Primary biliary cirrhosis: Difference between revisions
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==Therapy== | ==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. | 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.<ref>[[Modafinil#Primary_biliary_cirrhosis]]<br/>{{cite journal |author=Ian Gan S, de Jongh M, Kaplan MM |title=Modafinil in the treatment of debilitating fatigue in primary biliary cirrhosis: a clinical experience |journal=Dig. Dis. Sci. |volume=54 |issue=10 |pages=2242–6 |year=2009 |month=October |pmid=19082890 |doi=10.1007/s10620-008-0613-3 |url=http://www.springerlink.com/content/f0207x6110847113/}}<br/>{{cite journal |author=Kumagi T, Heathcote EJ |title=Primary biliary cirrhosis |journal=Orphanet J Rare Dis |volume=3 |pages=1 |year=2008 |pmid=18215315 |pmc=2266722 |doi=10.1186/1750-1172-3-1 |url=http://www.ojrd.com/content/3//1 |quote=[http://www.ojrd.com/content/3/1/1#B157 Ref 157 viz:]}}<br/>{{cite journal |author=Jones DE, Newton JL |title=An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis |journal=Aliment. Pharmacol. Ther. |volume=25 |issue=4 |pages=471–6 |year=2007 |month=February |pmid=17270003 |doi=10.1111/j.1365-2036.2006.03223.x |url=http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0269-2813&date=2007&volume=25&issue=4&spage=471}}</ref> 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.<ref>[[Modafinil#Patent_protection_and_antitrust_litigation]]<br/>{{cite journal |author=Carrier MA |title=Provigil: A Case Study of Anticompetitive Behavior |journal=Hastings Science & Technology Law Journal |volume=3 |issue=2 |pages=441–452 |year=2011 |url=http://hstlj.org/content/vol3/iss2/v3i2carrier.pdf |format=PDF}}</ref> The FTC has filed suit against Cephalon alleging anti-competitive behavior.<ref>http://www.ftc.gov/os/caselist/0610182/080213complaint.pdf</ref> | |||
* Patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K.<ref name="BaconO'Grady2006">{{cite book|author1=Bruce R. Bacon|author2=John G. O'Grady|title=Comprehensive clinical hepatology|url=http://books.google.com/?id=ec0G9HGiR8MC&pg=PA283|accessdate=29 June 2010|year=2006|publisher=Elsevier Health Sciences|isbn=978-0-323-03675-7|pages=283–}}</ref> Appropriate supplementation is recommended when bilirubin is elevated<ref>{{cite journal|last=Lindor|first=KD|coauthors=Gershwin, ME; Poupon, R; Kaplan, M; Bergasa, NV; Heathcote, EJ; American Association for Study of Liver, Diseases|title=Primary biliary cirrhosis.|journal=Hepatology (Baltimore, Md.)|date=2009 Jul|volume=50|issue=1|pages=291-308|pmid=19554543|doi=10.1002/hep.22906}}</ref>. Multivitamins (esp. Vitamin D) and calcium are also recommended. | |||
* Patients with PBC are at elevated risk of developing [[osteoporosis]]<ref>{{cite journal|last=Collier|first=Jane|title=Guidelines on the management of osteoporosis associated with chronic liver disease|journal=Gut|year=2002|volume=50|pages=i1-i9|pmid=11788576|accessdate=14 June 2012|pmc=1867644}}</ref> and [[esophageal varices]]<ref>{{cite journal|last=Ali|first=AH|coauthors=Sinakos, E; Silveira, MG; Jorgensen, RA; Angulo, P; Lindor, KD|title=Varices in early histological stage primary biliary cirrhosis.|journal=Journal of Clinical Gastroenterology|date=2011 Aug|volume=45|issue=7|pages=e66-71|pmid=20856137|doi=10.1097/MCG.0b013e3181f18c4e}}</ref> 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, [[alcoholic beverage]]s are contraindicated. | |||
As in all liver diseases, excessive consumption of [[alcohol]] is contraindicated. | |||
In advanced cases, a [[Liver transplantation|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 <ref>Medical care of the Liver Trasplant Patient, 3rd Edition published 2006, editied by Paul G. Killenberg, page 429</ref> | |||
[[Obeticholic acid]] is in phase III clinical trials for PBC.<ref>http://www.genengnews.com/gen-news-highlights/dainippon-sumitomo-pays-intercept-15m-for-phase-iii-liver-disease-drug/81244901/</ref> | |||
==References== | ==References== | ||
Revision as of 13:00, 27 July 2012
| 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]
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]
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.
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.[6]
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.[7]. Anti-np62[8] 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.[9]
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
- Xanthelasmata (focal collections of cholesterol in the skin, especially around the eyes)
- Complications of cirrhosis and portal hypertension:
- Esophageal varices
- Fluid retention in the abdomen (ascites)
- Hepatic encephalopathy, up to coma, in extreme cases.
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:
- Deranged liver function tests (high alkaline phosphatase, elevated AST, ALT)
- Presence of certain antibodies: antimitochondrial antibody antinuclear antibodies like Anti-glycoprotein-210 antibodies, Anti-centromere antibodies, anti-sp100. (the M2-IgG antimitochondrial antibody is the most specific test)
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.
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.
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.[10] 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.[11] The FTC has filed suit against Cephalon alleging anti-competitive behavior.[12]
- Patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K.[13] Appropriate supplementation is recommended when bilirubin is elevated[14]. Multivitamins (esp. Vitamin D) and calcium are also recommended.
- Patients with PBC are at elevated risk of developing osteoporosis[15] and esophageal varices[16] 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, alcoholic beverages are contraindicated.
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 [17]
Obeticholic acid is in phase III clinical trials for PBC.[18]
References
- ↑ 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.
- ↑ 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.
- ↑ Logan RF, Ferguson A, Finlayson ND, Weir DG (1978). "Primary biliary cirrhosis and coeliac disease: an association?". Lancet. 1 (8058): 230–3. PMID 74661.
- ↑ 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.
- ↑ 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.
- ↑ eMedicine > Primary Biliary Cirrhosis: Follow-up Author: Nikolaos T Pyrsopoulos. Coauthor: K Rajender Reddy. Updated: Dec 23, 2009
- ↑ 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.
- ↑ 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.
- ↑ Killenberg & Clavien (2006), p. 429.
- ↑ 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) - ↑ 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. - ↑ http://www.ftc.gov/os/caselist/0610182/080213complaint.pdf
- ↑ 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.
- ↑ 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) - ↑ 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) - ↑ 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) - ↑ Medical care of the Liver Trasplant Patient, 3rd Edition published 2006, editied by Paul G. Killenberg, page 429
- ↑ 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
- PBCers.org - patients' organisation
- Dr. Gershwin's research lab at UC Davis Many research papers online.
- PBC Foundation UK
- Howard J. Worman's Columbia University web site, with a clear overview of PBC
- AMA staining patterns
- Histopathology lecture on PBC
Template:SIB Template:Gastroenterology