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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.
- 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.
Epidemiology and associated diseases
- The prevalence is estimated to be about 6 cases per 100,000 population.
- Peak incidence is around age 40 years, but PSC can also occur in infants and children. There is a 2:1 male preponderance.
- PSC is strongly associated with inflammatory bowel disease, especially ulcerative colitis, and is often complicated by cholangiocarcinoma.
- There is also an increased risk of colorectal cancer in patients with ulcerative colitis and PSC.
- There is an association with coeliac disease.
- 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).
- Hepatomegaly (may also have splenomegaly at presentation).
Later stages: signs of cirrhosis, portal hypertension or hepatic failure.
The Child-Turcotte-Pugh scale which is used to assess severity of disease includes:
- Grade of encephalopathy
- Presence or absence of ascites
- Serum albumin level
- Prothrombin time
- Bilirubin level
- Autoimmune hepatitis.
- Overlap syndromes - eg, autoimmune hepatitis-primary sclerosing cholangitis.
- Hepatitis - infectious or chronic active hepatitis.
- Other bile duct diseases: acute and chronic cholangitis, strictures, cholangiocarcinoma.
- Primary biliary cirrhosis.
- Abnormal LFTs 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.
- There may also be hypergammaglobulinaemia, raised IgM levels, perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), anticardiolipin (aCL) antibodies and antinuclear antibodies.
- Ultrasound is the initial investigation and may show bile duct dilatation, and 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 is rarely diagnostic but may be useful for staging PSC.
- A newer technique, transient elastography (FibroScan®), has potential as a non-invasive method for detection of cirrhosis in patients with chronic liver disease.
There are four histological stages of the disease:
Stage 2: fibrosis, paucity of bile ductules, periportal inflammatory cell infiltration, and piecemeal necrosis of the periportal hepatocytes.
Stage 3: severe degenerative changes, with disappearance of the bile ducts, portal-to-portal fibrous septa, and periportal cholestasis.
Stage 4: end-stage disease with secondary biliary cirrhosis.
Despite years of research, medical treatments are only at best able to help manage symptoms. Many drugs have been evaluated and found to be ineffective at halting progression of disease. The results of research on other promising drugs including antibiotics, antifibrotic agents and bile acid derivatives are awaited. Liver transplantation remains the only life-prolonging treatment for patients with end-stage disease.
- Selective serotonin reuptake inhibitor (SSRI) antidepressants such as sertraline may improve symptoms.
- 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 corticosteroids and penicillamine; however, they found no evidence of benefit.
- Ursodeoxycholic acid:
- 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.
- A Cochrane review concluded that there is insufficient evidence either to support or refute the use of bile acids in the treatment of primary sclerosing cholangitis.
- Overlap syndromes: patients with the autoimmune hepatitis-primary sclerosing cholangitis overlap syndrome may respond to immunosuppressant treatment.
- Avoid alcohol - a risk factor for cholangiocarcinoma development. (See 'Complications and their management', below.)
Surgical and endoscopic interventions
- Strictures causing recurrent cholangitis can be treated by balloon dilatation (endoscopic or percutaneous). Stents are also used.
- 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. However, some authors suggest there is a role for extrahepatic biliary resection.
- Liver transplantation (see 'Complications and their management', below).
Complications and their management
- 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
- Portal hypertension.
- Oesophageal varices (these can also occur early in PSC, without established cirrhosis).
- Hepatic failure - orthotopic liver transplant is the ideal treatment for PSC patients with significant cirrhosis or liver failure.
- 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.
- In patients with ulcerative colitis, having PSC is an additional risk factor for bowel cancer.
- It has been recommended that:
- Total colonoscopy with biopsies should be:
- Performed in patients in whom the diagnosis of PSC has been established without known inflammatory bowel disease.
- Repeated annually in PSC patients with colitis from the time of diagnosis of PSC.
- Annual abdominal ultrasonography should be considered for gallbladder abnormalities.
- Total colonoscopy with biopsies should be:
- There is a slow progression to cirrhosis.
- The revised Mayo Clinic model for survival probability includes age, serum bilirubin, albumin, and aspartate aminotransferase levels, and history of variceal bleeding.
- PSC can be classified into small-duct or large-duct types, which seems to affect prognosis:
- 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:
- The outcome for liver transplant in PSC is good, with a five-year survival of 75-80%.
- PSC can recur after transplantation, and a retransplant may be required.
Further reading & references
- 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.
- Khurana V et al; Primary Sclerosing Cholangitis, Medscape, June 2012
- Piccoli DA et al; Pediatric Primary Sclerosing Cholangitis, Medscape, Aug 2012
- 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.
- Levy C, Lindor KD; Primary sclerosing cholangitis: epidemiology, natural history, and prognosis. Semin Liver Dis. 2006 Feb;26(1):22-30.
- 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.
- Sinakos E, Lindor K; Treatment options for primary sclerosing cholangitis. Expert Rev Gastroenterol Hepatol. 2010 Aug;4(4):473-88.
- Silveira MG, Lindor KD; Clinical features and management of primary sclerosing cholangitis. World J Gastroenterol. 2008 Jun 7;14(21):3338-49.
- Mayo MJ, Handem I, Saldana S, et al; Sertraline as a first-line treatment for cholestatic pruritus. Hepatology. 2007 Mar;45(3):666-74.
- Giljaca V, Poropat G, Stimac D, et al; Glucocorticosteroids for primary sclerosing cholangitis. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD004036.
- Klingenberg SL, Chen W; D-penicillamine for primary sclerosing cholangitis. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004182.
- Poropat G, Giljaca V, Stimac D, et al; Bile acids for primary sclerosing cholangitis. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD003626. doi: 10.1002/14651858.CD003626.pub2.
- Khan AN et al; Primary Sclerosing Cholangitis Imaging, Medscape, May 2011
- 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.
- 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.
- 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.
- Management of cholestatic liver diseases, European Association for the Study of the Liver (June 2009)
- 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.
- 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.
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Dr Naomi Hartree
Dr Colin Tidy
Dr Adrian Bonsall