Primary biliary cirrhosis

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Primary biliary cirrhosis
Classification and external resources

Micrograph of primary biliary cirrhosis showing bile duct inflammation and injury. H&E stain.
ICD-10K74.3
ICD-9571.6
OMIM109720
DiseasesDB10615
MedlinePlus000282
eMedicinemed/223
MeSHD008105
 
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Primary biliary cirrhosis
Classification and external resources

Micrograph of primary biliary cirrhosis showing bile duct inflammation and injury. H&E stain.
ICD-10K74.3
ICD-9571.6
OMIM109720
DiseasesDB10615
MedlinePlus000282
eMedicinemed/223
MeSHD008105

Primary biliary cirrhosis, often abbreviated PBC, is an autoimmune disease of the liver[1] marked by the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver. When these ducts are damaged, bile builds up in the liver (cholestasis) 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 (female to male).[2]

Contents

Signs and symptoms

Individuals with PBC may present with the following:

Diagnosis

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.

To diagnose PBC, distinctions should be established from other conditions with similar symptoms, such as autoimmune hepatitis or primary sclerosing cholangitis (PSC).

Diagnostic blood tests include:

Abdominal ultrasound or a CT scan is usually performed to rule out blockage to the bile ducts. Previously most suspected sufferers underwent a liver biopsy, and — if uncertainty remained — endoscopic retrograde cholangiopancreatography (ERCP, an endoscopic investigation of the bile duct). Now most patients are diagnosed without invasive investigation since the combination of anti-mitochondrial antibodies (see below) and typical (cholestatic) 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 progression toward end stage liver failure. Anti-centromere antibodies correlate with developing portal hypertension.[3] Anti-np62[4] 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:[5]

Summary of stages

Etiology

The cause of the disease is unknown at this time, but research indicates that there is an immunological basis for the disease, making it an autoimmune disorder. Most of the patients (>90%) seem to have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), 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.[6][7] 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.[8] 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.[9][10] 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.[11][12]

In 2003 it was reported that an environmental Gram negative alphabacterium — Novosphingobium aromaticivorans[13] was strongly associated with this disease. Subsequent reports appear to have confirmed this finding suggesting an aetiological role for this organism.[14][15][16] The mechanism appears to be a cross reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells.[17] The gene encoding CD101 may also play a role in host susceptibility to this disease.[18]

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. Specific treatment for fatigue, which may be debilitating in some patients, is limited and currently undergoing trials.

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.[26]

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.[2]

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.[27]

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.[28]

Patients with primary biliary cirrhosis have an increased risk of hepatocellular carcinoma.

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 1986.[29]

Additional images

References

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