Primary biliary cirrhosis
|Primary biliary cirrhosis|
|Classification and external resources|
|Patient UK||Primary biliary cirrhosis|
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver. It is marked by slow progressive destruction of the small bile ducts of the liver, with the intralobular ducts (Canals of Hering) affected early in the disease. When these ducts are damaged, bile and other toxins build up in the liver (cholestasis) and over time damages the liver tissue in combination with ongoing immune related damage. This can lead to scarring, fibrosis and cirrhosis.
As cirrhosis is only a feature of advanced disease, a change of name to primary biliary cholangitis was proposed in 2014. It has not as of April 2015 been adopted in scientific publications but has been accepted by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.
Signs and symptoms
Individuals with PBC with disease may present with the following:
- Pruritus (itchy skin)
- Jaundice (yellowing of the eyes and skin), due to increased bilirubin in the blood in more advanced disease.
- Xanthoma (local collections of cholesterol in the skin, especially around the eyes (xanthelasma))
- Complications of cirrhosis and portal hypertension: in more advanced disease
- Association with an extrahepatic autoimmune disorder such as rheumatoid arthritis or Sjögren's syndrome (in up to 80% of cases).
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.
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.
Diagnostic blood tests include:
- Elevated liver enzyme tests (elevated gamma-glutamyl transferase and alkaline phosphatase)
- Presence of certain antibodies: antimitochondrial antibody (AMA), antinuclear antibody (ANA)
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 an is some patients, endoscopic retrograde cholangiopancreatography or ERCP, where an endoscopic investigation of the bile duct is performed. Most patients are diagnosed without invasive investigation, as the combination of anti-mitochondrial antibodies (see below) and typical (cholestatic) liver enzyme tests are considered diagnostic. However, a liver biopsy is necessary to determine the stage of disease.
Anti-nuclear antibodies appear to be prognostic agents in PBC. Anti-glycoprotein-210 antibodies, and to a lesser degree anti-p62 antibodies, correlate with the disease's progression toward end stage liver failure. Anti-centromere antibodies often correlate with developing portal hypertension. Anti-np62 and anti-sp100 are also found in association with PBC.
- Inflammation of the bile ducts, characterized by intraepithelial lymphocytes, and
- Periductal epithelioid granulomata.
Summary of 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.
- 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.
- 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.
PBC is a chronic autoimmune liver disease with a female gender predominance with female:male ratio is at least 9:1 and a peak incidence in the fifth decade of life. In some areas of the US and UK the prevalence is estimated to be as high as 1 in 4000. This is much more common than in South America or Africa, which may be due to better recognition in the US and UK. First-degree relatives may have as much as a 500 times increase in prevalence, but there is debate if this risk is greater in the same generation relatives or the one that follows.
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.
Addison and Gull in 1851 described the clinical picture of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. Ahrens et al in 1950 coined the term primary biliary cirrhosis for this disease. The association with anti-mitochondrial antibodies was first reported in 1965 and their presence was recognized as a marker of early, pre-cirrhotic disease.
Society and culture
Patient support groups
The PBC Foundation was founded by Collette Thain in 1996, after she was diagnosed with the condition. It campaigns for increasing recognition of the disorder, improved diagnosis and treatments, and estimates over 8000 people are undiagnosed in the UK. The Foundation supported development of the PBC-40 quality of life measure published in 2004 and helped establish the PBC Genetics Study. Thain was awarded an MBE Order of the British Empire in 2004 for her work with the foundation.
In 2014, the PBC Foundation, along with the US-based advocacy group, the PBCers, launched an initiative to change the name from "primary biliary cirrhosis" to "primary biliary cholangitis". Clinician support for this name change has come from the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver, and it is proposed that this change be reflected in the International Classification of Disease (ICD11).
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