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Effect of Micronutrients on Thyroid Parameters

Written by: Hari Krishnan Krishnamurthy, Swarnkumar Reddy, Vasanth Jayaraman, Karthik Krishna, Qi Song, Karenah E. Rajasekaran, Tianhao Wang, Kang Bei and John J. Rajasekaran

Vibrant Sciences LLC., San Carlos, CA, USA/Vibrant America LLC., San Carlos, CA, USA


Abstract


Micronutrients are involved in various vital cellular metabolic processes including thyroid hormone metabolism. This study aimed to investigate the correlation between serum levels of micronutrients and their effects on thyroid parameters. The correlation of serum levels of micronutrients and thyroid markers was studied in a group of 387 healthy individuals tested for thyroid markers (T4, T3, FT4, FT3, TSH, anti-TPO, RT3, and anti-Tg) and their micronutrient profile at Vibrant America Clinical Laboratory. The subjects were rationalized into three groups (deficient, normal, or excess levels of micronutrients), and the levels of their thyroid markers were compared. According to our results, deficiency of vitamin B2, B12, B9 and Vit-D25[OH] (p < 0.05) significantly affected thyroid functioning. Other elemental micronutrients such as calcium, copper, choline, iron, and zinc (p < 0.05) have a significant correlation with serum levels of free T3. Amino acids asparagine (r = 0.1765, p < 0.001) and serine (r = 0.1186, p < 0.05) were found to have a strong positive correlation with TSH. Valine, leucine, and arginine (p < 0.05) also exhibited a significant positive correlation with serum levels of T4 and FT4. No other significant correlations were observed with other micronutrients. Our study suggests strong evidence for the association of the levels of micronutrients with thyroid markers with a special note on the effect of serum levels of certain amino acids.


1. Introduction


The deficiency of micronutrients such as vitamins and minerals is of great concern in public health. The World Health Organization (WHO) reported more than 2 billion people are affected by micronutrient deficiency and its related health consequences [1]. Iodine, iron, vitamin A, and zinc are the primary micronutrients that have been the focus of development efforts since they have major health implications. Micronutrient deficiency is regarded as a preventable cause of various nonspecific physiological impartments such as suppressed immune responses, metabolic disorders, and delayed or impaired physical and psychomotor development [2]. Elimination of micronutrient deficiencies through nutrition supplementation programs is widely seen as the most promising and cost-effective way to eradicate nutrition deficiency. The optimal metabolic functioning of an individual requires a proper supply of micronutrients such as vitamins, coenzymes, and intracellular elements. Micronutrients play a crucial role in catalyzing various enzymatic reactions, regulating the permeability of cell membranes, and various other physiological activities [3].


Nutritional alterations result in various endocrine dysfunctions with a prime effect on thyroid functioning. Thyroid disorders are the most common endocrine disorders and are known to affect 5% to 6% of the US population. Thyroid hormone is a sensitive hormone and synthesized by an autoregulated feedback loop mechanism regulated by the hypothalamus-pituitary-thyroid (HPT) axis. Thyroid hormones are involved in various developmental and physiological functioning. Regular functioning of a thyroid gland is characterized by the synthesis of the appropriate amount of triiodothyronine (T3) and thyroxine (T4) in response to thyroid-stimulating hormone (TSH) synthesized by the pituitary gland. Any physiological or biochemical alterations in the feedback loop result in thyroid dysfunctions and result in catastrophic health consequences. These alterations may arise from several pathologies; autoimmune disorders are the most common cause of thyroid disorders which results in excess (hyperthyroidism) or diminished (hypothyroidism) levels of thyroid hormones. Other reasons may include various environmental factors and demographic and intrinsic factors [4].


Autoimmune responses, thyroid surgery, radiation therapy, congenital hypothyroidism, etc. are the most commonly studied factors of thyroid dysfunctions. The pathogenesis of thyroid disorders has also been shown to be highly influenced by dietary factors, i.e., the availability of micronutrients such as iodine, vitamin D, iron, selenium, copper, zinc, vitamin B12, etc. Micronutrients are involved in physiological functioning like hormone synthesis, hormone transportation, and its binding to a target receptor. Micronutrients also play a pivotal role in regulating autoimmune thyroid disorders (AITD). Hypothyroidism is an autoimmune thyroid disorder resulting from iodine deficiency. The synthesis of both thyroid hormones triiodothyronine (T3) and thyroxine (T4) is inhibited by iodine deficiency which in turn induces the autoantibodies against the thyroid gland and results in goiter [3]. Hashimoto’s thyroiditis (HT) is an autoimmune disorder characterized by hypothyroid functioning resulting from vitamin D deficiency. In addition to these nutrients, several other micronutrients such as amino acids, cofactors, and metal ions are essential for thyroid functioning. But only a few studies have reported the marginal possibilities of these micronutrients in altering thyroid functions. The present study is designed to evaluate the significant correlation between the serum levels of vital micronutrients and thyroid function.


2. Materials and Methods


2.1. Subjects and Study Design

The study population comprised 387 individuals aged between 13 and 85 subjects who were tested for various thyroid markers (thyroxine (T4), triiodothyronine (T3), free T4 hormone (FT4), thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), antithyroid peroxidase (anti-TPO), reverse T3 (RT3), and antithyroglobulin (anti-Tg)) and micronutrient panel at Vibrant America Clinical Laboratory. The female to male ratio was 2 : 1 (69% female, 31% male), and the mean age (±SD) of the subjects was 48 ± 16 years. The study was exempted from formal ethical reviews by Western IRB (Washington, USA) since the study comprises the retrospective analysis of deidentified clinical data and test results. The subjects were categorized on the serum levels of thyroid markers listed in Table 1.



2.2. Reference Range of Thyroid Markers and Micronutrients

The reference ranges of thyroid markers and micronutrients tested depend on the lab where the test is performed. The present study followed the reference ranges widely followed by commercial diagnostic labs and hospital labs. The reference range of thyroid hormones and autoantibodies is shown in Table 1. The optimum serum levels of essential micronutrients are provided in Table S1.


2.3. Serum Analysis

Serum levels of TSH, FT4, anti-TPO, and anti-Tg tests were measured using a commercial Roche e601 analyzer (Roche Diagnostics, Indianapolis, IN, USA) following the manufacturer’s instructions. All reagents were procured from Roche Diagnostics (Indianapolis, IN, USA).


Monoclonal antibodies specifically directed against human TSH were employed for the Elecsys TSH assay. The presence of chimeric construct from human- and mouse-specific components in antibodies labeled with ruthenium complex results in the elimination of interfering effects of HAMA (human anti-mouse antibodies).


For the Elecsys T4 and FT4 test, a specific anti-T4 antibody labeled with a ruthenium complex was used for the determination of free thyroxine. The use of a small quantity of the antibodies (equivalent to approx. 1-2% of the total T4 content of a normal serum sample) enables the equilibrium between bound and free T4 virtually unaffected. Serum levels of free triiodothyronine and bound triiodothyronine were determined using Elecsys FT3 assay, a specific anti-T3 antibody with a ruthenium complex.


Human antigen and monoclonal human anti-Tg antibodies were employed for the Elecsys anti-Tg assay whereas Elecsys anti-TPO assay used recombinant antigens and polyclonal anti-TPO antibodies for the determination of serum levels of anti-TPO.


Serum levels of RT3 were determined by a sensitive and reliable LC-MS/MS technique. Analytical standards of thyroid hormones were procured from Cerilliant Corporation (Round Rock, Texas), and the serum samples were analyzed using Waters TQ-S Tandem Mass Spectrometer. Serum levels of micronutrients were analyzed using Waters TQ-XS Tandem mass spectrometer (LC-MS MS), Waters GC-MS, and Perkin Elmer NexION ICP-MS using standard protocols.


2.4. Statistical Analysis

The processing of clinical data from deidentified subjects was performed via Java for windows version 1.8.161, and statistical analysis was performed using GraphPad Prism version 7.00 (Windows). Descriptive statistics were used to define continuous variables (mean ± SD, and median, minimum and maximum) with statistical significance set at p < 0.05. Mann–Whitney U test was used to compare two independent groups without normal distribution, and this method offers the advantage of possible comparison of small samples of subjects. Univariate relationships between variables were analyzed using Pearson’s correlation analysis with significance set at p < 0.05.


3. Results


The present study aimed to evaluate the significance of 37 micronutrients on selected thyroid parameters. The study was conducted on the general population without any clinical prevalence of thyroid disorders. The mean age of the candidates involved in the study was 44 ± 14.5, and the study includes 70% females (Table 1).


The subjects were categorized into three groups based on the serum concentrations of micronutrients being less than the reference range, within the reference range, and higher than the reference. The analysis showed a significant relationship of selected micronutrients on the expression of thyroid hormones; decreased levels of amino acids such as asparagine, glutamine, serine, valine, citrulline, and arginine had a significant effect on thyroid parameters. Deficiency in these amino acids significantly alters the thyroid functioning, specifically, the deficiency of citrulline increased the serum levels of T4 (p < 0.001), and low levels of arginine decreased the serum levels of T3 (<0.0001). Thyroid functions were significantly affected by the various vitamin deficiencies; the present study observed that Vit B2, Vit B12, Vit B9(Folate), and Vit-D25[OH] are the most significant for normal thyroid functioning. Serum levels of T4 were significantly lower in subjects with low Vit B2 (p < 0.01). Vitamin B9 (folate) deficiency is the most significant factor affecting thyroid functioning as it increases the serum TSH level (p < 0.01), increases anti-TPO levels (p < 0.05), and also elevates the serum levels of anti-Tg (p < 0.001).


Apart from amino acids and vitamins, other micronutrients such as calcium, copper, chromium, selenium, inositol, and carnitine have significance on thyroid functioning. Decreased serum levels of carnitine were characterized by a significant increase in the levels of anti-TPO levels (p < 0.001) and anti-Tg (p < 0.01). While low levels of micronutrients are a concern, high levels can also result in adverse effects. Elevated levels of inositol and copper beyond the reference range have a significant increase in the serum levels of T4 and T3 (p < 0.001). Increased levels of selenium also show considerable significance in decreasing the levels of T3 and Free T3 (p < 0.01) (Table 2).


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