Primary biliary cirrhosis, often abbreviated PBC, is an autoimmune disease of the liver
marked by the slow progressive destruction of the small bile ducts of the liver, with
the intralobular ducts affected early in the disease. When these ducts are damaged, bile
builds up in the liver and over time damages the tissue. This can lead to scarring, fibrosis
and cirrhosis. It was previously thought to be a rare disease, but more recent studies
have shown that it may affect up to 1 in 3–4,000 people; the sex ratio is at least 9:1.
Signs and symptoms Individuals with PBC may present with the
following: Fatigue
Pruritus Jaundice, due to increased bilirubin in the
blood. Xanthoma)
Complications of cirrhosis and portal hypertension: Fluid retention in the abdomen
Enlarged spleen Esophageal varices
Hepatic encephalopathy, including coma in extreme cases.
Association with an extrahepatic autoimmune disorder such as rheumatoid arthritis or Sjögren's
syndrome. Causes
The cause of the disease is currently unknown, but research indicates that there is an immunological
basis for the disease, making it an autoimmune disorder. Most of the patients seem to have
anti-mitochondrial antibodies against pyruvate dehydrogenase complex, an enzyme complex that
is found in the mitochondria. Primary biliary cirrhosis is considerably
more common in those with gluten sensitive enteropathy than the normal population. 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, distinctions should be established from other conditions with similar symptoms,
such as autoimmune hepatitis or primary sclerosing cholangitis.
Diagnostic blood tests include: Deranged liver function tests
Presence of certain antibodies: antimitochondrial antibody, antinuclear antibody
Abdominal ultrasound 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 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 and typical liver function 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.
Biopsy Primary biliary cirrhosis is characterized
by interlobular bile duct destruction. Histopathologic findings of primary biliary cirrhosis include
the following: 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.
Therapy 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 is the most frequently
used treatment. This helps reduce the cholestasis and improves blood test results. 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 may be prescribed to absorb bile acids in the gut and be eliminated,
rather than re-enter the blood stream. Alternative agents include naltrexone and rifampicin.
Specific treatment for fatigue, which may be debilitating in some patients, is limited
and undergoing trials. Some studies indicate that Provigil 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, excessive consumption of alcohol is contraindicated.
In advanced cases, a liver transplant, if successful, results in a favorable prognosis.
Obeticholic acid is in phase III clinical trials for PBC.
Epidemiology The female:male ratio is at least 9:1. 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. Prognosis
The serum bilirubin level is an indicator of the prognosis of primary biliary cirrhosis,
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 primary biliary cirrhosis 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.
History 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. In
1986, the presence of anti-mitochondrial antibodies as a marker of early, pre-cirrhotic disease
was recognised. Additional images
References
External links Primary Biliary Cirrhosis page from the National
Digestive Diseases Information Clearinghouse Primary Biliary Cirrhosis page from the American
Liver Foundation PBCers.org — patients' organisation
PBC-Society.ca — Canadian PBC patient and research support
PBC Foundation UK UK PBC - UK PBC research