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ORIGINAL ARTICLE
Year : 2018  |  Volume : 15  |  Issue : 1  |  Page : 23-28

Vitamin D levels in children with Hashimoto's thyroiditis: Before and after L-thyroxine therapy


1 Department of Paediatrics, Advanced Paediatrics Centre, Chandigarh, India
2 Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication23-Mar-2018

Correspondence Address:
Dr. Rakesh Kumar
Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/trp.trp_45_17

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  Abstract 


Background: Vitamin D deficiency has been associated with Hashimoto's thyroiditis (HT). Hypothyroidism per se can cause poor absorption and metabolism of Vitamin D leading to Vitamin D deficiency. It is unknown that Vitamin D deficiency in HT is a cause or effect of HT.
Objectives: To study Vitamin D level in children with newly diagnosed HT and to follow the changes in Vitamin D level after L-thyroxine therapy.
Material and Methods: A prospective observational study was conducted on 35 children recently diagnosed with HT who had not received Vitamin D supplementation in the past 6 months. Serum 25 hydroxy Vitamin D levels along with serum calcium profile were estimated before starting L-thyroxine and on follow-up after 3 months.
Results: The mean Vitamin D level at diagnosis of HT was significantly low as compared to controls (33.34 ± 16.93 nmol/L vs. 65.13 ± 30.57 nmol/L; P < 0.0001). Out of 22 Vitamin D-deficient patients who were treated, seven (31.8%) remained deficient at follow-up. Thirteen patients (sufficient/insufficient Vitamin D levels) who were not supplemented with Vitamin D had fall in Vitamin D levels in follow-up.
Conclusions: Children with HT have low Vitamin D levels at diagnosis, and L-thyroxine therapy can further compromise Vitamin D status. Children with recent diagnosis of HT should be screened and treated or supplemented with Vitamin D.

Keywords: Autoimmune thyroiditis, children, Vitamin D deficiency


How to cite this article:
Chaudhary N, Kumar R, Sachdeva N, Dayal D. Vitamin D levels in children with Hashimoto's thyroiditis: Before and after L-thyroxine therapy. Thyroid Res Pract 2018;15:23-8

How to cite this URL:
Chaudhary N, Kumar R, Sachdeva N, Dayal D. Vitamin D levels in children with Hashimoto's thyroiditis: Before and after L-thyroxine therapy. Thyroid Res Pract [serial online] 2018 [cited 2018 May 25];15:23-8. Available from: http://www.thetrp.net/text.asp?2018/15/1/23/228379




  Introduction Top


Vitamin D deficiency has been reported to be associated with various autoimmune diseases such as type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus, and rheumatoid arthritis.[1] The prevalence of thyroid autoimmunity in children has been found to be as high as 9%–13%.[2] Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis or chronic autoimmune thyroiditis, is the most common form of thyroiditis in childhood. If not treated, HT may lead to retardation in growth and development, resulting in short stature, decline in school performance, and anemia.[3] Vitamin D deficiency has been associated with HT; however, it is not clear whether it is a causal factor in HT or a consequence of HT. A few studies have shown that patients with HT have lower 25 hydroxy Vitamin D (25[OH] D) levels than healthy controls and Vitamin D insufficiency is more common in patients with HT than in healthy controls.[4] The activated vitamin D in blood inhibits production of cytokines important in development of HT. The effect of treatment of HT by L-thyroxine replacement on Vitamin D levels has not been studied as yet to the best of our knowledge. We planned to study Vitamin D levels in children with HT and subsequently the effect of L-thyroxine treatment on Vitamin D levels.


  Material and Methods Top


Study setting and design

A prospective observational study over 1½-year period was conducted in Pediatric Endocrine Clinic at a tertiary care pediatric hospital.

Study population

Study participants (Cases) were recruited from July 2012 to December 2013. All study participants and controls were native of Chandigarh and surrounding region of North India (30.74° N and 76.79° E) which receives cloud-free sunshine of 8–10 h daily throughout the year.[5]

Cases

Inclusion criteria

All consecutive children <12 years of age with autoimmune thyroiditis, who were started on thyroxine replacement over the 1 year study period.

Exclusion criteria

Concomitant chronic kidney/liver disease, patients with malabsorption syndrome (e.g., celiac disease), patients on anti-tubercular therapy/anti-epileptics or glucocorticoids, and patients who have received Vitamin D/calcium supplements in the last 6 months.

Controls

Vitamins D levels of 50 healthy controls were taken from a previous study [6] done in the same institute taken over same period/seasons of the 18 month period (July 2007 and December 2008) as of cases in the index study. The mean age of patients was 9.23 ± 2.7 years and that of controls was 8.48 ± 1.58 years.

Sample size

A total of 35 consecutive children who were newly diagnosed to have autoimmune thyroiditis over a 1½-year study period and satisfying inclusion and exclusion criteria were enrolled for the study.

Consent and ethical approval

A written informed consent was taken from patients/caregivers before enrollment. Study protocol was approved by Institute Ethics Committee before the start of enrollment.

Definitions

HT was defined by presence of clinical features of hypothyroidism and low serum total T4 and/or high TSH with or without goiter with at least one of the three positive laboratory criteria including (i) positive for anti-thyroid microsomal antibody or anti-thyroid peroxidase antibody (TPO Ab), (ii) positive for anti-thyroglobulin antibody, and (iii) lymphocytic infiltration in the thyroid gland on cytological examination.[7],[8] Anti-TPO titer >34 kIU/L (IU/ml) was considered positive.

Vitamin D deficiency (<37.5 nmol/L or 15 ng/ml), insufficiency (37.5–50 nmol/L or 15–20 ng/ml), and sufficiency (50–250 nmol/L or 20–100 ng/ml) were defined as per cutoff levels suggested by Misra et al.[9]

Thyroid status in autoimmune thyroiditis was defined as follows:

  • Overt hypothyroidism – Serum thyrotropin (TSH) >10 mIU/L and total thyroxine (T4) <61.7 nmol/L (4.8 ng/dl)
  • Subclinical hypothyroidism – Normal serum T4 and T3 levels but with serum TSH levels elevated to the range of 5–20 mIU/mL
  • Euthyroid status – Normal T4 and TSH levels.


Study procedure

A thorough clinical evaluation including clinical features of Vitamin D deficiency, hypothyroidism, anthropometry, and systemic examination was done at enrollment. All information was collected in a predesigned pro forma. Blood samples for estimation of 25(OH) D, intact parathyroid hormone (iPTH), calcium, phosphate, alkaline phosphatase (ALP), serum proteins (albumin/globulin), liver function tests, and kidney function tests were collected before the child was started on thyroxine replacement. Furthermore, values of serum T3, T4, TSH and anti-TPO Ab and other diagnostic tests were noted at enrollment and start of therapy with thyroxine. Blood tests for Vitamin D, iPTH, and calcium profile were repeated after 3 months. Children who were Vitamin D deficient at diagnosis of HT were treated with 10,000 units/kg of Vitamin D given orally over 10 days. Children with Vitamin D insufficiency were not treated/supplemented to see the effect of L-thyroxine therapy on their Vitamin D status.

Biochemical assays

Estimation of serum total 25(OH) D, iPTH, T3, T4, TSH, and anti-TPO Ab was done using electrochemiluminescence assay on Elecsys 2010 analyzer using specific kits (Roche Diagnostics, Germany). The analysis of sodium, potassium, chloride, urea, creatinine, total serum proteins, albumin, total serum bilirubin, aspartate transaminase, alanine transaminase, calcium, phosphorus, and ALP were carried out on Siemens Dimension ® RxL Max ® clinical chemistry analyzer using specific kits.

Statistical analysis

Statistical analysis was performed with SPSS statistical software version 17.0 (SPSS Inc., Chicago, IL, USA). For normally distributed continuous variables, independent t-test and for variables with nonnormal distribution, Mann–Whitney U-test was used to assess differences in various groups. Paired t-test was used to test significant difference in various parameters including Vitamin D and thyroid functions on two points of estimations to see for effect after treatment with L-thyroxine. P < 0.05 was considered statistically significant.


  Results Top


A total of 35 children were enrolled, including eight males and 27 females with F: M = 3.4:1. The median age of patients was 9.23 ± 2.7 years and mean body mass index was 16.99 ± 4.46 kg/m 2. The clinical profile of patients at enrollment is given in [Figure 1]. Baseline and follow-up biochemical parameters are presented in [Table 1]. Two patients did not come for follow-up due to personal reasons.
Figure 1: Clinical features of children with Hashimoto's thyroiditis (n = 35)

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Table 1: Baseline and serial value of serum biochemical parameters in children with Hashimoto's thyroiditis (n=33)

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The comparison between the enrol lment and follow-up Vitamin D status is as shown in [Table 2]. The mean Vitamin D level of children with HT at diagnosis (n = 35) was 33.34 ± 16.93 nmol/L (i.e.,13.39 ± 6.8 ng/ml) and was low compared to healthy controls of the same age group taken from a previous study done in the same institute [6] which was 65.13 ± 30.57 nmol/L (i.e., 26.16 ± 12.28 ng/ml) and the difference was statistically significant (P< 0.0001).
Table 2: Serum Vitamin D status of children with Hashimoto's thyroiditis compared with controls

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At enrollment, there were 22 patients in Vitamin D-deficient group, which was supplemented with Vitamin D. In follow-up, seven patients remained deficient (31.8%), 13 patients became sufficient (59.1%), and two patients were lost to follow-up (9.1%). Out of 9 patients in Vitamin D-insufficient group (not given Vitamin D), six (66.7%) became deficient, one (11.1%) patient remained insufficient and two (22.2%) patients became sufficient at follow-up [Table 3]. In the Vitamin D-sufficient group, there were four patients, who were not supplemented; one of them became insufficient at follow-up [Table 3].
Table 3: Changes in serum Vitamin D status during the course of study in children with Hashimoto's thyroiditis (n=35)

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[Table 4] shows TPO Ab and TSH levels at enrollment and follow-up in three groups of children as per their Vitamin D status at enrollment/diagnosis of HT.
Table 4: Mean serum Vitamin D, thyroid peroxidase antibody, and thyroid-stimulating hormone levels of 3 groups (as per Vitamin D status at enrollment) of children with Hashimoto's thyroiditis at enrollment and follow-up (n=33)

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  Discussion Top


In our study, the mean Vitamin D level of all children with HT at diagnosis was 33.34 ± 16.93 nmol/L (i.e., 13.39 ± 6.80 ng/ml) and prevalence of Vitamin D deficiency and insufficiency at diagnosis was 62.8% (22/35) and 25.7% (9/35), respectively. Children with Vitamin D deficiency were given Vitamin D treatment, and mean Vitamin D levels of all enrolled children at follow-up increased to 70.54 ± 56.97 nmol/L (i.e., 28.32 ± 22.88 ng/ml). However, mean Vitamin D levels in 13 children with HT who had insufficient or normal Vitamin D levels at diagnosis and were not given Vitamin D had mild fall in Vitamin D levels at follow-up. The prevalence of Vitamin D deficiency in children with new diagnosis of HT (62.8%) was found to be more than healthy controls who had Vitamin D deficiency and insufficiency in 32% and 44%, respectively. Mean Vitamin D levels in children with HT were also significantly low when compared to healthy controls. Kalra et al. also reported a very high prevalence (96.15%) of Vitamin D deficiency in adequately treated adult hypothyroidism patients in neighboring state in North India.[10]

Similar results were seen in a recent study by Camurdan et al., investigating Vitamin D status in 78 children with HT and 74 controls.[11] Higher rates of Vitamin D deficiency (73.1% vs. 17.6%, P < 0.0001) and lower Vitamin D levels (31.2 ± 11.5 versus 57.9 ± 19.7 nmol/L, P < 0.001) were found in the HT group. Tamer et al. also found low Vitamin D levels in adult patients with HT and reported a lower serum Vitamin D level in HT patients (16.3 ± 10 ng/ml) compared to healthy controls (29.6 ± 25.5 ng/ml).[12] Kivity et al. in their study found 25(OH) D levels below 10 ng/ml in 79% of patients with HT.[13] In a recent study by Bozkurt et al., the mean Vitamin D levels of newly diagnosed HT patients and controls were found to be 13.1 ± 5.9 ng/ml and 15.4 ± 6.8 ng/ml, respectively, comparable to our study.[14]

A recent meta-analysis of 20 case–control studies in adult patients with autoimmune thyroid disease showed lower levels of 25(OH) D (standard mean difference: −0.99, 95% confidence interval [CI]: −1.31, −0.66) and they were more likely to be deficient in 25(OH)D (with odds ratio of 2.99, 95% CI: 1.88, 4.74).[4]

In our study, we looked into the mean Vitamin D levels in the insufficient group (which did not receive Vitamin D) after treatment with L-thyroxine which was one of our primary objectives. The results showed a fall in mean Vitamin D levels during follow-up; however, the difference was not statistically significant (P = 0.919). The fall in mean Vitamin D levels may be attributed to increase in metabolic demand/increased metabolism of Vitamin D in response to euthyroid state being achieved after treatment with L-thyroxine. Similar trend was observed in the Vitamin D-sufficient group as well which was also not supplemented with Vitamin D. Bozkurt et al. also reported that 48.3% of HT patients on L-thyroxine therapy had severe Vitamin D deficiency while 35% of newly diagnosed HT patients and 20.5% of controls had severe Vitamin D deficiency (P< 0.001).[14] Authors suggested that L-thyroxine replacement may influence the metabolic clearance of Vitamin D thereby leading to severe Vitamin D deficiency. In their study, the mean Vitamin D levels in newly diagnosed HT patients and those on L-thyroxine treatment were also comparable to our patients.

In our study, the mean TPO Ab levels are highest in the Vitamin D-deficient group followed by Vitamin D-insufficient and Vitamin D-sufficient group, both at the time of enrollment and during follow-up, which may depict the inverse relation between the Vitamin D status and TPO Ab levels. A study by Goswami et al. also found that serum 25(OH) D values show a weak inverse correlation with TPO Ab titers. In their study, hypovitaminosis D was found in 87% of individuals with TPO Ab positivity.[15] A study by Shin et al. demonstrated a negative association between 25(OH) D and TPO Ab levels, and authors suggested that the low 25(OH) D level is a possible risk factor of TPO Ab positivity.[16] Similarly, a study by Kivity et al. reported that presence of antithyroid antibodies was significantly more common in patients with Vitamin D deficiency than in those with higher Vitamin D levels (43% vs. 17%, respectively; P = 0.01).[13]

The mean TSH levels in our study were highest in the Vitamin D-deficient group followed by sufficient and insufficient group at enrollment. Furthermore, it was observed that the higher TSH levels were associated with lower serum Vitamin D levels at enrollment (before L-thyroxine therapy). Similar results have been observed by Chailurkit et al. and Zhang et al.[17],[18]

It is evident from our study that Vitamin D deficiency and insufficiency is more prevalent in children with HT and Vitamin D levels tend to fall further during treatment with L-thyroxine without Vitamin D replacement. However, the fall in Vitamin D levels after treatment of HT was not statistically significant which may be due to small sample size (there were only 13 out of 35 patients who did not receive Vitamin D). Most of the studies have shown decreased Vitamin D levels to be associated with HT and hypothyroidism. However, it is not clear whether Vitamin D deficiency is a causal factor in HT or a consequence of HT or its treatment. Hypothyroidism can lead to the low level of Vitamin D by two mechanisms; by decreasing the absorption of Vitamin D in the intestine and by reducing activation of Vitamin D.[19] In addition, the present study and a study by Bozkurt et al. have shown that Vitamin D levels tend to fall further with treatment of hypothyroidism in HT.[14] This suggests that both hypothyroidism and its treatment are compromising Vitamin D status in individuals with HT.

One of the major limitations of our study is small sample size which may have led to statistically insignificant results despite there being a fall in mean Vitamin D levels, after L-thyroxine treatment, in children with insufficient and sufficient Vitamin D levels at diagnosis of HT. Short duration of follow-up (3 months) was another limitation of our study. A longer duration of follow-up could have given more idea of seasonal variations in Vitamin D levels. Due to cost constraints, we could not enroll parallel healthy controls for Vitamin D status in our study. However, this lacuna was taken care of by comparing Vitamin D levels of healthy control group of similar demographic profile from the same institute (region).[6]

To the best of our knowledge, this is the first study conducted in Indian children with HT which has assessed the prevalence of Vitamin D deficiency and insufficiency in this group. Furthermore, this is the first attempt to prospectively study the changes in Vitamin D levels after L-thyroxine treatment in children with HT.


  Conclusions Top


Our study has shown that there is high prevalence of Vitamin D deficiency in children with HT without having overt clinical and biochemical manifestations of rickets. Detection of Vitamin D deficiency in this high-risk group thus requires estimation of serum Vitamin D levels at diagnosis of HT which can guide treatment and supplementation with Vitamin D thereby decreasing related morbidity. Further, treatment with L-thyroxine also leads to fall in mean Vitamin D levels which may require Vitamin D supplementation to sustain the normal Vitamin D levels. However, to ascertain a significant change in Vitamin D levels after treatment with L-thyroxine, further prospective studies with large sample size and follow-up need to be conducted.

Financial support and sponsorship

Authors acknowledge Indian Council of Medical Research [ICMR], New Delhi, India for partial financial support in procuring test kits for serum 25 [OH] vitamin D assay, as a part of student thesis grant.

Conflicts of interest

There are no conflicts of interest.



 
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