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

Abstract

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.