Primary Sclerosing Cholangitis

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.

Foundation (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.

Prevalence and associated conditions

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 as well.

Appearance

Manifestations

May be asymptomatic (presenting with abnormal LFTs or hepatomegaly)

Jaundice and pruritis.

Right upper quadrant abdominal pain.

Fatigue, weight loss, fevers and sweats.

May present with complications (see ‘Complications and their management’, below).

Indications

Jaundice.

Hepatomegaly

splenomegaly

Later stages: signs of cirrhosis, portal hypertension or hepatic failure.

Distinguished interpretation

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.

Gallstones

Hepatomegaly

Primary billiary cirrhosis.

Probes

Blood examination

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.

Some more tests

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.

Advancement of condition

Histological staging

There are four histological stages of the disease:

Stage 1: degeneration of the epithelial cells lining the bile ducts, associated with inflammatory cell ductal and periportal triad infiltration and scarring.

Stage 2: fibrosis, paucity of bile ductules, periportal inflammatory cell infiltration, and piecemeal necrosis of theperiportal 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.

Maintenance

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.

Pruritis: Anti histamines are first line of drugs. Selective serotonin reuptake inhibitor (SSRI) antidepressants such as sertraline may improve symptoms.

Nutrition: 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.

Obliviating advancement of condition

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.

Overlap syndromes: patients with the autoimmune hepatitis-primary sclerosing cholangitis overlap syndrome may respond to immunosuppressant treatment

Alcohol to be avoided – a risk factor for cholangiocarcinoma development.

Surgical and endoscopic mediation

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 offers only hope in some cases.

Complexities and their handling

Biliary complications

Biliary obstruction due to stones or strictures – treat with endoscopic or drainage procedures

Bacterial cholangitis, acute or chronic – treat with antibiotics.

Cirrhosis and associated complications

Ascites

Portal Hypertension.

Oesophageal varicies (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.

Associated malignancies

Cholangiocarcinoma develops in some PSC patients.

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 for gallbladder abnormalities.

Speculations (The outlook)

There is a slow progression to cirrhosis.

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.