Thyroid function tests in patients taking thyroid medication in Germany: Results from the population-based Study of Health in Pomerania (SHIP)

Hypothyroidism and hyperthyroidism are common diseases, which are treated with hormone replacement or antithyroid drugs, respectively. Applied therapies are targeted at adjusting the serum thyroid stimulating hormone (TSH) concentration to values within the reference range. However, studies from the U.S. [1, 2] and the U.K. [3, 4] investigating therapy outcome have found that a considerable proportion of patients taking medication for thyroid diseases have TSH levels outside the reference range. In the U.S. National Health and Nutrition Examination Study (NHANES), about one-third of the 820 participants who reported having thyroid disease or taking thyroid medication, had TSH levels outside the reference range [2]. In the Colorado Thyroid Disease Prevalence Study, 40% of the 1,525 subjects undergoing thyroid hormone replacement or antithyroid drug therapy had either elevated or decreased TSH levels [1]. Next to patient compliance, inadequate dosing adjustment resulting in under- and over-treatment of thyroid diseases is a major cause of poor therapy outcomes. In two studies conducted in general medical practices in the U.K. [3, 4], more than 20% of patients taking thyroxine had suppressed TSH levels. The authors concluded that taking medication for hypothyroidism is, therefore, associated with an elevated risk for hyperthyroidism [3, 4].

Previously, Germany was an iodine-deficient region [5]. While salt iodinization was introduced in the U.S. in 1924 [6], Germany's first prophylactic measures were not introduced until the 1980s [5]. These measures were mandatory in the former eastern part and voluntary in the former western part of the country. After reunification in 1989, the principle of voluntary iodine prophylaxis was adopted throughout the entire country. At the beginning of the 1990s, Germany's iodine supply was still inadequate, causing a high prevalence of diseases related to iodine deficiency [5]. Since the use of iodised salt became more widespread in 1994, iodine intake has improved markedly and in 1996, Germany's iodine supply was almost adequate [5]. Today, with the exception pregnant women and other subgroups with higher demand [7], an adequate iodine intake is assured in the German population.

Among the 4,310 participants of the Study of Health in Pomerania (SHIP), 35.9% were diagnosed with goitre, and 20.2% with thyroid nodules [8]. The prevalence of hypo- and hyperthyroidism among subjects without known thyroid disease was 1.2%, and 2.2%, respectively. The high prevalence of thyroid disorders can be explained by the insufficient iodine supply in previous decades [8]. Under- or over-treatment due to inadequate thyroid therapy monitoring may result in a disturbance of the thyroid hormone profile. Therefore, we aim to examine thyroid function in subjects taking thyroid medication in West Pomerania, a previously iodine-deficient area of Europe.

The majority (71%) of the 266 SHIP participants taking thyroid medication were treated with thyroxine (Table 1). Another 12% of subjects took antithyroid drugs, and 17% received iodine supplementation (Table 1 and Figure 1). Participants were not asked for their daily dosage of their thyroid medication, but they were asked for the name of the preparation. Thyroxine preparations taken by SHIP participants contained 25-200 μg levothyroxine (23.2% in combination with iodine, 8.9% in combination with liothyronine), antithyroid drugs contained 5-20 mg thiamazol and iodine preparations contained 100-200 μg iodine.

Type of thyroid medication	TSH [mIU/L]
	Min	25%	Median	75%	Max
Thyroxine
Male (n = 36)	0.02	0.31	0.60	1.47	2.99
Female (n = 154)	0.02	0.25	0.47	1.10	11.30
Antithyroid drugs
Male (n = 4)	0.02	0.07	0.54	5.34	2.99
Female (n = 27)	0.02	0.13	0.56	1.21	11.30
Iodine supplementation
Male (n = 7)	0.27	0.35	0.65	0.99	1.76
Female (n = 38)	0.04	0.35	0.53	0.80	2.11
None
Male (n = 2042)	0.02	0.43	0.65	0.94	54.00
Female (n = 1932)	0.02	0.46	0.69	1.01	86.00

TSH, serum thyroid stimulating hormone; Min, minimum; Max, maximum

In subjects taking thyroid medication, TSH levels ranged from 0.02 to 11.30 mIU/L. TSH levels were within the SHIP reference range in 70.5% of the subjects taking thyroxine, in 61.3% of those taking antithyroid drugs and in 88.9% of patients receiving iodine supplementation (Figure 1). TSH levels were elevated in 10.0% of subjects taking thyroxine, in 9.7% of those taking antithyroid drugs and in 2.2% of patients receiving iodine supplementation. Decreased TSH values were observed in 19.5% of subjects taking thyroxine, in 29.0% of those taking antithyroid drugs and in 8.9% of subjects receiving iodine supplementation. Suppressed TSH levels were found in 34 individuals of whom 71% were treated with thyroxine, followed by 26% taking antithyroid drugs, and 3% with iodine supplementation (data not shown).

When the manufacturer's reference range was used instead of the SHIP-specific reference range, normal TSH levels were less frequent and decreased TSH levels were more frequent (Figure 2). This was observed for all classes of thyroid medication, while higher proportions of elevated TSH were only observed in patients using thyroxine or iodine supplementation. In subjects taking antithyroid drugs, the proportion of patients with elevated TSH levels was the same regardless of whether the SHIP-specific or the manufacturer's reference range was used.

In total, 27.4% of SHIP participants taking thyroid medication had TSH values outside the local reference range (8.6% elevated, 18.8% decreased). Using the manufacturer's reference range, 32.7% of the subjects had an elevated (3.8%) or a decreased (28.9%) TSH level. Among the SHIP participants not taking thyroid medication, the proportion of subjects with TSH levels outside the reference range was substantially lower (8.7% SHIP-specific, 12.2% manufacturer's).

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.

We suggest that general practitioners and other care providers for patients taking thyroid medication should more carefully monitor the effects of therapy, adjust dosages and encourage compliance. Further research, including a health economics evaluation, is needed to optimise thyroid disease monitoring.