January 10, 2024

Ursodeoxycholic acid improves outcomes in liver diseases

Chronic liver disease (CLD) is one of the leading causes of disability-adjusted life years (DALYs) in the total population. The global burden of CLD is increasing globally. Although screening, and antiviral treatment campaigns have reduced the CLD burden in some countries, concomitant increases in:

  • injection drug use,
  • alcohol misuse,
  • obesity
  • metabolic syndrome

threaten these trends.

Global Burden of Cirrhosis Mortality

Liver Cirrhosis: global mortality risk map

Age-adjusted risk of mortality (per 100,000 persons) attributed to cirrhosis. Legend (mortality per 100,000 persons): Dark to light blue (0-40). Yellow (40-50), Yellow-Orange (50-60), Orange-Red (60-70), Red (>70)
Edited from Reference [1]

Ursodeoxycholic acid (UDCA), known as ursodiol, a secondary bile acid (BA), has long been used in clinical practice for chronic liver disease such as cholelithiasis and the treatment of primary biliary cholangitis and other hepatobiliary disorders.
A recent understanding of nuclear BA receptor pathways has increased focus on the impact of linking between the gut, bile acids, and liver on liver pathology[2].

The role of ursodeoxycholic acid in liver disease

The large number of published studies and real-life data demonstrates therapeutic effect of UDCA on several forms of cholestatic liver disease. Its use in treating liver disease dates back more than a hundred years when it was first employed in traditional Chinese medicine. Before discovering the effectiveness of UDCA in dissolving gallstones, it has been recognized and used for centuries as ‘liver tonics[3].

Currently, UDCA at 13-15 mg/kg/day is the standard first line medication, and the only drug therapy approved by the U.S. Food and Drug Administration, for all people with primary biliary cholangitis (PBC), a chronic cholestatic liver disease where ursodeoxycholic acid (UDCA) clearly improves long-term survival[4].

The correct dosage of ursodeoxycholic acid should be calculated using different measurements based on body weight. A significant number of patients with primary biliary cholangitis in the world are being underdosed[5].

Ursodeoxycholic acid: mechanism of action

Ursodeoxycholic acid influences the liver through a combination of various and complementary mechanisms, including alterations in the bile acid pool, serving as a cytoprotectant, immunomodulating substance, and choleretic.

Multiple mechanisms of action of ursodeoxycholic acid have been described: UDCA markedly decreases biliary cholesterol saturation by inhibiting the absorption of cholesterol in the intestine and its secretion into bile, demonstrated by reduced cholesterol fraction of biliary lipids[6]. UDCA has a cytoprotective effect attributable to its ability to protect hepatocytes and cholangiocytes from bile acid-induced damage.

Recently, its anti-inflammatory and antiapoptotic abilities, make UDCA an attractive therapy for Non-alcoholic steatohepatitis (NASH). Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH is the most severe form of NAFL and can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Nowadays, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis or NASH.

BAs promote the intestinal absorption of lipid substances and improve lipid hydrolysis metabolism through regulating various lipid metabolism enzymes and enhancing the lipid metabolism of the pancreas. The level of total fecal BAs was elevated in patients with NAFL/NASH, suggesting that the progression of NAFL/NASH might be associated with altered BAs homeostasis[7].

Ursodeoxycholic acid: indications

Therapeutic concentrations of ursodeoxycholic acid can shift the concentration of bile acids from hydrophobicity (toxic effect on hepatocytes) to hydrophilicity. In fact, oral administration of UDCA produced a unique BA profile with high-abundance TUDCA and GUDCA and significantly accelerated BA enterohepatic circulation through the inhibition of intestinal farnesoid X receptor signaling (BA sensitive nuclear receptor) which in turn, induced the expression of BA transporters in the liver[8]. This activity supports the rational for UDCA improves liver condition in patients and it can be considered as a valuable agent in managing liver disease.

Recent data also suggest UDCA might have a role in managing PSC, cystic fibrosis, graft-versus-host-disease, and other hepatobiliary disorders; however, concrete data regarding therapeutic potential and long-term effects are currently lacking. In multiple cohort studies, the use of ursodeoxycholic acid (UDCA) after transplantation has been associated with a reduced incidence of rPBC. Biliary complications are reported in 10% to 35% of all LT recipients and are clearly associated with increased morbidity and mortality.

Is ursodeoxycholic acid safe?

The efficacy and safety of ursodeoxycholic acid (UDCA) for the treatment of liver disease associated with cystic fibrosis (CF) are under discussion, and clinical practice varies among centers.
As known, data from real-life experience suggest a hepatoprotective effect of UDCA by reducing serum liver parameters.

UDCA significantly reduces:

  • alanine aminotransferase,
  • aspartate aminotransferase,
  • gamma‐glutamyl transferase,
  • alkaline phosphatase,
  • and bilirubin levels,
  • regulates lipid profile and
  • ameliorates hepatic steatosis independent of weight loss[9].

Today, therapeutic approaches for liver diseases using ursodeoxycholic acid or other hydrophilic BA (i.e., tauroursodeoxycholic), have been updated, combination strategies synergistically targeting metabolic disturbances, inflammation, and fibrosis may be ultimately necessary for successful cure of these complicated and multifactorial diseases.

[1] Moon AM, Singal AG, Tapper EB. Contemporary Epidemiology of Chronic Liver Disease and Cirrhosis. Clin Gastroenterol Hepatol. 2020 Nov;18(12):2650-2666.

[2] Farooqui N, Elhence A, Shalimar. A Current Understanding of Bile Acids in Chronic Liver Disease. J Clin Exp Hepatol. 2022 Jan-Feb;12(1):155-173.

[3] Guarino MP, Cocca S, Altomare A, Emerenziani S, Cicala M. Ursodeoxycholic acid therapy in gallbladder disease, a story not yet completed. World J Gastroenterol. 2013 Aug 21;19(31):5029-34.

[4] Beuers U, Trampert DC. Ursodeoxycholzuur: geschiedenis en klinische toepassingen [Ursodeoxycholic acid: history and clinical implications]. Ned Tijdschr Geneeskd. 2022 Sep 28;166:D6970. Dutch.

[5] Chapman RW. Cost effectiveness of using ursodeoxycholic acid to treat primary biliary cholangitis. Br J Hosp Med (Lond). 2018 Aug 2;79(8):460-464. 

[6] Achufusi TGO, Safadi AO, Mahabadi N. Ursodeoxycholic Acid. 2023 Feb 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 

[7] Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther. 2022 Aug 13;7(1):287. 

[8] Zhang Y, Jiang R, Zheng X, Lei S, Huang F, Xie G, Kwee S, Yu H, Farrar C, Sun B, Zhao A, Jia W. Ursodeoxycholic acid accelerates bile acid enterohepatic circulation. Br J Pharmacol. 2019 Aug;176(16):2848-2863

[9] Trauner M, Fuchs CD. Novel therapeutic targets for cholestatic and fatty liver disease. Gut. 2022 Jan;71(1):194-209.