Primary biliary cirrhosis

Synonyms

3

Overview

Primary biliary cholangitis (PBC) is a chronic disease that affects the bile ducts within the liver. The bile ducts carry a fluid called bile from the liver to the gallbladder, where it is stored. The bile ducts become inflamed and damaged, which causes bile to build up in the liver. This abnormal buildup destroys liver tissue and in later stages results in cirrhosis.

Primary biliary cirrhosis usually occurs between the ages of 40 and 60 and affects women more often than men. The cause of this condition is unknown, but research suggests that it is an autoimmune disease. 

Symptoms

People with PBC experience fatigue (80%) that leads to sleepiness during the daytime; more half of those have severe fatigue. 20–70% have itching. Those with more severe disease may have jaundice (yellowing of the eyes and skin). PBC impairs bone density and there is an increased risk of fracture. Xanthelasma (skin lesions around the eyes) or other xanthoma may be present as a result of increased cholesterol levels.

PBC can eventually progress to cirrhosis of the liver. This in turn may lead to a number of symptoms or complications:

  • Fluid retention in the abdomen (ascites) in more advanced disease
  • Enlarged spleen in more advanced disease
  • Oesophageal varices in more advanced disease
  • Hepatic encephalopathy, including coma in extreme cases in more advanced disease.

People with PBC may have the findings of an associated extrahepatic autoimmune disorder such as rheumatoid arthritis or Sjögren's syndrome (in up to 80% of cases)

Causes

The cause of the disease is attributed to an immunological basis for the disease, making it an autoimmune disorder. Most of the patients (>90%) have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria. Those 'negative' for AMAs are usually found to be positive when more sensitive methods of detection are used.

Many PBC patients have a concomitant autoimmune disease, including rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological conditions, which suggests shared genetic and immune abnormalities. Common associations include Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, SLE, hypothyroidism and gluten sensitive enteropathy. In some cases of disease, protein expression may cause an immune tolerance failure, as might be the case with gp210 and p62, nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients. Both proteins appear to be prognostic of liver failure relative to anti-mitochondrial antibodies.

A genetic predisposition to disease has been thought important for some time, as evident by cases of PBC in family members, concordance in identical twins, and clustering of autoimmune diseases. In 2009, a Canadian-led group of investigators reported in the New England Journal of Medicine results from the first PBC genome-wide association study. This research revealed parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be important in the etiology of the disease in addition to the HLA region. In 2012, two independent PBC association studies increased the total number of genomic regions associated to 26, implicating many genes involved in cytokine regulation such as TYK2, SH2B3 and TNFSF11.

In 2003 it was reported that an environmental Gram negative alphabacterium — Novosphingobium aromaticivorans was strongly associated with this disease. Subsequent reports appear to have confirmed this finding suggesting an aetiological role for this organism. The mechanism appears to be a cross reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells. The gene encoding CD101 may also play a role in host susceptibility to this disease.

Diagnosis

To diagnose PBC, it needs to be distinguished from other conditions with similar symptoms, such as autoimmune hepatitis or primary sclerosing cholangitis.

  • Abnormalities in liver enzyme tests are usually present and elevated gamma-glutamyl transferase and alkaline phosphatase are found in early disease. Elevations in bilirubin occur in advanced disease.
  • Antimitochondrial antibodies (AMA) are the characteristic serological marker for PBC, being found in 90%-95% of patients and only 1% of controls. PBC patients have AMA against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria. Those people who are AMA negative but with disease similar to PBC have been found to have AMAs when more sensitive detection methods are employed.
  • Other auto-antibodies may be present:
Antinuclear antibody (ANA) are not diagnostic (as they are not specific) but are have a role in prognosis.
Anti-glycoprotein-210 antibodies, and to a lesser degree anti-p62 antibodies, correlate with the disease's progression toward end stage liver failure. Anti-gp210 antibodies are found in 47% of PBC patients.
Anti-centromere antibodies often correlate with developing portal hypertension.
Anti-np62 and anti-sp100 are also found in association with PBC.
  • Abdominal ultrasound, MR scanning (MRCP) or a CT scan is usually performed to rule out blockage to the bile ducts. Most suspected cases have a liver biopsy performed, and if uncertainty remains as in some patients, an endoscopic retrograde cholangiopancreatography or ERCP, where an endoscopic investigation of the bile duct is performed.

Most patients can be diagnosed without invasive investigation, as the combination of anti-mitochondrial antibodies and typical (cholestatic) liver enzyme tests are considered diagnostic. However, a liver biopsy is needed to determine the stage of disease.

Biopsy:

PBC is characterized by interlobular bile duct destruction. Histopathologic findings of primary biliary cholangitis include the following:

  • Inflammation of the bile ducts, characterized by intraepithelial lymphocytes, and
  • Periductal epithelioidgranulomata.
     

Stages:

  • Stage 1 — Portal Stage: Normal sized triads; portal inflammation, subtle bile duct damage. Granulomas are often detected in this stage.
  • Stage 2 — Periportal Stage: Enlarged triads; periportal fibrosis and/or inflammation. Typically characterized by the finding of a proliferation of small bile ducts.
  • Stage 3 — Septal Stage: Active and/or passive fibrous septa.
  • Stage 4 — Biliary Cirrhosis: Nodules present; garland or jigsaw puzzle pattern.

Prognosis

The serum bilirubin level is an indicator of the prognosis of PBC, with levels of 2–6 mg/dL having a mean survival time of 4.1 years, 6–10 mg/dL having 2.1 years and those above 10 mg/dL having a mean survival time of 1.4 years.

After liver transplant, the recurrence rate may be as high as 18% at 5 years, and up to 30% at 10 years. There is no consensus on risk factors for recurrence of the disease.

Patients with PBC have an increased risk of hepatocellular carcinoma compared to the general population, as is found in other cirrhotic patients. In patients with advanced disease, one series found an incidence of 20% in men and 4% in women.

Treatment

There is no known cure, but medication may slow the progression so that a normal lifespan and quality of life may be attainable for many patients.

  • Ursodeoxycholic acid (Ursodiol) is the most frequently used treatment. This helps reduce the cholestasis and improves blood test results (liver function tests). It has a minimal effect on symptoms and whether it improves prognosis is controversial.
  • The farnesoid X receptor agonist, obeticholic acid (Ocaliva), which is a modified bile acid, has been approved by the FDA in 2016 for the "Treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA".
  • To relieve itching caused by bile acids in circulation, which would normally be removed by the liver, cholestyramine (a bile acid sequestrant) may be prescribed to absorb bile acids in the gut and be eliminated, rather than re-enter the blood stream. Alternative agents include stanozolol, naltrexone and rifampicin.
  • Specific treatment for fatigue, which may be debilitating in some patients, is limited and undergoing trials. Some studies indicate that Provigil (modafinil) may be effective without damaging the liver. Though off-patent, the limiting factor in the use of modafinil in the U.S. is cost. The manufacturer, Cephalon, has made agreements with manufacturers of generic modafinil to provide payments in exchange for delaying their sale of modafinil. The FTC has filed suit against Cephalon alleging anti-competitive behavior.
  • Patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K. Appropriate supplementation is recommended when bilirubin is elevated.
  • Patients with PBC are at elevated risk of developing osteoporosis and esophageal varices as compared to the general population and others with liver disease. Screening and treatment of these complications is an important part of the management of PBC.

As in all liver diseases, consumption of alcohol is contraindicated.

In advanced cases, a liver transplant, if successful, results in a favorable prognosis.