Editing Primary biliary cholangitis (section)

==Causes==
PBC has an [[immunological]] basis, and is classified as an autoimmune disorder. It results from a slow, progressive destruction of the small bile ducts of the liver, with the [[intralobular duct]]s and the [[canals of Hering]] (intrahepatic ductules) being affected early in the disease.{{cn|date=March 2025}}

Most people with PBC (more than 90%) have [[Anti-mitochondrial antibody|antimitochondrial antibodies]] (AMAs) against [[pyruvate dehydrogenase complex]] (PDC-E2), an enzyme complex found in the [[mitochondria]]. People who are negative for AMAs are usually found to be positive when more sensitive methods of detection are used.<ref name="pmid15062200">{{cite journal | vauthors = Vierling JM | title = Primary Biliary Cirrhosis and Autoimmune Cholangiopathy | journal = Clinics in Liver Disease | volume = 8 | issue = 1 | pages = 177–194 | date = February 2004 | pmid = 15062200 | doi = 10.1016/S1089-3261(03)00132-6 }}</ref>

People with PBC may also have been diagnosed with another autoimmune disease, such as a rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological condition, suggesting shared genetic and immune abnormalities.<ref name="pmid25057958">{{cite journal | vauthors = Floreani A, Franceschet I, Cazzagon N | title = Primary biliary cirrhosis: overlaps with other autoimmune disorders | journal = Seminars in Liver Disease | volume = 34 | issue = 3 | pages = 352–360 | date = August 2014 | pmid = 25057958 | doi = 10.1055/s-0034-1383734 | hdl = 11577/3143751 | s2cid = 21382956 }}</ref>
Common associations include [[Sjögren's syndrome]], [[systemic sclerosis]], [[rheumatoid arthritis]], [[systemic lupus erythematosis|lupus]], [[hypothyroidism]], and [[coeliac disease]].<ref name=NarcisoSchiavonSchiavon2017>{{cite journal | vauthors = Narciso-Schiavon JL, Schiavon LL | title = To screen or not to screen? Celiac antibodies in liver diseases | journal = World Journal of Gastroenterology | volume = 23 | issue = 5 | pages = 776–791 | date = February 2017 | pmid = 28223722 | pmc = 5296194 | doi = 10.3748/wjg.v23.i5.776 | type = Review | doi-access = free }}{{free access}}</ref><ref name="pmid12385447">{{cite journal | vauthors = Volta U, Rodrigo L, Granito A, Petrolini N, Muratori P, Muratori L, Linares A, Veronesi L, Fuentes D, Zauli D, Bianchi FB | display-authors = 6 | title = Celiac disease in autoimmune cholestatic liver disorders | journal = The American Journal of Gastroenterology | volume = 97 | issue = 10 | pages = 2609–2613 | date = October 2002 | pmid = 12385447 | doi = 10.1111/j.1572-0241.2002.06031.x | s2cid = 17375127 }}</ref>

A genetic predisposition to disease has been thought to be important for some time. Evidence for this includes cases of PBC in family members, identical twins both having the condition (concordance), and clustering of PBC with other 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]].<ref>{{cite journal | vauthors = Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, Gu X, Walker EJ, Jing K, Juran BD, Mason AL, Myers RP, Peltekian KM, Ghent CN, Coltescu C, Atkinson EJ, Heathcote EJ, Lazaridis KN, Amos CI, Siminovitch KA | display-authors = 6 | title = Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants | journal = The New England Journal of Medicine | volume = 360 | issue = 24 | pages = 2544–2555 | date = June 2009 | pmid = 19458352 | pmc = 2857316 | doi = 10.1056/NEJMoa0810440 }}</ref><ref>{{Cite web | url=http://www.uk-pbc.com | title=UK-PBC – Stratified Medicine in Primary Biliary Cholangitis (PBC; formally known as Cirrhosis)}}</ref>  This research revealed parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be important in the aetiology 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]]''.<ref name = "Liu_2012">{{cite journal | vauthors = Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ, Ducker SJ, Day DB, Heneghan MA, Neuberger JM, Donaldson PT, Bathgate AJ, Burroughs A, Davies MH, Jones DE, Alexander GJ, Barrett JC, Sandford RN, Anderson CA | display-authors = 6 | title = Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis | journal = Nature Genetics | volume = 44 | issue = 10 | pages = 1137–1141 | date = October 2012 | pmid = 22961000 | pmc = 3459817 | doi = 10.1038/ng.2395 }}</ref><ref>{{cite journal | vauthors = Juran BD, Hirschfield GM, Invernizzi P, Atkinson EJ, Li Y, Xie G, Kosoy R, Ransom M, Sun Y, Bianchi I, Schlicht EM, Lleo A, Coltescu C, Bernuzzi F, Podda M, Lammert C, Shigeta R, Chan LL, Balschun T, Marconi M, Cusi D, Heathcote EJ, Mason AL, Myers RP, Milkiewicz P, Odin JA, Luketic VA, Bacon BR, Bodenheimer HC, Liakina V, Vincent C, Levy C, Franke A, Gregersen PK, Bossa F, Gershwin ME, deAndrade M, Amos CI, Lazaridis KN, Seldin MF, Siminovitch KA | display-authors = 6 | title = 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 | journal = Human Molecular Genetics | volume = 21 | issue = 23 | pages = 5209–5221 | date = December 2012 | pmid = 22936693 | pmc = 3490520 | doi = 10.1093/hmg/dds359 }}</ref>

A study of over 2,000 patients identified a gene, ''[[POGLUT1]]'', that appeared to be associated with this condition.<ref name=Hitomi2019>{{cite journal | vauthors = Hitomi Y, Ueno K, Kawai Y, Nishida N, Kojima K, Kawashima M, Aiba Y, Nakamura H, Kouno H, Kouno H, Ohta H, Sugi K, Nikami T, Yamashita T, Katsushima S, Komeda T, Ario K, Naganuma A, Shimada M, Hirashima N, Yoshizawa K, Makita F, Furuta K, Kikuchi M, Naeshiro N, Takahashi H, Mano Y, Yamashita H, Matsushita K, Tsunematsu S, Yabuuchi I, Nishimura H, Shimada Y, Yamauchi K, Komatsu T, Sugimoto R, Sakai H, Mita E, Koda M, Nakamura Y, Kamitsukasa H, Sato T, Nakamuta M, Masaki N, Takikawa H, Tanaka A, Ohira H, Zeniya M, Abe M, Kaneko S, Honda M, Arai K, Arinaga-Hino T, Hashimoto E, Taniai M, Umemura T, Joshita S, Nakao K, Ichikawa T, Shibata H, Takaki A, Yamagiwa S, Seike M, Sakisaka S, Takeyama Y, Harada M, Senju M, Yokosuka O, Kanda T, Ueno Y, Ebinuma H, Himoto T, Murata K, Shimoda S, Nagaoka S, Abiru S, Komori A, Migita K, Ito M, Yatsuhashi H, Maehara Y, Uemoto S, Kokudo N, Nagasaki M, Tokunaga K, Nakamura M | display-authors = 6 | title = POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33 | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 102 | date = January 2019 | pmid = 30643196 | pmc = 6331557 | doi = 10.1038/s41598-018-36490-1 | bibcode = 2019NatSR...9..102H }}</ref> Earlier studies have also suggested that this gene may be involved. The implicated protein is an [[endoplasmic reticulum]] O-glucosyltransferase.{{cn|date=March 2025}}

An environmental Gram-negative [[Alphaproteobacterium]] — ''[[Novosphingobium aromaticivorans]]''<ref name=Selmi2003>{{cite journal | vauthors = 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 | display-authors = 6 | title = Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium | journal = Hepatology | volume = 38 | issue = 5 | pages = 1250–1257 | date = November 2003 | pmid = 14578864 | doi = 10.1053/jhep.2003.50446 | s2cid = 22691658 | doi-access = free }}</ref> has been associated with this disease, with several reports suggesting an aetiological role for this organism.<ref name=Mohammed2009>{{cite journal | vauthors = Mohammed JP, Mattner J | title = Autoimmune disease triggered by infection with alphaproteobacteria | journal = Expert Review of Clinical Immunology | volume = 5 | issue = 4 | pages = 369–379 | date = July 2009 | pmid = 20161124 | pmc = 2742979 | doi = 10.1586/ECI.09.23 }}</ref><ref name=Kaplan2004>{{cite journal | vauthors = Kaplan MM | title = Novosphingobium aromaticivorans: a potential initiator of primary biliary cirrhosis | journal = The American Journal of Gastroenterology | volume = 99 | issue = 11 | pages = 2147–2149 | date = November 2004 | pmid = 15554995 | doi = 10.1111/j.1572-0241.2004.41121.x | s2cid = 19177405 }}</ref><ref name=Selmi2004>{{cite journal | vauthors = Selmi C, Gershwin ME | title = Bacteria and human autoimmunity: the case of primary biliary cirrhosis | journal = Current Opinion in Rheumatology | volume = 16 | issue = 4 | pages = 406–410 | date = July 2004 | pmid = 15201604 | doi = 10.1097/01.bor.0000130538.76808.c2 | s2cid = 23532625 }}</ref> 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 ''[[IGSF2|CD101]]'' may also play a role in host susceptibility to this disease.<ref name=Mohammed2003>{{cite journal | vauthors = 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 | display-authors = 6 | title = Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity | journal = Journal of Immunology | volume = 187 | issue = 1 | pages = 337–349 | date = July 2011 | pmid = 21613619 | pmc = 3134939 | doi = 10.4049/jimmunol.1003525 }}</ref>

A failure of [[immune tolerance]] against the mitochondrial pyruvate dehydrogenase complex (PDC-E2) is a primary cause, with shedding of the antigen into apoptotic bodies or "apotopes" leading to the anatomic localization.<ref name="pmid19185000">{{cite journal | vauthors = Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR, Gores GJ, Ansari AA, Van de Water J, Gershwin ME | display-authors = 6 | title = Apotopes and the biliary specificity of primary biliary cirrhosis | journal = Hepatology | volume = 49 | issue = 3 | pages = 871–879 | date = March 2009 | pmid = 19185000 | pmc = 2665925 | doi = 10.1002/hep.22736 }}</ref> Such autoreactivity may also be the case with other proteins, including the [[nucleoporin 210kDa|gp210]] and [[nucleoporin 62|p62]] nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients, and these proteins may be associated with prognosis.<ref name="pmid16337775">{{cite journal | vauthors = Nakamura M, Takii Y, Ito M, Komori A, Yokoyama T, Shimizu-Yoshida Y, Koyabu M, Matsuyama M, Mori T, Kamihira T, Daikoku M, Migita K, Yatsuhashi H, Nozaki N, Shimoda S, Ishibashi H | display-authors = 6 | title = Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis | journal = Journal of Autoimmunity | volume = 26 | issue = 2 | pages = 138–145 | date = March 2006 | pmid = 16337775 | doi = 10.1016/j.jaut.2005.10.007 }}</ref>