Primary biliary cirrhosis

Primary biliary cirrhosis
Synonyms	Primary biliary cholangitis
Micrograph of PBC showing bile duct inflammation and injury. H&E stain.
Classification and external resources
Specialty	Gastroenterology
ICD-10	K74.3
ICD-9-CM	571.6
OMIM	109720
DiseasesDB	10615
MedlinePlus	000282
eMedicine	med/223
Patient UK	Primary biliary cirrhosis
MeSH	D008105

Primary biliary cirrhosis, also known as primary biliary cholangitis (PBC), is an autoimmune disease of the liver.^[1][2][3] It is marked by slow progressive destruction of the small bile ducts of the liver, with the intralobular ducts and the Canals of Hering (intrahepatic ductules) affected early in the disease.^[4] When these ducts are damaged, bile and other toxins build up in the liver (cholestasis) and slowly damage the liver tissue in combination with ongoing immune-related damage. This can lead to scarring, fibrosis, and cirrhosis.

PBC is a relatively rare disease, with some studies showing that it affects up to 1 in 3–4,000 people.^[5][6] The sex ratio is at least 9:1 female to male.^[1]

It was named by Dauphinee and Sinclair in 1949.^[7] Because cirrhosis is a feature of only advanced disease, a change of its name to "primary biliary cholangitis" was proposed by patient advocacy groups in 2014.^[8][9] Use of the new name was advocated in the medical literature in September 2015.^[10]

Signs and symptoms

An explanation of cholestatic liver disease of which primary biliary cirrhosis is a type

People with PBC experience fatigue (80%) that leads to sleepiness during the daytime; more than half of those have severe fatigue. 20–70% have itching.^[11] Those with more severe disease may have jaundice (yellowing of the eyes and skin).^[11] PBC impairs bone density and there is an increased risk of fracture.^[11] Xanthelasma (skin lesions around the eyes) or other xanthoma may be present as a result of increased cholesterol levels.^[12]

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).^[12][13]

Causes

The cause of the disease is attributed to an immunological basis for the disease, making it an autoimmune disorder.^[14] 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.^[1] Those 'negative' for AMAs are usually found to be positive when more sensitive methods of detection are used.^[15]

Many PBC patients have a concomitant autoimmune disease, including rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological conditions, which suggests shared genetic and immune abnormalities.^[13] Common associations include Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, lupus, hypothyroidism and gluten sensitive enteropathy.^{[13][16][17][18]} 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.^[19] 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.^[14] 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.^[20][21] 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.^[22][23]

In 2003 it was reported that an environmental Gram negative alphabacterium — Novosphingobium aromaticivorans^[24] was strongly associated with this disease. Subsequent reports appear to have confirmed this finding suggesting an aetiological role for this organism.^[25][26][27] The mechanism appears to be a cross reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells.^[28] The gene encoding CD101 may also play a role in host susceptibility to this disease.^[29]

Diagnosis

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

• Abnormalities in liver enzyme tests are usually present and elevated gamma-glutamyl transferase and alkaline phosphatase are found in early disease.^[12] Elevations in bilirubin occur in advanced disease.
• Antimitochondrial antibodies 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.^[12] 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.^[30]
• Other auto-antibodies may be present:

Antinuclear antibody measurements are not diagnostic 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% of PBC patients.^[31][32]

Anti-centromere antibodies often correlate with developing portal hypertension.^[33]

Anti-np62^[34] 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.

• 
  Low magnification micrograph of PBC. H&E stain.
• 
  Intermediate magnification micrograph of PBC showing bile duct inflammation and periductal granulomas. Liver biopsy. H&E stain.
• 
  Immunofluorescence staining pattern of sp100 antibodies (nuclear dots) and AMA.

Biopsy

PBC is characterized by interlobular bile duct destruction. Histopathologic findings of primary biliary cholangitis include the following:^[35]

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

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.

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.^[12][36][37]

• Ursodeoxycholic acid (Ursodiol) 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 prognosis is controversial.^[38][12]
• 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.^[36][37][39]
• Specific treatment for fatigue, which may be debilitating in some patients, is limited and undergoing trials.^[40] Some studies indicate that Provigil (modafinil) may be effective without damaging the liver.^[41] 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.^[42] The FTC has filed suit against Cephalon alleging anti-competitive behavior.^[43]
• Patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K.^[44] Appropriate supplementation is recommended when bilirubin is elevated.^[12]
• Patients with PBC are at elevated risk of developing osteoporosis^[45] and esophageal varices^[46] 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.^[47][48]

The farnesoid X receptor agonist, obeticholic acid, which is a modified bile acid, was approved by the United States Food and Drug Administration on May 27, 2016, as an orphan drug in an accelerated approval program, based on its reduction in the level of the biomarker alkaline phosphatase, as a surrogate endpoint for clinical benefit.^[49][50] It is indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.^[51] Additional studies are being required to prove its clinical benefit.^[52]

Epidemiology

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.^[1][53] 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.^[5][6] 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.

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.^[54]

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.^[55]

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% in men and 4% in women.^[56]

History

In 1951, 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.^[7] The association with anti-mitochondrial antibodies was first reported in 1965^[57] and their presence was recognized as a marker of early, pre-cirrhotic disease.^[58]

Society and culture

Support groups

PBC Foundation

The PBC Foundation is a UK-based international charity offering support and information to people with PBC, their families and friends.^[59] It campaigns for increasing recognition of the disorder, improved diagnosis and treatments, and estimates over 8000 people are undiagnosed in the UK.^[60][61] The Foundation has supported research into PBC including the development of the PBC-40 quality of life measure published in 2004^[62] and helped establish the PBC Genetics Study.^[22][63] It was founded by Collette Thain in 1996, after she was diagnosed with the condition.^[60] Thain was awarded an MBE Order of the British Empire in 2004 for her work with the Foundation.^[64] The PBC Foundation helped initiate the name change campaign in 2014.^[8][9][65]

PBCers

The PBCers is a US-based patient support group that was founded in 1996 and advocates for greater awareness of the disease and new treatments.^[66] It has supported the initiative for a change in name.^[9]

Name

In 2014 the PBC Foundation, with the support of the PBCers, the PBC Society (Canada)^[67] and other patient groups, advocated a change in name from "primary biliary cirrhosis" to "primary biliary cholangitis", citing that most PBC patients did not have cirrhosis and that this often had negative connotations of alcoholism.^[8][9][65] Patient and professional groups were canvassed.^[68] Support for this name change came from professional bodies including the American Association for the Study of Liver Diseases^[69] and the European Association for the Study of the Liver.^[70] Advocates for the name change published calls to adopt the new name in multiple hepatology journals in the fall of 2015.^{[10][68][70][71]}

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External links

• Primary Biliary Cirrhosis page from the National Digestive Diseases Information Clearinghouse