Editing Primary biliary cholangitis (section)

===Cholestasis===
Medical therapy of PBC primarily targets disease progression and symptom control. The first-line treatment for PBC is [[ursodeoxycholic acid]] (UDCA).<ref name=AASLD_2018>{{cite journal | vauthors = Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M | title = Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases | journal = Hepatology | volume = 69 | issue = 1 | pages = 394–419 | date = January 2019 | pmid = 30070375 | doi = 10.1002/hep.30145 | doi-access = free }}</ref><ref name=EASL_2017>{{cite journal | title = EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis | journal = Journal of Hepatology | volume = 67 | issue = 1 | pages = 145–172 | date = July 2017 | pmid = 28427765 | doi = 10.1016/j.jhep.2017.03.022 | last1 = Hirschfield | first1 = Gideon M. | last2 = Beuers | first2 = Ulrich | last3 = Corpechot | first3 = Christophe | last4 = Invernizzi | first4 = Pietro | last5 = Jones | first5 = David | last6 = Marzioni | first6 = Marco | last7 = Schramm | first7 = Christoph | url = http://pure-oai.bham.ac.uk/ws/files/40812159/1_s2.0_S0168827817301861_main_EASL_PBC.pdf }}</ref><ref name=":2">{{Cite journal |last1=Trivella |first1=Juan |last2=John |first2=Binu V. |last3=Levy |first3=Cynthia |date=June 2023 |title=Primary biliary cholangitis: Epidemiology, prognosis, and treatment |journal=Hepatology Communications |language=en |volume=7 |issue=6 |doi=10.1097/HC9.0000000000000179 |issn=2471-254X |pmc=10241503 |pmid=37267215}}</ref> UDCA has been the only drug available for two decades and more recently [[obeticholic acid]] (OCA), a semi-synthetic hydrophobic bile acid analogue, has been licensed as a [[Second-line medication|second-line]] option for patients with inadequate UDCA response or who are intolerant to UDCA. Several other agents have been studied, including [[Immunosuppressive drug|immunosuppressants]], but robust evidence of benefit is lacking.<ref name="pmid=19554543"/><ref name="pmid12628068">{{cite journal | vauthors = Levy C, Lindor KD | title = Treatment Options for Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis | journal = Current Treatment Options in Gastroenterology | volume = 6 | issue = 2 | pages = 93–103 | date = April 2003 | pmid = 12628068 | doi = 10.1007/s11938-003-0010-0 | s2cid = 37469838 }}</ref><ref name="pmid15456326">{{cite journal | vauthors = Oo YH, Neuberger J | title = Options for treatment of primary biliary cirrhosis | journal = Drugs | volume = 64 | issue = 20 | pages = 2261–2271 | year = 2004 | pmid = 15456326 | doi = 10.2165/00003495-200464200-00001 | s2cid = 1288509 }}</ref>

UDCA improves liver enzyme levels, slows down histological progression, and improves liver transplant-free survival.<ref name=":0">{{cite journal | vauthors = Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C | title = Ursodeoxycholic acid for primary biliary cirrhosis | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD000551 | date = December 2012 | issue = 12 | pmid = 23235576 | pmc = 7045744 | doi = 10.1002/14651858.CD000551.pub3 }}</ref><ref name="pmid=19554543"/> UDCA also reduces the need for liver transplantation.<ref name=AASLD_2018 /> UDCA should be taken at a dose of 13 to 15&nbsp;mg per kg of body weight per day,<ref name=EASL_2017 /> usually in two divided doses each day.<ref name=AASLD_2018 /> Liver chemistries usually improve within a few weeks of starting UDCA, and 90% of any benefit is observed after 6–9 months of therapy.<ref name=AASLD_2018 /> Liver chemistries should be re-evaluated after 1 year of treatment.<ref name=AASLD_2018 /> UDCA is usually continued lifelong.<ref name=EASL_2017 /> Up to 40% of people do not respond to treatment with UDCA.<ref name=AASLD_2018 /> Patients with PBC who have an inadequate response to UDCA or those few (less than 3%) who are intolerant to UDCA are candidates for second-line therapies.<ref name=":2" />

==== Alternative therapies ====
The initial treatment for PBC is almost always ursodeoxycholic acid, but some patients may need alternative or additional medications for managing their [[cholestasis]]. For these patients, options include obeticholic acid, the [[Peroxisome proliferator-activated receptor|PPAR]] agonists elafibranor and seladelpar, and the off-label use of fibrates.<ref name=":2" /><ref name=":3">{{Cite web |title=Elafibranor: Drug information |url=https://www.uptodate.com/contents/elafibranor-drug-information |access-date=2025-04-24 |website=UpToDate}}</ref><ref name=":4">{{Cite web |title=Seladelpar: Drug information |url=https://www.uptodate.com/contents/seladelpar-drug-information |access-date=2025-04-24 |website=UpToDate}}</ref>

===== Obeticholic acid =====
[[Obeticholic acid]] (OCA) is FDA-approved for the treatment of PBC in individuals intolerant or unresponsive to UDCA.<ref name="AASLD_2018" /> OCA is a [[farnesoid X receptor]]  agonist, and results in increased bile flow ([[Choleretic|choleresis]]). OCA is started at 5&nbsp;mg daily, and liver chemistries should be rechecked after 3 months of treatment. If the liver chemistries remain elevated,{{Contradictory inline|reason=Wouldn't the dose need to be adjusted down if liver enzymes were increased?|date=April 2025}} then the dose of OCA may be increased to 10&nbsp;mg per day. The most common side effect of OCA is [[pruritus]].{{Citation needed|date=April 2025}}

In December of 2024, the FDA expanded upon an initial warning from 2021 about potential [[Liver disease|liver damage]] from OCA. Obeticholic acid has been found to increase incidence of severe liver disease in patients taking it, and patients taking OCA without pre-existing liver damage have been found to require liver transplantation at higher rates than similar patients taking a [[placebo]]. As a result, the use of OCA in patients with known [[cirrhosis]] is heavily cautioned.<ref>{{Cite journal |last=U.S. Food and Drug Administration |date=2024-12-12 |title=Ocaliva (obeticholic acid) by Intercept Pharmaceuticals: Drug Safety Communication - Serious Liver Injury Being Observed in Patients without Cirrhosis |url=https://www.fda.gov/safety/medical-product-safety-information/ocaliva-obeticholic-acid-intercept-pharmaceuticals-drug-safety-communication-serious-liver-injury |journal=FDA |language=en |archive-url=https://archive.today/20250424230427/https://www.fda.gov/safety/medical-product-safety-information/ocaliva-obeticholic-acid-intercept-pharmaceuticals-drug-safety-communication-serious-liver-injury |archive-date=2025-04-24}}</ref>

===== Fibrates =====
Fibric acid derivatives, or [[fibrates]], are agonists of the peroxisome proliferator activator receptor (PPAR), a nuclear receptor involved in several metabolic pathways. While fibrates are approved for the treatment of hypertriglyceridemia, they exert anticholestatic effects and have been studied for the treatment of PBC<ref name="AASLD_2018" /> and are used [[Off-label use|off-label]] as a second-line option for patients who do not respond sufficiently to UDCA.<ref name=":2" /> Among the fibrates, [[bezafibrate]] and [[fenofibrate]], PPAR-alpha selective agonists, have been extensively studied as therapeutic agents because of their potential ability to decrease bile acid synthesis and bile acid-related hepatic inflammation. A randomized, controlled trial in 2018 showed its efficacy in patients with inadequate response to UDCA. While fibrates can be considered as off-label treatment for PBC that does not respond to UDCA, they should not be used in decompensated cirrhosis.<ref name="AASLD_2018" />

===== Others =====
[[Elafibranor]] (Iqirvo) was approved for medical use as a second-line/alternative therapy for primary biliary cholangitis in the United States in June 2024.<ref>{{cite press release |title=Ipsen's Iqirvo receives U.S. FDA accelerated approval as a first-in-class PPAR treatment for primary biliary cholangitis |date=10 June 2024 |url=https://www.ipsen.com/press-releases/ipsens-iqirvo-receives-u-s-fda-accelerated-approval-as-a-first-in-class-ppar-treatment-for-primary-biliary-cholangitis/ |access-date=11 June 2024 |website=Ipsen}}</ref> Elafibranor is a [[peroxisome proliferator-activated receptor]] (PPAR) agonist, and while the mechanism of action is not fully understood, it is thought to reduce [[bile acid]] synthesis by downregulating [[CYP7A1]] activity dependent on [[fibroblast growth factor 21]] (FGF21).<ref name=":3" />

[[Seladelpar]] (Livdelzi) was approved for medical use as a second-line/alternative therapy for primary biliary cholangitis in the United States in August 2024.<ref>{{cite press release |title=Gilead's Livdelzi (Seladelpar) Granted Accelerated Approval for Primary Biliary Cholangitis by U.S. FDA |date=14 August 2024 |publisher=Gilead |url=https://www.businesswire.com/news/home/20240814469557/en/Gilead%E2%80%99s-Livdelzi-Seladelpar-Granted-Accelerated-Approval-for-Primary-Biliary-Cholangitis-by-U.S.-FDA |via=Business Wire |access-date=15 August 2024}}</ref> Like elafibranor, seladelpar is a PPAR agonist that reduces bile acid synthesis by downregulating FGF21-mediated CYP7A1 activity.<ref name=":4" />

Additional medications are being investigated as potential treatments for PBC, and found to be ineffective as single agents (monotherapy), including: [[chlorambucil]], [[colchicine]], [[cyclosporine]], [[corticosteroids]], [[azathioprine]], [[malotilate]], methotrexate, [[mycophenolate mofetil]], [[penicillamine]], and [[thalidomide]].<ref name="AASLD_2018" /> [[Budesonide]] is sometimes used as an off-label treatment for PBC, although its efficacy is controversial.<ref name="AASLD_2018" /> [[Seladelpar]], a [[PPAR-delta]] receptor agonist, is being studied for treatment of PBC.<ref>{{cite journal |last1=Hirschfield |first1=Gideon M. |last2=Shiffman |first2=Mitchell L. |last3=Gulamhusein |first3=Aliya |last4=Kowdley |first4=Kris V. |last5=Vierling |first5=John M. |last6=Levy |first6=Cynthia |last7=Kremer |first7=Andreas E. |last8=Zigmond |first8=Ehud |last9=Andreone |first9=Pietro |last10=Gordon |first10=Stuart C. |last11=Bowlus |first11=Christopher L. |last12=Lawitz |first12=Eric J. |last13=Aspinall |first13=Richard J. |last14=Pratt |first14=Daniel S. |last15=Raikhelson |first15=Karina |last16=Gonzalez-Huezo |first16=Maria S. |last17=Heneghan |first17=Michael A. |last18=Jeong |first18=Sook-Hyang |last19=Ladrón de Guevara |first19=Alma L. |last20=Mayo |first20=Marlyn J. |last21=Dalekos |first21=George N. |last22=Drenth |first22=Joost P.H. |last23=Janczewska |first23=Ewa |last24=Leggett |first24=Barbara A. |last25=Nevens |first25=Frederik |last26=Vargas |first26=Victor |last27=Zuckerman |first27=Eli |last28=Corpechot |first28=Christophe |last29=Fassio |first29=Eduardo |last30=Hinrichsen |first30=Holger |last31=Invernizzi |first31=Pietro |last32=Trivedi |first32=Palak J. |last33=Forman |first33=Lisa |last34=Jones |first34=David E.J. |last35=Ryder |first35=Stephen D. |last36=Swain |first36=Mark G. |last37=Steinberg |first37=Alexandra |last38=Boudes |first38=Pol F. |last39=Choi |first39=Yun-Jung |last40=McWherter |first40=Charles A. |title=Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study |journal=Hepatology |date=6 April 2023 |volume=78 |issue=2 |pages=397–415 |doi=10.1097/HEP.0000000000000395|pmid=37386786 |pmc=10344437 |hdl=11380/1319587 |hdl-access=free }}</ref><ref>{{cite journal |last1=Hasegawa |first1=Sho |last2=Yoneda |first2=Masato |last3=Kurita |first3=Yusuke |last4=Nogami |first4=Asako |last5=Honda |first5=Yasushi |last6=Hosono |first6=Kunihiro |last7=Nakajima |first7=Atsushi |title=Cholestatic Liver Disease: Current Treatment Strategies and New Therapeutic Agents |journal=Drugs |date=1 July 2021 |volume=81 |issue=10 |pages=1181–1192 |doi=10.1007/s40265-021-01545-7 |issn=1179-1950|doi-access=free |pmid=34142342 |pmc=8282588 }}</ref>