Which antithyroid drug is most commonly associated with cholestasis?

Which Antithyroid Drug Causes Cholestasis

Methimazole (and its prodrug carbimazole) is the antithyroid drug most commonly associated with cholestatic liver injury, though propylthiouracil can also cause cholestasis as part of its hepatotoxicity profile.

Pattern of Hepatotoxicity by Drug

Methimazole/Carbimazole

• Methimazole causes predominantly cholestatic liver injury, particularly in older adults, with the highest reporting ratios for mild cholestatic injury occurring in patients over 61 years of age 1
• The cholestatic pattern accounts for 41.3% of antithyroid drug-induced liver injury cases, with methimazole/carbimazole being the most common offending agent overall (55.7% of cases) 2
• This cholestatic injury is typically less severe than propylthiouracil-induced hepatotoxicity and has better outcomes 3

Propylthiouracil

• Propylthiouracil causes predominantly hepatocellular injury (41.8% of cases), though it can also present with cholestatic or mixed patterns 2, 4
• When propylthiouracil does cause cholestasis, it tends to be more severe with worse outcomes, including higher rates of liver transplantation (6.4%) and mortality (11.8%) compared to methimazole 2
• Propylthiouracil has significantly higher initial bilirubin, transaminases, and rates of severe/fatal drug-induced liver injury compared to methimazole 2

Clinical Implications

Drug Selection

• Methimazole should be preferred in most clinical situations due to its lower risk of severe hepatotoxicity, though clinicians must remain vigilant for cholestatic injury 3
• Propylthiouracil should be reserved for specific situations: first trimester pregnancy and thyroid storm in adults 3
• Propylthiouracil use in children should be avoided due to the black box warning for severe hepatotoxicity 1, 3

Monitoring Strategy

• Drug-induced cholestasis is diagnosed by elevated alkaline phosphatase >2× ULN or ALT/AP ratio <2 5
• The only effective treatment is immediate withdrawal of the suspected drug 5, 6
• Repeat liver function tests within 7-10 days after drug discontinuation to confirm the cholestatic pattern and assess trend 5
• Continue monitoring until alkaline phosphatase normalizes, total bilirubin normalizes, and clinical symptoms resolve 5

Treatment Considerations

• Ursodeoxycholic acid (13-15 mg/kg/day) may beneficially affect cholestasis in approximately two-thirds of cases, though evidence is limited 5, 6
• Do not use corticosteroids for cholestatic drug-induced liver injury with normal autoimmune markers 5
• Median time to resolution is 45 days (IQR 20-90 days) after drug discontinuation 2

Critical Pitfall to Avoid

Do not switch from one antithyroid drug to another when cholestasis develops, as cross-reactivity can occur between thioimidazoles and propylthiouracil 4. Instead, discontinue the antithyroid drug entirely and consider alternative treatments such as radioactive iodine or thyroidectomy for definitive management of hyperthyroidism.