When should Ursodeoxycholic acid (UDCA) be administered?

When to Give UDCA (Ursodeoxycholic Acid)

UDCA should be given at 13-15 mg/kg/day as first-line therapy for Primary Biliary Cholangitis (PBC), at 10-15 mg/kg/day for Intrahepatic Cholestasis of Pregnancy (ICP), and at moderate doses (15-20 mg/kg/day) for symptomatic pregnant women with cholestatic liver diseases during the second or third trimesters. 1, 2, 3

Primary Biliary Cholangitis (PBC) - The Gold Standard Indication

UDCA at 13-15 mg/kg/day administered as a single bedtime dose is the established first-line treatment for PBC. 2, 3 This dosing regimen:

• Significantly reduces serum bilirubin, alkaline phosphatase, cholesterol, and immunoglobulin M levels compared to placebo 2, 3
• Delays histological progression when initiated at early disease stages 2, 3
• Reduces the likelihood of liver transplantation or death in patients with moderate to severe PBC 2, 3
• Should be evaluated for biochemical response after 1 year to identify patients at risk of progressive disease who may need second-line therapies 2

Post-liver transplant PBC patients should receive UDCA at 10-15 mg/kg/day in two divided doses to prevent disease recurrence, which reduces long-term risk of graft loss, liver-related death, and all-cause death. 2

Intrahepatic Cholestasis of Pregnancy (ICP) - Strong Evidence for Use

UDCA at 10-15 mg/kg/day divided into 2-3 doses daily is recommended for ICP, where it ameliorates pruritus and improves serum liver tests. 1, 3 Key considerations include:

• Pruritus typically decreases within 1-2 weeks, with biochemical improvement in 3-4 weeks 3
• Dose can be titrated to a maximum of 21 mg/kg/day if pruritus is not relieved 3
• UDCA is considered safe during pregnancy and breastfeeding 1, 3
• Women with ICP should be advised that premature birth incidence is increased, though insufficient data exist regarding protection against fetal complications 1
• Vitamin K should be supplemented when prothrombin time is prolonged 1

Cholestatic Liver Diseases During Pregnancy - Symptomatic Treatment

For pregnant women with PBC or PSC who are symptomatic during the second or third trimesters, UDCA can be administered at 15-20 mg/kg/day. 1 The rationale includes:

• UDCA is FDA Category B (risk in animal studies but not in humans) 1
• No adverse effects in mothers or newborns have been observed in randomized controlled trials using UDCA for up to 8 weeks 1
• Medium-dose UDCA is regarded as safe during pregnancy 1
• Treatment with UDCA is recommended during breastfeeding, as significant amounts cannot be found in milk during lactation 1

For pregnant women with PBC or PSC, treatment should continue during pregnancy to prevent disease flares, which might be more deleterious to pregnancy outcome than any potential risk of the medication. 1

Primary Sclerosing Cholangitis (PSC) - Critical Dosing Warnings

UDCA is NOT recommended for routine treatment of newly diagnosed PSC, and specific dosing considerations are critical: 1, 2, 3

• High-dose UDCA (28-30 mg/kg/day) MUST BE AVOIDED due to increased mortality, serious adverse events, higher rates of death, liver transplantation, and development of varices 1, 2, 3
• Low-dose UDCA (10-15 mg/kg/day) improves liver biochemistry but does not improve clinical outcomes including death, transplantation, or disease progression 3
• Moderate-dose UDCA (15-20 mg/kg/day) may be considered in select PSC cases as it can improve serum liver tests and surrogate markers of prognosis, though available data does not support a firm recommendation 1, 3

The evidence from a large multicenter study that was terminated early showed definitively worse outcomes with high-dose UDCA in PSC, making this a critical safety consideration. 1

Genetic Cholestatic Diseases - Specialized Indications

UDCA at 8-10 mg/kg/day is strongly recommended for patients with at least one ABCB4 missense variant and clinical phenotype (MDR3 deficiency). 2, 4 This dosing:

• Achieves complete symptom resolution and normalization of liver tests 2
• Results in 91% transplant-free survival at 14-year follow-up 2, 4
• Should be lifelong therapy 4

Pruritus Management - Not First-Line

UDCA should NOT be used as first-line therapy for pruritus management, as cholestyramine, rifampicin, and other agents have stronger evidence for pruritus control. 2, 4 Important considerations:

• UDCA may paradoxically worsen itching in some patients 2, 4
• For cholestasis-associated pruritus in pregnancy, rifampicin (300-600 mg daily) and anion exchange resins (cholestyramine 4-8 g/day or colestipol 5-10 g/day) are recommended 1
• UDCA and cholestyramine administration should be separated by at least 4 hours 1

Drug-Induced Cholestatic Liver Injury - No Established Role

UDCA is NOT established therapy for drug-induced cholestatic liver injury (DILI). 2 The primary management approach involves:

• Discontinuation of the offending agent 2
• Ruling out alternative causes 2
• Supportive care 2

Common Pitfalls to Avoid

Never exceed 20 mg/kg/day in any cholestatic liver disease, as high-dose UDCA (>20 mg/kg/day) has been associated with worse outcomes, particularly in PSC. 2 Additional pitfalls include:

• Avoid using UDCA during the first trimester of pregnancy unless absolutely necessary, as it is not approved for early pregnancy use 1
• Do not use obeticholic acid during pregnancy or breastfeeding; it should be discontinued as soon as pregnancy is confirmed 1
• Monitor coagulation tests (INR) in women treated with cholestyramine or rifampicin, as these may exacerbate vitamin K deficiency 1
• Ensure neonates of women treated with rifampicin receive vitamin K 1