Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

Several influences modulate biochemical responses to a weight-adjusted levothyroxine (l-T(4)) replacement dose. We conducted a secondary analysis of the relationship of l-T(4) dose to TSH and free T(3) (FT(3)), using a prospective observational study examining the interacting equilibria between thyroid parameters. We studied 353 patients on steady-state l-T(4) replacement for autoimmune thyroiditis or after surgery for malignant or benign thyroid disease. Peripheral deiodinase activity was calculated as a measure of T(4)–T(3) conversion efficiency. In euthyroid subjects, the median l-T(4) dose was 1.3 μg/kg per day (interquartile range (IQR) 0.94,1.60). The dose was independently associated with gender, age, aetiology and deiodinase activity (all P<0.001). Comparable FT(3) levels required higher l-T(4) doses in the carcinoma group (n=143), even after adjusting for different TSH levels. Euthyroid athyreotic thyroid carcinoma patients (n=50) received 1.57 μg/kg per day l-T(4) (IQR 1.40, 1.69), compared to 1.19 μg/kg per day (0.85,1.47) in autoimmune thyroiditis (P<0.01, n=76) and 1.08 μg/kg per day (0.82, 1.44) in patients operated on for benign disease (P< 0.01, n=80). Stratifying patients by deiodinase activity categories of <23, 23–29 and >29 nmol/s revealed an increasing FT(3)–FT(4) dissociation; the poorest converters showed the lowest FT(3) levels in spite of the highest dose and circulating FT(4) (P<0.001). An l-T(4)-related FT(3)–TSH disjoint was also apparent; some patients with fully suppressed TSH failed to raise FT(3) above the median level. These findings imply that thyroid hormone conversion efficiency is an important modulator of the biochemical response to l-T(4); FT(3) measurement may be an additional treatment target; and l-T(4) dose escalation may have limited success to raise FT(3) appropriately in some cases.