eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Primary Sclerosing Cholangitis

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
Contributor Information and Disclosures

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.

More on Primary Sclerosing Cholangitis

Overview: Primary Sclerosing Cholangitis
Differential Diagnoses & Workup: Primary Sclerosing Cholangitis
Treatment & Medication: Primary Sclerosing Cholangitis
Follow-up: Primary Sclerosing Cholangitis
Multimedia: Primary Sclerosing Cholangitis
References
Further Reading
[ CLOSE WINDOW ]

References

  1. Aron JH, Bowlus CL. The immunobiology of primary sclerosing cholangitis. Semin Immunopathol. May 26 2009;[Medline].

  2. Bangarulingam SY, Gossard AA, Petersen BT, Ott BJ, Lindor KD. Complications of endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis. Am J Gastroenterol. Apr 2009;104(4):855-60. [Medline].

  3. Rustemovic N, Cukovic-Cavka S, Opacic M, Petrovecki M, Hrstic I, Radic D, et al. Endoscopic ultrasound elastography as a method for screening the patients with suspected primary sclerosing cholangitis. Eur J Gastroenterol Hepatol. Jun 2 2009;[Medline].

  4. Björnsson E. Management of primary sclerosing cholangitis. Minerva Gastroenterol Dietol. Jun 2009;55(2):163-72. [Medline].

  5. Shi J, Li Z, Zeng X, Lin Y, Xie WF. Ursodeoxycholic acid in primary sclerosing cholangitis: meta-analysis of randomized controlled trials. Hepatol Res. May 7 2009;[Medline].

  6. [Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. Jun 2005;41(6):1407-32. [Medline].

  7. [Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. Jun 2005;41(6):1407-32. [Medline].

  8. [Guideline] Mahadevan U, Kane S. American gastroenterological association institute medical position statement on the use of gastrointestinal medications in pregnancy. Gastroenterology. Jul 2006;131(1):278-82. [Medline].

  9. Abdo AA, Bain VG, Kichian K, Lee SS. Evolution of autoimmune hepatitis to primary sclerosing cholangitis: A sequentialsyndrome. Hepatology. Dec 2002;36(6):1393-9. [Medline].

  10. Angulo P, Larson DR, Therneau TM, et al. Time course of histological progression in primary sclerosing cholangitis. Am J Gastroenterol. Nov 1999;94(11):3310-3. [Medline].

  11. Angulo P, Pearce DH, Johnson CD, et al. Magnetic resonance cholangiography in patients with biliary disease: its role in primary sclerosing cholangitis. J Hepatol. Oct 2000;33(4):520-7. [Medline].

  12. Bambha K, Kim WR, Talwalkar J, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitisin a United States community. Gastroenterology. Nov 2003;125(5):1364-9. [Medline].

  13. Bergquist A, Glaumann H, Persson B, Broome U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology. Feb 1998;27(2):311-6. [Medline].

  14. Bharucha AE, Jorgensen R, Lichtman SN, et al. A pilot study of pentoxifylline for the treatment of primary sclerosing cholangitis. Am J Gastroenterol. Sep 2000;95(9):2338-42. [Medline].

  15. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology. Jan 2000;31(1):7-11. [Medline].

  16. Feld JJ, Heathcote EJ. Epidemiology of autoimmune liver disease. J Gastroenterol Hepatol. Oct 2003;18(10):1118-28. [Medline].

  17. Feldstein AE, Perrault J, El-Youssif M, et al. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology. Jul 2003;38(1):210-7. [Medline].

  18. Floreani A, Rizzotto ER, Ferrara F, Carderi I, Caroli D, Blasone L. Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol. Jul 2005;100(7):1516-22. [Medline].

  19. Gilger MA, Gann ME, Opekun AR, Gleason WA Jr. Efficacy of ursodeoxycholic acid in the treatment of primary sclerosing cholangitis in children. J Pediatr Gastroenterol Nutr. Aug 2000;31(2):136-41. [Medline].

  20. Gow PJ, Chapman RW. Liver transplantation for primary sclerosing cholangitis. Liver. Apr 2000;20(2):97-103. [Medline].

  21. Graziadei IW, Wiesner RH, Marotta PJ, et al. Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis. Hepatology. Nov 1999;30(5):1121-7. [Medline].

  22. Harrison PM. Diagnosis of primary sclerosing cholangitis. J Hepatobiliary Pancreat Surg. 1999;6(4):356-60. [Medline].

  23. Kim WR, Poterucha JJ, Wiesner RH, et al. The relative role of the Child-Pugh classification and the Mayo natural history model in the assessment of survival in patients with primary sclerosing cholangitis. Hepatology. Jun 1999;29(6):1643-8. [Medline].

  24. Kita R, Kita-Sasai Y, Hanaoka I, et al. Beneficial effect of bezafibrate on primary sclerosing cholangitis (three casereports). Am J Gastroenterol. Jul 2002;97(7):1849-51. [Medline].

  25. Kugelmas M, Spiegelman P, Osgood MJ, et al. Different immunosuppressive regimens and recurrence of primary sclerosing cholangitisafter liver transplantation. Liver Transpl. Jul 2003;9(7):727-32. [Medline].

  26. Lee YM, Kaplan MM. Medical treatment of primary sclerosing cholangitis. J Hepatobiliary Pancreat Surg. 1999;6(4):361-5. [Medline].

  27. Liden H, Norrby J, Friman S, Olausson M. Liver transplantation for primary sclerosing cholangitis--a single- center experience. Transpl Int. 2000;13 Suppl 1:S162-4. [Medline].

  28. Nakanuma Y, Harada K, Katayanagi K, et al. Definition and pathology of primary sclerosing cholangitis. J Hepatobiliary Pancreat Surg. 1999;6(4):333-42. [Medline].

  29. Narayanan Menon KV, Wiesner RH. Etiology and natural history of primary sclerosing cholangitis. J Hepatobiliary Pancreat Surg. 1999;6(4):343-51. [Medline].

  30. Pardi DS, Loftus EV, Kremers WK, et al. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerativecolitis and primary sclerosing cholangitis. Gastroenterology. Apr 2003;124(4):889-93. [Medline].

  31. Ponsioen CY, Lam K, van Milligen de Wit AW, et al. Four years experience with short term stenting in primary sclerosing cholangitis. Am J Gastroenterol. Sep 1999;94(9):2403-7. [Medline].

  32. Raj V, Lichtenstein DR. Hepatobiliary manifestations of inflammatory bowel disease. Gastroenterol Clin North Am. Jun 1999;28(2):491-513. [Medline].

  33. Revelon G, Rashid A, Kawamoto S, Bluemke DA. Primary sclerosing cholangitis: MR imaging findings with pathologic correlation. AJR Am J Roentgenol. Oct 1999;173(4):1037-42. [Medline].

  34. Roberts EA. Primary sclerosing cholangitis in children. J Gastroenterol Hepatol. Jun 1999;14(6):588-93. [Medline].

  35. Roozendaal C, de Jong MA, van den Berg AP, et al. Clinical significance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver diseases. J Hepatol. May 2000;32(5):734-41. [Medline].

  36. Saarinen S, Olerup O, Broome U. Increased frequency of autoimmune diseases in patients with primary sclerosing cholangitis. Am J Gastroenterol. Nov 2000;95(11):3195-9. [Medline].

  37. Sekido H, Takeda K, Morioka D, et al. Liver transplantation for primary sclerosing cholangitis. J Hepatobiliary Pancreat Surg. 1999;6(4):373-6. [Medline].

  38. Shetty K, Rybicki L, Brzezinski A, et al. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol. Jun 1999;94(6):1643-9. [Medline].

  39. Talwalkar JA, Lindor KD. Primary sclerosing cholangitis. Inflamm Bowel Dis. Jan 2005;11(1):62-72. [Medline].

  40. Tung BY, Emond MJ, Haggitt RC, et al. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med. Jan 16 2001;134(2):89-95. [Medline]. [Full Text].

[ CLOSE WINDOW ]

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

[ CLOSE WINDOW ]

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.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.