Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients

Abstract

Context: Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients.

Objective: To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback.

Design: Retrospective study.

Setting: Academic hospital.

Patients: 1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls.

Measurements: TSH, FT4 and FT3 concentrations by immunoassays.

Results: FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals. The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients.

Conclusions: Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.

Figure 1. Free thyroid hormones and FT3/FT4 ratio frequency distribution.

FT3 and FT4 serum levels and FT3/FT4 ratio distribution in 1,811 athyreotic patients under levothyroxine (L-T4) monotherapy. Shaded areas indicate the normal range (2.5–97.5 percentiles) calculated in 3,875 euthyroid controls. Vertical dotted lines indicate the median of the normal values. Percentages indicate the patients with values under or above the normal values.

Figure 2. Correlation between TSH and free thyroid hormones in euthyroid controls and in athyreotic patients.

The correlation between TSH serum levels (log values) and FT3 and FT4 serum levels in 3,875 euthyroid controls (solid lines) and 1,811 athyreotic patients under levothyroxine monotherapy (dotted lines). The linear regression equations between FT4 and log TSH levels in the euthyroid controls and the levothyroxine (L-T4)-treated patients were y = 14.0−1.1x (95%: slope −1.4 to −0.74) and y = 16.1−2.01x (95% CI: slope −2.48 to −1.53), respectively. The same curve fitting analysis was used between FT3 and log-TSH levels and resulted in the following: y = 4.4−0.029x (95% CI: slope −0.128 to 0.063) for euthyroid controls and y = 3.84−0.575x (95% CI: slope −0.697 to −0.453) for L-T4-treated patients. R square and P values are reported in the graph.

Figure 3. FT3/FT4 ratio in levothyroxine-treated athyreotic patients at different daily dose.

Median FT3/FT4 ratio in levothyroxine (L-T4) treated athyreotic patients with respect to the administered daily dose of L-T4. The median and interquartile range in the euthyroid controls are indicated by the shaded area. The number of patients with a FT3/FT4 ratio lower than the 2.5 percentile of the euthyroid controls is indicated in the right panel.