Ursodeoxycholic acid: effect on the liver and kidneys

Ursodeoxycholic acid is often called a «hepatoprotector», but its action is far more specific. The editors examined how UDCA affects the liver and biliary tract, in which conditions the effect is proven, what is known about the kidneys and where the line lies between evidence-based therapy and myth.

Bile acids and the liver: basic concepts

To understand the action of ursodeoxycholic acid (UDCA) on the liver, one must recall what bile acids are. The liver synthesizes them from cholesterol, secretes them into bile, and in the intestine they help absorb fats. Most bile acids are then reabsorbed and return to the liver — this is the so-called enterohepatic circulation.

Bile acids are by nature detergents. Hydrophobic acids, such as chenodeoxycholic and deoxycholic, can damage cell membranes and trigger apoptosis and inflammation if their concentration in the liver rises. This is exactly what happens in cholestasis — impaired bile outflow.

UDCA is a hydrophilic bile acid. With regular intake it becomes a notable part of the bile acid pool and partly displaces the more toxic hydrophobic acids. As a result, bile becomes less aggressive toward liver cells and bile ducts (Beuers, 2006).

After oral intake UDCA is absorbed in the small intestine, taken up by the liver, conjugated with glycine or taurine and secreted into bile. Only a small fraction is excreted by the kidneys, so the drug's main field of action is the liver, biliary tract and intestine.

Mechanisms of action of UDCA

Modern reviews describe several interrelated mechanisms of UDCA's protective action on the liver (Beuers, 2006):

• change in bile composition— a reduction in the proportion of toxic hydrophobic bile acids;
• choleretic effect— stimulation of the secretion of bile acids and other bile components by hepatocytes;
• protection of cholangiocytes— enhanced secretion of bicarbonate, which forms a protective «umbrella» on the surface of duct cells;
• antiapoptotic action— a reduction in cell death caused by toxic bile acids;
• immunomodulatory effects, whose significance in humans is still being clarified.

Importantly, all these mechanisms work precisely in cholestasis, that is, when the problem is related to bile. So UDCA is effective in diseases where liver damage is caused by the accumulation of bile acids, and much less useful in diseases with other mechanisms — viral hepatitis, fatty liver disease, alcoholic damage.

The choleretic effect explains why at the start of treatment for PBC the biochemical markers of cholestasis — alkaline phosphatase and gamma-glutamyltransferase — usually decline over several months. To assess effectiveness, doctors analyze the dynamics of precisely these markers (EASL, 2017).

At the same time, in patients with complete mechanical obstruction of the bile ducts (a stone, a tumor) stimulating bile secretion does not help and can be undesirable: the bile has nowhere to flow. So such conditions are contraindications.

When UDCA helps the liver

The best-proven action of UDCA on the liver is in primary biliary cholangitis. In patients with a good biochemical response, prolonged therapy substantially reduces the risk of progression to cirrhosis and improves survival (Poupon et al., 1991; Parés et al., 2006). The standard dose in guidelines is 13–15 mg/kg of body weight per day, with lifelong treatment (Lindor et al., 2019).

Other cholestatic conditions in which UDCA is used include certain forms of childhood cholestasis, cholestasis in cystic fibrosis and some drug-induced cholestatic injuries. However, in many of these situations the evidence base is limited, and the EASL guidelines on cholestatic diseases recommend assessing benefit individually (EASL, 2009).

Drug-induced liver injury, in particular cholestatic injury caused by anabolic androgenic steroids, is a separate topic. Such conditions have been described as a distinct phenotype of hepatotoxicity with marked jaundice and prolonged cholestasis (Robles-Diaz et al., 2015). UDCA is used in such cases symptomatically, but there are no randomized studies proving that it speeds recovery.

In fatty liver disease a randomized study did not confirm a histological benefit of UDCA at the standard dose (Lindor et al., 2004). This is important, because in everyday use the drug is often perceived as a universal «hepatoprotector» for any changes in liver markers.

Safety for the liver and the risks of high doses

Ursodeoxycholic acid in therapeutic doses is, as a rule, well tolerated by the liver. The most frequent side effect is diarrhea, related to the action of bile acids in the large intestine. Clinically significant worsening of liver markers occurs rarely and is usually related to progression of the underlying disease (LiverTox).

The exception is very high doses in primary sclerosing cholangitis. In a randomized study a dose of 28–30 mg/kg per day was associated with a higher frequency of serious adverse events, including liver transplantation and the development of varices (Lindor et al., 2009). The mechanism is not fully understood; one hypothesis is the formation of toxic lithocholic acid when there is an excess of UDCA in the intestine.

In patients with decompensated cirrhosis, the use of UDCA is limited: in the package inserts it is listed as a condition requiring special caution or as a contraindication depending on the indication. In such a situation the decision is made by a hepatologist.

The practical takeaway for the reader: UDCA is not a «vitamin for the liver» but a drug for specific diagnoses. Self-directed long-term intake «for prevention» has no evidence base and can mask the symptoms of a disease that needs to be diagnosed.

UDCA and the kidneys

For UDCA the kidneys are a secondary organ of excretion. However, the topic of «bile acids and the kidneys» has an important clinical aspect. In severe cholestasis with a high level of bilirubin and bile acids, so-called cholemic nephropathy (bile cast nephropathy) can develop: casts form in the renal tubules, and the epithelium is damaged by toxic components of bile (van Slambrouck et al., 2013).

This condition has been described, in particular, in severe drug-induced cholestasis, including that related to anabolic steroids. Theoretically, by reducing the toxicity of the bile acid pool, UDCA may be useful, but there are no controlled clinical studies on kidney protection in humans. Experimental work with a derivative substance — norursodeoxycholic acid — so far remains at the preclinical level.

For patients with chronic kidney disease who take UDCA for liver indications, the package inserts usually do not provide a separate dose adjustment, since the drug is excreted mainly with bile. However, there are few data on use in severe renal failure, so the doctor assesses the situation individually.

Direct nephrotoxicity of UDCA at therapeutic doses has not been described. If kidney markers worsen during treatment, other causes should be sought: the underlying liver disease, dehydration from diarrhea, concomitant drugs.

Editorial conclusions

Ursodeoxycholic acid protects the liver in cholestatic diseases by changing bile composition, stimulating its outflow and reducing cell death. Its effect is best proven in primary biliary cholangitis.

In fatty liver disease the benefit is not confirmed, and high doses in PSC can be harmful. The drug is not a universal hepatoprotector.

The kidneys are not a target of UDCA, and no direct toxicity toward them has been described; its potential role in preventing cholemic nephropathy so far remains a hypothesis.

The editors also recommend our materials on tests during UDCA intake, on its contraindications and on the effect of rosuvastatin on the liver and kidneys.

References

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2. 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.
3. 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.
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7. Robles-Diaz M, Gonzalez-Jimenez A, Medina-Caliz I, et al. Distinct phenotype of hepatotoxicity associated with illicit use of anabolic androgenic steroids. Aliment Pharmacol Ther. 2015;41(1):116–125.
8. van Slambrouck CM, Salem F, Meehan SM, Chang A. Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction. Kidney Int. 2013;84(1):192–197.