min D was an independent factor of the presence of TPOAb [8]. Fi- nally, in a recent .... cumbent position for at least
Thieme
Article
The Effect of Vitamin D on Thyroid Autoimmunity in Levothyroxine-Treated Women with Hashimoto’s Thyroiditis and Normal Vitamin D Status
Authors Robert Krysiak, Witold Szkróbka, Bogusław Okopień Affiliation Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland
Abs tr ac t Background:
Low vitamin D status is associated with autoimmune
thyroid disease. Oral vitamin D supplementation was found to reduce titers of thyroid antibodies in levothyroxine-treated women with postpartum thyroiditis and low vitamin D status. Methods:
The study included 34 women with Hashimoto’s thyroidi-
Key words
tis and normal vitamin D status (serum 25-hydroxyvitamin D levels
25-hydroxyvitamin D, thyroid autoimmunity, levothyroxine
above 30 ng/mL) who had been treated for at least 6 months with lev-
replacement, vitamin D supplementation
othyroxine. On the basis of patient preference, women were divided preparations (2000 IU daily). Serum levels of thyrotropin, free thyroxine,
first decision 14.11.2016
free triiodothyronine and 25-hydroxyvitamin D, as well as titers of thy-
accepted 02.12.2016
roid peroxidase and thyroglobulin antibodies were measured at the
Bibliography DOI http://dx.doi.org/10.1055/s-0042-123038
Published online: 2017 Exp Clin Endocrinol Diabetes © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence Robert Krysiak Department of Internal Medicine and Clinical Pharmacology Medical University of Silesia Medyków 18 40-752 Katowice
beginning of the study and 6 months later. Results: There were no significant differences in baseline values between both study groups. 25-hydroxyvitamin D levels inversely correlated with titers of thyroid antibodies. No changes in hypothalamic-pituitary-thyroid axis activity and thyroid antibody titers were observed in vitamin-naïve patients. Vitamin D increased serum levels of 25-hydroxyvitamin D, as well as reduced titers of thyroid antibodies. This effect was more pronounced for thyroid peroxidase than for thyroglobulin antibodies and correlated with their baseline titers. Conclusions: Vitamin D preparations may reduce thyroid autoimmunity in levothyroxine-treated women with Hashimoto’s thyroiditis and normal vitamin D status.
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Abbreviations SD TgAb TPOAb
standard deviation thyroglobulin antibodies thyroid peroxidase antibodies
Introduction Hashimoto’s thyroiditis is considered the most frequent autoimmune disorder in the United States, the most common thyroid disease in iodine-replete areas of the world, as well as the most frequent cause of thyroid hypofunction in the civilized countries 1–3]. Its incidence is estimated at between 0.3 and 1.5 cases per 1 000 people per year, while prevalence in women at more than 2 % [3]. Patients are characterized by a typical ultrasound pattern and the presence of autoantibodies against various thyroid antigens, particularly thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) antibodies [4, 5]. The progressive loss of follicular cells in this disorder is accompanied by replacement of the thyroid tissue by lymphoid lymphocytic infiltrate and fibrotic reaction [1, 4]. Krysiak R. et al. Hashimoto’s thyroiditis and vitamin D. Exp Clin Endocrinol Diabetes
The results of observational studies suggest that there exists a relationship between thyroid autoimmunity and low vitamin D status. Decreased serum levels of 25-hydroxyvitamin D were found in patients with Hashimoto’s thyroiditis and this association persisted after adjustment for age, sex and body mass index [6]. The degree of vitamin D deficiency correlated with the duration of this disease, thyroid volume, and TPOAb titers [7]. Low serum 25-hydroxyvitamin D was an independent factor of the presence of TPOAb [8]. Finally, in a recent meta-analysis, Wang et al. [9] found that patients with autoimmune thyroid disease had lower levels of 25-hydroxyvitamin D and were more likely to be deficient in 25-hydroxyvitamin D. Some [10, 11], but not all [12], studies have shown that p olymorphisms of the vitamin D receptor may make patients more prone to the development of Hashimoto’s thyroiditis. Its risk was increased in a Turkish population with vitamin D receptor gene TaqI TT and FokI FF genotypes [10] and in C/C homozygotes of the vitamin D receptor-FokI gene polymorphism in exon 2 inhabiting China [11].
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into 2 groups, receiving (n = 18) or not receiving (n = 16) oral vitamin D received 30.08.2016
Recently, we have found that levothyroxine increased 25-hydroxyvitamin D levels in women with postpartum thyroiditis [13], which is another autoimmune disorder of the thyroid gland [14], while no effect was observed in levothyroxine-treated women with non-autoimmune hypothyroidism [13]. Moreover, exogenous vitamin D reduced thyroid antibody titers in women with postpartum thyroiditis and vitamin D deficiency or insufficiency already receiving levothyroxine treatment [15]. Interestingly, exogenous levothyroxine itself decreased thyroid antibody titers in patients with Hashimoto’s thyroiditis [16–18]. Therefore, the aim of the present study was to investigate whether vitamin D supplementation enhances the effect of levothyroxine on thyroid antibody titers in women with Hashimoto’s thyroiditis and serum levels of 25-hydroxyvitamin D within the reference range.
Materials and Methods The participants were selected among women (aged 20–50 years) with Hashimoto’s thyroiditis treated for at least 6 months with levothyroxine. The patients were eligible for the study if, despite levothyroxine treatment, they met the following inclusion criteria: (a) TPOAb titers above 100 U/ml, (b) reduced echogenicity of the thyroid parenchyma on thyroid ultrasonography and (c) serum 25-hydroxyvitamin D levels more than 30 ng/mL. The study included only patients with normal thyroid function or mild subclinical hypothyroidism, defined as serum thyrotropin levels above 0.4 but less than 8 mU/l, combined with serum levels of free thyroid hormones within the reference range. The exclusion criteria were as follows: positive serum antibodies against thyrotropin receptor, other autoimmune disorders, body mass index above 40 kg/m2, Turner or Down syndrome, any form of coronary artery disease, moderate or severe arterial hypertension (ESC/ESH grade 2 or 3), symptomatic congestive heart failure, diabetes, impaired renal or hepatic function, pregnancy or lactation, and poor patient compliance. We also excluded patients treated with any drugs within 12 weeks preceding the study onset (with the exception of levothyroxine). The local ethics committee approved the study protocol and all enrolled patients gave written informed consent to participate in the study. All included patients were fully informed about the benefits and harms of vitamin D administration and on the basis of patient preference, the participants were then allocated to one of 2 treatment groups. The first group included 18 women who continued treatment with levothyroxine, while in 16 women belonging to the second group, levothyroxine was administered together with oral vitamin D preparations (2000 IU daily in the evening). Throughout the entire study period, the daily dose of levothyroxine was the same as before the study. Both drugs were administered once daily in 12-h time intervals. Levothyroxine was taken in the morning, at least half an hour before breakfast, while vitamin D in the evening. Each treatment group was divided into 2 subgroups: patients with normal thyroid function (thyrotropin levels in the range between 0.4 and 4.0 mIU/L) and patients with mild hypothyroidism (thyrotropin levels in the range between 4.0 and 8.0 mIU/L). Normal thyroid function was observed in 10 vitamin D-treated and 8 vitamin D-naïve patients, while mild subclinical hypothyroidism was diagnosed in 8 vitamin D-treated and 8 vitamin D-naïve women. Compliance was assessed at each visit by tablet counts.
Blood samples were collected at least a 12-h overnight fast before and at the end of the study. They were drawn from the antecubital vein in a quiet, temperature-controlled room (24–25 °C), between 8.00 and 9.00 a.m. after the patients had been in a recumbent position for at least 15 min. All measurements were performed in duplicate strictly according to manufacturers’ instructions by a person who was blinded to the study purpose. Serum levels of thyrotropin, free thyroxine and free triiodothyronine were measured using an electrochemiluminescence immunoassay method (Roche Diagnostics, Lewes, United Kingdom). Serum levels of 25-hydroxyvitamin D, as well as titers of TPOAb and TgAb were determined by enzyme-linked immunosorbent assays using reagents obtained from ALPCO Diagnostics (Windham, New Hampshire, United States) and IBL International (Hamburg, Germany), respectively. The intra- and interassay coefficients of variation for the assessed variables were less than 6.2 and 8.8 %, respectively. The obtained results were analyzed using the Kolmogorov-Smirnov test for data normality. Variables with a skewed distribution were log-transformed. Comparisons between both groups were carried out using Student’s t-test for independent samples. Student’s paired t test was used to identify differences between the means in each treatment group. Qualitative variables were compared using the χ2 test. Correlations were calculated using Pearson’s r-tests. Probability values of p below 0.05 was regarded as statistically significant.
Results There were no significant differences in the age, weight, medical background and clinical characteristics between both treatment groups. The mean concentrations/titers of thyrotropin, free thyroid hormones, 25-hydroxyvitamin D, TPOAb and TgAb were also similar in both groups of women (▶ Table 1, 2). Neither significant adverse effects nor any complications were observed throughout the study period and all participants completed the study. Continuation of levothyroxine treatment produced no effect on thyrotropin, free thyroid hormones, 25-hydroxyvitamin D and thyroid antibodies. Vitamin D add-on therapy increased 25-hydroxyvitamin D levels as well as reduced TPOAb titers and tended to reduce TgAb (p = 0.083). Vitamin D did not affect serum levels of thyrotropin and free thyroid hormones (▶ Table 2). Post-treatment 25-hydroxyvitamin D levels were higher, while TPOAb lower in vitamin D-treated than in vitamin D-naïve patients (▶ Table 2). The effect on TPOAb was stronger in women with subclinical hypothyroidism than women with normal thyroid function ( − 42 % vs. − 20 %, p
