What is the recommended dosing of Ursodeoxycholic acid (UDCA) for an adult patient with primary biliary cholangitis or drug-induced cholestatic liver injury?

UDCA Dosing for Liver Injury

For primary biliary cholangitis (PBC), use UDCA 13-15 mg/kg/day as a single bedtime dose; for drug-induced cholestatic liver injury, UDCA is not established therapy and should not be routinely used; for primary sclerosing cholangitis (PSC), avoid UDCA entirely at high doses (>28 mg/kg/day) due to increased mortality. 1

Primary Biliary Cholangitis (PBC) - Established Therapy

The standard dose is 13-15 mg/kg/day administered as a single bedtime dose. 1 This represents the most robust evidence-based dosing for any cholestatic liver disease, supported by multiple placebo-controlled trials demonstrating:

• Significant reduction in serum bilirubin, alkaline phosphatase, cholesterol, and immunoglobulin M levels compared to placebo 1
• Delayed histological progression when initiated at early disease stages 1
• Reduced likelihood of liver transplantation or death in patients with moderate to severe PBC 1
• Biochemical response should be evaluated after 1 year of therapy to identify patients at risk of progressive disease 1

Post-Liver Transplant PBC Management

UDCA should be given lifelong after liver transplantation at 10-15 mg/kg/day in two divided doses to prevent PBC recurrence. 2 This dosing was associated with:

• Lower risk of PBC recurrence 2
• Reduction in long-term risk of graft loss, liver-related death, and all-cause death 2

Primary Sclerosing Cholangitis (PSC) - Critical Dosing Warnings

UDCA is NOT recommended for routine treatment of newly diagnosed PSC. 2 The evidence demonstrates clear harm at certain doses:

High-Dose UDCA (28-30 mg/kg/day) - MUST BE AVOIDED

This dose is associated with increased mortality and serious adverse events. 2 Specific harms include:

• Higher rates of death 2
• Increased liver transplantation rates 2
• Development of varices 2
• Increased serious adverse events compared to placebo 2

Moderate-Dose UDCA (15-20 mg/kg/day) - Off-Label Use

Although commonly used off-label at approximately 20 mg/kg/day, there is no definitive recommendation endorsing this practice. 2 This dose may improve serum liver tests and surrogate markers of prognosis, but available data does not support a firm recommendation. 2

Low-Dose UDCA (10-15 mg/kg/day) - Biochemical Improvement Only

This dose improves liver biochemistry but does not improve clinical outcomes including death, transplantation, or disease progression. 1

Drug-Induced Cholestatic Liver Injury - No Established Role

UDCA is not established therapy for drug-induced cholestatic liver injury (DILI). The consensus guidelines on DILI management in clinical trials do not recommend UDCA as standard treatment. 2 The primary management approach involves:

• Discontinuation of the offending agent
• Ruling out alternative causes (viral hepatitis A-E, cholelithiasis, alcohol, other medications, herbs, supplements) 2
• Supportive care

Special Populations and Alternative Indications

Intrahepatic Cholestasis of Pregnancy

The recommended dose is 10-15 mg/kg/day divided into 2-3 doses daily. 1 Clinical response includes:

• Decrease in pruritus typically within 1-2 weeks 1
• Biochemical improvement usually within 3-4 weeks 1
• If pruritus persists, titrate to maximum 21 mg/kg/day 1
• UDCA is considered safe during pregnancy and breastfeeding 1

ABCB4/MDR3 Deficiency

Use UDCA 8-10 mg/kg/day for patients with at least one ABCB4 missense variant and clinical phenotype. 3 This dosing achieves:

• Complete symptom resolution and normalization of liver tests 3
• 91% transplant-free survival at 14-year follow-up 3
• Lifelong treatment is recommended 3

Common Pitfalls to Avoid

Do not use UDCA as first-line therapy for pruritus management - cholestyramine, rifampicin, and other agents have stronger evidence for pruritus control. 3 UDCA may paradoxically worsen itching in some patients. 3

Do not exceed 20 mg/kg/day in any cholestatic liver disease - high-dose UDCA (>20 mg/kg/day) has been associated with worse outcomes, particularly in PSC. 3

Do not delay evaluation of UDCA response beyond 1 year in PBC - early identification of non-responders is critical for considering second-line therapies. 1

Mechanism Supporting Dosing Rationale

UDCA works through multiple mechanisms that justify the specific dosing ranges:

• Changes bile acid composition from hydrophobic to hydrophilic, reducing toxic bile acid accumulation 4
• Stimulates hepatobiliary secretion via Ca²⁺- and protein kinase C-alpha-dependent mechanisms 4
• Protects hepatocytes against bile acid-induced apoptosis by inhibiting mitochondrial membrane permeability transition 4
• Provides cytoprotection by displacing toxic hydrophobic bile acids from hepatocellular membranes 3

The 13-15 mg/kg/day dose for PBC represents the optimal balance between achieving therapeutic bile acid enrichment and avoiding excessive dosing that provides no additional benefit. 5