What is Ursodeoxycholic acid (UDCA)?

Ursodeoxycholic Acid (UDCA): A Therapeutic Bile Acid

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid that is naturally occurring in small quantities in normal human bile, used primarily for treating certain cholestatic liver diseases including primary biliary cirrhosis (PBC), but not recommended for routine treatment of primary sclerosing cholangitis (PSC).

Definition and Chemical Properties

Ursodeoxycholic acid (also known as ursodiol) is:

• A naturally occurring bile acid found in small quantities in normal human bile and in the bile of certain mammals 1
• Chemically described as 3α,7β-dihydroxy-5β-cholan-24-oic acid (C24H40O4) with a molecular weight of 392.58 1
• A white powder that is freely soluble in ethanol and methanol but insoluble in water 1
• A semisynthetic bile acid with hydrophilic properties, distinguishing it from more toxic hydrophobic bile acids 2

FDA-Approved Indications

UDCA is FDA-approved for:

• Treatment of patients with radiolucent, noncalcified gallbladder stones <20 mm in greatest diameter in whom elective cholecystectomy would be undertaken except for increased surgical risk 1
• Prevention of gallstone formation in obese patients experiencing rapid weight loss 1

Mechanisms of Action

UDCA works through several key mechanisms:

1. Protection of cholangiocytes against cytotoxicity:

   • Modulates the composition of mixed phospholipid-rich micelles
   • Reduces bile acid cytotoxicity
   • Decreases concentration of hydrophobic bile acids in cholangiocytes 2

2. Stimulation of hepatobiliary secretion:

   • Acts via Ca²⁺- and protein kinase C-alpha-dependent mechanisms
   • Activates p38(MAPK) and extracellular signal-regulated kinases (Erk)
   • Facilitates insertion of transporter molecules into the canalicular membrane of hepatocytes 2

3. Protection against bile acid-induced apoptosis:

   • Inhibits mitochondrial membrane permeability transition
   • Stimulates cellular survival pathways 2

Clinical Applications in Liver Diseases

Primary Biliary Cirrhosis (PBC)

• Recommended treatment: UDCA at doses of 13-15 mg/kg/day 3
• Benefits: Improves serum liver chemistries, may delay disease progression to severe fibrosis or cirrhosis, and may prolong transplant-free survival 2
• Safety: UDCA is considered safe during pregnancy and breastfeeding in PBC patients 3

Primary Sclerosing Cholangitis (PSC)

• Not recommended for routine treatment of PSC 3
• Despite showing improvement in liver biochemistry in some studies, high-quality evidence does not support its use for improving clinical outcomes 3
• A large multicentre study using high doses (28-30 mg/kg/day) was terminated early due to higher rates of serious adverse events in the UDCA treatment group 3

Other Cholestatic Conditions

• May have beneficial effects in:
  • Intrahepatic cholestasis of pregnancy
  • Liver disease of cystic fibrosis
  • Progressive familial intrahepatic cholestasis
  • Chronic graft-versus-host disease 2

Dosing Considerations

• For PBC: The optimal dose is 13-15 mg/kg/day 4
• For gallstone dissolution: Typically administered at 8-10 mg/kg/day
• During pregnancy: Medium-dose UDCA is considered safe 3

Important Clinical Considerations

Monitoring

• Regular monitoring of liver biochemistry is recommended to assess response
• In PBC, improvement in alkaline phosphatase and bilirubin levels are important markers of treatment response 5

Limitations

• Despite biochemical improvements, evidence for mortality benefit is inconsistent across studies 5
• The Cochrane systematic review did not demonstrate significant benefits on all-cause mortality or liver transplantation in PBC patients 5

Pregnancy and Breastfeeding

• UDCA should be continued during pregnancy in PBC patients as it is safe in pregnancy and breastfeeding 3
• Can be used for treatment of cholestasis-associated pruritus in pregnancy 3

Conclusion

Ursodeoxycholic acid represents an important therapeutic option for specific cholestatic liver diseases, particularly PBC. However, its use should be guided by disease-specific evidence, with recognition that while it consistently improves biochemical parameters, its impact on long-term clinical outcomes varies by condition.