AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Historically, the term pericholangitis has referred to the entity of chronic hepatitis and cholestatic biochemical features typically in patients with inflammatory bowel disease (IBD). Recently, the nomenclature of this disease has been questioned because of the recognition that pericholangitis and classic (or large-duct) primary sclerosing cholangitis (PSC) might be parts of a disease spectrum. In particular, studies comparing patients with chronic IBD, cholestatic liver biochemistry, and typical cholangiographic evidence of PSC with similar patients having normal findings on cholangiograms reveal similarities in clinical features and liver biopsy findings.

Furthermore, some patients with pericholangitis and initially negative findings on cholangiograms have been demonstrated on long-term follow-up to develop typical cholangiographic features of PSC. For this reason, the disease previously termed pericholangitis is now more properly referred to as small-duct PSC. For the purpose of this review, these terms are used interchangeably. Pericholangitis and large-duct PSC should be considered as part of a disease spectrum, best referred to as PSC with small- and/or large-duct involvement.

Pathophysiology

Pericholangitis is a chronic cholestatic liver disease of unknown etiology characterized by inflammation and fibrosis of microscopically identifiable (interlobular and septal) bile ducts. Although changes in large cholangiographically visible bile ducts may accompany pericholangitis, this entity is more appropriately designated classic or large-duct PSC. The clinical course may be characterized by progressive hepatic fibrosis, and ultimately (in the absence of liver transplantation), complications of cirrhosis, liver failure, and even death. Other organ systems remain unaffected by the primary disease process.

Frequency

United States

The incidence and the prevalence of pericholangitis in the United States have not been specifically studied; however, inferences can be made based on PSC data. In a recent Mayo Clinic study (2003), the overall age- and sex-adjusted incidence and prevalence of classic PSC were 0.9 cases per 100,000 population and 13.6 cases per 100,000 population, respectively. Since approximately 10% of patients with PSC have the small-duct variant, the data suggest a pericholangitis incidence and prevalence of approximately 0.9 cases per 1 million population and 13.6 cases per 1 million population, respectively.

A strong association exists between IBD and PSC. Approximately 70-80% of patients with PSC also have IBD. Most patients have UC, but as many as 13% of PSC patients with IBD have Crohn disease. An estimated 2-7.5% of patients with UC have PSC.

International

The international frequency of pericholangitis has only recently been investigated. In a population-based study from Calgary, Alberta, Canada (2005), Kaplan and colleagues reported an annual incidence of 0.1 cases per 100,000 population for pericholangitis, compared with an annual incidence of 0.9 cases per 100,000 population for classic PSC.

The prevalence in patients with IBD is variable. For example, in a Finnish study by Heikius et al (1997) of 237 unselected patients with IBD, the prevalence of PSC was 11%. Of these patients, 11.5% had the small-duct variant (pericholangitis). In a Turkish study by Bayraktar et al (1998), none of the 81 patients with IBD had PSC. The nature of these international differences in PSC prevalence is unknown.

Mortality/Morbidity

• Classic PSC is associated with a progression of fibrosis to cirrhosis, end-stage liver disease, and liver transplantation requirement in a significant proportion of patients. The median duration from diagnosis to death or liver transplantation is approximately 12 years. Patients are also at an increased risk of malignancy, including cholangiocarcinoma, hepatocellular carcinoma, and colorectal dysplasia and adenocarcinoma in the presence of IBD. For example, 7-20% of patients with classic PSC will eventually develop cholangiocarcinoma (annual incidence, 0.5-1.5%).
• Pericholangitis appears to represent a more benign variant of classic PSC. In a recent study from Oxford and Oslo, Bjornsson et al (2002) described the natural history of 33 patients with pericholangitis and 260 patients with classic PSC over a mean follow-up of nearly 9 years. In this study, only 4 (12%) of the 33 patients with pericholangitis died or required liver transplantation versus 122 (47%) of the 260 patients with classic PSC (P <0.05). These findings were confirmed in a smaller study from the Mayo Clinic. In this report, Angulo and colleagues (2002) described a median survival without liver transplantation of 29.5 years in patients with pericholangitis (n=18) versus only 17 years in the classic PSC group (n=36). Survival in the pericholangitis group was similar to that expected in the white US population, whereas that of the classic PSC group was significantly lower. In contrast to patients with classic PSC, an increased risk of malignancy has not been reportedinpatientswithpericholangitis.For example, in the natural history studies of Bjornsson and Angulo, no patient with pericholangitis developed an intestinal or hepatobiliary malignancy.
• A minority of patients with pericholangitis ultimately develop cholangiographic evidence of large-duct PSC. In the Bjornsson et al study, cholangiography was repeated in 19 (58%) of the 33 patients with pericholangitis. Only 4 patients (12%) developed large-duct PSC, with typical intrahepatic and/or extrahepatic changes on cholangiography. In the Mayo Clinic study, 5 of the 18 patients with pericholangitis had repeat cholangiography due to worsening liver biochemistry. Three of these patients (17% of the total) developed typical cholangiographic features of large-duct PSC.

Race

No consistent relationship to ethnicity has been reported.

Sex

The impact of sex on the prevalence of pericholangitis is unclear. Classic PSC is thought to be more common in males than in females; the male-to-female ratio is approximately 2:1. In the Bjornsson et al study (2002), 19 (58%) of the 33 patients with pericholangitis were male, whereas 188 (72%) of the 260 patients with classic PSC (P=NS) were male.

Age

In the Bjornsson et al study (2002), the mean age at diagnosis was 38 years in the pericholangitis group versus 39 years in the classic PSC group. Similar figures were reported in the Mayo Clinic study, 40 years versus 39 years, respectively. Thus, pericholangitis does not seem to be an early stage of PSC in most cases; rather, it likely represents a more benign form of the disease (see Mortality/Morbidity).

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Symptoms of patients with pericholangitis are highly variable depending on the reported series.
• • Frequently, the diagnosis is made in asymptomatic patients with IBD when routine liver biochemistry reveals a cholestatic liver profile.
  • Other patients present with cholestatic features, including jaundice and pruritus. Jaundice may develop insidiously or occur as abrupt intermittent episodes of icterus.
  • Finally, some patients may present with typical features of acute cholangitis, namely fever, jaundice, and abdominal pain.
• In a minority of patients, pericholangitis progresses to severe fibrosis and cirrhosis. In these patients, features of hepatic decompensation may predominate, such as the development of ascites, edema, bleeding related to portal hypertension, or hepatic encephalopathy.

Physical

• The physical examination findings in patients with pericholangitis are usually unremarkable.
• Abnormal physical findings
• • Jaundice
  • Hepatomegaly
  • Splenomegaly
  • Ascites and edema
  • Stigmata of chronic liver disease (spider angiomata), leukonychia, muscle wasting, gynecomastia and testicular atrophy (in men), palmar erythema
  • Excoriations due to pruritus

Causes

• The etiology of pericholangitis is unknown.
• Proposed theories include the following:
• • Autoimmunity
  • Portal bacteremia
  • Absorption of colonic toxins
  • Ischemic injury to the biliary tree
  • Viral infections
  • Toxic bile acids in a genetically predisposed individual

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

AIDS cholangiopathy
Autoimmune cholangitis
Benign recurrent intrahepatic cholestasis
Cystic fibrosis
Drug-induced cholestasis
Idiopathic adulthood ductopenia
Primary biliary cirrhosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Liver enzymes (alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transpeptidase)
• • Patients typically have a cholestatic liver profile with predominant elevations of alkaline phosphatase and gamma-glutamyl transpeptidase.
  • Aminotransferase levels may be within the reference range or be moderately elevated.
• Bilirubin
• • Serum bilirubin levels may range from within the reference range to displaying marked elevation.
  • The bilirubin level may rise insidiously in association with gradual progression of the disease or rise abruptly with intermittent episodes of fever and abdominal pain suggesting acute cholangitis.
• Prothrombin time, albumin
• • In the early stages of the disease, these test results typically are within the reference range, although the albumin level may be decreased due to coexistent IBD.
  • As the disease progresses to later stages, the prothrombin time (PT) may rise and the albumin may fall.
• Perinuclear antineutrophil cytoplasmic antibody
• • This test reveals a reported prevalence of 26-85% in classic PSC.
  • In one study, the sensitivity and specificity of perinuclear antineutrophil cytoplasmic antibody (pANCA) by the immunofluorescence technique were 51% and 73%, respectively.
  • The usefulness of pANCA in pericholangitis is not clear.
• Antimitochondrial antibody
• • Order this test to rule out primary biliary cirrhosis (PBC), a common cause of cholestatic liver disease.
  • Patients with pericholangitis characteristically lack this antibody.
• Other autoantibodies
• • Antinuclear antibodies (ANA) and/or smooth muscle antibodies (SMA) have been reported in 28% of patients with pericholangitis.
  • These tests should be ordered to rule out autoimmune hepatitis as a cause of liver biochemical abnormalities, although this condition typically presents with elevated levels in the aminotransferases rather than a cholestatic liver profile.

Imaging Studies

• Abdominal ultrasonography
• • Complete an abdominal ultrasound to screen for other causes of hepatic pathology, including fatty liver and cholelithiasis, which also may affect patients with IBD.
  • Although insensitive, ultrasonography may detect findings suggestive of cirrhosis such as a nodular, shrunken liver, or portal hypertensive changes, including splenomegaly, altered portal venous blood flow, or the formation of venous collaterals.
  • No specific ultrasonographic findings exist for the diagnosis of pericholangitis.
• Magnetic resonance cholangiopancreatography
• • The role of magnetic resonance cholangiopancreatography (MRCP) in pericholangitis is unclear. Preliminary studies suggest that MRCP may be as useful as endoscopic retrograde cholangiopancreatography (ERCP) in detecting the typical cholangiographic features of PSC (see Procedures).
  • MRCP findings are normal in patients with pericholangitis.

Other Tests

• Hepatitis serology
• • Patients may have coexistent risk factors for the acquisition of viral hepatitis, including blood transfusions often necessary for the management of anemia in patients with IBD.
  • Rule out chronic hepatitis B and C with hepatitis B surface antigen (HBsAg) and antihepatitis C (anti-HCV) antibody tests.
• Hypergammaglobulinemia and hypercholesterolemia have been reported in some patients.
  

Procedures

• Endoscopic retrograde cholangiopancreatography
• • Complete an ERCP to rule out large-duct PSC, a much more common cause of cholestasis in patients with IBD.
  • Findings include stricturing and beading of the intrahepatic and/or extrahepatic bile ducts.
  • By definition, ERCP findings are normal in patients with pericholangitis. However, some patients with large-duct PSC may have histological evidence of pericholangitis or small-duct disease.
• Liver biopsy
• • Performing a liver biopsy is essential for the diagnosis and staging of pericholangitis and to rule out other causes of liver disease (see Staging).
  • Bleeding is the predominant risk of liver biopsy. Fatal and nonfatal hemorrhages have been reported in 0.04% and 0.16% of patients, respectively.
  • Ultrasound guidance may reduce the risk of complications.

Histologic Findings

See Staging.

Staging

Pericholangitis is staged from 1-4 based on histologic findings. The histologic stage is an important predictor of survival in PSC and likely bears the same importance in pericholangitis.

• Stage 1 (portal stage)
• • Lymphocytic portal inflammation is accompanied by variable amounts of edema, fibrosis, and bile ductular proliferation.
  • Most ducts are without abnormality, but some show degenerative changes, periductal fibrosis, and nonsuppurative fibrous cholangitis (the typical "onion skin lesion" of PSC).
• Stage 2 (periportal stage)
• • Periportal fibrosis with or without periportal hepatitis and expansion of the portal triads with seemingly intact newly formed limiting plates occurs.
  • Focal ductopenia often is noted in this stage.
• Stage 3 (septal stage)
• • Septal fibrosis and/or bridging necrosis are prominent.
  • Bile ducts often are severely damaged or absent.
  • Other features include piecemeal necrosis and prominent copper deposition.
• Stage 4 (cirrhotic stage)
• • The liver is cirrhotic, and bile ducts often have disappeared.
  • At this stage, differentiation from other cholestatic liver diseases, particularly PBC, may be difficult.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

No effective medical treatment exists for pericholangitis.

• Several medications, including penicillamine, colchicine, corticosteroids, azathioprine, methotrexate, nicotine, and pentoxifylline, have been tried and proven ineffective in PSC, although they have not been tested specifically in patients with pericholangitis.
• Ursodeoxycholic acid may have a role in this disorder (see Medication).

Surgical Care

• Liver transplantation is the only proven effective treatment for PSC. Preliminary evidence suggests that patients with late pericholangitis also do well with liver transplantation.
• Most series have reported a dismal prognosis for liver transplantation if cholangiocarcinoma is present, and results discourage transplantation.
• Patients with PSC seem to have a higher incidence of chronic ductopenic rejection after liver transplantation compared with those transplanted for other indications.
• • Large-duct PSC recurs in approximately 20% of liver allografts.
  • Recurrence of pericholangitis has yet to be reported.

Consultations

• Gastroenterologist - Management of associated IBD, including screening for colorectal dysplasia and cancer
• Endocrinologist and metabolism specialist - Management of associated osteopenia or osteoporosis

Diet

No specific diet is required.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Gallstone dissolution agents

No effective medical treatment exists for pericholangitis. Ursodeoxycholic acid might have a role in this disorder.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients with complications of end-stage pericholangitis, such as ascites, spontaneous bacterial peritonitis, portal hypertensive bleeding, and hepatic encephalopathy, should be treated as patients with other causes of chronic liver disease.

In/Out Patient Meds

• Replace fat-soluble vitamins (ie, A, D, E, K) in patients with documented deficiencies.
• Prescribe calcium (>1000 mg/d) and vitamin D (800 IU/d) to patients who are osteopenic.
• Patients who are osteoporotic should receive bisphosphonate therapy. These agents can cause esophageal irritation when taken orally, raising concern about their safety in patients with esophageal varices. Patients with documented esophageal varices probably should receive intermittent intravenous infusions of bisphosphonates such as pamidronate.

Transfer

• Transfer patients with end-stage pericholangitis to a center specializing in liver transplantation.

Deterrence/Prevention

• No effective preventive therapy exists for pericholangitis.
• Neither colectomy in patients with UC nor medical management of associated IBD prevents the development of pericholangitis.

Complications

• End-stage liver disease
• • Portal hypertensive bleeding (esophageal and gastric varices, portal hypertensive gastropathy)
  • Ascites, edema
  • Jaundice
  • Malnutrition
• Classic large-duct PSC
• Cholangiocarcinoma (very rarely)
• Fat-soluble vitamin (ie, A, D, E, K) deficiency
• Osteopenia and osteoporosis
• Colonic dysplasia and adenocarcinoma in patients with IBD

Prognosis

• The natural history of pericholangitis has been investigated only recently.
• In a European study of 293 patients with PSC, 33 patients (11%) met strict criteria for the diagnosis of pericholangitis.
• • Over a median follow-up time of approximately 9 years, 4 patients (12%) with pericholangitis developed cholangiographic features of classic PSC.
  • Two of these patients underwent liver transplantation for end-stage liver disease. An additional patient, who did not develop cholangiographic evidence of classic PSC, died from liver-related complications.
  • No patients developed cholangiocarcinoma; however, this complication has been reported very rarely in association with pericholangitis.
  • The cumulative survival free of liver transplantation or death was significantly higher in patients with pericholangitis (88%) versus those with classic PSC (53%, P <0.05).
• Medical or surgical therapy of associated IBD does not appear to affect the prognosis of pericholangitis.

Patient Education

• Warn patients of the potential for pericholangitis to progress to end-stage liver disease and necessitate consideration of liver transplantation.
• Patients should watch for symptoms suggestive of hepatic decompensation, including ascites, edema, GI bleeding, jaundice, encephalopathy, and malnutrition, which may warrant referral for transplantation assessment.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to refer patients with end-stage liver disease to a center with access to liver transplantation

Special Concerns

• Patients with PSC and IBD are reported to have an increased risk of colonic dysplasia and adenocarcinoma. The exact risk in pericholangitis is unknown but is presumed to be similar to that in classic PSC.
• Those with long-standing IBD should undergo surveillance colonoscopy every 1-2 years.
• Patients with IBD who have received a liver transplant for pericholangitis may have an increased risk due to the effects of immunosuppression. They require more intense colonoscopic surveillance.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Angulo P, Lindor KD. Primary sclerosing cholangitis. Hepatology. Jul 1999;30(1):325-32. [Medline].
• Bambha K, Kim WR, Talwalkar J. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology. Nov 2003;125(5):1364-9. [Medline].
• Bansi DS, Bauducci M, Bergqvist A. Detection of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis: a comparison of the alkaline phosphatase and immunofluorescent techniques. Eur J Gastroenterol Hepatol. Jun 1997;9(6):575-80. [Medline].
• Bayraktar Y, Arslan S, Saglam F. What is the association of primary sclerosing cholangitis with sex and inflammatory bowel disease in Turkish patients?. Hepatogastroenterology. Nov-Dec 1998;45(24):2064-72. [Medline].
• Bergquist A, Ekbom A, Olsson R. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol. Mar 2002;36(3):321-7. [Medline].
• Bjornsson E, Boberg KM, Cullen S. Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis. Gut. Nov 2002;51(5):731-5. [Medline].
• Broome U, Glaumann H, Lindstom E. Natural history and outcome in 32 Swedish patients with small duct primary sclerosing cholangitis (PSC). J Hepatol. May 2002;36(5):586-9. [Medline].
• Burak K, Angulo P, Pasha TM. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. Mar 2004;99(3):523-6. [Medline].
• D'Haens GR, Lashner BA, Hanauer SB. Pericholangitis and sclerosing cholangitis are risk factors for dysplasia and cancer in ulcerative colitis. Am J Gastroenterol. Aug 1993;88(8):1174-8. [Medline].
• Graziadei IW, Wiesner RH, Marotta PJ. Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis. Hepatology. Nov 1999;30(5):1121-7. [Medline].
• Heathcote EJ, Cauch-Dudek K, Walker V. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. May 1994;19(5):1149-56. [Medline].
• Heikius B, Niemela S, Lehtola J. Hepatobiliary and coexisting pancreatic duct abnormalities in patients with inflammatory bowel disease. Scand J Gastroenterol. Feb 1997;32(2):153-61. [Medline].
• Kaplan G, Laupland K, Butzner D. Population-based study of the incidence of and the risk factors for developing primary sclerosing cholangitis. Gastroenterology. 2005;128 (4 Suppl 2):A773.
• Kim WR, Ludwig J, Lindor KD. Variant forms of cholestatic diseases involving small bile ducts in adults. Am J Gastroenterol. May 2000;95(5):1130-8. [Medline].
• Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med. Mar 6 1997;336(10):691-5. [Medline].
• Ludwig J. Small-duct primary sclerosing cholangitis. Semin Liver Dis. Feb 1991;11(1):11-7. [Medline].
• McGill DB, Rakela J, Zinsmeister AR. A 21-year experience with major hemorrhage after percutaneous liver biopsy. Gastroenterology. Nov 1990;99(5):1396-400. [Medline].
• Mistilis SP. Pericholangitis and ulcerative colitis I. Pathology, etiology, and pathogenesis. Ann Intern Med. 1965;63:1-16.
• Nikolaidis NL, Giouleme OI, Tziomalos KA. Small-duct primary sclerosing cholangitis. A single-center seven-year experience. Dig Dis Sci. Feb 2005;50(2):324-6. [Medline].
• Poupon R, Chazouilleres O, Poupon RE. Chronic cholestatic diseases. J Hepatol. 2000;32(1 Suppl):129-40. [Medline].
• Raj V, Lichtenstein DR. Hepatobiliary manifestations of inflammatory bowel disease. Gastroenterol Clin North Am. Jun 1999;28(2):491-513. [Medline].
• Wee A, Ludwig J. Pericholangitis in chronic ulcerative colitis: primary sclerosing cholangitis of the small bile ducts?. Ann Intern Med. May 1985;102(5):581-7. [Medline].
• Wee A, Ludwig J, Coffey RJ. Hepatobiliary carcinoma associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hum Pathol. Jul 1985;16(7):719-26. [Medline].

Article Last Updated: Feb 21, 2007