Ursodeoxycholic Acid: What the Clinical Trials Show
Ursodeoxycholic acid, also known as ursodiol or UDCA, is a bile acid with a long history in hepatology. In some liver diseases it is first-line treatment; in others, large trials have shown no benefit or even harm. In fitness circles it is sometimes described as a universal "liver protector". Our editors look at what the controlled trials really demonstrate.
What UDCA is and how it works
UDCA is a naturally occurring bile acid present in small amounts in human bile. It was historically isolated from bear bile, which was used in traditional medicine. Today it is synthesised and sold as a prescription medicine in the UK.
Unlike some other bile acids, UDCA is hydrophilic, meaning it is less toxic to cell membranes. When taken regularly it makes up a larger share of the bile acid pool, displacing more harmful bile acids.
Several mechanisms have been proposed: protection of bile duct cells against toxic bile acids, stimulation of bile flow, reduced cholesterol saturation of bile, and effects on inflammation and cell death. Which mechanisms dominate depends on the disease.
Its licensed uses in the UK include dissolution of certain cholesterol gallstones and the treatment of primary biliary cholangitis. It is also widely used off-label in other cholestatic conditions, under specialist supervision.
Primary biliary cholangitis: the clearest success
Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is an autoimmune disease that slowly destroys the small bile ducts in the liver. It mainly affects middle-aged women.
A multicentre controlled trial by Poupon and colleagues, published in 1991, showed that UDCA improved liver blood tests and reduced the progression of disease compared with placebo. Further trials and pooled analyses supported a benefit on transplant-free survival, particularly in patients who respond biochemically.
The European Association for the Study of the Liver (EASL) guideline recommends UDCA at 13–15 mg per kilogram per day as first-line therapy for PBC, continued long-term. Patients whose alkaline phosphatase and bilirubin do not respond adequately may need additional treatment.
Response matters greatly. Patients who achieve good biochemical response have survival close to that of the general population, while non-responders have a higher risk of progression. This makes PBC the best example of UDCA's real benefits.
| Condition | Key trial(s) | Overall finding |
|---|---|---|
| Primary biliary cholangitis | Poupon 1991 and later trials | Effective; first-line therapy |
| Primary sclerosing cholangitis | Lindor 2009 (high dose) | No benefit; more serious events at high dose |
| Intrahepatic cholestasis of pregnancy | PITCHES 2019 | No reduction in adverse perinatal outcomes |
| Non-alcoholic steatohepatitis | Lindor 2004 | No significant benefit over placebo |
| Cholesterol gallstones | Older dissolution studies | Works only for selected small, non-calcified stones |
Primary sclerosing cholangitis: a cautionary tale
Primary sclerosing cholangitis (PSC) causes inflammation and scarring of the larger bile ducts and is often associated with inflammatory bowel disease. Given UDCA's success in PBC, it seemed a logical candidate.
Early studies at moderate doses improved liver blood tests but did not show clear effects on clinical outcomes. Researchers then tested a high dose: Lindor and colleagues randomised patients to UDCA at 28–30 mg/kg/day or placebo.
The high-dose trial was stopped early. Patients receiving UDCA had a higher rate of serious adverse outcomes, including progression to cirrhosis, varices, transplant and death, despite better liver enzymes.
This trial is a powerful lesson. Improving a surrogate marker, such as liver enzymes, does not guarantee better health outcomes. That principle is directly relevant to anyone using UDCA to "normalise" blood tests without a diagnosis.
Pregnancy, fatty liver and gallstones
Intrahepatic cholestasis of pregnancy causes intense itching and raised bile acids, and is associated with risks to the baby. For years UDCA was standard treatment. The UK PITCHES trial by Chappell and colleagues, involving over 600 women, found that UDCA did not reduce a composite of adverse perinatal outcomes compared with placebo.
Following PITCHES, guidance from the Royal College of Obstetricians and Gynaecologists changed, and UDCA is no longer routinely recommended to improve outcomes for the baby, though it may still be offered for symptom relief in some cases.
In non-alcoholic steatohepatitis (NASH, now often termed MASH), Lindor and colleagues ran a two-year randomised trial and found that UDCA was no better than placebo in improving liver histology. Fatty liver is managed primarily through weight loss, physical activity and treatment of metabolic risk factors.
For gallstones, UDCA can dissolve small, cholesterol-rich, non-calcified stones in a functioning gallbladder, but the process takes months and stones often recur. It is also used to reduce gallstone formation during rapid weight loss, for example after bariatric surgery.
The "liver protection" claim in sport
Some people who use oral anabolic steroids take UDCA in the belief that it protects the liver. This belief draws on its effects in cholestasis, because certain oral 17-alpha-alkylated steroids can cause cholestatic liver injury.
There are no controlled trials showing that UDCA prevents steroid-induced liver damage, peliosis hepatis or liver tumours. Taking UDCA may lower liver enzymes on a blood test and create false reassurance, as the PSC experience shows.
The practical risks include:
- masking warning signs that should lead to stopping a harmful substance;
- diarrhoea and, rarely, other side effects of UDCA itself;
- interactions, for example with ciclosporin, bile acid sequestrants and aluminium-containing antacids;
- delayed diagnosis of jaundice, itching or abdominal pain that requires urgent assessment.
Anyone with abnormal liver tests should see a doctor rather than self-treat. Symptoms such as yellowing of the skin or eyes, dark urine, pale stools or severe itching need prompt medical attention.
Conclusions of the editorial team
UDCA is a clear success in primary biliary cholangitis, where it slows disease progression and is first-line therapy.
In other conditions, including PSC, pregnancy cholestasis and fatty liver, rigorous trials have not shown the expected benefits, and high doses in PSC were associated with harm.
It is not a universal liver protector, and normalising blood tests does not equal protection. For further reading, see our articles on how losartan was tested in clinical trials, on atorvastatin research, and on liver function tests for athletes.
References
- Poupon RE, Balkau B, Eschwège E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med. 1991;324(22):1548–1554.
- European Association for the Study of the Liver. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145–172.
- Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50(3):808–814.
- Chappell LC, Bell JL, Smith A, et al. Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial. Lancet. 2019;394(10201):849–860.
- Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39(3):770–778.
