This is a chronic cholestatic liver disease with obliterative inflammatory fibrosis of the bile ducts. The term 'primary' is used to distinguish this condition from bile duct strictures that are secondary to bile duct injury, cholelithiasis or ischaemia.

Aetiology

• The aetiology is unknown but an autoimmune basis is suspected.
• It may also be related to infection and the ability of certain organisms to traverse the bowel wall in inflammatory bowel disease.
• It is associated with certain HLA types.
• One small study found a 100-fold increase in the risk of acquiring primary sclerosing cholangitis (PSC) in first-degree relatives of patients, suggesting a genetic component.¹

Epidemiology and associated diseases

• PSC is rare. It seems most common in Northern Europe.²
• Peak incidence is around age 40 years, but PSC can also occur in infants and children.³ There is a 2:1 male preponderance.⁴
• Of those with PSC, 75% have inflammatory bowel disease, usually ulcerative colitis. The PSC may precede the onset of bowel disease.⁴
• There is an association with coeliac disease.⁵

Presentation³

Symptoms

• May be asymptomatic (presenting with abnormal LFTs or hepatomegaly).
• Jaundice and pruritus.
• Right upper quadrant abdominal pain.
• Fatigue, weight loss, fevers and sweats.
• May present with complications (see 'Complications and their management' below).

Signs

• Jaundice.
• Hepatomegaly (may also have splenomegaly at presentation).
• Later stages: signs of cirrhosis, portal hypertension or hepatic failure.

Differential diagnosis

• Autoimmune hepatitis.
• Overlap syndromes, e.g. autoimmune hepatitis-primary sclerosing cholangitis.⁶
• Hepatitis - infectious or chronic active hepatitis.
• Other bile duct diseases: acute and chronic cholangitis, strictures, cholangiocarcinoma.
• Gallstones.
• Hepatomegaly.
• Primary biliary cirrhosis.

Investigations³

Blood tests

• Abnormal liver function tests are usual. The most common abnormality is elevation of alkaline phosphatase or gamma-glutamyltransferase (GGT) level.
• Serum transaminase levels may be normal or elevated to several times normal.
• Bilirubin is raised in advanced PSC.
• Serum albumin and prothrombin time (PTT) become abnormal as the disease progresses.
• Immunoglobulin G (IgG), IgM and the serum globulin fraction levels may be raised.
• Antineutrophil cytoplasmic antibodies (ANCAs) have been found in 60% of patients with PSC. The presence of ANCAs is associated with a more severe course of autoimmune liver disease.⁷

Other investigations

• Ultrasound is the initial investigation and may show bile duct dilatation, liver and splenic changes; however, it is not diagnostic for PSC.
• Endoscopic retrograde cholangiopancreatography (ERCP) is the 'first choice' test for diagnosis, but is invasive.
• Transhepatic cholangiography can be used if ERCP is unsuccessful, but again is invasive.
• Magnetic resonance cholangiopancreatography (MRCP) is a non-invasive alternative to ERCP, which is increasingly used.
• MRI may be useful to exclude other disease and evaluate the biliary system.
• Liver biopsy may be needed for staging the disease. However, the usefulness of serial liver biopsy in monitoring the disease is limited: there is considerable variability with place of sampling, as the disease is not homogeneous.⁸
• A new technique, transient elastography (FibroScan®), has potential as a non-invasive method for detection of cirrhosis in patients with chronic liver disease.⁹

Staging

Histological staging

There are 4 histological stages of the disease. They have limited value in predicting survival from PSC, perhaps due to the high degree of sampling variability:⁸

Mayo clinic risk score¹⁰

• A multivariate statistical survival model from long-term survival data has been developed at the Mayo Clinic.
• It 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 scoring system has advantages over histological staging, in that it is non-invasive and was found to be well correlated to actual survival.
• It also performed better than the well-known Child-Pugh classification for cirrhosis, which did not predict survival with PSC.¹¹

Management

Despite years of research, medical treatments are only at best able to help manage symptoms.¹² Many drugs have been evaluated and found to be ineffective at halting progression of disease.¹² The results of research on other promising drugs including antibiotics, antifibrotic agents and bile acid derivatives are awaited.¹² Liver transplantation remains the only life-prolonging treatment for patients with end-stage disease.¹²

Pruritus:

• Selective serotonin reuptake inhibitor (SSRI) antidepressants such as sertraline may improve symptoms.¹³

• As with other cholestatic disorders, supplements for the fat-soluble vitamins (vitamins A, D, E, K) may be required.
• In children, nutritional support may be needed to ensure adequate growth.

• Systematic reviews have evaluated corticosteroids¹⁴ and penicillamine,¹⁵ but found no evidence of benefit.
• Ursodeoxycholic acid:¹⁶
  • This gives a a significant improvement in liver biochemistry and is usually well tolerated.
  • However, it has not so far been shown to give any clinical benefit and high-dose ursodeoxycholic acid (28-30 mg/kg/day) has recently been shown to increase the adverse events rate.¹² A Cochrane review concluded that there is insufficient evidence either to support or to refute its clinical effects in PSC.¹⁶
• Overlap syndromes: patients with the autoimmune hepatitis-primary sclerosing cholangitis overlap syndrome may respond to immunosuppressant treatment.⁶
• Avoid alcohol (a risk factor for cholangiocarcinoma development, see 'Complications and their management' below).

• Strictures causing recurrent cholangitis can be treated by balloon dilatation (endoscopic or percutaneous). Stents are also used.¹⁷
• Surgical drainage procedures are possible, but do not alter prognosis because of the intrahepatic component of the disease. There is a postoperative risk of cholangitis, and the procedures may make later transplantation more difficult.³ However, some authors suggest there is a role for extrahepatic biliary resection.¹⁸
• Liver transplantation (see 'Complications and their management' below).

Complications and their management

Biliary complications:

• Biliary obstruction due to stones or strictures - treat with endoscopic or drainage procedures (see 'Surgical and endoscopic interventions' above).
• Bacterial cholangitis, acute or chronic - treat with antibiotics.

Cirrhosis and associated complications:

• Ascites.
• Portal hypertension.
• Oesophageal varices (these can also occur early in PSC, without established cirrhosis).¹⁹
• Hepatic failure - orthotopic liver transplant is the ideal treatment for PSC patients with significant cirrhosis or liver failure.^5,18

Related cancers:

• Cholangiocarcinoma develops in some PSC patients. One study found a 7% rate of cholangiocarcinoma over 11 years. Alcohol consumption and variceal bleeding are risk factors for developing cholangiocarcinoma with PSC.^3,20
• In patients with ulcerative colitis, having PSC is an additional risk factor for bowel cancer. Folate may be protective.²¹

Prognosis

• There is a slow progression to cirrhosis.
• The Mayo Clinic staging (above) helps indicate prognosis.
• PSC can be classified into small-duct or large-duct types, which seems to affect prognosis:²²
  • Small-duct PSC has a better prognosis, with longer transplant-free survival.
  • Also, it appears that cholangiocarcinoma is unlikely with small-duct PSC.
• Prognosis after liver transplant:^6,22,23
  • The outcome for liver transplant in PSC is good, with a 5-year survival of 75-80%.
  • PSC can recur after transplantation, and a retransplant may be required.

Document references

1. Bergquist A, Lindberg G, Saarinen S, et al; Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol. 2005 Feb;42(2):252-6. [abstract]
2. Schrumpf E, Boberg KM; Epidemiology of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol. 2001 Aug;15(4):553-62. [abstract]
3. Gillis L; Primary Sclerosing Cholangitis (Paediatric perspective), eMedicine, Jun 2009
4. Kumar P; Clarke M; Clinical Medicine, 6th Ed, (2005). WB Saunders: London
5. Lawson A, West J, Aithal GP, et al; Autoimmune cholestatic liver disease in people with coeliac disease: a population-based study of their association. Aliment Pharmacol Ther. 2005 Feb 15;21(4):401-5. [abstract]
6. Levy C, Lindor KD; Primary sclerosing cholangitis: epidemiology, natural history, and prognosis. Semin Liver Dis. 2006 Feb;26(1):22-30. [abstract]
7. 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. 2000 May;32(5):734-41. [abstract]
8. Angulo P, Larson DR, Therneau TM, et al; Time course of histological progression in primary sclerosing cholangitis. Am J Gastroenterol. 1999 Nov;94(11):3310-3. [abstract]
9. Foucher J, Chanteloup E, Vergniol J, et al; Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut. 2006 Mar;55(3):403-8. Epub 2005 Jul 14. [abstract]
10. Kim WR, Therneau TM, Wiesner RH, et al; A revised natural history model for primary sclerosing cholangitis. Mayo Clin Proc. 2000 Jul;75(7):688-94. [abstract]
11. 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. 1999 Jun;29(6):1643-8. [abstract]
12. Sinakos E, Lindor K; Treatment options for primary sclerosing cholangitis. Expert Rev Gastroenterol Hepatol. 2010 Aug;4(4):473-88. [abstract]
13. Mayo MJ, Handem I, Saldana S, et al; Sertraline as a first-line treatment for cholestatic pruritus. Hepatology. 2007 Mar;45(3):666-74. [abstract]
14. Giljaca V, Poropat G, Stimac D, et al; Glucocorticosteroids for primary sclerosing cholangitis. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD004036. [abstract]
15. Klingenberg SL, Chen W; D-penicillamine for primary sclerosing cholangitis. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004182. [abstract]
16. Chen W, Gluud C; Bile acids for primary sclerosing cholangitis. Cochrane Database Syst Rev. 2003;(2):CD003626. [abstract]
17. Khan AN et al; Primary Sclerosing Cholangitis Imaging, eMedicine, Jul 2010
18. Pawlik TM, Olbrecht VA, Pitt HA, et al; Primary sclerosing cholangitis: role of extrahepatic biliary resection. J Am Coll Surg. 2008 May;206(5):822-30; discussion 830-2. Epub 2008 Mar 4. [abstract]
19. Bressler B, Pinto R, El-Ashry D, et al; Which patients with primary biliary cirrhosis or primary sclerosing cholangitis should undergo endoscopic screening for oesophageal varices detection? Gut. 2005 Mar;54(3):407-10. [abstract]
20. Burak K, Angulo P, Pasha TM, et al; Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004 Mar;99(3):523-6. [abstract]
21. 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. 1999 Jun;94(6):1643-9. [abstract]
22. Bjornsson E, Olsson R, Bergquist A, et al; The natural history of small-duct primary sclerosing cholangitis. Gastroenterology. 2008 Apr;134(4):975-80. Epub 2008 Jan 17. [abstract]
23. Campsen J, Zimmerman MA, Trotter JF, et al; Clinically recurrent primary sclerosing cholangitis following liver transplantation: a time course. Liver Transpl. 2008 Feb;14(2):181-5. [abstract]

Internet and further reading

• Jorgensen RA, Lindor KD, Sartin JS, et al; Serum lipid and fat-soluble vitamin levels in primary sclerosing cholangitis. J Clin Gastroenterol. 1995 Apr;20(3):215-9. [abstract]
• Durazzo M, Premoli A, Fagoonee S, et al; Overlap syndromes of autoimmune hepatitis: what is known so far. Dig Dis Sci. 2003 Mar;48(3):423-30. [abstract]

Acknowledgements