What is ursodeoxycholic acid and what are its indications, dosing, side effects, and contraindications?

Ursodeoxycholic Acid (UDCA): Clinical Overview

What is Ursodeoxycholic Acid?

Ursodeoxycholic acid (UDCA, also called ursodiol) is a naturally occurring hydrophilic bile acid that serves as the first-line treatment for primary biliary cirrhosis and has FDA approval for gallstone dissolution and prevention during rapid weight loss. 1, 2

UDCA is a bitter-tasting white powder with molecular weight 392.58 (chemical formula C24H40O4), available as 300 mg oral capsules. 2 It works through multiple mechanisms: replacing toxic hydrophobic bile acids with hydrophilic ones, protecting hepatocytes and cholangiocytes from apoptosis, stimulating impaired bile secretion, and exerting immunomodulatory effects. 3, 4

Primary Indications

Primary Biliary Cirrhosis (PBC) - First-Line Therapy

• UDCA at 13-15 mg/kg/day is the established first-line treatment for PBC, recommended by both the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. 1, 5
• This dosing significantly decreases serum bilirubin, alkaline phosphatase, cholesterol, and immunoglobulin M levels. 1, 5
• Long-term treatment delays histological progression when started early and reduces the likelihood of liver transplantation or death in moderate to severe disease. 1, 5
• Treatment should be lifelong, including after liver transplantation at 10-15 mg/kg/day to prevent recurrence. 5

Intrahepatic Cholestasis of Pregnancy (ICP)

• UDCA at 10-15 mg/kg/day divided into 2-3 doses is recommended as first-line therapy for maternal symptoms. 5
• Pruritus typically decreases within 1-2 weeks, with biochemical improvement in 3-4 weeks. 5
• If pruritus persists, titrate to maximum 21 mg/kg/day. 5
• UDCA is considered safe during pregnancy and breastfeeding. 1, 5

FDA-Approved Indications

• Radiolucent, noncalcified gallbladder stones <20 mm in patients with increased surgical risk (safety beyond 24 months not established). 2
• Prevention of gallstone formation during rapid weight loss in obese patients. 2

Primary Sclerosing Cholangitis (PSC) - NOT Routinely Recommended

• Both the American Association for the Study of Liver Diseases and the British Society of Gastroenterology recommend AGAINST routine use of UDCA for PSC due to limited efficacy. 1, 5
• High-dose UDCA (>20 mg/kg/day, particularly 28-30 mg/kg/day) is associated with worse outcomes including increased risk of liver transplantation and variceal development, and should be avoided. 1, 5, 3
• If used at all, doses of 15-20 mg/kg/day may improve serum liver tests, but clinical benefit remains uncertain. 5

Other Cholestatic Conditions

• ABCB4 deficiency: Low-to-medium dose (10-15 mg/kg/day) may provide anticholestatic and anti-inflammatory effects. 5
• Chronic graft versus host disease, cystic fibrosis-associated liver disease, and pediatric cholestatic disorders may benefit. 6

Dosing Regimens

Standard dosing by indication:

• PBC: 13-15 mg/kg/day in two divided doses 1, 5
• ICP: 10-15 mg/kg/day divided into 2-3 doses (maximum 21 mg/kg/day) 5
• Post-liver transplant PBC: 10-15 mg/kg/day lifelong 5
• PSC (if used despite lack of recommendation): 15-20 mg/kg/day, NEVER >20 mg/kg/day 5

Mechanisms of Action

UDCA works through multiple complementary pathways:

Bile Acid Pool Modification

• Replaces toxic hydrophobic bile acids with hydrophilic UDCA, reducing hepatocyte injury. 3, 4

Anti-Apoptotic Effects

• Modulates mitochondrial membrane perturbation and reduces reactive oxygen species production. 3
• Activates survival pathways to prevent apoptosis induced by toxic bile acids like deoxycholic acid. 3
• Inhibits caspase-6-dependent apoptotic pathways. 3

Immunomodulatory Actions

• Influences monocyte cytokine production and activates glucocorticoid receptors. 3
• Suppresses IFN-gamma-induced MHC class II gene expression. 3

Anti-Fibrotic Properties

• Inhibits hepatic stellate cell proliferation through FXR nuclear receptor activation. 3

Stimulation of Bile Secretion

• Corrects deficits in bile acid secretion by modifying transcription and translation of bile acid transport proteins. 7

Side Effects and Tolerability

UDCA is generally well tolerated, with mild side effects occurring in up to 25% of patients. 1

Common side effects:

• Nausea 1
• Mild dizziness 1
• Diarrhea (dose-related) 8

Important safety note: The drug has an excellent safety profile with minimal drug interactions documented. 8

Contraindications

Absolute contraindications per FDA labeling: 2

• Calcified cholesterol stones
• Radiopaque stones
• Radiolucent bile pigment stones (UDCA will not dissolve these)
• Compelling indications for cholecystectomy: unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-gastrointestinal fistula
• Allergy to bile acids

Clinical contraindication:

• High-dose therapy (>20 mg/kg/day) in PSC patients due to documented harm 1, 5

Monitoring Requirements

Regular monitoring of liver biochemistry is essential to assess treatment response: 1, 5

• Alkaline phosphatase and GGT are the earliest cholestasis markers and should be monitored regularly. 1
• Response should be evaluated after 1 year of therapy to identify patients at risk for progressive disease. 5
• AMA-positive individuals with normal liver tests require annual reassessment of biochemical cholestasis markers. 1, 5
• In ICP, measure serum bile acids at least weekly starting at 32 weeks gestation. 5

Critical Clinical Pitfalls

Do not use UDCA for symptom management alone in PBC: UDCA has not demonstrated significant effects on fatigue or pruritus, so additional treatments (such as rifaximin for pruritus) may be needed. 1

Avoid high doses in PSC: Doses exceeding 20 mg/kg/day are associated with enhanced risk of adverse outcomes including liver transplantation and variceal development. 5, 3

Consider discontinuation in hepatic decompensation: In patients with advanced disease and decompensation, discontinuation may be necessary. 5