Pediatric Primary Sclerosing Cholangitis 

Updated: Apr 26, 2017
Author: Henry C Lin, MD; Chief Editor: Carmen Cuffari, MD 

Overview

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.

 

Presentation

History and Physical Examination

The clinical presentation of primary sclerosing cholangitis (PSC) in children varies widely and frequently lacks the obvious features of cholestasis. Patients may be asymptomatic with elevated liver function test findings or hepatomegaly, prompting further workup for primary sclerosing cholangitis. Approximately 55% of patients have hepatomegaly and 30% have splenomegaly at presentation. Patients may also present with fatigue, pruritus, fever of unknown origin, intermittent jaundice, or weight loss. Some patients present with the stigmata of chronic liver disease and cirrhosis. The onset and progression tend to be insidious.

Modes of presentation include the following:

  • Asymptomatic patients present with incidental findings of hepatomegaly on examination or abnormal liver function test results

  • Symptomatic patients may present with nonspecific complaints, including fatigue, pruritus, abdominal pain, fever, weight loss, and intermittent jaundice

  • Patients with cholestasis present with complications of cholestasis, including pruritus, cholangitis, and fat malabsorption

  • Patients with cirrhosis present with complications of portal hypertension, including ascites, variceal bleeding, and splenomegaly

Staging

The hepatic progression of primary sclerosing cholangitis is divided into 4 histologic stages, as follows:[20]

  1. Portal hepatitis, degeneration of bile ducts with inflammatory cells infiltrate

  2. Extension of disease to periportal areas, with prominent bile ductopenia

  3. Septal fibrosis and necrosis

  4. Frank cirrhosis

These stages are used to document histologic progression and may help evaluate treatment effect in clinical trials. At present, these stages have limited value in predicting the natural history of the disease, most likely because of the high degree of sampling variability in the hepatic pathology of primary sclerosing cholangitis.

Researchers at the Mayo Clinic have developed a multivariate statistical survival model from long-term survival data (Mayo risk score). The Mayo natural history model of primary sclerosing cholangitis computes the score on the basis of the patient's age, history of variceal bleeding, and serum levels of albumin, bilirubin, and aspartate aminotransferase. This has been a major step in identifying patients at low, moderate, and high risk of dying while early in the course of primary sclerosing cholangitis.[21, 22, 23]

In an age-adjusted multivariate analysis, each unit increase in the Mayo risk score was associated with a 2.5-fold increased risk of death, whereas the Child-Pugh classification for advanced cirrhosis had no significant impact on survival rate. The histologic stage of disease has consistently been useful in predicting survival rate, most likely because of a large sampling variability with liver biopsies.[21, 22, 23, 24]

Complications

Cholangiocarcinoma (CCA) develops in 10-15% of adult patients with primary sclerosing cholangitis (PSC). CCA has been reported in children with primary sclerosing cholangitis.[25, 26, 27] Early detection of CCA is limited by a lack of reliable serologic, radiologic, and endoscopic findings. Serum CA 19-9 appears useful (75% sensitivity, 80% specificity) in discriminating which patients with primary sclerosing cholangitis have CCA.

The risk of colorectal cancer or dysplasia is increased in patients with ulcerative colitis (UC) and primary sclerosing cholangitis. Chronically active disease may be a risk factor, whereas folate may have a protective effect. Colorectal cancers associated with primary sclerosing cholangitis are more likely to be proximal, diagnosed at a more advanced stage, and fatal. Colectomy in patients with UC and primary sclerosing cholangitis does not alter the natural history of primary sclerosing cholangitis.

Patients who have undergone liver transplantation are susceptible to a wide array of complications secondary to chronic immunosuppression. The incidence of acute cellular and chronic ductopenic rejection is higher in patients with primary sclerosing cholangitis than in individuals of a non–primary sclerosing cholangitis control group. Chronic ductopenic rejection adversely affects patient and graft survival. Biliary strictures, both anastomotic and nonanastomotic, can occur.

Recurrent sclerosing cholangitis occurs in 10-33% of patients with primary sclerosing cholangitis who have undergone liver transplantation.[13, 18, 28, 29, 30, 31, 32] Data from the Mayo Clinic's review of 150 consecutive patients with primary sclerosing cholangitis who received 174 liver allografts suggests that postoperative biliary strictures or recurrence of primary sclerosing cholangitis does not impact patient survival.

 

DDx

Diagnostic Considerations

Chronic hepatitis needs to be considered, including infectious hepatitis, idiopathic autoimmune hepatitis (can coexist with primary sclerosing cholangitis [PSC], termed overlap syndrome), and autoimmune hepatitis .

Causes of sclerosis secondary to bile duct abnormalities include choledocholithiasis ,cholangiocarcinoma ,biliary trauma ,and congenital anomalies of the biliary tract.

Differential Diagnoses

 

Workup

Approach Considerations

In patients with primary sclerosing cholangitis (PSC), the most valuable lab studies are liver function tests, including serum alkaline phosphatase, serum aminotransferase, and hypergammaglobulinemia. Endoscopic retrograde cholangiopancreatography (ERCP) is the most important imaging study. Magnetic resonance cholangiography and ultrasonography are also utilized. The most characteristic histologic findings of primary sclerosing cholangitis are periductal fibrosis with inflammation, bile duct proliferation, and ductopenia.

Liver biopsy findings are nonspecific and are infrequently diagnostic. However, liver histology remains important to exclude other causes of chronic cholestasis and to stage the disease.

Current challenges in the diagnosis and treatment of primary sclerosing cholangitis in pediatrics are well recognized.[33]

Laboratory Studies

No laboratory studies are specific for primary sclerosing cholangitis (PSC), but the most common abnormality is an elevated alkaline phosphatase or gamma-glutamyl transferase (GGT) level. Abnormal GGT levels have been noted in as many as 96% of children with PSC at the time of diagnosis. Serum transaminase levels may be normal or elevated to several times normal. The serum bilirubin level is elevated in advanced stages of primary sclerosing cholangitis.[13, 15, 17]

Liver synthetic function tests (eg, serum albumin, prothrombin time [PT]) become abnormal with advanced disease activity. Serum cholylglycine is often markedly elevated, out of proportion to the elevation of serum bilirubin.

Immunoglobulin G (IgG) and immunoglobulin M (IgM) levels (see Immunoglobulins) are elevated in 48% and 80% of cases of PSC, respectively. The serum globulin fraction may also be elevated in some patients with primary sclerosing cholangitis. Autoimmune markers noted at diagnosis include antinuclear antibody (ANA), found in 45%; anti–smooth muscle antibody (ASMA), found in 36%; and perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs), found in 60-82% of patients with primary sclerosing cholangitis. However, these all lack diagnostic specificity.

Assessment of the target antigens for ANCA (eg, catalase, alpha-enolase, lactoferrin) does not significantly contribute to their clinical importance. The presence of ANCA is associated with a more severe course of autoimmune liver disease. The anti– Saccharomyces cerevisiae antibody is also found in some patients with PSC, independent of inflammatory bowel disease status.

A serum carbohydrate antigen 19-9 (CA 19-9) level greater than 100 U/mL has 75% sensitivity and 80% specificity in identifying patients with primary sclerosing cholangitis who have cholangiocarcinoma.

Magnetic Resonance Cholangiography

Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive tool that images abnormalities of the pancreaticobiliary tress. Peripheral wedge-shaped areas of high T2-signal intensity and dilatation of bile ducts are characteristic MRCP in primary sclerosing cholangitis (PSC). Pathologic correlation of MRCP findings suggests that these features may be related to underlying perfusion changes and bile duct inflammation.

The overall diagnostic accuracy of MRCP in patients with PSC is 90%, compared to 97% for endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC).[34] The advantages of MRCP include less risk of complications, as compared with ERCP. In addition, MRCP has the advantage of visualizing bile ducts proximal to obstructed areas, especially in small children in whom ERCP is not a feasible option. The main limitation of MRCP is that it does not allow for therapeutic interventions.[35, 36, 37, 38]

Ultrasonography

Ultrasonography may reveal intrahepatic and extrahepatic ductal dilatation; increased echogenicity and heterogeneity observed with cirrhosis; and splenomegaly and ascites observed with portal hypertension.[39] Ultrasonographic findings may be normal in as many as 50% of patients.

Endoscopic Retrograde Cholangiopancreatography

Endoscopic retrograde cholangiopancreatography (ERCP) remains the criterion standard for establishing the diagnosis of primary sclerosing cholangitis (PSC). ERCP demonstrates irregularly distributed areas of segmental bile duct fibrosis interposed by areas of saccular dilation that result in the characteristic appearance of beading.[40, 41]

As many as 40% of children with PSC lack extrahepatic duct involvement at the time of diagnosis. Serial cholangiograms have shown that in most patients with disease limited to the intrahepatic ducts, the disease progresses to involvement of the extrahepatic ducts.

Therapeutic interventions, such as dilation of strictures or placement of an endoprosthesis, can be performed during ERCP, but they carry an increased complication rate. Short-term stenting for symptomatic dominant strictures may have a role in PSC[42] , with a decrease in cholestatic complaints and improvement of the cholestatic biochemical profile (alkaline phosphatase, gamma-glutamyl transferase, conjugated bilirubin) for several years.

Liver Biopsy

Certain liver histologic findings are highly suggestive of primary sclerosing cholangitis. More often, liver biopsy findings are nonspecific and infrequently diagnostic. Nevertheless, liver histology remains important to exclude other causes of chronic cholestasis and to stage the disease.

Sampling variability is observed in needle or core liver biopsies secondary to the heterogeneous distribution of biliary lesions.

Histologic Findings

A wide range of histologic findings is observed in primary sclerosing cholangitis (PSC). Nonspecific features include a periductal concentration of mononuclear cells and ductular proliferation. Less specific liver histology can present with a picture resembling chronic active hepatitis. One series of childhood cases described consistent periportal copper-associated protein (orcein stain) positivity.

The most characteristic findings of primary sclerosing cholangitis is focal concentric edema and fibrosis around the interlobular bile ducts (“onion-skinning”). The pathognomonic fibro-obliterative cholangiopathy (see the image below) typically occurs in the early stage and over this lesion is replaced by loss of bile ducts. This ductopenia may be local, and in nonobliterated zones, bile duct proliferation may occur instead. With progression of portal fibrosis, biliary cirrhosis may develop.[43]

Fibro-obliterative cholangiopathy. Image courtesy Fibro-obliterative cholangiopathy. Image courtesy of Dr. Kay Washington.
 

Treatment

Approach Considerations

No pharmacologic therapy has been proven effective for primary sclerosing cholangitis (PSC). The goals of treatment of PSC are to slow and potentially reverse the disease process, but treatment may ultimately involve managing disease progression and the associated complications. Drug therapy is aimed at treating symptoms and managing complications. Orthotopic liver transplantation (OLT) has been proven successful in treating children with primary sclerosing cholangitis. Liver transplantation is the only therapy that can alter the eventual outcome.

Surgical drainage procedures (eg, portoenterostomy, choledochoenterostomy) are insignificant in the management of PSC. These procedures may provide palliation but do not alter the natural history of the disease because of the consistent involvement of the intrahepatic biliary tree. Surgical drainage procedures are associated with an increased risk of cholangitis postoperatively, and subsequent liver transplantation may become technically more difficult.

Dominant strictures of the extrahepatic biliary tree, most often at the bifurcation of the hepatic ducts, are major problems for patients with PSC. Transhepatic or endoscopic balloon dilatation of strictures has been shown to be useful in children with PSC. Short-term stenting of strictures has also demonstrated clinical improvement of symptomatic strictures.

Surgical, endoscopic, and interventional radiologic procedures to relieve symptomatic dominant strictures have been demonstrated to prolong survival time of the native liver in patients with PSC, but none of these interventions have altered the ultimate rate of progression of PSC to end-stage liver disease.

Bacterial cholangitis, which can occur spontaneously, is more common after endoscopic or surgical manipulation of the biliary tree. Episodes of cholangitis require prompt antibiotic therapy.

Pharmacologic Therapy

Pharmacologic treatment of patients with primary sclerosing cholangitis (PSC) should be directed at managing the following:[44]

  • Cirrhosis and portal hypertension

  • Chronic cholestasis with pruritus and malabsorption

  • Ductular complications, such as dominant strictures, cholelithiasis, and ascending bacterial cholangitis

  • Other associated diseases, such as inflammatory bowel disease (IBD) or other autoimmune diseases

Choleretic therapy with ursodeoxycholic acid (UDCA) reportedly improves symptoms and biochemical abnormalities in adult patients with PSC. Some observational and controlled trial data also suggest a reduction in colonic dysplasia rates with UDCA.[45] Children with PSC experience significant improvements in their liver biochemical indices when treated with UDCA; however, the long-term effect of UDCA on the clinical outcome of PSC has not been determined.[46, 47, 48]

The efficacy of immunosuppressive agents such as glucocorticoids, methotrexate, cyclosporine, and tacrolimus has been studied in adults but has not demonstrated long-term benefit, specifically with regards to histology.[49, 50, 51, 52, 53, 54] The potential therapeutic effect of antibiotics has also been studied in children with primary sclerosing cholangitis. Observational studies using oral vancomycin demonstrated improved symptoms and liver function tests but no consistent improvement in liver histology.[55] Likewise, adult studies with oral vancomycin or metronidazole have been shown to decrease select liver biochemistries,[56] but long-term follow-up studies are needed to assess the efficacy of antibiotic therapy.

Liver Transplantation

Orthotopic liver transplantation (OLT) has been proven successful in treating children with primary sclerosing cholangitis (PSC). Data from numerous liver transplantation centers demonstrate excellent long-term patient and graft survival for patients with end-stage primary sclerosing cholangitis.[30, 31, 32, 57, 58, 59, 60]

Actual patient survival rates after OLT for primary sclerosing cholangitis have been shown to be greater than 90% at 1 year and approximately 90% at 5 years. In one study, although children with primary sclerosing cholangitis had patient-survival rates and graft-survival rates equaling those of age-matched children who underwent transplantation for other indications, patients with coexisting IBD demonstrated poorer outcomes. Overall, posttransplant recurrence was noted in 9.8%, and compared with other graft recipients, patients with primary sclerosing cholangitis had higher mean liver enzyme levels 5 years posttransplant.[29]

Diet

As with other cholestatic disorders, provide fat-soluble vitamin supplementation (vitamins A, D, E, K) and nutritional support to ensure adequate growth. If the patient has steatorrhea, medium-chain triglycerides should be added to the diet. If pancreatic enzyme deficiency is present, oral supplementation is necessary, and calcium supplementation for bone disease may also be needed.

Consultations

Despite progress in early recognition, optimal treatment of patients with primary sclerosing cholangitis remains a challenge and requires a multidisciplinary approach between hepatologists, endoscopists, surgeons, and interventional radiologists. Consultation with a gastroenterologist is necessary, and an endocrinologist may be consulted for management of bone disease.

 

Medication

Medication Summary

No effective medical therapies are recognized for primary sclerosing cholangitis (PSC). The potential effect of anti-inflammatory and immunosuppressive agents have been studied in adults. Choleretic therapy with ursodiol (ie, ursodeoxycholic acid [UDCA]) has been reported to improve symptoms and biochemical abnormalities, but the long-term effect on clinical outcome remains undetermined. Likewise, the long-term efficacy of immunosuppressive agents and antibiotics remains to be determined.

Overall, the treatment of pediatric primary sclerosing cholangitis remains a significant clinical challenge. Shimizu et al reported successful treatment of a child with primary sclerosing cholangitis and undetermined colitis with a combination of a steroid, salazosulfapyridine, and a probiotic.[61]

Gallstone Solubilizing Agents

Class Summary

Ursodiol enhances bile salt–dependent biliary flow. It may prove to be a valuable addition to therapy in repeated and refractory cholangitis.

Ursodiol (URSO Forte, Actigall)

Also called ursodeoxycholic acid, or UDCA, choleretic therapy is used to improve bile flow, treat cholestasis, and dissolve gallbladder stones. It has been shown to promote bile flow in cholestatic conditions associated with a patent extrahepatic biliary system.