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-T4) replacement dose. We conducted a secondary analysis of the relationship of l-T4 dose to TSH and free T3 (FT3), using a prospective observational study examining the interacting equilibria between thyroid parameters. We studied 353 patients on steady-state l-T4 replacement for autoimmune thyroiditis or after surgery for malignant or benign thyroid disease. Peripheral deiodinase activity was calculated as a measure of T4-T3 conversion efficiency. In euthyroid subjects, the median l-T4 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 FT3 levels required higher l-T4 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-T4 (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 FT3-FT4 dissociation; the poorest converters showed the lowest FT3 levels in spite of the highest dose and circulating FT4 (P<0.001). An l-T4-related FT3-TSH disjoint was also apparent; some patients with fully suppressed TSH failed to raise FT3 above the median level. These findings imply that thyroid hormone conversion efficiency is an important modulator of the biochemical response to l-T4; FT3 measurement may be an additional treatment target; and l-T4 dose escalation may have limited success to raise FT3 appropriately in some cases.

Keywords: TSH; conversion; deiodinase; l-T4 therapy; levothyroxine; thyroid hormone replacement; triiodothyronine.

© 2015 The authors.

Figures

Figure 1

TSH (A) or FT3 (B) vs weight-adjusted l-T4 dose in three groups of patients on thyroid hormone replacement, with autoimmune thyroiditis (n=96), after surgery for benign goitre (n=111) or thyroid carcinoma (n=143). Between group differences in both panels were significant (P<0.01) and remained so after adjusting for volume (not shown, P<0.01), as evidenced by linear models with the diagnostic group as a covariate. See text for further details. AIT, autoimmune thyroiditis; Goitre, goitre post surgery for benign nodular thyroid disease.

Figure 2

FT3 (A), FT4 (B) and TSH (C) levels in l-T4-treated patients stratified by disease and conversion efficiency. The disease entities were closely associated with categories of the thyroid volume (see Table 1 and text). The red box refers to poor converters (calculated deiodinase activity <23 nmol/s), green to intermediate converters (deiodinase activity 23–29 nmol/s) and blue to good converters (deiodinase activity >29 nmol/s). Remarkably, absolute FT3 concentrations were lowest in the poor converter group in all disease categories, while FT4 levels were highest in the poor converters. Wilcoxon test, revealed significant differences compared to each first group; *P<0.05, **P<0.001. AIT, autoimmune thyroiditis; goitre, goitre post surgery for benign nodular thyroid disease.

Figure 3

Probability plot of weight adjusted l-T4 dose to (A) suppress TSH below its lower reference limit (0.4 mU/l) or (B) raise FT3 above the median of euthyroid controls (>5 pmol/l) in the carcinoma patients (n=143), and (C) suppress TSH <1 mU/l or (D) elevate FT3 above 5 pmol/l in benign disease (patients with autoimmune thyroiditis, n=75 and nodular thyroid disease post surgery, n=111). Probability plots were created by logistic regression. The shaded areas indicate the confidence interval surrounding the fitted curve. The TSH targets were more frequently reached at a lower dose than the FT3 target (see Results).