ReviewUrsodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’☆
Section snippets
Introduction and overview
The use of ursodeoxycholic acid (UDCA) in the treatment of liver maladies originates in ancient Chinese folk medicine. Indeed, for centuries, the Chinese drug ‘yutan’ a powder preparation derived from dried bile of adult bears was utilized to alleviate hepatobiliary disorders [1].
In 1902, Hammarsten first reported the presence of an unknown bile acid in the bile of the polar bear that he called ‘ursocholeinic acid’ [2]. At that time, given the lack of knowledge on steroid compounds, Hammarsten
Chemical structure, characteristics and origin
Bile acids are acidic steroids that are synthesized from cholesterol within the hepatocytes. UDCA represents a hydrophilic dihydroxy (i.e. 3α, 7β-dihydroxy-5β-cholan-24-oic acid) bile acid (Fig. 1). The solubility of its protonated form is ~ 9 μmol/l and it has a melting point of 203°C [8]. In humans, UDCA accounts for up to 4% of the bile acid pool and because it is not synthesized in the liver it likely originates in the colon by bacterial 7β epimerization of the primary bile acid
Cholesterol and bile acid metabolism
UDCA therapy decreases the cholesterol secretion into bile as indicated by a decline in the cholesterol fraction of biliary lipids. Indeed, UDCA reduces the biliary cholesterol by 40–60%. These UDCA induced changes are greater compared to equal doses of chenodeoxycholic acid [15]. In humans, UDCA at 15 mg/kg per day does not suppress HMG CoA reductase in contrast to chenodeoxycholic acid [8]. Thus, it is likely that UDCA either decreases the intestinal absorption of cholesterol and/or increases
Mechanisms of ursodeoxycholic acid action
UDCA exerts its action(s) in liver through multiple possibly interrelated pathways including alterations of bile acid pool, choleresis, immune modulation effects and cytoprotection mechanisms as shown in an overview on Fig. 2 and explained in detail on the following pages.
Clinical use and efficacy
UDCA has been used for the treatment of cholestatic and other liver diseases. We review here the main studies conducted for these hepatic disorders and discuss the use of UDCA in clinical practice.
Summary
UDCA exerts its beneficial effect in liver diseases through a diverse, probably, complementary array of mechanisms. The clinical use and efficacy of UDCA in PBC have been evident. UDCA may also have a place in the management of PSC, ICP, cystic fibrosis, PFIC and GVHD involving the liver, although, more studies are needed to further determine its therapeutic potential in these diseases and in other hepatobiliary disorders such as liver allograft rejection, drug and TPN-induced cholestasis,
Acknowledgements
We are indebted to Dr Alan Hofmann for his valuable critiques in this manuscript.
References (129)
- et al.
Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Part I
Dig Dis Sci
(1982) Untersuchungen uber die gallen einiger polarthiere. I. Ueber die galle des eisbaren. I Abschnitt
Hoppe-Seyler's. Z Physiol Chem
(1901)Uber die ursodesoxycholsaure aus barengallen und ihre physiologische wirkung
J Biochem
(1927)Uber die konstitution der urso-desoxycholsaure
Z Physiol Chem
(1936)- et al.
Dissolution of cholesterol gallstones by ursodeoxycholic acid
Jpn J Gastroenterol
(1975) - et al.
Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up. A pilot study
Dig Dis Sci
(1985) - et al.
Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis
Lancet
(1987) Pharmacology of ursodeoxycholic acid, an enterohepatic drug
Scand J Gastroenterol
(1994)- et al.
Ursodiol for hepatobiliary disorders
Ann Intern Med
(1994) - et al.
Primary biliary cirrhosis
Curr Treat Option Gastroentrol
(1999)
Effect of cholestyramine on bile acid pattern and synthesis during administration of ursodeoxycholic acid in man
Eur J Clin Invest
Influence of cholestasis on absorption of ursodeoxycholic acid
Dig Dis Sci
Hepatic transport of bile salts
Semin Liver Dis
Ursodeoxycholic acid in the treatment of liver diseases
Postgrad Med J
Ursodeoxycholic acid: a review of its pharmacological properties and therapeutic efficacy
Drugs
Metabolism of ursodeoxycholic acid in normal subjects and in patients with cholestatic liver disease: biotransformation by conjugation and urinary excretion
Changes in bile acid composition in patients with primary biliary cirrhosis induced by ursodeoxycholic acid administration
Hepatology
Cholesterol-lowering effect of ursodeoxycholic acid in patients with primary biliary cirrhosis
Hepatology
Ursodeoxycholic acid therapy of chronic cholestatic conditions in adults and children
Pharmacol Ther
Mechanism of hepatoprotective action of bile salts in liver disease
Gastroenterol Clin North Am
Hepatoprotective properties of ursodeoxycholic acid
Gastroenterology
Effects of ursodeoxycholic acid on the kinetics of the major hydrophobic bile acids in health and in chronic cholestatic liver disease
Hepatology
Effects of ursodeoxycholic acid on the kinetics of cholic acid and chenodeoxycholic acid in patients with primary sclerosing cholangitis
Hepatology
Review article: mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver diseases
Aliment Pharmacol Ther
Kinetics of hepatic bile acid handling in cholestatic liver disease: effect of ursodeoxycholic acid
Gastroenterology
Effects of tauroursodeoxycholic acid on cytosolic Ca2+ signals in isolated rat hepatocytes
Gastroenterology
Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca2+ mechanisms defective in cholestasis
J Clin Invest
Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes
Gastroenterology
Mitogen-activated protein kinases mediate the stimulation of bile acid secretion tauroursodeoxycholate in rat liver
Gastroenterology
Abnormal expression of anion exchanger genes in primary biliary cirrhosis
Gastroenterology
Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis
Hepatology
Ursodeoxycholate increases cytosolic calcium concentration and activates Cl− currents in a biliary cell line
Gastroenterology
Hypercholeresis induced by ursodeoxycholic acid and 7-ketolitho-cholic acid in the rat: possible role of bicarbonate transport
Gastroenterology
Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents
Gastroenterology
Inhibition of Na+/H+ exchange in the rat is associated with decreased ursodeoxycholate hypercholeresis, decreased secretion of unconjugated ursodeoxycholate, and increased ursodeoxycholate glucuronidation
Gastroenterology
Hypercholeresis induced by unconjugated bile acid infusion correlates with recovery in bile of unconjugated bile acids
Hepatology
Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium dependent bile acid transporter
J Clin Invest
Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties
Proc Natl Acad Sci USA
ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (Mrp3)
J Biol Chem
Immunomodulatory effects of ursodeoxycholic acid on immune responses
Hepatology
Bile acids with differing hydrophylic-hydrophobic properties do not influence cytokine production by human monocytes and murine Kuppfer cells
Hepatology
A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis
N Engl J Med
Ursodeoxycholic acid treatment lowers the serum level of antibodies against pyruvate dehydrogenase and influences their inhibitory capacity for the enzyme complex in patients with primary biliary cirrhosis
J Mol Med
Increased expression of major histocompatibility antigens in the liver as a result of cholestasis
Transplantation
Aberrant expression of HLA-DR antigens on bile duct epithelium in primary biliary cirrhosis: relevance to pathogenesis
Lancet
Cholestasis induces major histocompatibility complex class I expression in hepatocytes
Gastroenterology
Effects of bile acids and cholestasis on major histocompatibility complex class I in human and rat hepatocytes
Gastroenterology
Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid
Hepatology
Hepatocellular and biliary expression of HLA antigens in primary biliary cirrhosis before and after ursodeoxycholic acid therapy
Am J Gastroenterol
Effect of cholestasis and bile acids on interferon-induced 2′,5′ -adenylate synthetase and NK cell activities
Gastroenterology
Cited by (347)
Studies of peach gum polysaccharide on gut microbiota in vitro fermentation by human feces
2025, Journal of Future FoodsSeparation of bile acid isomer plays a pivotal role in bioequivalence evaluation of ursodeoxycholic acid
2024, Journal of Pharmaceutical and Biomedical AnalysisHepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation in adult patients: Diagnosis, incidence, prophylaxis, and treatment
2022, Transfusion and Apheresis ScienceCitation Excerpt :Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid that has one of the major therapeutic mechanisms of action in cholestatic liver diseases. It displaces endogenous hepatotoxic bile via expansion of the hydrophilic bile acid pool [74]. Several studies demonstrate the role of UDCA in the prevention of VOD/SOS.
Research advances in primary biliary cholangitis with dyslipidemia
2024, Journal of Clinical Hepatology
- ☆
This article concerns Drugs.
- †
There is no direct pharmaceutical company support for this work. However, Doctor Lindor has received research support from Axcan Pharma off and on since 1988 for clinical trials involving ursodeoxycholic acid.