The History of the Drug Ursodeoxycholic Acid

Ursodeoxycholic acid is one of the few modern drugs whose history begins in traditional medicine. From bear bile to a synthetic molecule with an evidence base — the editorial team traced how UDCA became the standard treatment for cholestatic liver diseases and where its possibilities turned out to be limited.

Bear bile and traditional medicine

The history of ursodeoxycholic acid (UDCA) begins not in a laboratory but in the traditional medicine of East Asia. Dried bear bile was used for centuries in Chinese medicine as a remedy for “liver diseases”, jaundice, abdominal pain, and eye diseases. References to such remedies are found in ancient pharmacopoeial treatises.

Of course, ancient physicians did not know the chemical composition of bile. Modern science explained that bear bile has an unusual composition: it is dominated precisely by ursodeoxycholic acid, whereas in humans this substance is present only in a small amount. The name of the acid comes from the Latin ursus — “bear”.

The traditional use of bear bile also has a dark side: for its sake, animals were and still are kept in cruel conditions on special farms in some countries. The advent of synthetic UDCA made it possible to obtain the same substance without the use of animals, which animal-welfare organizations regard as an important argument against this practice.

Traditional experience is not in itself proof of effectiveness. But in this case it drew chemists’ attention to a substance that later underwent modern clinical studies and became the standard treatment for several liver diseases.

Isolation and synthesis of UDCA

The chemical study of bear bile began in Japan. In 1927, the Japanese researcher M. Shoda isolated a crystalline bile acid from it, which he named ursodeoxycholic. Its structure was later established: 3α,7β-dihydroxy-5β-cholanic acid (Hofmann & Hagey, 2014).

Interestingly, UDCA is a stereoisomer of chenodeoxycholic acid (CDCA), one of the main primary bile acids in humans. The only difference is in the spatial orientation of one hydroxyl group at position 7. Yet this small detail makes UDCA far more hydrophilic and less toxic to cells than most other bile acids.

In the 1950s, Japanese chemists developed a method for synthesizing UDCA from cholic acid, which is obtained from cattle bile. This made it possible to abandon bear-derived raw material for producing the drug. In Japan, UDCA began to be produced as a medicine as early as the mid-20th century, initially for a wide range of “liver” and digestive indications.

In the human body, UDCA is also formed naturally: gut bacteria convert part of the chenodeoxycholic acid into ursodeoxycholic acid. However, its share in the total pool of human bile acids is small, so an external supply is needed for a therapeutic effect.

Gallstones: the first evidence-based indication

The first clinical indication that received scientific confirmation in the West was the dissolution of cholesterol gallstones. In the 1970s, chenodeoxycholic acid, which reduces the cholesterol saturation of bile, was already in use. However, it often caused diarrhea and an increase in liver enzymes.

In 1975, Japanese researchers reported that UDCA is also able to dissolve cholesterol stones but is tolerated much better. Subsequent European and American work confirmed this. UDCA reduces cholesterol secretion into bile and promotes the transition of cholesterol into a soluble form.

In the USA, the drug for dissolving gallstones was registered in the late 1980s. Later, an indication for the prevention of stone formation during rapid weight loss also appeared: in a randomized study, in participants of a very-low-calorie diet program, UDCA substantially reduced the frequency of stone appearance (Shiffman et al., 1995).

With the advent of laparoscopic cholecystectomy, the role of drug-based stone dissolution decreased. Current EASL guidelines limit this approach to a small group of patients with small, non-calcified cholesterol stones and a functioning gallbladder (EASL, 2016).

Primary biliary cholangitis: the breakthrough

A true breakthrough was the use of UDCA in primary biliary cirrhosis — a disease now called primary biliary cholangitis (PBC). This is an autoimmune disease in which the small bile ducts are gradually destroyed and toxic bile acids accumulate in the liver.

In the late 1980s, a French group led by Raoul Poupon published pilot results, and in 1991 — a multicenter controlled study in the New England Journal of Medicine. In it, UDCA improved the biochemical indicators of cholestasis and reduced the likelihood of adverse events compared with placebo (Poupon et al., 1991).

Subsequent studies and long-term observations showed that in patients with a good biochemical response to UDCA, survival approaches that of the general population (Parés et al., 2006). In 1997, the FDA registered the drug for the treatment of PBC, and UDCA became the first line of therapy, which it remains to this day (Lindor et al., 2019).

In parallel, understanding of the mechanism of action developed. Researchers showed that UDCA displaces toxic hydrophobic bile acids, stimulates bile secretion, and protects the cells of the ducts and hepatocytes from damage (Beuers, 2006).

Limits of use: what new studies showed

Success in PBC prompted trials of UDCA in other diseases as well. Not all expectations were met. In primary sclerosing cholangitis, a high dose (28–30 mg/kg per day) in a randomized study not only failed to improve the prognosis but was also associated with a higher frequency of serious complications (Lindor et al., 2009).

In non-alcoholic steatohepatitis, a two-year randomized study showed no advantage of UDCA over placebo by histological signs (Lindor et al., 2004). Therefore, current guidelines do not recommend UDCA for the treatment of fatty liver disease.

In intrahepatic cholestasis of pregnancy, UDCA was long considered the standard. The large PITCHES study showed that the drug does not reduce the frequency of a composite adverse perinatal endpoint (Chappell et al., 2019), which forced a reconsideration of approaches.

Thus, the history of UDCA is an example of how a traditional remedy traveled the road to evidence-based medicine, and evidence-based medicine, in turn, clearly delineated the limits of its use.

• proven: PBC, dissolution of certain gallstones, prevention of stones during rapid weight loss;
• not confirmed: NASH, high doses in PSC;
• reconsidered: cholestasis of pregnancy.

Editorial Conclusions

Ursodeoxycholic acid traveled the road from a component of bear bile in traditional medicine to a synthetic drug with a clear evidence base.

Its main achievement is the transformation of the prognosis in primary biliary cholangitis, as well as its role in dissolving and preventing cholesterol gallstones.

At the same time, randomized studies showed that in many other conditions UDCA does not give the expected effect, and in high doses in PSC it can be harmful.

The editorial team also recommends reading our materials on the effect of ursodeoxycholic acid on the liver and kidneys, on tests during its use, and on the history of rosuvastatin.

References

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2. 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.
3. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130(3):715–720.
4. Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394–419.
5. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol. 2016;65(1):146–181.
6. Shiffman ML, Kaplan GD, Brinkman-Kaplan V, Vickers FF. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program. Ann Intern Med. 1995;122(12):899–905.
7. 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.
8. 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.