Primary biliary cholangitis
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.
|Primary biliary cholangitis|
|Other names||Primary biliary cirrhosis|
|Micrograph of PBC showing bile duct inflammation and injury. H&E stain.|
|Symptoms||Cholestasis, pruritus, fatigue|
|Complications||Cirrhosis, hepatic failure, portal hypertension|
|Usual onset||Usually middle-aged women|
|Diagnostic method||Anti-mitochondrial antibodies, liver biopsy|
PBC is a relatively rare disease, affecting up to 1 in 3–4,000 people. It is much more common in women, with a sex ratio of at least 9:1 female to male.
The condition has been recognised since at least 1851 and was named "primary biliary cirrhosis" in 1949. Because cirrhosis is a feature only of advanced disease, a change of its name to "primary biliary cholangitis" was proposed by patient advocacy groups in 2014.
Signs and symptoms
People with PBC experience fatigue (80 percent) that leads to sleepiness during the daytime; more than half of those have severe fatigue. Dry skin and dry eyes are also common. Itching (pruritus) occurs in 20–70 percent. People with more severe PBC 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.
PBC has an immunological basis, and is classified as an autoimmune disorder. It results from a slow, progressive destruction of the small bile ducts of the liver, with the intralobular ducts and the Canals of Hering (intrahepatic ductules) being affected early in the disease. This progresses to the development of fibrosis, cholestasis and, in some people, cirrhosis.
Most people with PBC (>90 percent) have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria. People who are negative for AMAs are usually found to be positive when more sensitive methods of detection are used.
People with PBC may also have been diagnosed with another autoimmune disease, such as a rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological condition, suggesting shared genetic and immune abnormalities. Common associations include Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, lupus, hypothyroidism and gluten sensitive enteropathy.
A genetic predisposition to disease has been thought to be important for some time. Evidence for this includes cases of PBC in family members, identical twins both having the condition (concordance), and clustering of PBC with other 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 aetiology 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.
A study of over 2000 patients identified a gene - POGLUT1 - that appeared to be associated with this condition. Earlier studies have also suggested that this gene may be involved. The implicated protein is an endoplasmic reticulum O-glucosyltransferase.
An environmental Gram negative alphabacterium — Novosphingobium aromaticivorans has been associated with this disease with several reports 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.
There is a failure of immune tolerance against the mitochondrial pyruvate dehydrogenase complex (PDC-E2), and this may also be the case with other proteins, including the gp210 and p62 nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients, and these proteins may be associated with prognosis.
- Abnormalities in liver enzyme tests are usually present and elevated gamma-glutamyl transferase and alkaline phosphatase (ALP) are found in early disease. Elevations in bilirubin occur in advanced disease.
- Antimitochondrial antibodies are the characteristic serological marker for PBC, being found in 90-95 percent of patients and only 1 percent 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 measurements are not diagnostic for PBC because they are not specific, but may 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 percent 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. This may be needed if a condition causing secondary biliary cirrhosis, such as other biliary duct disease or gallstones, needs to be excluded. A liver biopsy may help, and if uncertainty remains as in some patients, an endoscopic retrograde cholangiopancreatography (ERCP), an endoscopic investigation of the bile duct, may be 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.
On microscopic examination of liver biopsy specimens, PBC is characterized by interlobular bile duct destruction. These histopathologic findings in primary biliary cholangitis include the following:
- 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 (UDCA), marketed as Ursodiol and others, is the most frequently used treatment. It helps reduce the cholestasis and improves liver function tests. It has a minimal effect on symptoms and whether it improves outcomes is controversial. A Cochrane review from 2012 did not show any significant benefits on important outcomes including mortality, liver transplantation or PBC symptoms, even if some biochemical and histological parameters were improved.
- To relieve itching caused by bile acids in circulation, which are normally 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. Other drugs that do this 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 modafinil is no longer covered by patents, the limiting factor in its use 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.
- People with PBC may have poor lipid-dependent absorption of Vitamins A, D, E, K. Appropriate supplementation is recommended when bilirubin is elevated.
- People 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.
- The farnesoid X receptor agonist, obeticholic acid (marketed as Ocaliva), has been licensed by various regulatory authorities, including the United States Food and Drug Administration, as an orphan drug in an accelerated approval program. Obeticholic acid, which is a modified bile acid, produced a reduction in the level of the biomarker alkaline phosphatase, a surrogate endpoint for clinical benefit in PBC. It is indicated for the treatment of PBC in combination with ursodeoxycholic acid in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. Additional studies are being undertaken to verify and describe clinical benefit.
- Other drugs that are undergoing clinical studies in UDCA non-responders include fibrates, such as fenofibrate and bezafibrate, which are pan–peroxisome proliferator–activated receptor (PPAR) agonists with anti-inflammatory and choleretic (enhanced bile secretion) effects. Bezafibrate has been shown to improve biomarkers including alkaline phosphatase, but has not been licensed in PBC.
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.
Complications of PBC can be related to chronic cholestasis or cirrhosis of the liver. Chronic cholestasis leads to osteopenic bone disease and osteoporosis, alongside hyperlipidaemia and vitamin deficiencies.
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 percent in men and 4 percent in women.
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.
In 1851, Addison and Gull described the clinical picture of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. Although most sources credit Ahrens with coining the term in 1950, Dauphinee and Sinclair had used the name primary biliary cirrhosis for this disease in 1949. 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
The PBC Foundation is a UK-based international charity offering support and information to people with PBC, their families and friends. It campaigns for increasing recognition of the disorder, improved diagnosis and treatments, and estimates over 8000 people are undiagnosed in the UK. The Foundation has supported research into PBC including the development of the PBC-40 quality of life measure published in 2004 and helped establish the PBC Genetics Study. It was founded by Collette Thain in 1996, after she was diagnosed with the condition. Thain was awarded an MBE Order of the British Empire in 2004 for her work with the Foundation. The PBC Foundation helped initiate the name change campaign in 2014.
The PBCers Organization is a US-based non-profit patient support group that was founded by Linie Moore in 1996 and advocates for greater awareness of the disease and new treatments. It has supported the initiative for a change in name.
In 2014 the PBC Foundation, with the support of the PBCers Organization, the PBC Society (Canada) and other patient groups, advocated a change in name from "primary biliary cirrhosis" to "primary biliary cholangitis," noting that most PBC patients did not have cirrhosis and that "cirrhosis" often had negative connotations of alcoholism. Patient and professional groups were canvassed. Support for the name change came from professional bodies including the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Advocates for the name change published calls to adopt the new name in multiple hepatology journals in the fall of 2015.
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