absence of underlying bile duct abnormalities, a generalized beading and stenosis of the intrahepatic and extrahepatic biliary tree characterize primary sclerosing cholangitis. [1, 2, 3, 4, 5]
Primary sclerosing cholangitis is usually progressive, leading to cirrhosis, portal hypertension, and liver failure. Effective medical treatment modalities for childhood primary sclerosing cholangitis are undetermined. Liver transplantation remains the only effective therapeutic option for patients with end-stage liver disease from primary sclerosing cholangitis. [1]
For more information, see Primary Sclerosing Cholangitis and Primary Sclerosing Cholangitis Imaging.
Pathophysiology
The mechanisms responsible for the development of primary sclerosing cholangitis are unknown. It is often seen in association with inflammatory bowel disease (IBD) but also occurs in association with other disorders or in isolation. The relationship between primary sclerosing cholangitis and IBD offers several clues. The biliary injury may be initiated by an immune-mediated destruction of the hepatobiliary tract that is perhaps caused by transient infection or the absorption of bacterial by-products in genetically predisposed individuals with colonic disease. [6, 7]
Etiology
Primary sclerosing cholangitis is a progressive disorder of unknown etiology. Bacteria, toxins, viral infections, and immunologic and genetic factors have been proposed as etiologic agents. [8]
The high degree of association of primary sclerosing cholangitis with inflammatory bowel disorder (IBD) suggests a common pathogenetic mechanism; however, no causal relationship has been established. An abnormal colonic mucosal barrier may lead to portal bacteremia or abnormal absorption of toxic metabolites or bile acids. [6, 8]
Reovirus and cytomegalovirus (CMV) are possible etiologic agents; primary sclerosing cholangitis is analogous to a reovirus-induced cholestasis in mice.
Immunologically mediated damage to the biliary tree remains the most likely etiology of primary sclerosing cholangitis. The presence of portal tract infiltration with CD3+ T cells, serum autoantibodies, and abnormal expression of human leukocyte antigen (HLA) on biliary epithelial cells all support an immune-mediated process.
A high prevalence of the perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) is seen in primary sclerosing cholangitis and ulcerative colitis (UC). Autoimmune disorders are more frequent in patients with primary sclerosing cholangitis than in patients with IBD without liver disease; 25% of patients with primary sclerosing cholangitis have at least one autoimmune disorder outside of the liver and colon.
In children, primary sclerosing cholangitis is commonly associated with markers suggestive of an autoimmune process. Some patients have elevated levels of circulating immune complexes, immunoglobulins, and autoantibodies that are not organ specific. [8, 9] Histologic and clinical overlap (ie, overlap syndrome) with autoimmune hepatitis may be observed.
The close association between primary sclerosing cholangitis and various human leukocyte antigen (HLA) haplotypes is well established. An increased frequency of HLA-B8 and HLA-DR3 is observed in patients with primary sclerosing cholangitis. HLA-B8 is also associated with other autoimmune disorders. [8, 9]
In addition, other gene polymorphisms have been suggested in the immunopathogenesis of primary sclerosing cholangitis, including TNFa, CTLA-4, ICAM, and metalloproteinases. [10] One study also observed a high prevalence of cystic fibrosis transmembrane receptor (CFTR)–mediated transport dysfunction in patients with childhood primary sclerosing cholangitis, suggesting a possible role of CFTR protein in the mechanism. [11]
Epidemiology
Primary sclerosing cholangitis can occur at any age but primarily affect adults. The overall incidence of pediatric primary sclerosing cholangitis is unknown. A 2:1 male predominance is noted in primary sclerosing cholangitis but is not observed in children. Peak incidence of primary sclerosing cholangitis occurs in the third and fourth decades of life, but primary sclerosing cholangitis has also been described in infancy.
Primary sclerosing cholangitis is frequently seen in association with IBD. IBD is present in 70-80% of patients who have primary sclerosing cholangitis. Primary sclerosing cholangitis may precede the onset of, coincide with, or follow the diagnosis of IBD such as following proctocolectomy. Conversely, 2.5-7.5% of patients with IBD develop primary sclerosing cholangitis. [12, 13] . In large pediatric series of patients with primary sclerosing cholangitis and IBD, 50% had UC and 11% had Crohn disease, and the remainder with indeterminate colitis. [13, 14, 15, 16, 17, 18]
Prognosis
Primary sclerosing cholangitis is characterized by a slow insidious progression to cirrhosis. In adult patients, the median period of survival from the time of diagnosis is 9-11 years with up to 40% of patients asymptomatic at the time of initial presentation. The median period of survival is shorter for patients who are symptomatic at the time of diagnosis. [19]
The identification of abnormal liver function tests (LFTs) in patients with inflammatory bowel disease (IBD) has led to earlier diagnosis of primary sclerosing cholangitis, with apparent survival times that are likely longer.
Despite progress in early recognition, optimal treatment of patients with primary sclerosing cholangitis remains a challenge, requiring a multidisciplinary approach among hepatologists, endoscopists, surgeons, and interventional radiologists.
The coexistence of ulcerative colitis is not predictive of an increased risk of death in primary sclerosing cholangitis. Ulcerative colitis may be associated with an increased posttransplantation survival.
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Fibro-obliterative cholangiopathy. Image courtesy of Dr. Kay Washington.
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Endoscopic retrograde cholangiopancreatography performed in a patient with abnormal liver function test results shows multiple intrahepatic bile duct strictures and beading.
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Double-contrast barium enema (same patient as in the previous image) shows filiform polyps and an ahaustral colon resulting from ulcerative colitis.
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Percutaneous transhepatic cholangiogram shows dilatation, stricturing, and beading of the intrahepatic bile ducts. Note the surgical clips from a previous cholecystectomy.
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T-tube cholangiogram shows irregularity of the common bile duct, stricturing, beading, and dilatation of the intrahepatic bile ducts. Note a calculus in the termination of the left hepatic duct (arrow).
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Magnetic resonance cholangiopancreatography shows a normal-sized common bile duct, but strictures of both the left and right ducts are noted as well as a dilated proximal left hepatic duct.
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Technetium-99m iminodiacetic acid scan shows retention of the radionuclide proximal to strictures in the distribution of the left hepatic duct. Note the lack of filling of the gallbladder because of a previous cholecystectomy. Isotope has entered the small bowel.
