Primary biliary cirrhosis

Primary biliary cirrhosis
Classification and external resources
Micrograph of primary biliary cirrhosis showing bile duct inflammation and injury. H&E stain.
ICD-10	K74.3
ICD-9	571.6
OMIM	109720
DiseasesDB	10615
eMedicine	med/223
MeSH	D008105

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]

Signs and symptoms

The following signs may present in PBC:

• Fatigue
• Pruritus (itchy skin)
• Jaundice (yellowing of the eyes and skin), due to increased bilirubin in the blood.
• Xanthoma (local collections of cholesterol in the skin, especially around the eyes (Xanthelasma))
• Complications of cirrhosis and portal hypertension:
  • Fluid retention in the abdomen (ascites)
  • Hypersplenism
  • Esophageal varices
  • Hepatic encephalopathy, up to coma, in extreme cases.
• Association with an extrahepatic autoimmune disorder such as Rheumatoid arthritis or Sjögren's syndrome (up to 80% incidence).

Diagnosis

Intermediate magnification micrograph of PBC showing bile duct inflammation and periductal granulomas. Liver biopsy. H&E stain.

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:

• Deranged liver function tests (elevated gamma-glutamyl transferase and alkaline phosphatase)
• Presence of certain antibodies: antimitochondrial antibody(AMA), antinuclear antibody(ANA)

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]

• 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

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. In addition, a more specific test to confirm this disease from a bone disorder such as Paget's disease which also has increases in Alkaline phosphatase is the Gamma-glutamyl transpeptidase test (GGT). An increase in GGT could indicate presence of Primary Biliary Cirrhosis. 57% of patients with acute liver failure have anti-transglutaminase antibodies^[6] suggesting a role of gluten sensitivity in primary biliary cirrhosis, and primary biliary cirrhosis is considerably more common in gluten sensitive enteropathy than the normal population.^[7][8] 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.^[9] 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 genome scan of PBC patients.^[10][11] 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, suggesting future therapeutic targets.

In 2003 it was reported that an environmental Gram negative alphabacterium — Novosphingobium aromaticivorans^[12] was strongly associated with this disease. Subsequent reports appear to have confirmed this finding suggesting an aetiological role for this organism. ^[13][14][15] The mechanism appears to be a cross reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells.^[16] The gene encoding CD101 may also play a role in host susceptability to this disease.^[17]

Therapy

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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.

• 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

• To relieve fatigue associated with primary biliary cirrhosis, current studies indicate that Provigil (modafinil) may be effective without damaging the liver. ^[18] 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.^[19] The FTC has filed suit against Cephalon alleging anti-competitive behavior.^[20] Currently, Modalert® 200 modafinil tablets, manufactured by Sun Pharma Sikkim, has a "Maximum Retail Price Rs per strip of 10 Tablets, inclusive of all Taxes" of 129.00 INR which is equivalent to approximately $0.25 US per pill. The equivalent cost for 200mg Provigil tablets in the US at a Costco in Portland, OR is approximately $17.00 US per pill. As usage of modafinil for PBC related fatigue is an off-label use, insurance companies will not cover it's cost.

• Patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K.^[21] Multivitamins (esp. Vitamin D) and calcium are recommended.^{[citation needed]}

As in all liver diseases, alcoholic beverages are contraindicated.

In advanced cases, a liver transplant, if successful, results in a favorable prognosis.

Obeticholic acid is in phase III clinical trials for PBC.^[22]

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.^[23]

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.^[24]

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.^[25]

Additional images

• 

  Low magnification micrograph of PBC. H&E stain.

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