Primary biliary cirrhosis

Jump to navigation Jump to search
Primary biliary cirrhosis
ICD-10 K74.3
ICD-9 571.6
DiseasesDB 10615
MeSH D008105

Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Prashanth Saddala M.B.B.S

Overview

Primary biliary cirrhosis is an autoimmune disease of the liver 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, cirrhosis, and ultimately liver failure.

Historical Perspective

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.[1]

Pathophysiology

Histopathology

{{#ev:youtube|Jj8ozr_IttM&mode=related&search=}}

Causes

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 of bone) which also has increases in Alkaline phosphatase is the Gamma-glutamyl trans peptidase test (GGTP). An increase in GGTP could indicate presence of Primary Biliary Cirrhosis.

57% of patients with acute liver failure have anti-transglutaminase antibodies[2] suggesting a role of gluten sensitivity in primary biliary cirrhosis, and primary biliary cirrhosis is considerable more common in gluten sensitive enteropathy than the normal population.[3][4]

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.[5] 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.[6][7] 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[8] was strongly associated with this disease. Subsequent reports appear to have confirmed this finding suggesting an aetiological role for this organism.[9][10][11] The mechanism appears to be a cross reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells.[12] The gene encoding CD101 may also play a role in host susceptibility to this disease.[13]

Epidemiology and Demographics

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.

Natural history, Complications and Prognosis

Complicatons

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

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.[14]

Anti-nuclear antibodies appear to be prognostic agents in PBC. Anti-glycoprotein-210 antibodies, and to a lessor degree anti-p62 antibodies correlate with progression toward end stage liver failure. Anti-centromere antibodies correlate with developing portal hypertension.[15]. Anti-np62[16] and anti-sp100 are also found in association with PBC.

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.[17]

Diagnosis

History and Symptoms

The following symptoms may be present in PBC:

  • Fatigue
  • Pruritus (itchy skin)
  • Jaundice (yellowing of the eyes and skin), due to increased bilirubin in the blood.
  • Association with an extrahepatic autoimmune disorder such as Rheumatoid Arthritis or Sjögren syndrome (up to 80% incidence).

Physical Examination

On physical examination, the following may be present

Laboratory tests

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:

Liver Biopsy

Primary biliary cirrhosis is characterized by interlobular bile duct destruction. Histopathologic findings of primary biliary cirrhosis include:[18]

A liver biopsy is necessary to determine the stage of disease.

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 pattern.

Other Diagnostic studies

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.

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.

  • 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. Alternative agents include naltrexone and rifampicin.
  • To relieve fatigue associated with primary biliary cirrhosis, current studies indicate that Provigil (modafinil) may be effective without damaging the liver.[19] 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.[20] The FTC has filed suit against Cephalon alleging anti-competitive behavior.[21]
  • Patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K.[22] Appropriate supplementation is recommended when bilirubin is elevated[23]. Multivitamins (esp. Vitamin D) and calcium are also recommended.
  • Patients with PBC are at elevated risk of developing osteoporosis[24] and esophageal varices[25] 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. 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 [26]

Obeticholic acid is in phase III clinical trials for PBC.[27]

References

  1. Mitchison HC, Bassendine MF, Hendrick A; et al. (1986). "Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis?". Hepatology. 6 (6): 1279–84. doi:10.1002/hep.1840060609. PMID 3793004.
  2. Leung PS, Rossaro L, Davis PA; et al. (2007). "Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis". doi:10.1002/hep.21828. PMID 17657817.
  3. Logan RF, Ferguson A, Finlayson ND, Weir DG (1978). "Primary biliary cirrhosis and coeliac disease: an association?". Lancet. 1 (8058): 230–3. PMID 74661.
  4. Volta U, Rodrigo L, Granito A; et al. (2002). "Celiac disease in autoimmune cholestatic liver disorders". Am. J. Gastroenterol. 97 (10): 2609–13. PMID 12385447.
  5. 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.
  6. Hirschfield GM, Liu X, Xu C; et al. (2009). "Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants". N. Engl. J. Med. 360 (24): 2544–55. doi:10.1056/NEJMoa0810440. PMC 2857316. PMID 19458352. Unknown parameter |month= ignored (help)
  7. http://www.torontoliver.ca
  8. Selmi C, Balkwill DL, Invernizzi P; et al. (2003). "Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium". Hepatology. 38 (5): 1250–7. doi:10.1053/jhep.2003.50446. PMID 14578864. Unknown parameter |month= ignored (help)
  9. Mohammed JP, Mattner J (2009). "Autoimmune disease triggered by infection with alphaproteobacteria". Expert Rev Clin Immunol. 5 (4): 369–379. doi:10.1586/ECI.09.23. PMC 2742979. PMID 20161124. Unknown parameter |month= ignored (help)
  10. Kaplan MM (2004). "Novosphingobium aromaticivorans: a potential initiator of primary biliary cirrhosis". Am. J. Gastroenterol. 99 (11): 2147–9. doi:10.1111/j.1572-0241.2004.41121.x. PMID 15554995. Unknown parameter |month= ignored (help)
  11. Selmi C, Gershwin ME (2004). "Bacteria and human autoimmunity: the case of primary biliary cirrhosis". Curr Opin Rheumatol. 16 (4): 406–10. PMID 15201604. Unknown parameter |month= ignored (help)
  12. Mattner J, Savage PB, Leung P; et al. (2008). "Liver autoimmunity triggered by microbial activation of natural killer T cells". Cell Host Microbe. 3 (5): 304–15. doi:10.1016/j.chom.2008.03.009. PMC 2453520. PMID 18474357. Unknown parameter |month= ignored (help)
  13. Mohammed JP, Fusakio ME, Rainbow DB; et al. (2011). "Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity". J. Immunol. 187 (1): 337–49. doi:10.4049/jimmunol.1003525. PMC 3134939. PMID 21613619. Unknown parameter |month= ignored (help)
  14. eMedicine > Primary Biliary Cirrhosis: Follow-up Author: Nikolaos T Pyrsopoulos. Coauthor: K Rajender Reddy. Updated: Dec 23, 2009
  15. 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): 118–27. doi:10.1002/hep.21472. PMID 17187436.
  16. Nesher G, Margalit R, Ashkenazi YJ (2001). "Anti-nuclear envelope antibodies: Clinical associations". Semin. Arthritis Rheum. 30 (5): 313–20. doi:10.1053/sarh.2001.20266. PMID 11303304.
  17. Killenberg & Clavien (2006), p. 429.
  18. Nakanuma Y, Tsuneyama K, Sasaki M, Harada K (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. Unknown parameter |month= ignored (help)
  19. Modafinil#Primary_biliary_cirrhosis
    Ian Gan S, de Jongh M, Kaplan MM (2009). "Modafinil in the treatment of debilitating fatigue in primary biliary cirrhosis: a clinical experience". Dig. Dis. Sci. 54 (10): 2242–6. doi:10.1007/s10620-008-0613-3. PMID 19082890. Unknown parameter |month= ignored (help)
    Kumagi T, Heathcote EJ (2008). "Primary biliary cirrhosis". Orphanet J Rare Dis. 3: 1. doi:10.1186/1750-1172-3-1. PMC 2266722. PMID 18215315. Ref 157 viz:
    Jones DE, Newton JL (2007). "An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis". Aliment. Pharmacol. Ther. 25 (4): 471–6. doi:10.1111/j.1365-2036.2006.03223.x. PMID 17270003. Unknown parameter |month= ignored (help)
  20. Modafinil#Patent_protection_and_antitrust_litigation
    Carrier MA (2011). "Provigil: A Case Study of Anticompetitive Behavior" (PDF). Hastings Science & Technology Law Journal. 3 (2): 441–452.
  21. http://www.ftc.gov/os/caselist/0610182/080213complaint.pdf
  22. Bruce R. Bacon; John G. O'Grady (2006). Comprehensive clinical hepatology. Elsevier Health Sciences. pp. 283–. ISBN 978-0-323-03675-7. Retrieved 29 June 2010.
  23. Lindor, KD (2009 Jul). "Primary biliary cirrhosis". Hepatology (Baltimore, Md.). 50 (1): 291–308. doi:10.1002/hep.22906. PMID 19554543. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  24. Collier, Jane (2002). "Guidelines on the management of osteoporosis associated with chronic liver disease". Gut. 50: i1–i9. PMC 1867644. PMID 11788576. |access-date= requires |url= (help)
  25. Ali, AH (2011 Aug). "Varices in early histological stage primary biliary cirrhosis". Journal of Clinical Gastroenterology. 45 (7): e66–71. doi:10.1097/MCG.0b013e3181f18c4e. PMID 20856137. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  26. Medical care of the Liver Trasplant Patient, 3rd Edition published 2006, editied by Paul G. Killenberg, page 429
  27. http://www.genengnews.com/gen-news-highlights/dainippon-sumitomo-pays-intercept-15m-for-phase-iii-liver-disease-drug/81244901/

Sources

Medical

  • Online Mendelian Inheritance in Man (OMIM) 109720
  • M. Eric Gershwin, John M. Vierling, Michael P. Manns, eds. Liver Immunology. Philadelphia, Pa.: Hanley and Belfus, 2003. ISBN 1-56053-499-0. (State of the art; technical.)
  • Marshall M. Kaplan, and M. Eric Gershwin, "Primary Biliary Cirrhosis", New Engl. J. of Medicine, 353:1261-1273 September 22, 2005 Number 12 . Review article
  • Carlo Selmi, Ross L. Coppel, and M. Eric Gershwin, "Primary Biliary Cirrhosis", in Noel R. Rose, Ian R. Mackey, eds, The Autoimmune Diseases, 4th edition, Academic Press, 2006

General

  • Sanjiv Chopra. The Liver Book: A Comprehensive Guide to Diagnosis, Treatment, and Recovery, Atria, 2002, ISBN 0-7434-0585-4
  • Melissa Palmer. Dr. Melissa Palmer's Guide to Hepatitis and Liver Disease: What You Need to Know, Avery Publishing Group; Revised edition May 24, 2004, ISBN 1-58333-188-3. her webpage.
  • Howard J. Worman. The Liver Disorders Sourcebook, McGraw-Hill, 1999, ISBN 0-7373-0090-6.

See also

External links

de:Primär biliäre Zirrhose sv:primär biliär cirrhos


Template:WikiDoc Sources