Primary biliary cirrhosis
|PBC (Primary biliary cholangitis or primary biliary cirrhosis)|
|Classification and external resources|
|Patient UK||Primary biliary cirrhosis|
The condition known by its abbreviation PBC, standing for primary biliary cirrhosis, is an autoimmune disease of the liver. It is marked by slow progressive destruction of the small bile ducts of the liver, with the intralobular ducts (Canals of Hering) affected early in the disease. When these ducts are damaged, bile and other toxins build up in the liver (cholestasis) and over time damages the liver tissue in combination with ongoing immune related damage. This can lead to scarring, fibrosis and cirrhosis. As cirrhosis is only a feature of advanced disease, a change of name to primary biliary cholangitis was proposed in 2014. This retains the initials of PBC but reflects more accurately the nature of the disease. It has not yet (April 2015) been adopted in scientific publications.
Signs and symptoms
Individuals with PBC with disease may present with the following:
- Pruritus (itchy skin)
- Jaundice (yellowing of the eyes and skin), due to increased bilirubin in the blood in more advanced disease.
- Xanthoma (local collections of cholesterol in the skin, especially around the eyes (xanthelasma))
- Complications of cirrhosis and portal hypertension: in more advanced disease
- Association with an extrahepatic autoimmune disorder such as rheumatoid arthritis or Sjögren's syndrome (in up to 80% of cases).
The cause of the disease is attributed to an immunological basis for the disease, making it an autoimmune disorder. Most of the patients (>90%) have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria.
Many PBC patients have a concomitant autoimmune disease, including rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological conditions, which suggests shared genetic and immune abnormalities. Common associations include Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, SLE, hypothyroidism and gluten sensitive enteropathy. 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. 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. 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.
In 2003 it was reported that an environmental Gram negative alphabacterium — Novosphingobium aromaticivorans was strongly associated with this disease. Subsequent reports appear to have confirmed this finding suggesting an aetiological role for this organism. The mechanism appears to be a cross reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells. The gene encoding CD101 may also play a role in host susceptibility to this disease.
Diagnostic blood tests include:
- Elevated liver enzyme tests (elevated gamma-glutamyl transferase and alkaline phosphatase)
- Presence of certain antibodies: antimitochondrial antibody (AMA), antinuclear antibody (ANA)
Abdominal ultrasound, MR scanning (MRCP) or a CT scan is usually performed to rule out blockage to the bile ducts. Most suspected cases have a liver biopsy performed, and if uncertainty remains an is some patients, endoscopic retrograde cholangiopancreatography or ERCP, where an endoscopic investigation of the bile duct is performed. Most patients are diagnosed without invasive investigation, as the combination of anti-mitochondrial antibodies (see below) and typical (cholestatic) liver enzyme 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 the disease's progression toward end stage liver failure. Anti-centromere antibodies often correlate with developing portal hypertension. Anti-np62 and anti-sp100 are also found in association with PBC.
- 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 or jigsaw puzzle pattern.
- 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 stanozolol, naltrexone and rifampicin.
- Specific treatment for fatigue, which may be debilitating in some patients, is limited and undergoing trials. Some studies indicate that Provigil (modafinil) may be effective without damaging the liver. 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. The FTC has filed suit against Cephalon alleging anti-competitive behavior.
- Patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K. Appropriate supplementation is recommended when bilirubin is elevated.
- Patients with PBC are at elevated risk of developing osteoporosis and esophageal varices 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, consumption of alcohol is contraindicated.
PBC is a chronic autoimmune liver disease with a female gender predominance with female:male ratio is at least 9:1 and a peak incidence in the fifth decade of life. 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.
The serum bilirubin level is an indicator of the prognosis of PBC, 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.
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.
Patients with PBC have an increased risk of hepatocellular carcinoma compared to the general population, as is found in other cirrhotic patients. In patients with advanced disease, one series found an incidence of 20% in men and 4% in women.
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 1965 and their presence was recognised as a marker of early, pre-cirrhotic disease.
A wave of activity to change the name from "Primary Biliary Cirrhosis" to "Primary Biliary Cholangitis", initiated in the patient community, has moved forward rapidly since 2014. This name change initiative is justified as over 80% of patients at the time of diagnosis of “PBC” do not have cirrhosis. Patients' organisations (PBCers.org, PBC Foundation UK) have been strong advocates for this name change. The seed for this change was planted at the PBC meeting in London, prior to EASL 2014, with a panel of patient advocates and experts expressing support after the meeting. At the EASL symposium in Milan in May 2014 of the PBC Foundation, many of the presentations by experts embraced the name change, and the results of a global survey were presented supporting this new moniker. This global survey, with over 1100 respondents from the patient and provider community, reached a nearly unanimous “vote” in favor of name change, and supported using "Primary Biliary Cholangitis", to preserve the PBC initials. The United States PBCers group has been involved with this name change initiative from its inception in April 2014. It has sought support for this from the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver, and also advocated that this change be reflected in the International Classification of Disease (ICD11).
- Hirschfield, GM; Gershwin, ME (Jan 24, 2013). "The immunobiology and pathophysiology of primary biliary cirrhosis.". Annual review of pathology 8: 303–30. doi:10.1146/annurev-pathol-020712-164014. PMID 23347352.
- Dancygier, Henryk (2010). Clinical Hepatology Principles and Practice of. Springer. pp. 895–. ISBN 978-3-642-04509-7. Retrieved 29 June 2010.
- Saxena R, Theise N; Theise (February 2004). "Canals of Hering: recent insights and current knowledge". Semin. Liver Dis. 24 (1): 43–8. doi:10.1055/s-2004-823100. PMID 15085485.
- PBCers Organization. ""Primary Biliary Cirrhosis Name Change Initiative"" (PDF).
- Clavien, Pierre-Alain; Killenberg, Paul G. (2006). Medical Care of the Liver Transplant Patient: Total Pre-, Intra- and Post-Operative Management. Wiley-Blackwell. p. 155. ISBN 1-4051-3032-6.
- Floreani A, Franceschet I, Cazzagon N (2014). "Primary biliary cirrhosis: overlaps with other autoimmune disorders". Semin. Liver Dis. 34 (3): 352–60. doi:10.1055/s-0034-1383734. PMID 25057958.
- Watt FE, James OF, Jones DE (2004). "Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study". QJM 97 (7): 397–406. PMID 15208427.
- Logan RF, Ferguson A, Finlayson ND, Weir DG; Ferguson; Finlayson; Weir (1978). "Primary biliary cirrhosis and coeliac disease: an association?". Lancet 1 (8058): 230–3. doi:10.1016/S0140-6736(78)90480-4. 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. doi:10.1111/j.1572-0241.2002.06031.x. 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.
- Hirschfield GM, Liu X, Xu C et al. (June 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.
- Liu JZ, Almarri MA, Gaffney DJ et al. (October 2012). "Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis". Nat. Genet. 44 (10): 1137–41. doi:10.1038/ng.2395. PMC 3459817. PMID 22961000.
- Juran BD, Hirschfield GM, Invernizzi P; and others; Invernizzi; Atkinson; Li; Xie; Kosoy; Ransom; Sun; Bianchi; Schlicht; Lleo; Coltescu; Bernuzzi; Podda; Lammert; Shigeta; Chan; Balschun; Marconi; Cusi; Heathcote; Mason; Myers; Milkiewicz; Odin; Luketic; Bacon; Bodenheimer Jr; Liakina (December 2012). "Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants". Hum. Mol. Genet. 21 (23): 5209–21. doi:10.1093/hmg/dds359. PMC 3490520. PMID 22936693.
- Selmi C, Balkwill DL, Invernizzi P et al. (November 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.
- Mohammed JP, Mattner J; Mattner (July 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.
- Kaplan MM (November 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.
- Selmi C, Gershwin ME; Gershwin (July 2004). "Bacteria and human autoimmunity: the case of primary biliary cirrhosis". Curr Opin Rheumatol 16 (4): 406–10. doi:10.1097/01.bor.0000130538.76808.c2. PMID 15201604.
- Mattner J, Savage PB, Leung P et al. (May 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.
- Mohammed JP, Fusakio ME, Rainbow DB et al. (July 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.
- Nakamura M, Kondo H, Mori T; and others; Mori; Komori; Matsuyama; Ito; Takii; Koyabu; Yokoyama; Migita; Daikoku; Abiru; Yatsuhashi; Takezaki; Masaki; Sugi; Honda; Adachi; Nishi; Watanabe; Nakamura; Shimada; Komatsu; Saito; Saoshiro; Harada; Sodeyama; Hayashi; Masumoto; Sando (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.
- Nesher G, Margalit R, Ashkenazi YJ; Margalit; Ashkenazi (2001). "Anti-nuclear envelope antibodies: Clinical associations". Semin. Arthritis Rheum. 30 (5): 313–320. doi:10.1053/sarh.2001.20266. PMID 11303304.
- Nakanuma Y, Tsuneyama K, Sasaki M, Harada K; Tsuneyama; Sasaki; Harada (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.
- Levy C, Lindor KD; Lindor (April 2003). "Treatment Options for Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis". Curr Treat Options Gastroenterol 6 (2): 93–103. doi:10.1007/s11938-003-0010-0. PMID 12628068.
- Oo YH, Neuberger J; Neuberger (2004). "Options for treatment of primary biliary cirrhosis". Drugs 64 (20): 2261–71. doi:10.2165/00003495-200464200-00001. PMID 15456326.
- Gluud C, Christensen E; Christensen (2002). "Ursodeoxycholic acid for primary biliary cirrhosis". Cochrane Database Syst Rev (1): CD000551. doi:10.1002/14651858.CD000551. PMID 11869580.
- Walt RP, Daneshmend TK, Fellows IW, Toghill PJ (1988). "Effect of stanozolol on itching in primary biliary cirrhosis". Br Med J (Clin Res Ed) 296 (6622): 607. PMC 2545238. PMID 3126923.
- Abbas G, Jorgensen RA, Lindor KD; Jorgensen; Lindor (June 2010). "Fatigue in primary biliary cirrhosis". Nat Rev Gastroenterol Hepatol 7 (6): 313–9. doi:10.1038/nrgastro.2010.62. PMID 20458334.
- Modafinil#Primary biliary cirrhosis
Ian Gan S, de Jongh M, Kaplan MM; De Jongh; Kaplan (October 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.
Kumagi T, Heathcote EJ; Heathcote (2008). "Primary biliary cirrhosis". Orphanet J Rare Dis 3: 1. doi:10.1186/1750-1172-3-1. PMC 2266722. PMID 18215315.
Jones DE, Newton JL; Newton (February 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.
- 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.
- 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; Gershwin, ME; Poupon, R; Kaplan, M; Bergasa, NV; Heathcote, EJ; American Association for Study of Liver, Diseases (July 2009). "Primary biliary cirrhosis". Hepatology (Baltimore, Md.) 50 (1): 291–308. doi:10.1002/hep.22906. PMID 19554543.
- Collier, Jane; Ninkovic, M; Compston, JE (2002). "Guidelines on the management of osteoporosis associated with chronic liver disease". Gut 50 (Suppl 1): i1–i9. doi:10.1136/gut.50.suppl_1.i1. PMC 1867644. PMID 11788576.
- Ali, AH; Sinakos, E; Silveira, MG; Jorgensen, RA; Angulo, P; Lindor, KD (August 2011). "Varices in early histological stage primary biliary cirrhosis". Journal of Clinical Gastroenterology 45 (7): e66–71. doi:10.1097/MCG.0b013e3181f18c4e. PMID 20856137.
- Kaneko J, Sugawara Y, Tamura S et al. (January 2012). "Long-term outcome of living donor liver transplantation for primary biliary cirrhosis". Transpl. Int. 25 (1): 7–12. doi:10.1111/j.1432-2277.2011.01336.x. PMID 21923804.
- Ali AH, Carey EJ, Lindor KD (2015). "Recent advances in the development of farnesoid X receptor agonists". Ann Transl Med 3 (1): 5. doi:10.3978/j.issn.2305-5839.2014.12.06. PMC 4293481. PMID 25705637.
- Weinmann, A; Sattler, T; Unold, HP; Grambihler, A; Teufel, A; Koch, S; Schuchmann, M; Biesterfeld, S; Wörns, MA; Galle, PR; Schulze-Bergkamen, H (2014). "Predictive scores in primary biliary cirrhosis: a retrospective single center analysis of 204 patients.". Journal of clinical gastroenterology 49 (5): 438–47. doi:10.1097/MCG.0000000000000176. PMID 25014239.
- Primary Biliary Cirrhosis~followup at eMedicine
- Clavien & Killenberg 2006, p. 429
- Jones DE, Metcalf JV, Collier JD, Bassendine MF, James OF; Metcalf; Collier; Bassendine; James (November 1997). "Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes". Hepatology 26 (5): 1138–42. doi:10.1002/hep.510260508. PMID 9362353.
- WALKER, JG; DONIACH, D; ROITT, IM; SHERLOCK, S (Apr 17, 1965). "SEROLOGICAL TESTS IN DIAGNOSIS OF PRIMARY BILIARY CIRRHOSIS". Lancet 1 (7390): 827–31. PMID 14263538.
- 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.
- Vierling, John. "What's in a name". Retrieved 6 April 2015.
- 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
- UK PBC - UK PBC research