Ursodeoxycholic acid (UDCA), also known asursodiol, is a secondarybile 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 inbile of bears of genusUrsus, from which its name derived.[8] In purified form, it has been used to treat or prevent several diseases of theliver orbile ducts.
UDCA has been used as medical therapy ingallstone disease (cholelithiasis) and forbiliary sludge.[11][12] UDCA helps reduce thecholesterol saturation of bile and leads to gradual dissolution of cholesterol-rich gallstones.[11]
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.[13]
UDCA is used as therapy inprimary biliary cholangitis (PBC; previously known as primary biliary cirrhosis) where it can produce an improvement in biomarkers.[14] Meta-analyses have borne out conflicting results on the mortality benefit.[15] However analyses that exclude trials of short duration (i.e. < 2 years) have demonstrated a survival benefit and are generally considered more clinically relevant.[16] A Cochrane systematic review in 2012 found no significant benefit in reducing mortality, the rate of liver transplantation,pruritus or fatigue.[17] Ursodiol andobeticholic acid are FDA-approved for the treatment of primary biliary cholangitis.[18]
UDCA use inprimary sclerosing cholangitis is associated with improved serum liver tests that do not always correlate with improved liver disease status.[19] WHO Drug Information advises against its use in primary sclerosing cholangitis in unapproved doses beyond 13–15 mg/kg/day.[20]
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.[21]
UDCA has been used forintrahepatic 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.[22][23]
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.[24][25][26][27]
UDCA has been suggested to be an adequate treatment of bile refluxgastritis.[28]
Ursodeoxycholic acid has been used to treatcystic fibrosis relatedcholestasis and liver disease; 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.[29]
UDCA has been in effective innon-alcoholic fatty liver disease, in liver bile duct-paucity syndromes. It has been used as adjunct therapy in conditions with biliary tract obstruction such asbiliary atresia; however liver transplant is often still required as definitive treatment for atresia. It is not effective in liver allograft rejection, and ingraft-versus-host disease involving the liver.[medical citation needed]
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 withchenodeoxycholic 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.[30] Additional symptoms may include bloating, weight gain, and occasionally, thinning of hair.[31]
Primary bile acids are produced by theliver and stored in thegall 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 bodydigestfats. Ursodeoxycholic acid helps regulatecholesterol by reducing the rate at which theintestine absorbs cholesterol molecules while breaking upmicelles containing cholesterol. The drug reduces cholesterol absorption and is used to dissolve (cholesterol)gallstones inpatients who want an alternative tosurgery.[32] There are multiple mechanisms involved in cholestatic liver diseases.[33]
Ursodeoxycholic acid has also been shown experimentally to suppressimmune response such as immune cellphagocytosis. Prolonged exposure and/or increased quantities of systemic (throughout the body, not just in the digestive system) ursodeoxycholic acid can be toxic.[34]
Ursodeoxycholic acid has been shown to exert anti-inflammatory and protective effects in human epithelial cells of thegastrointestinal tract. It has been linked to regulation of immunoregulatory responses by regulation ofcytokines,[35] antimicrobial peptidesdefensins,[36] and take an active part in increased restitution of wound in the colon.[37] Moreover, UDCA's effects has been shown to have exert actions outside the epithelial cells.[38]
While some bile acids are known to be colon tumor promoters (e.g.deoxycholic acid),[39][40][41] others such as ursodeoxycholic acid are thought to bechemopreventive, perhaps by inducing cellular differentiation and/or cellular senescence in colon epithelial cells.[42][43][44]
Ursodeoxycholic acid is anepimer ofchenodeoxycholic 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.[45]
Among mammals, only bears (Ursidae; excludinggiant pandas) produce UDCA at useful amounts[45] (>30%). It is produced in the bear liver, but the pathway remains unknown.[8]
Other vertebrates produce UDCA in much smaller amounts by gut bacteria. CDCA is oxidized into 7-oxo-CDCA then reduced into UDCA.[46]
UDCA is most commonly produced fromcholic acid (CA) derived from bovine bile, a by-product of the beef industry. The current yield of thissemisynthesis is about 30%.[47]
Bear bile, a natural source of UDCA, has been used intraditional Chinese medicine since the seventh century. Japanese scientists successfully synthesized UDCA chemically in 1955.[45] The earliest reference to UDCA inPubMed dates to 1957 under an alternative spelling "ursodesoxycholic acid", in a small-scale clinical trial.[50]
Ursodeoxycholic acid (application filed byAllergan) was approved for use in the United States in December 1987,[51] and was designated anorphan drug.[52]
^abHofmann AF (September 1989). "Medical dissolution of gallstones by oral bile acid therapy".American Journal of Surgery.158 (3):198–204.doi:10.1016/0002-9610(89)90252-3.PMID2672842.
^Jüngst C, Kullak-Ublick GA, Jüngst D (2006). "Gallstone disease: Microlithiasis and sludge".Best Practice & Research. Clinical Gastroenterology.20 (6):1053–1062.doi:10.1016/j.bpg.2006.03.007.PMID17127187.
^Magouliotis DE, Tasiopoulou VS, Svokos AA, Svokos KA, Chatedaki C, Sioka E, et al. (November 2017). "Ursodeoxycholic Acid in the Prevention of Gallstone Formation After Bariatric Surgery: an Updated Systematic Review and Meta-analysis".Obesity Surgery.27 (11):3021–3030.doi:10.1007/s11695-017-2924-y.PMID28889240.S2CID4622165.
^Goulis J, Leandro G, Burroughs AK (September 1999). "Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis".Lancet.354 (9184):1053–1060.doi:10.1016/S0140-6736(98)11293-X.PMID10509495.S2CID25562983.
^Shi J, Wu C, Lin Y, Chen YX, Zhu L, Xie WF (July 2006). "Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials".The American Journal of Gastroenterology.101 (7):1529–1538.doi:10.1111/j.1572-0241.2006.00634.x.PMID16863557.S2CID32076958.
^Kotb MA (July 2008). "Review of historical cohort: ursodeoxycholic acid in extrahepatic biliary atresia".Journal of Pediatric Surgery.43 (7):1321–1327.doi:10.1016/j.jpedsurg.2007.11.043.PMID18639689.
^Paediatric Formulary Committee (2008).British National Formulary for Children 2008. London: Pharmaceutical Press. p. 91.ISBN978-0-85369-780-0.
^"Urso package insert"(PDF). Birmingham, AL: Axcan Pharma U.S. January 2000. Archived fromthe original(PDF) on 17 October 2006. Retrieved25 April 2009.
