Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients

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

Hashimoto's thyroiditis: similar and dissimilar characteristics in neighboring areas. Possible implications for the epidemiology of thyroid cancer.

CONTEXT: Medical centers worldwide report an increased frequency of Hashimoto's thyroiditis (HT) and thyroid cancer (TC), two environmentally influenced diseases. In Sicily, data on HT are available for the province of Messina (1975-2005); data on TC are available for the whole island (2002-2004), with the volcanic province of Catania having the highest incidence. OBJECTIVE: To replicate in Catania, on comparable years, the HT data of Messina. DESIGN METHODS SETTING: Review of the clinical records of patients in years 1995-2005 to compare presentation and yearly changes of HT. During 1995-2005, records were computer stored in the Endocrine Divisions of the University Hospitals of Catania and Messina, two tertiary referral centers. RESULTS: Catania is outnumbered by Messina (742 vs. 3,409 HT patients). Similar were the linear increase in the yearly number of HT patients, rates of thyroid dysfunctions though with different proportions of subclinical and overt hypothyroidism, and rates of positiveness for TgAb or TPOAb. Different were age and its yearly trend; gender distribution and rates of the sonography variants, though yearly trends were similar. CONCLUSION: The HT epidemics is smaller in Catania, with changes in presentation overlapping partially those in Messina. Whatever environmental factors might be involved, they (and/or their intensity) were not necessarily the same in these provinces. Intriguingly, the expected number of TC in HT patients with thyroid nodules in Catania is congruent with that of the general population of this province, but it is far less than in the Messina province. Thus, TC and HT incidences could be influenced by distinct environmental factors

Yearly prevalence of the serum positiveness for thyroglobulin autoantibodies (TgAb, left panel) and thyroperoxidase autoantibodies (TPOAb, right panel), <i>viz.</i> proportion of patients with higher-than-normal serum levels of TgAb and TPOAb, in the two cohorts of patients with Hashimoto's thyroiditis.

<p>Yearly prevalence of the serum positiveness for thyroglobulin autoantibodies (TgAb, left panel) and thyroperoxidase autoantibodies (TPOAb, right panel), <i>viz.</i> proportion of patients with higher-than-normal serum levels of TgAb and TPOAb, in the two cohorts of patients with Hashimoto's thyroiditis.</p

Geographic location of the Catania and Messina provinces.

<p>Approximately, 14% of the Catania cohort is represented by HT patients coming from the neighboring provinces of Siracusa (6%), Ragusa (2.5%), Enna (2%), Caltanissetta (2.5%) and Agrigento (0.7%). This compares with approximately 18% of the Messina cohort of HT patients coming from Southern Calabria, particularly from the province of Reggio Calabria. Population in these provinces is approximately 1.1 million (Catania), 660,000 (Messina), 400,000 (Siracusa), 300,000 (Ragusa), 275,000 (Caltanissetta), 175,000 (Enna), 450,000 (Agrigento), and 560,000 (Reggio Calabria).</p

Yearly prevalence of the indicated variants of Hashimoto's thyroiditis (HT) based on thyroid size and nodules as assessed by thyroid ultrasonography in the two HT patients cohorts.

<p>Yearly prevalence of the indicated variants of Hashimoto's thyroiditis (HT) based on thyroid size and nodules as assessed by thyroid ultrasonography in the two HT patients cohorts.</p

Expected epidemiology of thyroid cancer in patients with the nodular variant of Hashimoto's thyroiditis (HT) from the provinces of Messina and Catania (based on data reported here for the period 1995–2005) and observed epidemiology (years 2002–2004, as reported in ref. 11).

<p>The possible scenarios assume three rates of prevalence of HT in the general population (2, 5 or 10%) and two rates of malignancy for thyroid nodules (5 or 10%). The one-fourth or one-fifth lower magnitude of the HT prevalence in the Catania province is because the 1 to 4.5 ratio observed between Catania and Messina (742 and 3,409 cases, respectively) can be rounded off to either 1.0 to 4.0 or 1.0 to 5.0. The rates of thyroid nodules in HT patients (55% for Messina or 25% for Catania) were taken from the variant “thyroid nodules regardless of goiter” in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055450#pone-0055450-t001" target="_blank">Table 1</a> of the present paper. Expected numbers do not change substantially by referring to the period 2002–2004, because cases of HT were 352 in the Catania cohort and 1,351 in the Messina cohort (ratio of 1 to 3.84), with a rate of 26.4% and 56.5% for the variant “nodules regardless of goiter”.</p

Summary of the relationships between the calendar year (1995–2005) and the indicated characteristic in the Catania or the Messina cohort of Hashimoto's thyroiditis (HT) patients.

<p>P values<0.05 are typed boldface.</p

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

<p>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 <i>y</i> = 14.0−1.1<i>x</i> (95%: slope −1.4 to −0.74) and <i>y</i> = 16.1−2.01<i>x</i> (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: <i>y</i> = 4.4−0.029<i>x</i> (95% CI: slope −0.128 to 0.063) for euthyroid controls and <i>y</i> = 3.84−0.575<i>x</i> (95% CI: slope −0.697 to −0.453) for L-T4-treated patients. R square and <i>P</i> values are reported in the graph.</p