Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients

Abstract

ContextLevothyroxine 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.ObjectiveTo evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback.DesignRetrospective study.SettingAcademic hospital.Patients1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls.MeasurementsTSH, FT4 and FT3 concentrations by immunoassays.ResultsFT4 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.ConclusionsAthyreotic 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.

THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect?

“…In the 1980s it was already observed that in hypothyroid patients on T4, the serum T4 required to reach a normal serum TSH, is higher than that in controls (10). This was recently confirmed in a large survey of athyreotic patients with normal TSH during T4 treatment: it showed -relative to a healthy population-a shift to the right in the distribution curve of FT4 values; FT4 levels above the upper normal limit occurred in 7.2% of the population (11). The distribution curve of FT3 was shifted to the left, with FT3 values below the lower normal limit in 15.2%.…”

Individually-tailored thyroxine requirement in the same patients before and after thyroidectomy: a longitudinal study

“…In our study, following total thyroidectomy, patients also received radioiodine treatment for DTC, allegedly leading to the absence of functional thyroid tissue. The absence of thyroid-derived T 3 in these patients led some authors to assume that a partial T 3 deficiency may be an issue during L-T 4 treatment after surgery (8,26). However, in a prospective study carried out in the same patients before and after thyroidectomy, no difference has been shown by comparing FT 3 levels before and after replacement T 4 dose (18).…”

“…A type 2 deiodinase polymorphism has been described in patients where a defective D2 activity was associated with an increased need for T 4 (32). However, it seems not sufficient to explain why some patients may not fully recover despite an appropriate dose of T 4 (8,33). On this ground, some studies analyzed the effects of combined T 3 /T 4 treatment in hypothyroid patients, including those who have undergone thyroidectomy (10,27,28,33,34), but mostly failed to show advantages when compared with L-T 4 therapy alone (10,25,34).…”

“…The main goal of T 4 treatment is to promptly achieve the therapeutic target, avoiding overor under-treatments (5), but some patients require several dose adjustments prior to attaining an adequate pharmacological T 4 homeostasis (6,7). Despite some reports on the inability of T 4 alone to warrant euthyroidism in all tissues (8), L-T 4 monotherapy is as yet the preferred treatment (9). Oral T 4 is asymmetrically deiodinated to triiodothyronine (T 3 ) in peripheral tissues and mimics a nearly physiological T 4 /T 3 ratio (9,10).…”

“…Several studies dealing with T 4 requirement have been carried out on patients with primary hypothyroidism, with or without thyroid in situ (see (6,9) for a review). Some of these studies focused on factors affecting the therapeutic dose, such as body weight (6,12), BMI (13), amount of residual thyroid tissue, patients' age and drugs (14,15,16), and only a fraction of them examined T 4 requirement after total thyroidectomy (7,8,9,10,11). However, most of these latter reports were retrospective and/or compared results obtained in different groups of patients (15,16,17), and/or in heterogeneous therapeutic settings (7,16).…”