Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder characterised by inflammation and fibrosis of intrahepatic and extrahepatic bile ducts, resulting in multifocal biliary strictures. The cause of PSC remains unclear but hypotheses include genetic factors, lymphocyte recruitment and activation, portal bacteraemia and bile salt toxicity. Secondary sclerosing cholangitis includes conditions where infections, thrombosis, iatrogenic causes or trauma can give rise to similar clinical characteristics to PSC.
- PSC is a rare disease with a prevalence of 0.2-16 per 100,000.
- PSC commonly affects males with a median age at diagnosis of 35 years.
- PSC accounts for 10% of all UK liver transplants.
- There is a significant association with inflammatory bowel disease, hepatobiliary malignancies and colorectal cancer.
- 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.
- Vascular: hepatic artery thrombosis, portal hypertension biliopathy, portal cavernoma associated cholangiopathy, intra-arterial chemotherapy, sickle cell disease related cholangiopathy.
- Trauma: trauma post-cholecystectomy, abdominal trauma.
- Infections: AIDS-related cholangiopathy, recurrent pyogenic cholangitis.
- Benign: intraductal stone disease.
- Malignancy: cholangiocarcinoma.
- Autoimmune: autoimmune sclerosing cholangitis, IgG4-related sclerosing cholangitis, systemic vasculitis.
- Other: recurrent pancreatitis, sclerosing cholangitis in a critically ill patient, total parenteral nutrition-related cholangiopathy, histiocytosis X.
- 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.
- Magnetic resonance cholangiopancreatography (MRCP) is now the standard procedure to visualise the intrahepatic and extrahepatic bile ducts.
- Endoscopic retrograde cholangiopancreatography (ERCP) or transhepatic cholangiography may also have a role but are invasive.
- 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.
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.Liver transplantation remains the only life-prolonging treatment for patients with end-stage disease.
- Treatment options for patients with cholestatic pruritus include the anion exchange resin colestyramine, rifampicin, the opioid antagonist naltrexone and the serotonin reuptake inhibitor sertraline.
- 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 found no evidence of any benefit with either corticosteroids or penicillamine.[9, 10]
- 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 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 PSC.
- Avoid alcohol, which is a risk factor for cholangiocarcinoma development.
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.
- Liver transplantation is an effective treatment. The indications for liver transplantation are similar to other causes of chronic liver disease but also include intractable pruritus and recurrent cholangitis.
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.
- Hepatic failure - orthotopic liver transplant is indicated for PSC patients with significant cirrhosis or liver failure.
- Cholangiocarcinoma and colorectal cancer are both increased in patients with PSC.
- 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:
- PSC is a progressive disease of the liver characterised by inflammation and destruction of the intrahepatic and/or extrahepatic bile ducts, leading to fibrosis and ultimately liver failure, cirrhosis and an increased risk of malignancy.
- 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:
Primary Billiary Cholangitis and Primary Sclerosing Cholangitis
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are similarly named, so there is potential for confusion.
- Both involve primary sclerosis of bile ducts:
- PBC affects small interlobular bile ducts, PSC affects intrahepatic and extrahepatic bile ducts.
- PBC occurs predominantly in women, and PSC predominantly in men.
- PBC is an autoimmune condition linked to the presence of antimitochrondrial antibodies.
- The cause of PSC is unclear, although the process is inflammatory and there is an association with inflammatory bowel disease.
- Mayo clinic scoring systems are used to assess prognosis; the two scoring systems differ.
- Liver transplantation can be curative for PBC and PSC. Each has a significant recurrence rate.
Further reading and references
Nayagam JS, Pereira SP, Devlin J, et al; Controversies in the management of primary sclerosing cholangitis. World J Hepatol. 2016 Feb 188(5):265-72. doi: 10.4254/wjh.v8.i5.265.
Goode EC, Rushbrook SM; A review of the medical treatment of primary sclerosing cholangitis in the 21st century. Ther Adv Chronic Dis. 2016 Jan7(1):68-85. doi: 10.1177/2040622315605821.
Rizvi S, Eaton JE, Gores GJ; Primary Sclerosing Cholangitis as a Premalignant Biliary Tract Disease: Surveillance and Management. Clin Gastroenterol Hepatol. 2015 Nov13(12):2152-65. doi: 10.1016/j.cgh.2015.05.035. Epub 2015 Jun 5.
Lutz H, Trautwein C, Tischendorf JW; Primary sclerosing cholangitis: diagnosis and treatment. Dtsch Arztebl Int. 2013 Dec 23110(51-52):867-74. doi: 10.3238/arztebl.2013.0867.
Williamson KD, Chapman RW; Primary sclerosing cholangitis. Dig Dis. 201432(4):438-45. doi: 10.1159/000358150. Epub 2014 Jun 23.
Sinakos E, Lindor K; Treatment options for primary sclerosing cholangitis. Expert Rev Gastroenterol Hepatol. 2010 Aug4(4):473-88.
Silveira MG, Lindor KD; Clinical features and management of primary sclerosing cholangitis. World J Gastroenterol. 2008 Jun 714(21):3338-49.
Kremer AE, Bolier R, van Dijk R, et al; Advances in pathogenesis and management of pruritus in cholestasis. Dig Dis. 201432(5):637-45. doi: 10.1159/000360518. Epub 2014 Jul 14.
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.
Management of cholestatic liver diseases; European Association for the Study of the Liver (June 2009)
Ali AH, Carey EJ, Lindor KD; Current research on the treatment of primary sclerosing cholangitis. Intractable Rare Dis Res. 2015 Feb4(1):1-6. doi: 10.5582/irdr.2014.01018.
Bjornsson E, Olsson R, Bergquist A, et al; The natural history of small-duct primary sclerosing cholangitis. Gastroenterology. 2008 Apr134(4):975-80. Epub 2008 Jan 17.