Ursodeoxycholic acid

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Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of bears of genus Ursus, from which its name derived.<ref name="pmid8263415">Template:Cite journal</ref> In purified form, it has been used to treat or prevent several diseases of the liver or bile ducts.

It is available as a generic medication.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

UDCA has been used as medical therapy in gallstone disease (cholelithiasis) and for biliary sludge.<ref name="PMID2672842">Template:Cite journal</ref><ref>Template:Cite journal</ref> UDCA helps reduce the cholesterol saturation of bile and leads to gradual dissolution of cholesterol-rich gallstones.<ref name=PMID2672842/>

UDCA may be given after bariatric surgery to prevent cholelithiasis, which commonly occurs due to the rapid weight loss producing biliary cholesterol oversaturation and also biliary dyskinesia secondary to hormonal changes.<ref>Template:Cite journal</ref>

Primary biliary cholangitis

UDCA is used as therapy in primary biliary cholangitis (PBC; previously known as primary biliary cirrhosis) where it can produce an improvement in biomarkers.<ref>Template:Cite journal</ref> Meta-analyses have borne out conflicting results on the mortality benefit.<ref>Template:Cite journal</ref> However analyses that exclude trials of short duration (i.e. < 2 years) have demonstrated a survival benefit and are generally considered more clinically relevant.<ref>Template:Cite journal</ref> A Cochrane systematic review in 2012 found no significant benefit in reducing mortality, the rate of liver transplantation, pruritus or fatigue.<ref>Template:Cite journal</ref> Ursodiol and obeticholic acid are FDA-approved for the treatment of primary biliary cholangitis.<ref>Template:Cite journal</ref>

Primary sclerosing cholangitis

UDCA use is associated with improved serum liver tests that do not always correlate with improved liver disease status.<ref>Template:Cite journal</ref> WHO Drug Information advises against its use in primary sclerosing cholangitis in unapproved doses beyond 13–15 mg/kg/day.<ref>Template:Cite journal</ref>

UDCA in a dose of 28–30 mg/kg/day increases risk of death and need for liver transplant by 2.3-fold among those with primary sclerosing cholangitis, despite decrease in liver enzymes.<ref>Template:Cite journal</ref>

Intrahepatic cholestasis of pregnancy

UDCA has been used for intrahepatic cholestasis of pregnancy. UDCA lessens itching in the mother and may reduce the number of preterm births. Effects on fetal distress and other adverse outcomes are unlikely to be great.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Cholestasis

UDCA use is not licensed in children, as its safety and effectiveness have not been established. Evidence is accumulating that ursodeoxycholic acid is ineffective, unsafe and its use is associated with significant risk of morbidity and mortality in neonatal hepatitis and neonatal cholestasis.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

Other conditions

UDCA has been suggested to be an adequate treatment of bile reflux gastritis.<ref name=newprb>Template:Cite journal</ref>

Ursodeoxycholic acid has been used to treat cystic fibrosis; however, a 2021 study aimed at evaluating whether the incidence of severe liver disease differed between CF centers routinely prescribing or not prescribing UDCA found no reduction in portal hypertension.<ref>Template:Cite journal</ref>

UDCA has been in effective in non-alcoholic fatty liver disease, in liver bile duct-paucity syndromes. It has been used as adjunct therapy in conditions with biliary tract obstruction such as biliary atresia; however liver transplant is often still required as definitive treatment for atresia. It is not effective in liver allograft rejection, and in graft-versus-host disease involving the liver.Template:Medical citation needed

Adverse effects

Diarrhea was the most frequent adverse event seen in trial of UDCA in gallstone dissolution, occurring in 2 to 9%, which is less frequent than with chenodeoxycholic acid therapy. Bacterial conversion of UDCA to chenodeoxycholic acid may be the mechanism for this side effect. Right upper quadrant abdominal pain and exacerbation of pruritus was occasionally reported in trials in patients with PBC.<ref name="pmid14616161">Template:Cite journal</ref> Additional symptoms may include bloating, weight gain, and occasionally, thinning of hair.<ref name=Lleo>Template:Cite journal</ref>

Mechanisms of action

Choleretic effects

Primary bile acids are produced by the liver and stored in the gall bladder. When secreted into the intestine, primary bile acids can be metabolized into secondary bile acids by intestinal bacteria. Primary and secondary bile acids help the body digest fats. Ursodeoxycholic acid helps regulate cholesterol by reducing the rate at which the intestine absorbs cholesterol molecules while breaking up micelles containing cholesterol. The drug reduces cholesterol absorption and is used to dissolve (cholesterol) gallstones in patients who want an alternative to surgery.<ref>Template:Cite journal</ref> There are multiple mechanisms involved in cholestatic liver diseases.<ref name="PMID12198643">Template:Cite journal</ref>

Immunomodulating effects

Ursodeoxycholic acid has also been shown experimentally to suppress immune response such as immune cell phagocytosis. Prolonged exposure and/or increased quantities of systemic (throughout the body, not just in the digestive system) ursodeoxycholic acid can be toxic.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Anti-inflammatory effects

Ursodeoxycholic acid has been shown to exert anti-inflammatory and protective effects in human epithelial cells of the gastrointestinal tract. It has been linked to regulation of immunoregulatory responses by regulation of cytokines,<ref>Template:Cite journal</ref> antimicrobial peptides defensins,<ref>Template:Cite journal</ref> and take an active part in increased restitution of wound in the colon.<ref>Template:Cite journal</ref> Moreover, UDCA's effects has been shown to have exert actions outside the epithelial cells.<ref>Template:Cite journal</ref>

While some bile acids are known to be colon tumor promoters (e.g. deoxycholic acid),.<ref>Fogelson KA, Dorrestein PC, Zarrinpar A, Knight R (June 2023). "The gut microbial bile acid modulation and its relevance to digestive health and diseases". Gastroenterology. 164 (7): 1069–1085. doi:10.1053/j.gastro.2023.02.022. PMC 10205675. PMID 36841488. </ref><ref>Bernstein H, Bernstein C (January 2023). "Bile acids as carcinogens in the colon and at other sites in the gastrointestinal system". Experimental Biology and Medicine (Maywood). 248 (1): 79–89. doi:10.1177/15353702221131858. PMC 9989147. PMID 36408538.</ref><ref>Yang S, Wang Y, Sheng L, Cui W, Ma C (January 2025). "The effect of fecal bile acids on the incidence and risk-stratification of colorectal cancer: an updated systematic review and meta-analysis". Scientific Reports. 15 (1): 740. Bibcode:2025NatSR..15..740Y. doi:10.1038/s41598-024-84801-6. PMC 11698987. PMID 39753873</ref> others such as ursodeoxycholic acid are thought to be chemopreventive, perhaps by inducing cellular differentiation and/or cellular senescence in colon epithelial cells.<ref>Template:Cite journal</ref><ref>Kühn T, Stepien M, López-Nogueroles M, Damms-Machado A, Sookthai D, Johnson T, Roca M, Hüsing A, Maldonado SG, Cross AJ, Murphy N, Freisling H, Rinaldi S, Scalbert A, Fedirko V, Severi G, Boutron-Ruault MC, Mancini FR, Sowah SA, Boeing H, Jakszyn P, Sánchez MJ, Merino S, Colorado-Yohar S, Barricarte A, Khaw KT, Schmidt JA, Perez-Cornago A, Trichopoulou A, Karakatsani A, Thriskos P, Palli D, Agnoli C, Tumino R, Sacerdote C, Panico S, Bueno-de-Mesquita B, van Gils CH, Heath AK, Gunter MJ, Riboli E, Lahoz A, Jenab M, Kaaks R. Prediagnostic Plasma Bile Acid Levels and Colon Cancer Risk: A Prospective Study. J Natl Cancer Inst. 2020 May 1;112(5):516-524. doi: 10.1093/jnci/djz166. Erratum in: J Natl Cancer Inst. 2020 Oct 1;112(10):1077. doi: 10.1093/jnci/djaa094. PMID 31435679; PMCID: PMC7225675.</ref><ref>Alberts DS, Martínez ME, Hess LM, Einspahr JG, Green SB, Bhattacharyya AK, Guillen J, Krutzsch M, Batta AK, Salen G, Fales L, Koonce K, Parish D, Clouser M, Roe D, Lance P; Phoenix and Tucson Gastroenterologist Networks. Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. J Natl Cancer Inst. 2005 Jun 1;97(11):846-53. doi: 10.1093/jnci/dji144. PMID 15928305.</ref>

Chemistry

Ursodeoxycholic acid is an epimer of chenodeoxycholic acid, which has similar choleretic effects and a wider species distribution. However, CDCA is not as well-tolerated in humans and it does not show immunomodulating or chemoprotective effects. Both are 7-hydroxyl derivatives of deoxycholic acid, but UDCA has the group in the beta instead of the alpha orientation.<ref name="Feng"/>

Biosynthesis

Among mammals, only bears (Ursidae; excluding giant pandas) produce UDCA at useful amounts<ref name="Feng"/> (>30%). It is produced in the bear liver, but the pathway remains unknown.<ref name="pmid8263415" />

Other vertebrates produce UDCA in much smaller amounts by gut bacteria. CDCA is oxidized into 7-oxo-CDCA then reduced into UDCA.<ref>Template:Cite journal</ref>

Industrial production

UDCA is most commonly produced from cholic acid (CA) derived from bovine bile, a by-product of the beef industry. The current yield of this semisynthesis is about 30%.<ref>Template:Cite journal</ref>

Society and culture

Names

The term is from the Latin noun ursus meaning bear, as bear bile contains the substance.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Ursodeoxycholic acid can be chemically synthesized and is marketed under multiple trade names, including Ursetor, Udikast, Actibile, Actigall,<ref name="Actigall FDA label"/> Biliver, Deursil, Egyurso, Heptiza 300/150, Stener, Udcasid, Udiliv, Udinorm, Udoxyl, Urso, Urso Forte, Ursocol, Ursoliv, Ursofalk,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Ursosan, Ursoserinox, Udimarin, and Ursonova.Template:Citation needed

History

Bear bile, a natural source of UDCA, is used in traditional Chinese medicine since the seventh century. Japanese scientists successfully synthesized UDCA chemically in 1955.<ref name="Feng">Template:Cite journal</ref> The earliest reference to UDCA in PubMed dates to 1957 under an alternative spelling "ursodesoxycholic acid", in a small-scale clinical trial.<ref>Template:Cite journal</ref>

Ursodeoxycholic acid (application filed by Allergan) was approved for use in the United States in December 1987,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and was designated an orphan drug.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>