An increase in plasma cholesterol independent of thyroid function during long-term amiodarone therapy. A dose-dependent relationship. OBJECTIVE: To determine whether long-term amiodarone treatment is associated with a rise in plasma cholesterol, and, if so, to analyze its relation with thyroid function. DESIGN: Consecutive entry trial, including cardiac patients who initiated amiodarone medication but excluding those with abnormal thyroid function (defined as peak thyroid-stimulating hormone [TSH] response to thyrotropin-releasing hormone [TRH] less than 2.8 or greater than 22.0 mU/L) either before or during amiodarone treatment. PATIENTS: Twenty-three patients who remained euthyroid were studied. INTERVENTION: Oral administration of amiodarone (mean duration of treatment, 17 months; range, 6 to 30 months). MEASUREMENTS: Fasting plasma lipids, thyroid hormones, and peak TSH to TRH values were recorded before and every 6 months during amiodarone treatment. RESULTS: Plasma cholesterol gradually increased from 5.1 +/- 0.2 mmol/L before treatment to 6.9 +/- 0.8 mmol/L after 30 months of amiodarone medication (P less than 0.001); the peak TSH response to TRH did not change. When age- and sex-specific reference values were applied, 30% of the patients had cholesterol values above the 75th percentile before treatment; this number rose to 69% after 2 years of treatment. The rise in plasma cholesterol was associated with an equal increase in apoprotein B. Plasma cholesterol was not related to the daily dose of amiodarone or to plasma concentrations of amiodarone, desethylamiodarone, thyroxine (T4), triiodothyronine (T3), or reverse triiodothyronine (rT3). Linear regression analysis indicated a positive relation between plasma cholesterol and the cumulative dose of amiodarone (r = 0.25, P less than 0.05). CONCLUSION: Long-term amiodarone treatment is associated with a dose-dependent increase in plasma cholesterol that is independent of thyroid function. 