eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Primary Sclerosing Cholangitis

Lynette Gillis, MD, Assistant Professor, Director of Pediatric Hepatology and Liver Transplant, Division of Pediatric Gastroenterology, Hepatology and Nutrition and Division of Medical Genetics, Vanderbilt University

Updated: Jun 19, 2009

Introduction

Background

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology that is recognized increasingly 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 histology 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. 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.

Pathophysiology

The mechanisms responsible for the development of primary sclerosing cholangitis are unknown. The relationship with primary sclerosing cholangitis and inflammatory bowel disease (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 byproducts in genetically predisposed individuals with colonic disease.¹

Frequency

United States

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 ulcerative colitis (UC) or may develop following proctocolectomy. Conversely, 2.5-7.5% of patients with IBD develop primary sclerosing cholangitis.

Sex

A male predominance is noted in primary sclerosing cholangitis.

Age

Peak incidence of primary sclerosing cholangitis occurs in the third and fourth decades of life. Primary sclerosing cholangitis has also been described in infancy.

Clinical

History

The clinical presentation in children with primary sclerosing cholangitis (PSC) widely varies 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. 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 finding of hepatomegaly on examination or abnormal liver function test (LFT) results.
• Symptomatic patients may present with nonspecific complaints, including fatigue, pruritus, abdominal pain, fevers, 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.

Physical

• Findings on physical examination vary with the degree of disease activity at the time of initial presentation.
• Approximately 55% of patients have hepatomegaly and 30% have splenomegaly at presentation.

Causes

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.

• 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.
• Rats with experimental small-bowel bacterial overgrowth develop a hepatobiliary injury similar to primary sclerosing cholangitis. The hepatobiliary injury is mediated by activation of Kupffer cells and by release of cytokines, such as tumor necrosis factor alpha.
• 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.
  • 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. 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.
  • These lend support to the theory that immunologic and genetic mechanisms may be involved in the pathogenesis.
• Significant alcohol consumption is never advisable in patients with chronic liver disease. Alcohol consumption has been shown to be an independent risk factor for the development of cholangiocarcinoma in patients with primary sclerosing cholangitis.

Differential Diagnoses

Autoimmune Chronic Active Hepatitis
Cholestasis
Histiocytosis
Human Immunodeficiency Virus Infection

Other Problems to Be Considered

• Chronic hepatitis
  • Infectious hepatitis
  • Idiopathic autoimmune hepatitis (can coexist with primary sclerosing cholangitis [PSC], termed overlap syndrome)
  • Autoimmune Hepatitis
• Causes of sclerosis secondary to bile duct abnormalities
  • Choledocholithiasis
  • Cholangiocarcinoma
  • Biliary Trauma
  • Congenital anomalies of the biliary tract

Workup

Laboratory Studies

The following studies may be indicated in primary sclerosing cholangitis (PSC):

• Liver function tests
  • The most common abnormality is an elevated alkaline phosphatase or γ-glutamyltransferase (GGT) level.
  • 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.
  • Results from hepatic 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 are elevated in 48% and 80% of cases of primary sclerosing cholangitis, respectively. The serum globulin fraction may also be elevated in some patients with primary sclerosing cholangitis.
• Perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) have been found to be present in 60-82% of patients with primary sclerosing cholangitis but lack diagnostic specificity for primary sclerosing cholangitis; frequency in ulcerative colitis (UC) is similar. 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 primary sclerosing cholangitis, independent of inflammatory bowel disease (IBD) 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.

Imaging Studies

• Magnetic resonance (MR) cholangiography
  • Peripheral wedge-shaped areas of high T2 signal intensity and dilatation of bile ducts are characteristic MR findings in primary sclerosing cholangitis.
  • Pathologic correlation of MR cholangiography (MRC) findings suggests that these features may be related to underlying perfusion changes and bile duct inflammation.
  • The overall diagnostic accuracy of MRC in patients with primary sclerosing cholangitis is 90%, compared to 97% for endoscopic retrograde cholangiography (ERCP) or percutaneous transhepatic cholangiography (PTC).²
  • The advantages of MRC include less risk for complications as compared with ERCP. In addition, MRC has the advantage of visualizing bile ducts proximal to obstructed areas.
• Ultrasonography
  • Ultrasonography may reveal intrahepatic and extrahepatic ductal dilatation, increased echogenicity and heterogeneity observed with cirrhosis, and splenomegaly and ascites observed with portal hypertension.³
  • Ultrasonographic findings may be normal in as many as 50% of patients.

Procedures

• ERCP
  • Cholangiography remains the criterion standard for establishing the diagnosis of primary sclerosing cholangitis.
  • Cholangiography demonstrates irregularly distributed areas of segmental bile duct fibrosis interposed by areas of saccular dilation that result in the characteristic appearance of beading. As many as 40% of children with primary sclerosing cholangitis 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 primary sclerosing cholangitis, with a decrease in cholestatic complaints and improvement of the cholestatic biochemical profile (alkaline phosphatase, γ-glutamyltransferase, 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. 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 are periductal fibrosis with inflammation, bile duct proliferation, and ductopenia. This pathognomonic fibro-obliterative cholangiopathy has been occasionally observed in children with primary sclerosing cholangitis.
  
  

  

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

  
  

Staging

• The hepatic progression of primary sclerosing cholangitis is divided into 4 histologic stages. 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. 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.

Treatment

Medical Care

• Treatment of patients with primary sclerosing cholangitis (PSC) should be directed at managing the following:⁴
  • 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
• Pharmacologic therapies that have been evaluated in adult patients with primary sclerosing cholangitis include prednisone, azathioprine, budesonide, methotrexate, cyclosporine, pentoxifylline, tacrolimus, bezafibrate, and antibiotics.
  • To date, none of the available treatment modalities has been shown to affect patient survival or need for liver transplantation.
  • Choleretic therapy with ursodeoxycholic acid (UDCA) reportedly improves symptoms and biochemical abnormalities in adult patients with primary sclerosing cholangitis. Some observational and controlled trial data also suggest a reduction in colonic dysplasia rates with UDCA.⁵
  • Children with primary sclerosing cholangitis experience significant improvements in their liver biochemical indices when treated with UDCA; however, the long-term effect of UDCA on the clinical outcome of primary sclerosing cholangitis has not been determined.
• Dominant strictures of the extrahepatic biliary tree, most often at the bifurcation of the hepatic ducts, are major problems for patients with primary sclerosing cholangitis.
  • Transhepatic or endoscopic balloon dilatation of strictures has been shown to be useful in children with primary sclerosing cholangitis.
  • 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 primary sclerosing cholangitis. None of these interventions have altered the ultimate rate of progression of primary sclerosing cholangitis 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.

Surgical Care

• Surgical drainage procedures (eg, portoenterostomy, choledochoenterostomy) are insignificant in the management of primary sclerosing cholangitis.
  • 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.
• Orthotopic liver transplantation (OLT) has been proven successful in treating children with primary sclerosing cholangitis.
  • Data from numerous liver transplant centers demonstrate excellent long-term patient and graft survival for patients with end-stage primary sclerosing cholangitis.
  • Actuarial patient survival rates after OLT for primary sclerosing cholangitis at 1 and 5 years have been shown to be greater than and approximately equal to 90%, respectively.

Consultations

• Despite progress in early recognition, optimal treatment of patients with primary sclerosing cholangitis remains a challenge and requires a multidisciplinary approach among hepatologists, endoscopists, surgeons, and interventional radiologists.

Diet

• As with other cholestatic disorders, provide fat-soluble vitamin supplementation (vitamins A, D, E, K) and nutritional support to ensure adequate growth.

Medication

No effective medical therapies are recognized for primary sclerosing cholangitis (PSC). 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.

Choleretic agents

These agents enhance bile salt-dependent biliary flow. They may prove to be a valuable addition to therapy in repeated and refractory cholangitis.

Ursodiol (URSO, Actigall)

Also called UDCA. Choleretic therapy to improve bile flow, treat cholestasis, and dissolve gallbladder stones. Shown to promote bile flow in cholestatic conditions associated with a patent extrahepatic biliary system.

Dosing

Adult

250-500 mg PO bid

Pediatric

15-30 mg/kg/d PO divided bid/tid

Interactions

Aluminum-based antacids, cholestyramine, or PO contraceptives may decrease absorption

Contraindications

Documented hypersensitivity; cholesterol, radiopaque, or bile pigment gallstones; extrahepatic biliary tree obstruction

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May affect CNS (eg, fatigue, headache, anxiety, depression), dermal system (eg, pruritus, rash, hair thinning), GI system (eg, nausea, vomiting, dyspepsia, metallic taste, abdominal pain, biliary pain, diarrhea, flatulence), liver (eg, rarely increased liver enzymes), and neuromuscular system (eg, arthralgias, myalgia, back pain)

Follow-up

Complications

• Cholangiocarcinoma (CCA) develops in 10-15% of adult patients with primary sclerosing cholangitis (PSC).
  • Early detection of CCA is limited by a lack of reliable serologic, radiologic, and endoscopic findings.
  • CCA is often cholangiographically indistinguishable from a benign dominant stricture.
  • Brush cytology of dominant strictures has not shown predictive value.
  • Serum CA 19-9 recently appears useful (75% sensitivity, 80% specificity) in discriminating which patients with primary sclerosing cholangitis have CCA.
  • Indices of disease severity, such as the Mayo risk or Child-Pugh score, do not correlate with the likelihood of CCA development in patients with primary sclerosing cholangitis.
  • Risk factors are poorly understood, but alcohol consumption has been shown to be an independent risk factor for development of CCA in patients with primary sclerosing cholangitis. An association between previous or current smoking status and CCA has also been suggested.
• 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 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 10-20% of patients with primary sclerosing cholangitis who have undergone transplantation.
  • 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.

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. The median period of survival is shorter for patients who are symptomatic at the time of diagnosis.
• 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 UC is not predictive of an increased risk of death in primary sclerosing cholangitis. UC may be associated with an increased posttransplantation survival.

Multimedia

Media file 1: Fibro-obliterative cholangiopathy. Image courtesy of Dr. Kay Washington.

References

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Keywords

primary sclerosing cholangitis, PSC, liver disease, cirrhosis, portal hypertension, liver failure, end-stage liver disease, hepatomegaly, liver transplantation, inflammatory bowel disease, IBD, ulcerative colitis, UC, hepatomegaly, cholestasis, pruritus, cholangitis, fat malabsorption, treatment, diagnosis

Contributor Information and Disclosures

Author

Lynette Gillis, MD, Assistant Professor, Director of Pediatric Hepatology and Liver Transplant, Division of Pediatric Gastroenterology, Hepatology and Nutrition and Division of Medical Genetics, Vanderbilt University
Lynette Gillis, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Liver Foundation, and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
Disclosure: Nothing to disclose.

Medical Editor

Robert Baldassano, MD, Director, Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition, Associate Professor, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania
Robert Baldassano, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David A Piccoli, MD, Chief, Division of Gastroenterology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia; Professor, University of Pennsylvania School of Medicine
David A Piccoli, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

• Relevant clinical guidelines include the following:
  • American Association for the Study of Liver Disease practice guidelines: Evaluation of the patient for liver transplantation ⁶
  • American Gastroenterological Association Institute medical position statement on the use of gastrointestinal medications in pregnancy ⁷
  • American Society for Gastrointestinal Endoscopy guideline: The role of endoscopy in the management of variceal hemorrhage, updated July 2005 ⁸
• Relevant clinical trials include the following:
  • Probiotics in Patients With Primary Sclerosing Cholangitis
  • Compare Conventional Colonoscopy to Endoscopic AFI, NBI for Dysplasia Detection for Ulcerative Colitis & Cholangitis
• Related eMedicine topics include the following:
  • Primary Sclerosing Cholangitis
  • Cholangitis, Primary Sclerosing
  • Bile Duct Strictures
  • Biliary Disease
  • Biliary Obstruction

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