Why do we use ursodeoxycholic acid (UDCA) in cholestatic liver disease?

Ursodeoxycholic acid (or UDCA, Ursodiol) is a very commonly-used medication in the hepatologist’s arsenal. But have you ever wondered what it is? Why does it work? I know I have.

Let’s try and answer some of those questions for you today!

What’s in a name?

Romeo and Juliet may disagree, but in this case, the name means everything.

We all remember our star-gazing days. Whose favorites were Ursa major and Ursa minor? How about Ursa deoxycholic acid?

Ok, that’s not a constellation. But ursodeoxycholic acid (UDCA) is so named because it is the predominant compound in bear bile (and ‘ursus’ is Latin for bear).

Bear bile has apparently been used for centuries in eastern Asian cultures, particularly in traditional Chinese medicine, where it has been thought to “clear heat, relieve toxin, and clear away liver fire.”

The more recent timeline of UDCA is as follows:

In 1902: a Swedish professor, Olof Hammarsten, published a report of a “new” compound discovered in the bile of the Polar bear, which he named “ursocholeinsaure.”

In 1927: Masato Shoda published further on the chemical structure of this compound, re-naming it urso-deoxycholic acid, recognizing it is a compound similar to other bile acids found in humans.

In 1975: Makino and others reported the first prospective study of patients with gallbladder stones, demonstrating that UDCA administration led to dissolution of gallstones.

In 1987: Poupon et al. reported that long-term UDCA is safe and effective in PBC.

What exactly is ursodeoxycholic acid (besides bear bile)?

Let’s start basic. A bile acid (BA) is a steroid synthesized from cholesterol within hepatocytes. Bile acids are but one component of bile. As the secretion of bile acid increases, bile flow increases as well.

The predominant bile acids in human bile are cholic acid and cheno-deoxycholic acid.

UDCA, on the other hand, normally comprises a very small amount (3-4%) of human bile (but a large proportion of bear bile!). 

UDCA is a hydrophilic bile acid. This is important! Why?

  • The naturally-occurring human BAs (cholic acid and chenodeoxycholic acid [DCA]) are more hydrophobic.
  • As I’ll show later, it’s these hydrophobic bile acids that, upon building upon in the liver, can cause hepatocyte toxicity.

UDCA Pharmacokinetics:

  • UDCA is exogenously administered in oral form
  • ~30-60% is absorbed, mostly in small intestine
    • Absorption is enhanced by solubilization in micelles (therefore, taking during meals helps; and one must avoid concomitant medications that reduce absorption such as cholestyramine)
  • After absorption:
    • UDCA enters portal circulation and is taken up by hepatocytes at sinusoidal domain via bile acid transporters (NTCP, OATP)
    • In the hepatocyte → UDCA is conjugated to glycine or taurine, which allows its secretion across hepatocyte canalicular membrane into bile ducts
    • UDCA then becomes part of the bile acid pool within bile. Just like other bile acids, UDCA enters the small intestine and then undergoes uptake in the terminal ileum through the enterohepatic circulation
  • UDCA has high first-pass metabolism (near 70%)
    • Administration of 13-15mg/kg leads to ~40-50% of human bile acid containing UDCA
  • Its half-life is ~3.5 to 5.8 days

How does UDCA actually work?

There exists a significant body of research into the possible mechanisms by which UDCA treats cholestatic liver disease. A full discussion of the intricacies of these mechanisms is beyond the scope of this article. My purpose here is to just list a few of the common theories so that as clinicians, when we are prescribing this medication, we have a general understanding of how it may work.

From my reading, there appears to be three major mechanisms to highlight. I have included a figure from a paper by Konstantinos Lazaridis below.

  1. UDCA alters the bile acid pool, protecting cholangiocytes against toxic hydrophobic bile acids
    1. In cholestatic liver disease, the toxic BAs, which make up a majority of bile acids in humans, begin to accumulate within hepatocytes
    2. This leads to cell-damaging events
    3. UDCA may help expand the hydrophilic component of the bile pool, thereby decreasing the overall component of hydrophobic (i.e., toxic) BAs
  2. UDCA has a “choleretic” effect (stimulates hepatobiliary secretion)
    1. UDCA increases secretion of bile acids across the canalicular membrane into the biliary system
    2. Experiments with tauro-UDCA show that it leads to increased intracellular calcium, which then promotes expression of membrane transplant proteins and vesicular exocytosis, all of which leads to increased BA secretion
  3. UDCA alters intracellular pathways that cause BA-induced apoptosis
    1. UDCA may stabilize the plasma membrane by reducing disruption of cholesterol-rich membrane by toxic BAs 
    2. UDCA may also inhibit the mitochondrial damage induced by toxic BAs

Remember, from my previous article on bilirubin and alkaline phosphatase — by reducing intrahepatic build-up of bile acids, UDCA will reduce the stimulus for alkaline phosphatase generation.

Great, so when do we use UDCA?

I will not go through all of the evidence for the use of UDCA in each of the below diseases, but will highlight some important points:


  1. UDCA at a dose of 13-15mg/kg has been shown to have the following effects:
    • Improves serum liver chemistries, including bilirubin and alkaline phosphatase
    • Reduces Mayo risk score
    • Improves liver histology
    • Delays progression of fibrosis and development of cirrhosis


  1. There is a lot of back and forth regarding UDCA in PSC
  2. 13-15mg/kg may improve labs but not shown to impact disease progression or survival
  3. Investigators have tried higher doses, but a trial of 25-30mg/kg/day resulted in higher risk of death, need of LT, and development of varices
  4. It might be that “medium-dose” UDCA (15-20mg/kg/day) can benefit patients without significant harm but this is not fully clarified as of yet 

Intrahepatic cholestasis of pregnancy (ICP)

  1. UDCA is a first-line therapy in ICP
  2. Dose of 20-25mg/kg/day improves liver tests, pruritis
  3. However, convincing evidence of an improvement on outcomes has NOT been shown
  4. PITCHES trial (Lancet, 2019) — DBRCT of UDCA vs placebo for 605 patients with ICP, showed no difference in the primary outcome of composite of perinatal death, pre-term delivery, or NICU admission

Gallstone dissolution

  1. Cholesterol gallstones are formed when the bile becomes overly saturated with cholesterol, in the setting of gallbladder stasis and increased rates of cholesterol crystallization
  2. UDCA therapy is proposed to help dissolve gallstones by helping to unsaturate the bile (possibly by reducing intestinal absorption of cholesterol) and increasing the solubilization of cholesterol from gallstone surfaces
  3. When cholecystectomy is not possible, in patients with recurrent biliary colic, UDCA can be used, provided the following conditions are met:
    • Radiolucent gallstones (which suggests cholesterol stones)
    • Patency of cystic duct
  4. Recommended dose 8-10mg/kg
  5. Dissolution rate 30-60% but with high recurrence rates

And that’s it. There you have it! I hope you have a better understanding of what UDCA is, how it works, and some instances in which we use it in hepatology. Please reach out on Twitter or by e-mail with any feedback!


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