Reduction of thyroid nodule volume by levothyroxine and iodine alone and in combination: a randomized, placebo-controlled trial

Abstract

Context: Nodular goiter is common worldwide, but there is still debate over the medical treatment.

Objective: The objective of the study was the measurement of the effect of a treatment with (nonsuppressive) T(4), iodine, or a combination of both compared with placebo on volume of thyroid nodules and thyroid.

Design: This was a multicenter, randomized, double-blind trial in patients with nodular goiter in Germany [LISA (Levothyroxin und Iodid in der Strumatherapie Als Mono-oder Kombinationstherapie) trial].

Setting: The study was conducted in outpatient clinics in university hospitals and regional hospitals and private practices.

Participants: One thousand twenty-four consecutively screened and centrally randomized euthyroid patients aged 18-65 yr with one or more thyroid nodules (minimal diameter 10 mm) participated in the study.

Intervention: Intervention included placebo, iodine (I), T(4), or T(4)+I for 1 yr. T(4) doses were adapted for a TSH target range of 0.2-0.8 mU/liter.

Outcome measures: The primary end point was percent volume reduction of all nodules measured by ultrasound, and the main secondary end point was a change in goiter volume.

Results: Nodule volume reductions were -17.3% [95% confidence interval (CI) -24.8/-9.0%, P < 0.001] in the T(4)+I group, -7.3% (95% CI -15.0/+1.2%, P = 0.201) in the T(4) group, and -4.0% (95% CI -11.4/+4.2%, P = 0.328) in the I group as compared with placebo. In direct comparison, the T(4)+I therapy was significantly superior to T(4) (P = 0.018) or I (P = 0.003). Thyroid volume reductions were -7.9% (95% CI -11.8/-3.9%, P < 0.001), -5.2% (95% CI -8.7/-1.6%, P = 0.024) and -2.5% (95% CI -6.2/+1.4%, P = 0.207), respectively. The T(4)+I therapy was significantly superior to I (P = 0.034) but not to T(4) (P = 0.190).

Conclusion: In a region with a sufficient iodine supply, a 1-yr therapy with a combination of I and T(4) with incomplete suppression of thyrotropin reduced thyroid nodule volume further than either component alone or placebo.

Fig. 1.

Changes of TSH (A) and iodine (B) levels and corresponding percent changes from baseline of nodule (C) and thyroid (D) volumes in different treatment groups. Marginal means from longitudinal mixed models, with 95% CI (A and B) or presented as percent change from group-specific baseline mean (C and D) Intention-to-treat population, missing value imputation by direct maximum likelihood.

Fig. 2.

Percent change in nodule volume (black lines) and thyroid volume (gray lines) from baseline to end of follow-up within 1 yr by randomization group, with 95% CI.

Fig. 3.

Frequency histograms of individual percent changes from baseline to end of follow-up of total nodule volumes (A) and thyroid volumes (B) by randomization group. The scale is logarithmic for optical symmetry of increases and decreases of comparable size. Reductions of more than 50% in nodular volume are marked red and given as percentages. In both panels, reductions of 30% are marked by a broken line.

Fig. 4.

Forest plot of the results of two multilevel regression models with identical covariates but different outcomes. BMI, Body mass index.