As seen in previous studies [1, 2, 12], our results indicate that a considerable proportion of subjects taking thyroid medication are either under- or overtreated. About 27.4% of the SHIP participants taking thyroid medication had TSH levels outside the local reference range. Among the participants on thyroxine, nearly one-fifth (19.5%) were over-treated, as indicated by decreased TSH levels. Another 10.0% had elevated TSH values. In this group it was not possible to differentiate between poor compliance and under-treatment. In subjects taking antithyroid drugs, TSH levels can remain suppressed for weeks or months after the initiation of therapy [13]. Therefore, it would have been preferable to include the duration of treatment in the analysis. However, this information was not gathered, and such an analysis was not possible.
Iodine intake is the main determinant of regional patterns and prevalence of thyroid disorders [14]. In previously iodine-deficient regions, such as Germany, hyperthyroidism caused by goitre and thyroid nodules is common [8, 15]. In regions with high or previously high iodine intake, such as the U.S. [16] or Iceland [14], a lower prevalence of hyperthyroidism and a higher prevalence of hypothyroidism have been reported [2, 14]. Differences in iodine intake and thyroid disorders are reflected in the reference intervals for TSH. The SHIP-specific reference interval is lower than those for the general U.S. population and the manufacturer's [11]. It seems that SHIP patients taking thyroxine are adjusted to the local reference range, with less subjects classified as over-treated than when using the manufacturer's reference range (19.5% SHIP-specific vs. 30.5% manufacturer's).
Despite regional disparities in the prevalence and patterns of thyroid diseases, we found comparable proportions of subjects with elevated or decreased TSH levels between the SHIP region, the U.S. and the UK. About 27.4% of subjects from our study population had elevated or decreased TSH levels, compared to 33% in the U.S. NHANES study [2]. Among the SHIP participants treated with thyroxine, about one-fifth (19.5%) were over-treated, which is equal to the proportions observed in the U.K (21% [3] and 23% [4]).
In Germany, huge efforts have been made to raise awareness and increase and stabilise the iodine intake in the population. Those efforts have improved the situation markedly. However, efforts should also be made to improve thyroid therapy monitoring. As previously shown, inadequate or excessive thyroxine dosing causes mild thyroid hypo- and hyperfunction [3].
The standard treatment in patients with hypothyroidism is thyroxine. However, in the absence of screening programs, patients with thyroid failure may remain undiagnosed [12, 17]. Even mild thyroid hypofunction may have adverse effects on circulating lipid levels and may increase the risk of ischemic heart disease [2, 18, 19]. An elevated TSH level, characteristic of hypothyroidism, was seen in 10.0% of the SHIP participants taking thyroxine. A decreased TSH level, which represents a risk factor for developing atrial fibrillation [20] and osteoporosis [21], was observed in 19.5% of SHIP participants taking thyroxine. By exact dose monitoring, adverse effects resulting from under- or over-treatment can be minimised. Furthermore, there may be a positive impact on the cost of thyroid medications, which accounted for 296.5 million € in Germany in 2007 [22].
Potential limitations of our study arise from the use of medications for non-thyroid diseases in our study population. Circulating concentrations of thyroid hormones are altered by several drugs, such as lithium, amiodarone, testosterone, and oestrogen [12, 15, 23]. Lithium and amiodarone are both associated with increases in TSH levels [12]. However, these two substances were rarely used by SHIP participants. Among the 266 study subjects taking thyroid medication, lithium was used by two, and amiodarone was not used by any subject. Therefore, the impact of these drugs on the population level is assumed to be much smaller than that of the effects of under- and over-treatment. The same reasoning applies to the use of testosterone, because only 1 of 47 men taking thyroid medication was also using testosterone. Oestrogen, in contrast, was widely used, with 51 of 219 women reporting concomitant use of thyroid medication and oestrogen. Since the oestrogen-TSH association has been shown to be weak [12], we do not suspect a relevant influence of this medication on our results. The timing of blood sampling is also unlikely to be a relevant influence on our results, as the pulsatile and circadian secretion of TSH is of minor importance in thyroid disease diagnostics [24]. Furthermore, we do not consider the missing data on indication for thyroid medication use or prescribed dose as a limitation, as the adverse effects of under- or over-treatment with thyroid medication are independent of these treatment characteristics.
Major limitations include the small study population and the low proportion of male subjects, which are due to the population-based study design. Moreover, information on the duration of thyroid medication intake was not collected. We know that among participants who reported a history of thyroid surgery, less than 5% underwent an operation in the year prior to the SHIP examination. Among the remaining subjects, though, we cannot rule out that a significant number started thyroid therapy shortly before participating in SHIP. If this were the case, those subjects were probably still undergoing dose adjustment at the time of the SHIP examination and may not have reached a stable TSH level, which may have introduced some bias in our study.