How ursodeoxycholic acid works

Ursodeoxycholic acid is often called a "hepatoprotector", but this name does not explain much. The editors analyzed how exactly the molecule affects bile, liver cells and bile ducts and why its effect is primarily related to bile stagnation.

Bile acids: friends and enemies of the liver

Bile acids are cholesterol derivatives that the liver synthesizes to digest fats. Together with bile, they enter the intestine, emulsify fats and help the absorption of fat-soluble vitamins, and then about 95% return to the liver. This circulation is called enterohepatic circulation.

Human bile acids differ in "hydrophobicity". Hydrophobic acids - chenodeoxycholic, deoxycholic, lithocholic - are strong detergents. In normal concentrations, they do their job, but when bile stagnates (a condition called cholestasis), they accumulate in liver cells and bile ducts and damage membranes, mitochondria, trigger cell death and inflammation.

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid. Normally, it is not much in human bile, a few percent of the total pool. Chemically, it is the 7β-epimer of chenodeoxycholic acid: it differs only in the spatial position of one hydroxyl group, but it is this detail that makes the molecule much less toxic (Hofmann, 1999).

Historically, UDCA is known as the main component of bear bile, which has been used for centuries in traditional East Asian medicine. Modern drugs are obtained synthetically, and the substance itself has become the standard for the treatment of a number of cholestatic liver diseases.

Replacement of toxic bile acids

The first and simplest mechanism of action of UDCA is a change in the composition of the pool of bile acids. With regular intake in therapeutic doses, UDCA gradually becomes one of the main bile acids in bile, displacing hydrophobic acids. As a result, bile becomes less aggressive towards cells.

This is partly due to competition for intestinal absorption and hepatic reuptake. The more UDCA in the circulation, the less room there is for toxic compounds. However, researchers emphasize that it is impossible to explain all the effects of the drug by "dilution" of toxic acids alone (Paumgartner, Beuers, 2002).

In the liver, UDCA, like other bile acids, is conjugated with glycine or taurine. Conjugates, especially tauro-UDCA, have their own biological activity and, according to experimental work, they mediate part of the signaling effects of the drug.

Part of UDCA in the intestine is converted into lithocholic acid, which is potentially toxic, under the influence of bacteria. At normal doses, this process has no clinical significance, but at very high doses it may be one of the causes of the unwanted effects described in the studies.

Bile outflow stimulation and "bicarbonate umbrella"

The second key mechanism is increased bile secretion (choleresis). In experimental models, tauro-UDCA activates signaling pathways involving calcium, protein kinase C-α, and MAP kinases in hepatocytes. This promotes the incorporation of BSEP and MRP2 transporters into the bile canalicular membrane of hepatocytes, the “pumps” that move bile acids and other substances out of the cell into the bile (Beuers, 2006).

Imagine a hepatocyte in which the bile pumps are partially "hidden" inside the cell. With cholestasis, there are few of them on the surface, and toxic substances accumulate. UDCA helps move these pumps to where they are needed and thus speeds up excretion.

The third mechanism concerns cholangiocytes — cells that line the bile ducts. The "bicarbonate umbrella" hypothesis describes a layer of bicarbonate on the surface of the ducts that prevents hydrophobic bile acids from entering cells in an uncharged form. UDCA stimulates the secretion of bicarbonate through the AE2 exchanger and thereby “strengthens” this umbrella (Beuers et al., 2010).

This concept helps to explain why the drug is effective precisely in diseases where small bile ducts are primarily affected, for example in primary biliary cholangitis.

Cell protection and influence on the immune response

The fourth mechanism is direct cytoprotection. Hydrophobic bile acids damage mitochondrial membranes and trigger apoptosis — programmed cell death. In experiments, UDCA stabilized mitochondrial membranes and reduced the release of cytochrome c, which inhibits this process (Beuers et al., 2015).

The effect of UDCA on nuclear receptors, in particular glucocorticoid receptors, and a decrease in the expression of molecules of the main histocompatibility complex on the surface of hepatocytes are also described. These effects are considered as a possible explanation for the moderate immunomodulatory effect of the drug in autoimmune liver diseases.

It is important to understand the level of evidence: most data on molecular mechanisms are obtained in cell cultures and animals. Clinical effectiveness has been proven for specific diseases, but not for abstract "liver protection" from any factors.

That is why it is incorrect to call UDCA a universal "hepatoprotector". Benefits depend on the particular disease, dose and clinical evidence.

Gallstones: a separate mechanism

Historically, the first clinical application of UDCA was the dissolution of cholesterol gallstones. Another mechanism is at work here: the drug reduces the saturation of bile with cholesterol, reducing the absorption of cholesterol in the intestine and its secretion by the liver into bile.

When bile ceases to be supersaturated, cholesterol from the surface of the stone gradually passes into solution. The process is slow and takes months, and only works for small, non-calcified cholesterol stones in a functioning gallbladder (EASL, 2016).

The same mechanism explains the prophylactic use of UDCA during rapid weight loss, such as after bariatric surgery, when the risk of stone formation increases dramatically (Stokes et al., 2014).

UDCA does not dissolve pigmented and calcified stones, so an ultrasound examination must be performed before the appointment.

• effective: small cholesterol stones in the functioning gallbladder;
• ineffective: calcified and pigment stones;
• after withdrawal, stones may form again.

Editorial conclusions

Ursodeoxycholic acid is a hydrophilic bile acid that acts in several ways: it replaces toxic hydrophobic acids, stimulates the outflow of bile, protects the cells of the ducts and liver, and reduces the lithogenicity of bile.

These mechanisms explain the effectiveness of the drug specifically in cholestatic diseases and cholesterol stones, and not in any liver damage.

Much of the molecular data is experimental, so clinical application should be based on the results of human studies and guidelines.

We also advise you to read our materials about the side effects of ursodeoxycholic acid, about clinical studies of the drug and why it is discussed by athletes.

References

1. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med. 1999;159(22):2647–2658.
2. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36(3):525–531.
3. Beuers U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2006;3(6):318–328.
4. Beuers U, Hohenester S, de Buy Wenniger LJ, et al. The biliary HCO3⁻ umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology. 2010;52(4):1489–1496.
5. Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol. 2015;62(1 Suppl):S25–S37.
6. 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.
7. Stokes CS, Gluud LL, Casper M, Lammert F. Ursodeoxycholic acid and diets higher in fat prevent gallbladder stones during weight loss: a meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2014;12(7):1090–1100.