Abstract
Contex
The first trimester of pregnancy is the most sensitive period in terms of thyroid hypofunction. Iron deficiency has been associated with both thyroid function and thyroid autoimmunity.
Objective
We aimed to investigate whether iron deficiency is a risk factor for thyroid autoimmunity in non-pregnant women at childbearing age.
Design
This cross- sectional study was conducted in non-pregnant women who presented to the Internal Medicine Policlinic between January 2018 and December 2018 in the University of Health Sciences “Fatih Sultan Mehmet” Training and Research Hospital.
Methods
Three hundred fifty-eight non-pregnant women of reproductive ages (203 iron deficient-ID, 155 control) participated in this study. Women with known thyroid disease, currently undergoing treatment for thyroid disease or whose thyroid function tests were outside the reference range were excluded from the study. Blood sample was taken after at least 8-10 hours of fasting for measurement of serum iron (Fe), total iron binding capacity (TIBC), serum ferritin (SF), whole blood count, thyroid function tests (fT4, TSH), anti-thyroid peroxidase antibodies (TPOAb) and anti-thyroglobulin antibody (TgAb). The patients with SF levels ≤ 15 ng/dL were accepted as iron deficiency.
Results
The group with ID had higher TSH and lower T4 values that did not reach statistical significance compared to the control group (p=0.101 and p=0.098, respectively). Antibody positivity was more frequent in the ID group than in the control group (35.96% vs. 20.65%, p = 0.002).
Conclusions
Iron deficiency is associated with thyroid autoimmunity and it should be considered as a risk factor for screening thyroid antibody, particularly in pregnancy planning women.
Keywords: iron deficiency, thyroid autoimmunity, reproductive age
INTRODUCTION
Anemia affects one-quarter of the world's population and is concentrated in preschool-aged children and women (1). Iron deficiency (ID) with or without anemia has been associated with thyroid dysfunction and shown to cause hypothyroidism through several mechanisms (2-4). Studies in rats have suggested that ID reduces plasma thyroid hormone concentrations by decreasing hepatic thyroxine deiodinase activity, disrupting peripheral conversion of T4 to T3, and decreasing TSH response to TRH (5). Presumably, ID affects thyroid hormone feedback by disturbing the pituitary threshold leading to TSH secretion. Additionally, ID may also lead to decreased TPO activity, which impairs the metabolism of iodine in the thyroid [6]. Few studies have shown a relationship between thyroid autoimmunity (TAI) and ID (7, 8).
In this study, thyroid antibodies as well as thyroid function were examined in women of reproductive ages with ID and compared with age-match controls without ID.
MATERIALS AND METHODS
This cross-sectional study was conducted in 358 women between the ages of 18 and 45 who presented to the Internal Medicine Policlinic between January 2018 and December 2018 in the University of Health Sciences “Fatih Sultan Mehmet” Training and Research Hospital. The women who did not have chronic disease history, did not use any medication that would affect their thyroid function, and who were not pregnant were included the study. Women with known thyroid disease such as thyroidectomy and radioactive iodine therapy or with a positive history of autoimmune thyroid disease, who already use thyroid hormone replacement and have a thyroid function test result outside the normal reference ranges (free T3, free T4, TSH) were not included in the study. Likewise, patients with high C-reactive protein levels were excluded from the study. The study protocol was approved by the Local Ethics Committee and an informed consent form was taken from each of the participants.
Blood sample was taken after at least 8-10 hours of fasting for measurement of serum iron (Fe), total iron binding capacity (TIBC), serum ferritin (SF), whole blood count, C-reactive protein, anti-thyroid peroxidase antibodies (TPOAb) and anti-thyroglobulin antibody (TgAb). Serum Fe levels and TIBC were measured by Abbott Architect C8000 Clinical Chemistry Analyzer. SF levels were measured by chemiluminescent microparticle immunoassay(CMIA) method (Architect i2000, Abbott Laboratories). Serum transferring saturation (TSAT) was calculated using formula serum Fe/TIBC x 100. The patients with SF levels ≤ 15 ng/dL were included in the iron deficiency group and women with SF levels above these values were control subjects. TSH, free T4, free T3, TPOAb and TgAb were measured by the CMIA method (Architect i2000, Abbott Laboratories). The range of 0.35-4.2 mIU/L for TSH, 0.58-1.64 ng/dL for free T4 and 1.71-3.71 pg/mL for free T3 were accepted as normal values. Values above 5.6 IU/mL for TPOAb and 10 IU/ mL for TgAb were considered as positive.
Statistical analysis was conducted by using Statistical Package for Social Sciences (IBM SPSS, Armonk, NY USA) for Windows 22 programs. Results were expressed as means ± standard deviation. Distribution of parameters was tested by Kolmogorov Smirnov test. Comparisons between ID and the control groups were made using student t test for parameters with normal distribution and Mann Whitney U test for parameters with non-normal distribution. Comparison of frequency distribution was performed by means of the Chi-Square test. Results were analyzed with 95% confidence interval and probability levels less than 0.05 were considered significant.
RESULTS
Of the 358 women, 203 were in the ID group and 155 were in the control group. There was no statistically significant difference between groups in terms of age (p=0.736). As expected, the ID group had lower hemoglobin (Hb) (p < 0.001), Fe (p <0.001), the TSAT (p <0.001), SF levels (p <0.001) and higher TIBC (p <0.001) (Table 1). The group with ID had higher TSH and lower T4 values that did not reach statistical significance compared to the control group (p=0.101 and p=0.098, respectively). Antibody positivity was significantly higher in the ID group than in the control group (35.96% vs. 20.65%, p = 0.002). There was no significant difference in TPO Ab and TgAb positivity between the groups (p>0.05), but TPOAb plus TgAb positivity was significantly more common in the iron deficiency group (p=0.031) (Table 2). Of the women with positive antibodies, 50.48% were at or under the median age of 32, 49.52% were above the median age.
Table 1.
Iron parameters and demographic characteristics among the groups
| Iron deficiency group (n=203) | The control group (n=155) | P value | |
|---|---|---|---|
| Age (years) | 31.63 ± 8.19 | 31.33 ± 8.61 | 0.736 |
| BMI (kg/m2) | 27.04 ± 4.55 | 26.70 ± 5.63 | 0.538 |
| Hb (g/dL) | 11.57 ± 1.36 | 12.88 ± 0.97 | <0.001 |
| Iron (µg/dL) | 48.34 ± 29.47 | 78.68 ± 31.80 | <0.001 |
| TSAT (%) | 13.07 ± 8.80 | 25.52 ± 11.64 | <0.001 |
| ferritin(ng/dL) | 7.46 ± 3.59 | 37.80±33.04 | <0.001 |
The data is expressed as mean ± SD. P value was calculated at 95 % confidence interval.
Table 2.
Thyroid functions and antibodies among the groups
| Iron deficiency group (n=203) | The control group (n=155) | P value | |
|---|---|---|---|
| TSH (mIU/L) | 1.90 ± 0.97 | 1.74 ± 0.91 | 0.101 |
| Free T4 (ng/dL) | 0.96 ± 0.11 | 0.97 ± 0.11 | 0.098 |
| Free T3 (pg/mL) | 2.77 ± 0.42 | 2.81 ± 0.60 | 0.481 |
| Total antibody positivity (%) | 35.96 | 20.65 | 0.002 |
| TPOAb (%) | 8.37 | 3.87 | 0.085 |
| TgAb (%) | 9.85 | 7.10 | 0.358 |
| TPOAb + TgAb (%) | 17.73 | 9.68 | 0.031 |
The data is expressed as mean ± SD for TSH, free T4 and T3 and as percentage for Auto-antibodies. P value was calculated at 95 % confidence interval.
DISCUSSION
Thyroid auto-antibodies are present in 2% to 17% of unselected pregnant women (9). On the other hand, iron deficiency has been associated with both thyroid autoimmunity and thyroid function (2-4). In a previous cross-sectional study, Zimmermann et al. reported that the anemia of iron deficiency reduced the conversion of T4 to T3 in the periphery and increased TSH levels while reducing plasma T3 and T4 levels (2). Li et al. reported that TPO positivity was more frequent, TSH levels were higher and T4 levels were lower in Chinese women with iron deficiency in early gestation (8). In another study, Veltri et al. reported that women with ID in their first trimester of pregnancy had higher prevalence of thyroid autoimmunity, higher serum TSH, and lower FT4 levels (7). On the other hand, thyroid autoimmunity has been associated with adverse obstetric or child outcomes such as miscarriage, recurrent spontaneous pregnancy loss, premature delivery, perinatal death, increased risk for placental abruption, postpartum depression and neonatal respiratory distress syndrome (10-16). In women with thyroid autoimmunity, overt or sub-clinical hypothyroidism may occur during the pregnancy because the ability of the thyroid to augment hormone production is compromised (17). The first trimester of pregnancy is the most sensitive period to the adverse effects of overt or sub-clinical hypothyroidism.
It is a continuing debate about whether all pregnant women or only those with risk factors should be screened for thyroid function. Only by risk-based screening, it has been reported that TPO positivity missed in 33% of pregnant women (18). Many patients with autoimmune thyroiditis are clinically and hormonally euthyroid. Our results support that ID is associated with thyroid autoimmunity. Although it does not reach statistical significance, the change in TSH and T4 is also consistent with the literature. Considering the relation between thyroid autoimmunity and thyroid dysfunction and the sensitivity of early gestation to thyroid dysfunction, pre-pregnancy recognition of thyroid autoimmunity may be important. Our results and some others suggest that iron deficiency is a risk factor for thyroid autoimmunity. In particular, if a risk-based screening is to be carried out, ID should be considered as a risk factor in pregnant or pregnancy planning women and they should be screened not only for thyroid hormones but also for thyroid autoimmunity. It can also be said that women with autoimmune thyroiditis tend to develop iron deficiency anemia. Even so, it does not eliminate the need for women with iron deficiency to be evaluated for thyroid autoimmunity.
The most important limitation of this study is that the study population is living in the mild iodine deficient region. Previously, it has been reported that dietary iodine intake may be associated with thyroid antibody positivity. The iodine status was not assessed in our study. Since the iron-deficient group and the control group live in the same region, the effect of iodine status can be neglected. However, there may be individual differences in iodine uptake.
In conclusion, the results of this study support the association of iron deficiency with thyroid autoimmunity. In cases where the outcome of clinical or sub-clinical thyroid dysfunction is substantial such as pregnancy and/ or pregnancy planning, we recommend that iron deficiency should be considered as a risk factor for screening thyroid antibody.
Conflict of interest
The authors declare that they have no conflict of interest.
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