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]

Contents

Signs and symptoms

The following signs may present in PBC:

Diagnosis

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. 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

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, 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.[19]

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.[20]

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.[21]

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.[22]

Additional images

References

  1. ^ Henryk Dancygier (1 January 2010). Clinical Hepatology Principles and Practice of. Springer. pp. 895–. ISBN 9783642045097. http://books.google.com/?id=lrPX8C4p90QC&pg=PA895. Retrieved 29 June 2010. 
  2. ^ a b Clavien, Pierre-Alain; Killenberg, Paul G. (2006). Medical Care of the Liver Transplant Patient: Total Pre-, Intra- and Post-Operative Management. Wiley-Blackwell. pp. 155. ISBN 1-4051-3032-6. 
  3. ^ Nakamura M, Kondo H, Mori T, et al. (2007). "Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis". Hepatology 45 (1): 118–127. doi:10.1002/hep.21472. PMID 17187436. 
  4. ^ Nesher G, Margalit R, Ashkenazi YJ (2001). "Anti-nuclear envelope antibodies: Clinical associations". Semin. Arthritis Rheum. 30 (5): 313–320. doi:10.1053/sarh.2001.20266. PMID 11303304. 
  5. ^ Nakanuma Y, Tsuneyama K, Sasaki M, Harada K (August 2000). "Destruction of bile ducts in primary biliary cirrhosis". Baillieres Best Pract Res Clin Gastroenterol 14 (4): 549–70. doi:10.1053/bega.2000.0103. PMID 10976014. 
  6. ^ Leung PS, Rossaro L, Davis PA, et al. (2007). "Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis". Hepatology 46 (5): 1436–42. doi:10.1002/hep.21828. PMID 17657817. 
  7. ^ Logan RF, Ferguson A, Finlayson ND, Weir DG (1978). "Primary biliary cirrhosis and coeliac disease: an association?". Lancet 1 (8058): 230–3. doi:10.1016/S0140-6736(78)90480-4. PMID 74661. 
  8. ^ Volta U, Rodrigo L, Granito A, et al. (2002). "Celiac disease in autoimmune cholestatic liver disorders". Am. J. Gastroenterol. 97 (10): 2609–13. doi:10.1111/j.1572-0241.2002.06031.x. PMID 12385447. 
  9. ^ Nakamura M, Takii Y, Ito M, et al. (2006). "Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis". J. Autoimmun. 26 (2): 138–45. doi:10.1016/j.jaut.2005.10.007. PMID 16337775. 
  10. ^ http://content.nejm.org/cgi/content/full/NEJMoa0810440
  11. ^ http://www.torontoliver.ca
  12. ^ Selmi C, Balkwill DL, Invernizzi P, Ansari AA, Coppel RL, Podda M, Leung PS, Kenny TP, Van De Water J, Nantz MH, Kurth MJ, Gershwin ME (2003) Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology 38(5):1250-1257
  13. ^ Mohammed JP, Mattner J (2009) Autoimmune disease triggered by infection with alphaproteobacteria. Expert Rev Clin Immunol 5(4):369-379
  14. ^ Kaplan MM (2004) Novosphingobium aromaticivorans: a potential initiator of primary biliary cirrhosis. Am J Gastroenterol 99(11):2147-2149
  15. ^ Selmi C, Gershwin ME (2004) Bacteria and human autoimmunity: the case of primary biliary cirrhosis. Curr Opin Rheumatol 16(4):406-410
  16. ^ Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, Pendem K, Teyton L, Hart J, Ridgway WM, Wicker LS, Gershwin ME, Bendelac A (2008) Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe 3(5):304-315
  17. ^ Mohammed JP, Fusakio ME, Rainbow DB, Moule C, Fraser HI, Clark J, Todd JA, Peterson LB, Savage PB, Wills-Karp M, Ridgway WM, Wicker LS, Mattner J (2011) Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity. J Immunol 187(1):337-349
  18. ^ Bruce R. Bacon; John G. O'Grady (2006). Comprehensive clinical hepatology. Elsevier Health Sciences. pp. 283–. ISBN 9780323036757. http://books.google.com/?id=ec0G9HGiR8MC&pg=PA283. Retrieved 29 June 2010. 
  19. ^ http://www.genengnews.com/gen-news-highlights/dainippon-sumitomo-pays-intercept-15m-for-phase-iii-liver-disease-drug/81244901/
  20. ^ eMedicine > Primary Biliary Cirrhosis: Follow-up Author: Nikolaos T Pyrsopoulos. Coauthor: K Rajender Reddy. Updated: Dec 23, 2009
  21. ^ Killenberg & Clavien (2006), p. 429.
  22. ^ Mitchison HC, Bassendine MF, Hendrick A, Bennett MK, Bird G, Watson AJ, James OF (1986) Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis? Hepatology 6(6):1279-1284

External links