ASSOCIATION BETWEEN THYROID FUNCTION TESTS, LIVER ENZYMES AND VITAMIN D IN HEALTHY CHILDREN

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1 Journal of International Research in Medical and Pharmaceutical Sciences 9(1): 7-12, 2016 ISSN: (P), ISSN: (O) International Knowledge Press ASSOCIATION BETWEEN THYROID FUNCTION TESTS, LIVER ENZYMES AND VITAMIN D IN HEALTHY CHILDREN ESRA AKYÜZ ÖZKAN 1* AND AYŞE YEŞiM GÖÇMEN 2 1 Department of Pediatrics, Bozok University, Medical Faculty, Yozgat, Turkey. 2 Department of Biochemistry, Bozok University, Medical Faculty, Yozgat, Turkey. AUTHORS CONTRIBUTIONS This work was carried out in collaboration between both authors. Author EAO designed the study, wrote the protocol, managed the literature searches and interpreted the data and performed preliminary data analysis. Author AYG anchored the field study, produced the initial draft, and gathered the initial data. Both authors read and approved the final manuscript. Received: 11 th December 2015 Accepted: 12 th January 2016 Published: 12 th February 2016 Original Research Article *Corresponding author: esra.akyuz@mynet.com; ABSTRACT Background: Hypovitaminosis D is a common health problem in the worldwide. Vitamin D has a significant role in the management of calcium-phosphorus metabolism and in the immune system as well. We aimed to investigate the association between vitamin D, thyroid and liver enzymes in healthy children. Methods: A total of 55 children between ages 3 and 16 years were evaluated retrospectively. Serum 25(OH)D3 levels 20 ng/ml, and 20 ng/ ml were accepted as vitamin D deficiency and sufficiency, respectively. Patients with 25(OH)D3 deficiency and sufficiency were compared according to their serum thyroid stimulating hormone (TSH), FreeT3, FreeT4, glucose, alanine transaminase (ALT), aspartate transaminase (AST), vitamin B12 and folic acid and Pearson correlation analyses and multivariate regression analyses were performed to assess correlation between vitamin D and other parameters. Results: While FT4 levels were found lower in vitamin D deficiency group (1.18±0.22 versus 1.38±0.19, p= 0.001), TSH (3.77±1.40 versus 2.53±1.11 p= 0.001), AST (32.17±7.19 versus 17.12±8.72, p= 0.000) and ALT (18.05±5.45 versus 10.28±4.39, p=0.000) were significantly higher in this group. Vitamin D was positively correlated with FreeT3, FreeT4 and negatively correlated with age, TSH, AST and ALT. On multivariate regression analysis, age, FreeT4, TSH, AST were independently associated with low vitamin D concentrations. Conclusion: Children with vitamin D deficiency are more susceptible to hypothyroidism and any conditions that affect the liver enzymes can lead to hypovitaminosis D. So children with vitamin D deficiency should be treated properly. Keywords: Children; liver enzymes; thyroid disease; vitamin D. 1. INTRODUCTION Vitamin D is a group of sterol of hormones and hormone precursors that synthesized endogenously and fat-soluble vitamins [1]. Vitamin D that forms in the skin or intake with dietary is not biologically active. At first it converts to the 25-hydroxyvitamin D (25(OH)D) by 25 hydroxylase enzyme in the liver and

2 then turns to the biologically active form 1.25-dihydroxyvitamin D (1.25(OH)D) by 1 alpha-hydroxylase in the kidney, also known as calcitriol [2]. Vitamin D receptors locate in bone, intestine, kidney, and in the immune system and also muscles, skin, endocrine system and liver [3]. The biological activities of vitamin D are primarily take part in the management of calcium-phosphorus metabolism, vitamin D have an significant role in the immune system as well [4]. It is shown that 1,25(OH)D3 can avoid or suppress type 1 diabetes, encephalomyelitis, autoimmune rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease and Vitamin D supplementation may reduce the prevalence of type 1 diabetes, multiple sclerosis and rheumatoid arthritis in children [5]. It has been showed that automimmune disease patients had lower vitamin D levels than healthy subjects [6]. It is reported that there was a significant correlation between autoimmune thyroid disease (AITD) and vitamin D receptor gene polymorphisms [7]. And also there are some conditions that are found to be related to vitamin D status such as non-alcoholic fatty liver disease (NAFLD) or cirrhosis, associated with liver. NAFLD is an obesity-related condition and it is shown that serum 25(OH)D3 levels were conversely related with NAFLD [8]. Others showed that serum vitamin D levels were not significantly related to the presence of NAFLD [9]. Rhee EJ et al. [10] found that there was a relation between decreased serum 25(OH)D3 levels and NAFLD prevalence in patients with non-type 2 diabetes mellitus. There are several studies on vitamin D status in sick children. We aimed to investigate the association between vitamin D, thyroid and liver enzymes in healthy children. 2. METHODS The serum vitamin D levels of 55 children between ages 3 and 16 years who admitted to the Bozok University Medical Faculty, pediatric outpatient clinic were evaluated. The blood samples were drawn between February 2013 and June Exclusion criteria were treated with vitamin D previously and having chronic diseases such as hypothyroidism, hyperthyroidism or liver disease. Serum 25(OH)D3 levels 20 ng/ml, and 20 ng/ ml were accepted as vitamin D deficiency and sufficiency, respectively. Thus, patients and controls were grouped as 25(OH)D3 deficient and sufficient. Patients with 25(OH)D3 deficiency and sufficiency were compared according to their serum thyroid stimulating hormone (TSH), FreeT3, FreeT4, glucose, alanine transaminase (ALT), aspartate transaminase (AST), vitamin B12 and folic acid. Serum TSH, FT3, FT4, glucose, ALT, AST, vitamin B12, folic acid and vitamin D levels were measured in venous blood samples. 2.1 Statistical Analyses The statistical analyses were carried out by Statistical Package for Social Sciences (SPSS 18). Variables were expressed as mean±sd. Comparisons of variables were performed using unpaired Student t test. Bivariate associations of the variables were assessed using Pearson s correlation coefficients. To find the parameters that explain the significance of the variance of the dependent variables, stepwise multivariate linear regression analyses was performed and p value <0.05 was considered as indication of statistical significance. 3. RESULTS The children were divided according to vitamin D levels as under 20 ng/ml and above 20 ng/ml. The comparisons of laboratory findings are listed in Table 1. While FT4 levels were found lower in the vitamin D deficiency group (1.18±0.22 versus 1.38±0.19, p= 0.001), TSH (3.77±1.40 versus 2.53±1.11 p= 0.001), AST (32.17±7.19 versus 17.12±8.72, p= 0.000) and ALT (18.05±5.45 versus 10.28±4.39, p=0.000) were significantly higher in this group than controls (Table 1). To assess the correlation between vitamin D and other parameters we used Pearson correlation analyses. Vitamin D was positively correlated with FT3 (p=0.028 r=0.296), FT4 (p=0.000 r=0.638) and negatively correlated with age (p=0.000 r=-0.616), TSH (p=0.001 r=-0.451), AST (p=0.000 r=-0.765) and ALT (p=0.000 r=-0.599) (Table 2). On multivariate regression analysis, age (p=0.008 β=-0.232), FT4 (p=0.044 β=0.192), TSH (p=0.036 β=-0.159), AST (p=0.000 β=-0.481) were independently associated with low vitamin D concentrations (Table 3). 4. DISCUSSION Hypovitaminosis D is a common health problem in the worldwide. Even in tropical climates, the population is at high risk of vitamin D deficiency due to changing lifestyle [11]. In a study conducted recently in the United Kingdom; vitamin D deficiency 8

3 is reported more than 50% of the adult population during winter and spring term and also severe vitamin D deficiency detected in 16% of [12]. In our country, a study conducted in Ankara by Uçar et al. [13]; quite a high proportion of vitamin D deficiency (51.8%) and in the 20.7% of Vitamin D insufficiency has been identified. In current study, 24 children (43.6%) were diagnosed as vitamin D deficiency. Table 1. Comparison (mean ± SD) of laboratory findings according to vitamin D level Variable Children with vitamin Children with vitamin p value D<20 ng/ml D>20 ng/ml 24 (M/F=10/14) 31 (M/F=13/18) Age (year) 9.41± ± Vitamin D (ng/ml) 11.90± ± * Glucose (mg/dl) 85.64± ± FT3 (pg/ml) 3.58± ± FT4 (NG/DL) 1.18± ± * TSH (uiu/ml) 3.77± ± * AST (U/L) 32.17± ± * ALT (U/L) 18.05± ± * Vitamin B ± ± Folic acid 6.81± ± * Statistically significant (p <0.05) FT3: Free T3, FR4: Free T4, TSH: Thyroid stimulating hormone, ALT: Alanine transaminase, AST: Aspartate transaminase Table 2. Correlation between vitamin D and other laboratory parameters Age Vit D Glucose FT3 FT4 TSH AST ALT Vitamin B12 Folic acid Age 1 Vit D -.616** 1 glucose FT **.296* FT **.638** ** 1 TSH ** AST.355** -.765** **.380** 1 ALT.309* -.599** * ** 1 B * Folic acid ** 1 ** Correlation is significant at the.01 level (2-tailed), * Correlation is significant at the.05 level (2-tailed). FT3: Free T3, FR4: Free T4, TSH: Thyroid stimulating hormone, ALT: Alanine transaminase, AST: Aspartate transaminase Table 3. Stepwise multiple linear regression analysis Model Unstandardized coefficients Standardized coefficients t Sig. B Std. error Beta 1 (Constant) Age * FT FT * TSH * AST * ALT Dependent variable: Vit D.* Correlation is significant at the.05 level (2-tailed). FT3: Free T3, FR4: Free T4, TSH: Thyroid stimulating hormone, ALT: Alanine transaminase, AST: Aspartate transaminase 9

4 For the identification of vitamin D deficiency and insufficiency, and to define normal range of 25 (OH) D levels many studies have been performed. In light of these studies; 25 (OH) D levels lower than 20 ng / ml considered as vitamin D deficiency, 21 to 29 ng / ml as vitamin D insufficiency, higher than 30 mcg/ml levels as sufficient value (preferred range is ng/ml) and higher than 150 ng/ml is considered to be vitamin D intoxication [14]. The Institute of Medicine; to prevent vitamin D deficiency (Institute of Medicine, IOM); they have suggested that 400 IU daily of vitamin D supplementation to infants up to one year commenced immediately. In practice guidelines of endocrine society; various treatment strategies have proposed for patients with vitamin D deficiency based on age and underlying medical conditions [14]. For infants with vitamin D deficiency between 0-1 years of age; 2000 miu / day or 50,000 IU / week vitamin D2 or D3 for six months and IU / day for maintenance therapy in order to keep 25 (OH) D blood levels more than 30 ng / ml. Children between 1-18 years of age with vitamin D deficiency; 2000 IU / day or 50,000 IU / week vitamin D2 or D3 for six weeks and IU / day for maintenance therapy in order to keep vitamin D blood levels more than 30 ng / ml. Vitamin D has a significant role in calcium homeostasis thus decreasing the risk of rickets, fractures, osteoporosis and osteomalacia. Besides skeletomuscular functions of vitamin D, it has an effect in both innate and adaptive immunity and autoimmune conditions such as type 1 diabetes mellitus, rheumatoid arthritis, crohn disease, multiple sclerosis and systemic lupus erythematosus and supplementation of vitamin D is known to prevent progression of autoimmune diseases [15]. Hypovitaminosis D may also cause malignancy especially gastrointestinal tumors [16,17]. Some studies have shown that hypovitaminosis D had an effect on Hashimoto thyroiditis and Graves disease and to prescribe vitamin D with anti-thyroid drugs or thyroid hormone may benefit to the treatment of AITD by suppressing the autoimmune reaction and decreasing serum levels of thyroid autoantibodies [18]. However in some other studies vitamin D deficiency has shown not to increase the risk of AITD and is not related with early-stage AITD [19]. In current study vitamin D deficiency group had negative correlation with TSH. We suggest that the children with vitamin D deficiency are more prone to hypothyroidism. Vitamin D takes part in the regulation of some of the cytokines and leptin, which are play important role in AITD. Thus, it is thought that Vitamin D affects thyroid hormone levels by immunoregulation. Abe J et al. [20] demonstrated that 25(OH)D administration could prevent the induction of autoimmune thyroiditis. Other study found that vitamin D deficient BALB/c mice were more prone to persistent hyperthyroidism than the controls that receiving adequate vitamin D after immunizations with TSH receptor [21]. Goswami et al. [22] showed that serum 25(OH)D level was similar among TPOAb-positive and TPOAb-negative individuals. Kivity et al. [23] found that the occurrence of antithyroid antibodies and abnormal thyroid functions was more frequent in vitamin D deficient subjects. Vitamin D levels may detect the prognosis of Graves s disease [24]. Yasuda et al. [25] suggested that the female patients had decreased vitamin D levels and this level was related with thyroid volume. Although there are controversial data, vitamin D has shown to be a new developing topic in the pathogenesis of AITD. Also hypovitaminosis D has found to be more common in insulin resistant states [26]. It is suggested that hypovitaminosis D was associated with the degree of NAFLD [27]. Dasarathy J et al. [28] revealed that hypovitaminosis D was an independent factor of the severity of NAFLD. It is suggested that hypovitaminosis D can quickened advanced stages of liver disease [29]. In current study there were negative correlations between vitamin D and liver enzymes in children without NAFLD. Any conditions that affect liver can lead to hypovitaminosis D. Several studies revealed that patients with hepatitis C virus had a significant decreasing in the level of vitamin D and its active metabolite and they found a significant negative correlation between viral load and vitamin D status [30]. Hypovitaminosis D levels were related to poor liver function and stage of cirrhosis [31]. Arteh et al. [32] revealed that severe vitamin D deficiency was more frequent in cirrhotic patients than the noncirrhotics. 5. CONCLUSION In conclusion, vitamin D influence the level of liver enzymes and thyroid hormones even in healthy children. In healthy children, to elucidate the effects of hypovitaminosis D, further studies with larger sample size and greater number of children should be done. 10

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