Abstract
Objective
To determine the prevalence of thyroid autoantibodies and the associated factors in euthyroid subjects.
Methods
300 euthyroid subjects, chosen by stratified sampling from an inception cohort of 1335 individuals, were included. Thyroid function was evaluated by measuring the serum levels of TSH (0.3–4.5 μIU/mL) and FT4 (5.2–12.7μg/dL). Anti-peroxidase (TPOAbs), anti-thyroglobulin (TgAbs), and anti-TSH receptor (TrAbs) antibodies were evaluated with 23 additional autoantibodies as well as vitamin D (VitD) levels. The analysis included sociodemographic, clinical, and environmental characteristics. Data were analyzed by bivariate and multivariate tests.
Results
Thyroid autoimmunity was observed in 15.3% of the subjects (TPOAbs 11.3% and TgAbs 2.0%). In six individuals, both autoantibodies were positive. TrAbs were not detected in any individual. Familial thyroid disease (β = 3.4, 95% CI: 1.2–9.5, P = 0.021), the presence of other autoimmune diseases (β = 10.8, 95% CI: 1.6–72.9, P = 0.014) VitD insufficiency (P = 0.030), never smoke (β = 6.9, 95% CI: 1.6–30.4, P = 0.010), drinking more than 4 cups of coffee (β = 3.8, 95% CI: 1.1–13.1, P = 0.036), and a higher number of years exposed to wood smoke (P = 0.04) were associated with thyroid autoimmunity. In the case of TPOAbs, familial thyroid disease (β = 4.9, 95% CI: 1.7–14.0, P = 0.003), never smoke (β = 5.7, 95% CI: 1.4–21.0, P = 0.002), and drinking more than 4 cups of coffee (β = 3.6, 95% CI: 1.1–13.1, P = 0.047) were associated with their positivity. In addition, the presence of anti–SS–A/Ro52 (β = 36.7, 95% CI: 2.5–549.9, P = 0.009) and anti-Ku antibodies (β = 10.2, 95% CI: 1.1–100.7, P = 0.046) was also associated with TPOAbs. The presence of African ancestry (β = 10.5, 95% CI: 1.7–63.2, P = 0.01), anti–SS–A/Ro52 (β = 15.8, 95% CI: 1.2–198.6, P = 0.03), and anti-CENP-B antibodies (β = 31.2, 95% CI: 1.8–565.9 P = 0.02) were associated with TgAbs.
Conclusion
Latent thyroid autoimmunity is not rare. Environmental, genetic, and immunological factors as well as ancestry are associated risk factors. These results would facilitate the implementation of screening strategies in order to provide timely diagnosis and treatment.
Keywords: Euthyroidism, Anti-peroxidase autoantibodies, Anti-thyroglobulin autoantibodies, Autoimmune thyroid disease, Latent autoimmunity.
Highlights
-
•
Latent autoimmunity is common in colombian eutyrhoid subjects.
-
•
Autoimmune diseases and familial autimmunity are associated to thyroid autoimmunity.
-
•
Tobacco, cofee compsumption and VitD insufficiency influence thyroid autoimmunity.
-
•
Early recognition of latent autoimmunity allows prediction of overt autoimmunity.
1. Introduction
Hypothyroidism is an endocrine disease characterized by the presence of elevated serum levels of Thyroid-Stimulating Hormone (TSH) and low levels of free thyroxine (FT4). This disorder is described in up to 10% of the population and its etiology originates mainly from autoimmunity, particularly Hashimoto Thyroiditis (HT) [1]. One of the main clinical challenges relies on the absence of specific symptoms, therefore many individuals are affected for this disease without knowing it. This high prevalence of undiagnosed hypothyroidism leads to a high rate of associated comorbidities, including cardiovascular disease, hypercholesterolemia, atrial fibrillation, and depression [[2], [3], [4]].
Hyperthyroidism, in turn, is the opposite of hypothyroidism. In this case, the levels of TSH secreted by adenohypophysis are suppressed due to the high secretion of FT4 by the thyroid gland [5]. Its prevalence varies between 0.8% in Europe [6], to 1.3% in the United states [7]. Unlike hypothyroidism, the prevalence of asymptomatic patients is low. Therefore, the symptoms are clearly defined at the beginning of the disease. Excess of thyroid hormone produces a wide variety of symptoms such as fatigue, sweating, tremor, anxiety, disturbed sleep, palpitations, weight loss, and heat intolerance [5]. The main nosology of hyperthyroidism is autoimmunity being Graves’ disease (GD) the most important cause [5].
The prevalence of autoimmune thyroid disease (AITD) is around 5% [8], and the prevalence of thyroid autoantibodies in healthy subjects may be even higher [9]. This data is relevant, since the presence of thyroid autoantibodies could be a predictive tool of thyroid failure in genetically predisposed subjects, and in those individuals exposed to some environmental agents. In view of the high prevalence of AITD, many studies have sought to determine the prevalence of thyroid autoimmunity before the thyroid disease becomes overt by documenting the presence of thyroid autoantibodies in euthyroid individuals [7,[10], [11], [12], [13], [14], [15]]. The reports from these studies ranged from the NHANES III study with a prevalence of 11.3% and 10.4% for anti-peroxidase antibodies (TPOAbs) and anti-thyroglobulin antibodies (TgAbs) respectively, to a prevalence of 13.1% in the Danish population. This is significant considering the importance of the thyroid autoantibodies as predictors of AITD [16,17]. The Whickham study reported a 2.1 risk per year in euthyroid subjects with TPOAbs of developing AITD [16].
Detection of risk factors for hypo- or hyperthyroidism allows the introduction of new approaches for primary prevention strategies. However, the risk factors influencing the appearance of thyroid autoimmunity are not fully understood. Therefore, given the high prevalence of AITD in areas with iodine sufficiency and the risk of comorbidity including polyautoimmunity (PolyA), the identification of thyroid autoimmunity in the general population becomes of high interest [[2], [3], [4],[18], [19], [20], [21]]. Several studies have shown female:male ratios between 2:1 to 3:1 [7,11] and an age-associated increase in thyroid autoantibodies [22]. Genetic factors play also a role. A first approach to investigate their presence could be evaluated by analyzing the family history of AITD and other autoimmune diseases (ADs) [21]. Concerning environmental factors (i.e., autoimmune ecology), iodine, infections, vitamin D (vitD) deficiency, stress, drugs, and tobacco have been widely described in AITD [23]. In the current study we aimed to investigate the prevalence of thyroid autoantibodies in euthyroid individuals and the factors associated with latent thyroid autoimmunity in such individuals.
2. Methods
2.1. Population
Three hundred euthyroid Colombian individuals belonging to different socioeconomic strata as well as level of education and occupation participated in this study. The sample size was obtained by randomized stratified sampling of a population of 1335 individuals paired by age and gender using Epidat®, version 4.1. A confidence level of 95%, a power of 80%, and an estimated 11% prevalence of autoantibodies in euthyroid patients was obtained with a minimum sample size of 300 subjects (Fig. 1) [7]. None of the participants was on levothyroxine treatment, were under 18, presented undefined thyroid disease, history of hypothyroidism/hyperthyroidism, previous thyroid disease during pregnancy, had thyroid surgery nor history of thyroid cancer.
Fig. 1.
Flow Diagram of Patient Recruitment.
2.2. Sociodemographic and clinical factors
Sociodemographic information such as age, gender, ethnicity, socio-economic stratum, and place of birth was obtained as previously described [20,24]. Additionally, subjects were asked about clinical antecedents such as contraceptive methods, comorbidities, obstetric, surgical, and pharmacological antecedents. Furthermore, habits such as consumption of coffee and tobacco, occupational and home exposures to toxic agents were also recorded [20,24] as were symptoms related to thyroid dysfunction and the presence of hypo or hyperthyroidism [1,5]. The clinical evaluation and data collection were done at the CREA between July and November of 2017. The clinical evaluation included the assessment of weight, height, abdominal perimeter, blood pressure, and reflex assessment.
2.3. Laboratory measurements
The thyroid function was evaluated by measuring TSH and FT4 serum levels. In addition, vitD levels, TPOAbs, TgAbs, and anti-TSH receptor antibodies (TrAbs) were detected as markers for thyroid autoimmunity. Furthermore, a panel of 23 autoantibodies were evaluated. TSH, FT4, and vitD levels were measured by electroquimioluminiscence using the following thresholds: TSH (0.3–4.5 μIU/mL), FT4 (5.2–12.7 UI/dL), and vitD, a level above 30 ng/mL was considered to be sufficiency; below 30 ng/mL, insufficiency; and below 20 ng/mL, deficiency [25].
TPOAbs, TgAbs, rheumatoid factor (RF) IgM, the anti-citrullinated protein antibodies (ACPA) IgG, the anti-cardiolipin antibodies (ACA) IgM and IgG, the Beta 2-glycoprotein (β2GP1) antibodies IgM and IgG were measured using indirect ELISA (Inova Diagnostics, Inc. San Diego, CA, USA), while TrAbs were measured with competitive ELISA (Eagle Biosciences, Nashua, NH, USA). The remaining 17 autoantibodies were evaluated by immunoblot assay (double-stranded DNA [dsDNA], nucleosomes, histones, SmD1, proliferating cell nuclear antigen [PCNA], P0, Anti-Sjögren’s syndrome type A [SS-A/Ro60], SS-A/Ro52, Anti-Sjögren’s syndrome type B [SS-B/La], centromere autoantigen B [CENP-B], Scl70, U1-snRNP, Anti-mitochondrial M2 antibody [AMA M2], Jo-1, PM-Scl, Mi-2, Ku) using IMTEC ANA-LIA Maxx from Human diagnostics, Magdeburg Germany. Latent autoimmunity was defined as presence of autoantibodies without fulfillment of international classification criteria [26].
2.4. Statistical analysis
Categorical variables were analyzed by frequencies, and quantitative continuous variables were expressed as mean and standard deviations (SD) and in the median and interquartile ranges (IQR) [27]. To assess associations between outcomes of interest and other variables, the χ2, Kruskal-Wallis and Mann–Whitney U test were used. Binary Logistic regression analysis was done. Shortly, TPOAbs and TgAbs were included as dependent variables, while those variables with biological plausibility were selected as independent variables. Obtained models were tested for goodness of fit by Hosmer–Lemeshow test, and their discrimination capacity were considered relevant if c-statistic was higher than 0.7. The significance level of the study was set to 0.05. Statistical analyses were done in SPSS statistics version 2.4.
3. Results
The sociodemographic, clinical, and thyroid variables are shown in Table 1, Table 2. The group of subjects mainly consists of women and young people. Thyroid autoimmunity was observed in 15.3% of the cases, TPOAbs in 11.3%, and TgAbs in 2%. Both autoantibodies were described in six individuals. TrAbs were not detected in any individual.
Table 1.
Sociodemographic and clinical characteristics.
| Characteristics | n = 300 (%) |
|---|---|
| Gender | |
| Women | 287 (95.7) |
| Age | |
| Median (IQR) | 34 (27–40) |
| Ethnicity | |
| Amerindian origin | 275/292 (94.2) |
| African origin | 13/292 (4.5) |
| Native | 4/292 (1.4) |
| SES | |
| 1,2,3 | 294/298 (98.7) |
| 4,5,6 | 4/298 (1.3) |
| Comorbidities | |
| Arterial hypertension | 6 (2.0) |
| Diabetes mellitus 2 | 4 (1.3) |
| Dyslipidemia | 6 (2.0) |
| Cancer | 3/299 (1.0) |
| Abortion | 61/285 (21.4) |
| Polycystic ovary syndrome | 10/282 (3.5) |
| VitD status | |
| VitD level (IQR) | 15.9 (11.0–23.6) |
| VitD sufficiency | 25/238 (10.5) |
| VitD insufficiency | 70/238 (29.4) |
| VitD deficiency | 143/238 (60.1) |
SES: Socioeconomic status, VitD: Vitamin D.
Table 2.
Thyroid data.
| Characteristics | n = 300 (%) |
|---|---|
| Thyroid autoimmunity | |
| TPOAbs | 34 (11.3) |
| TgAbs | 6 (2.0) |
| TgAbs and TPOAbs | 6 (2.0) |
| Biological data | |
| TSH (IQR) | 2.3 (1.7–3.3) |
| FT4 (IQR) | 8.4 (7.6–9.1) |
| Clinical data | |
| Familial thyroid disease* | 38 (12.7) |
| Fatigue | 98/297 (33.0) |
| Anxiety | 80/297 (26.9) |
| Weight gain | 75/295 (25.4) |
| Weight loss | 31/298 (10.4) |
| Cold intolerance | 30/299 (10.0) |
| Heat intolerance | 24/299 (8.0) |
| Menstrual disorders | 105/278 (37.8) |
| Dry Skin | 79/298 (26.5) |
| Diaphoresis | 34 (11.3) |
| Alopecia | 81 (27.0) |
| Constipation | 83 (27.7) |
| Voice Alteration | 14 (4.7) |
| Fullness of throat | 37 (12.3) |
| Bradilalia, Bradipsiquia | 34 (11.3) |
| Hyporeflexia | 13/297 (4.4) |
| Tremor | 30 (10.0) |
| Palpitations | 50 (10.7) |
| Diplopia | 18 (6.0) |
| Infertility | 9 (3.0) |
| Low libido | 37 (12.3) |
TPOAbs: Anti-peroxidase antibodies, TgAbs: Anti-thyroglobulin antibodies, TSH: Thyroid-Stimulating Hormone, FT4: Free thyroxine. First degree relatives*.
Table 3 shows habits and environmental factors. Unlike tobacco consumption, which was low, coffee consumption was very important in this population. Organic solvents were the main toxin they have been exposed throughout life, followed by using of hair dyes and exposure to wood smoke. With respect to exposure at work or home, the main working or housing areas in which these individuals were exposed to toxins were farms followed by airports and laundries. Immunological data are described in Table 4. RF, ACA IgM, and β2GP1 IgM were the most prevalent autoantibodies in these subjects. In addition, an interesting percentage of familial autoimmunity and the presence of other ADs was found.
Table 3.
Environmental characteristics.
| Characteristics | n = 300 (%) |
|---|---|
| Habits | |
| Never smoke | 232 (77.3) |
| Former smoker | 44 (14.7) |
| Active smoker | 24 (8.0) |
| 1–5 pack-year | 20 (6.7) |
| 6–15 pack-year | 2 (0.7) |
| More than 15 pack-year | 2 (0.7) |
| Never coffee | 22 (7.3) |
| Former coffee drinker | 9 (3.0) |
| Coffee drinker | 266/297 (89.6) |
| Less than a cup/day | 85/299 (28.4) |
| One cup/day | 53/298 (17.8) |
| 2–4 cups/day | 110/298 (36.9) |
| More than 4 cups/day | 19/298 (6.4) |
| Environmental exposures | |
| Organic solvents | 255 (85.0) |
| Hair dyes | 184/299 (61.3) |
| Wood smoke | 94 (31.3) |
| Psychoactive substances | 7 (2.3) |
| Pesticides | 8 (2.7) |
| Asbestos | 18 (6.0) |
| Ever live/work | |
| Farms | 41 (13.7) |
| Airports | 32 (10.7) |
| Laundry | 27 (9.0) |
| Factories | 13 (4.3) |
| Garbage deposits | 10 (3.3) |
Table 4.
Immunological data.
| Characteristics | n = 300 (%) |
|---|---|
| Familial autoimmunity | 21 (7.0) |
| Other autoimmune diseases | 9 (3.0) |
| Autoantibodies | |
| RF | 116 (38.7) |
| ACA IgM | 15 (5.0) |
| β2GP1 IgM | 13 (4.3) |
| SS-B/La | 12 (4.0) |
| SmD1 | 9 (3.0) |
| SS-A/Ro60 | 7 (2.3) |
| PM-Scl | 7 (2.3) |
| PCNA | 7 (2.3) |
| β2GP1 IgG | 5 (1.7) |
| ACPA | 3 (1.0) |
| Ku | 4 (1.3) |
| SS-A/Ro52 | 3 (1.0) |
| CENP-B | 3 (1.0) |
| U1-snRNP | 2 (0.7) |
| Mi-2 | 2 (0.7) |
| dsDNA | 1 (0.3) |
| Nucleosomes | 1 (0.3) |
RF: Rheumatoid factor, ACA: Anti-cardiolipin antibodies, β2GP1: Beta 2-glycoprotein 1 antibodies, SS-B/La: Anti-Sjögren’s syndrome type B antibodies, SS-A/Ro: Anti-Sjögren’s syndrome type A antibodies, ACPA: Anti-citrullinated protein antibodies, dsDNA: Anti-double stranded DNA antibodies, PCNA: Anti-proliferating cell nuclear antigen antibodies, Sm: Anti-Smith antibodies, RNP: Anti-ribonucleoprotein antibodies, CENP-B: Anti-centromere antibody subunit B.
The bivariate analysis showed an association between thyroid autoantibodies and familial thyroid disease (OR: 2.2, 95% CI: 1.1–5.0, P = 0.04), and low libido (OR: 2.3 95% CI: 1.1–5.2, P = 0.04). Furthermore, regarding environmental and biological factors, never smoke (OR: 2.7 95% CI: 1.1–7.1, P = 0.04), vitD insufficiency (P = 0.03), and a greater number of years of exposure to wood smoke (P = 0.04) were associated with the presence of thyroid autoimmunity.
In a further analysis, TPOAbs and TgAbs were studied separately. Familial thyroid disease (OR: 2.8 95% CI: 1.2–6.2, P = 0.01), never smoke (OR: 2.9 95% CI: 1.1–8.6, P = 0.04), and low libido (OR: 2.9 95% CI: 1.3–6.5, P = 0.009) were associated with anti-TPO positivity. Moreover, an association between TSH levels and TPOAbs was observed (Fig. 2). An association of TgAbs with the presence of menstrual irregularity (OR: 0.3 95% CI: 0.08–0.9, P = 0.022) and SS-A/Ro52 (OR: 13 95% CI: 1.1–154, P = 0.009) was observed. No association between TSH levels and TgAbs was seen despite a suggestive trend (Fig. 3).
Fig. 2.
There was a significant association between TSH levels and TPOAbs levels. An increase in TSH levels in same proportion to TPOAbs levels was observed.
Fig. 3.
Although there was not statistically significant association between the TSH levels and levels of TgAbs, a trend in the influences of these autoantibodies on TSH levels was observed.
The multivariate analysis included a logistic regression with the presence of thyroid autoantibodies as dependent variable. In this analysis, the history of familial thyroid disease, the presence of other ADs, never smoke, drinking more than 4 cups of coffee per day, and low libido were significantly associated with the presence of thyroid autoimmunity (Table 5).
Table 5.
Factors associated with thyroid autoantibodies.
| Characteristic | β | 95% CI | P | |
|---|---|---|---|---|
| Familial thyroid disease | 3.384 | 1.200 | 9.542 | 0.021 |
| Other autoimmune diseases | 10.811 | 1.603 | 72.901 | 0.014 |
| Never smoke | 6.942 | 1.586 | 30.378 | 0.010 |
| Drinking more than 4 cups of coffee | 3.776 | 1.090 | 13.075 | 0.036 |
| Low libido | 3.753 | 1.324 | 10.633 | 0.013 |
Multivariate analysis using TPOAbs as the dependent variable shows that the presence of familial thyroid disease, never smoke, drinking more than 4 cups of coffee per day, and low libido were associated with anti-TPO positivity. In addition, the presence of anti–SS–A/Ro52 and anti- Ku antibodies was associated with the presence of TPOAbs (Table 6). The multivariate analysis using the TgAbs as a dependent variable showed that african ethicity, anti–SS–A/Ro52, and anti-CENP-B antibodies were associated with TgAbs positivty (Table 7).
Table 6.
Factors associated with TPOAbs.
| Characteristic | β | 95% CI | P | |
|---|---|---|---|---|
| Familial thyroid disease | 4.894 | 1.705 | 14.049 | 0.003 |
| Never smoke | 5.428 | 1.397 | 21.090 | 0.015 |
| Drinking more than 4 cups of coffee | 3.641 | 1.015 | 13.055 | 0.047 |
| Low libido | 5.680 | 2.013 | 16.028 | 0.001 |
| SS-A/Ro52 | 36.729 | 2.453 | 549.874 | 0.009 |
| Ku | 10.235 | 1.040 | 100.734 | 0.046 |
TPOAbs: Anti-peroxidase antibodies, SS-A/Ro: Anti-Sjögren’s syndrome type A antibodies.
Table 7.
Factors associated with TgAbs.
| Characteristic | β | 95% CI | P | |
|---|---|---|---|---|
| African ancestry | 10.500 | 1.745 | 63.196 | 0.010 |
| β2GP1 IgG | 7.875 | 0.761 | 81.522 | 0.084 |
| SS-A/Ro52 | 15.750 | 1.249 | 198.573 | 0.033 |
| CENP-B | 31.500 | 1.753 | 565.945 | 0.019 |
TgAbs: Anti-thyroglobulin antibodies, β2GP1: Beta 2-glycoprotein 1 antibodies, SS-A/Ro: Anti-Sjögren’s syndrome type A antibodies, CENP-B: Centromere autoantigen B antibodies.
4. Discussion
Environmental factors (i.e., autoimmune ecology) that impair the immune response and give rise to the recognition of thyroid self-antigens in susceptible individuals is pivotal to the development of AITD. This causes an autoimmune response which eventually culminates in overt disease. All these steps are immersed in the natural history of the disease as it goes through a series of states from the pre-pathogenic phase, which is asymptomatic, to the pathogenic period, characterized by the presence of symptoms [28]. Considering the current evidence, this study sought to confirm the role of some factors which had previously been studied in relation to the presence of thyroid autoantibodies as well as to find new ones that might contribute to the understanding of latent AITD.
The evaluation of these autoantibodies is relevant because they represent the highest risk of developing AITD [7,16]. An annual risk of 2.1% per year of developing hypothyroidism in the presence of thyroid autoantibodies has been documented [7]. Spite of diverse heritability, our study showed a prevalence of TPOAbs and TgAbs similar to other studies [15] (Table 8) [7,[10], [11], [12], [13], [14],29].
Table 8.
Prevalence of thyroid autoantibodies.
| Publication date | Geographic location | Number of cases |
Female prevalence n (%) | Male prevalence n (%) | Ref | |
|---|---|---|---|---|---|---|
| Female | Male | |||||
| 1990 | United Kingdom | 698 | – | 124 (17.8) | – | [13] |
| 1993 | Japan | 1134 | 2896 | 133 (11.7) | 167 (5.7) | [12] |
| 1995 | United Kingdom | 942 | 762 | 248 (26.4) | 67 (8.8) | [11] |
| 2000 | Norway | 582 | 360 | 81 (13.9) | 10 (2.8) | [14] |
| 2002 | United States | 8619 | 7914 | 1258 (14.6) | 633 (8.0) | [7] |
| 2003 | Germany | 455 | 840 | 117 (25.8) | 120 (14.4) | [10] |
| 2010 | Netherlands | 1216 | 1178 | 144 (11.9) | 56 (4.8) | [30] |
One relevant finding was the relationship between autoantibodies and ethnicity. Although African ethnicity was only observed in 4.5%, it could act as a risk factor for developing thyroid autoimmunity, particularly, TgAbs. These results are different from other studies, where AITD was lower in African people [7,30]. In fact, a study done on military personnel in the United States, where the prevalence of AITD by ethnicity was assessed, showed that the incidence of HT was highest in whites as compared to blacks unlike GD, where the incidence was higher in the latter population [31]. Thus, given the link between the thyroglobulin locus and GD reported in some studies [32,33], it is tempting to speculate that the association found in our black population may be caused by genetic susceptibility and the presence of thyroid autoantibodies [34]. However, the studies that report this association come from non-black population groups; thus, further studies are warranted to define the influence of this locus on AITD in black population.
The environmental factors to which this population is exposed could be crucial for the development of thyroid autoimmunity [23]. Smoking has a significant effect on thyroid function [35]. Some authors have observed the presence of thyroid autoantibodies with the cessation of smoking [36]. This means that tobacco could be protective for AITD in current-smokers [37]. The first epidemiological descriptions of the effect of tobacco and the presence of thyroid autoantibodies and hypothyroidism were addressed in the NHANES III survey which showed that active smokers have lower TSH levels compared to non-smokers [37]. In addition, other studies have provided new evidence regarding the role of tobacco in AITD showing that up to 85% of ex-smokers had higher rates of hypothyroidism attributable to cessation of smoking [36]. This information opens a debate on a parodoxical effect of tobacco on thyroid autoimmunity. Several experimental studies have shown that some components of tobacco such as the alkaloids – nicotine and anatabine – exhibit an immunomodulatory effect. Nicotine is widely known for its anti-inflammatory effects [38]. This mechanism is mediated by the link between nicotine and its receptor. The link is expressed not only centrally and peripherally in pre-ganglionic fibers and neuromuscular synapses, but also in immune cells such as macrophages, dendritic cells, and CD4+ T-cells. The expression of the nicotinic receptor in these immune cells has been studied as a therapeutic target in order to enhance its anti-inflammatory effect [39].
Another component of tobacco which has been object of recent studies is anatabine. This alkaloid, like nicotine, has anti-inflammatory properties that could influence the control of an immune response against the thyroid. However, it is not associated with the toxicity and addiction rates shown with nicotine. Also, it has a longer plasma half-life [40,41]. The first studies of anatabine were done on murine models and showed that the mice exposed to this alkaloid had a lower incidence and severity of thyroiditis (RR 0.59, P = 0.0174) [42]. This study showed a reduction in the immune response mediated by thyroid autoantibodies (i.e., TgAbs) and a control of the macrophage production of inducible nitric oxide synthase and cyclooxygenase 2 [42]. The previous results were confirmed in clinical trial in which anatabine decreased thyroid autoimmunity [43].
In addition, the presence of cyanide in cigarette smoke and metabolized to thiocyanate could be associated with a mild immunomodulatory response given the interference of thiocyanate in the transportation and uptake of iodine [37,44]. Therefore, the preparation of screening strategies for the population is necessary in order to evaluate the presence of thyroid autoantibodies in patients at risk of developing AITD, and who have recently abandoned tobacco.
The relationship between vitD levels and autoimmunity is widely known since low levels are associated with the risk of developing ADs, and once the AD is overt, the low levels of vitD have been associated with disease activity [45]. The results of our study confirm the association between low levels of VitD and thyroid autoimmunity [46,47]. However, the prevalence of individuals with vitD insufficiency should be considered a public health problem and not exclusively a matter of ADs [48].
Despite the extensive study of environmental factors associated with AITD, the effect of coffee has been poorly studied. The results of this study showed an association between the presence of thyroid autoimmunity and coffee consumption, especially for those consuming more than 4 cups per day. With respect to these results, it could be presumed that the consumption of this amount of coffee may encourage the release of thyroglobulin as previously described [49] thus triggering an autoimmune response against this antigen. However, this is controversial since in other reports the effect of caffeine was protective [50]. This study documented a strong association between the presence of familial autoimmune disease and PolyA and the presence of thyroid autoantibodies. These are validated by different studies that have reported a heritability between 0.54 and 0.66 for the presence of thyroid autoantibodies [51].
5. Conclusions
The prevalence and associated factors of latent thyroid autoimmunity were determined in a sample of Colombian population. The results from the present study will facilitate the implementation of screening strategies in order to provide timely diagnosis and treatment. For now, there is still a lack of genetic studies that proffer in the genetic cause of AITD. The study of exposures evaluated in this study was carried out through a questionnaire. In that sense, it is necessary to study this type of exposition through the analysis of exposome.
Funding
This work was supported by Universidad del Rosario (ABN-011).
Conflict of interest
None.
Acknowledgments
We thank all the members of the CREA for fruitful discussions.
References
- 1.Chaker L., Bianco A.C., Jonklaas J., Peeters R.P. Hypothyroidism. Lancet. 2017;390:1550–1562. doi: 10.1016/S0140-6736(17)30703-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Duntas L.H. Thyroid disease and lipids. Thyroid. 2002;12:287–293. doi: 10.1089/10507250252949405. [DOI] [PubMed] [Google Scholar]
- 3.Cappola A.R., Ladenson P.W. Hypothyroidism and atherosclerosis. J. Clin. Endocrinol. Metab. 2003;88:2438–2444. doi: 10.1210/jc.2003-030398. [DOI] [PubMed] [Google Scholar]
- 4.Parle J.V., Maisonneuve P., Sheppard M.C., Boyle P., Franklyn J.A. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358:861–865. doi: 10.1016/S0140-6736(01)06067-6. [DOI] [PubMed] [Google Scholar]
- 5.De Leo S., Lee S.Y., Braverman L.E. Hyperthyroidism. Lancet. 2016;388:906–918. doi: 10.1016/S0140-6736(16)00278-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Garmendia Madariaga A., Santos Palacios S., Guillén-Grima F., Galofré J.C. The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J. Clin. Endocrinol. Metab. 2014;99:923–931. doi: 10.1210/jc.2013-2409. [DOI] [PubMed] [Google Scholar]
- 7.Hollowell J.G., Staehling N.W., Flanders W.D., Hannon W.H., Gunter E.W., Spencer C.A., Braverman L.E. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): national health and nutrition examination survey (NHANES III) J. Clin. Endocrinol. Metab. 2002;87:489–499. doi: 10.1210/jcem.87.2.8182. [DOI] [PubMed] [Google Scholar]
- 8.Jacobson D.L., Gange S.J., Rose N.R., Graham N.M.H. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol. 1997;84:223–243. doi: 10.1006/clin.1997.4412. [DOI] [PubMed] [Google Scholar]
- 9.Pearce S.H.S., Leech N.J. Toward precise forecasting of autoimmune endocrinopathy. J. Clin. Endocrinol. Metab. 2004;89:544–547. doi: 10.1210/jc.2003-032142. [DOI] [PubMed] [Google Scholar]
- 10.Zöphel K., Saller B., Wunderlich G., Grüning T., Koch R., Wilde J., Mann K., Franke W.-G. Autoantibodies to thyroperoxidase (TPOAb) in a large population of euthyroid subjects: implications for the definition of TPOAb reference intervals. Clin. Lab. 2003;49:591–600. http://www.ncbi.nlm.nih.gov/pubmed/14651330 [PubMed] [Google Scholar]
- 11.Vanderpump M.P., Tunbridge W.M., French J.M., Appleton D., Bates D., Clark F., Grimley Evans J., Hasan D.M., Rodgers H., Tunbridge F. The incidence of thyroid disorders in the community: a twenty-year follow-up of the whickham survey. Clin. Endocrinol. (Oxf). 1995;43:55–68. doi: 10.1111/j.1365-2265.1995.tb01894.x. [DOI] [PubMed] [Google Scholar]
- 12.Konno N., Yuri K., Taguchi H., Miura K., Taguchi S., Hagiwara K., Murakami S. Screening for thyroid diseases in an iodine sufficient area with sensitive thyrotrophin assays, and serum thyroid autoantibody and urinary iodide determinations. Clin. Endocrinol. (Oxf). 1993;38:273–281. doi: 10.1111/j.1365-2265.1993.tb01006.x. [DOI] [PubMed] [Google Scholar]
- 13.Prentice L.M., Phillips D.I., Sarsero D., Beever K., McLachlan S.M., Smith B.R. Geographical distribution of subclinical autoimmune thyroid disease in Britain: a study using highly sensitive direct assays for autoantibodies to thyroglobulin and thyroid peroxidase. Acta Endocrinol. (Copenh). 1990;123:493–498. doi: 10.1530/acta.0.1230493. [DOI] [PubMed] [Google Scholar]
- 14.Bjoro T., Holmen J., Krüger O., Midthjell K., Hunstad K., Schreiner T., Sandnes L., Brochmann H. Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The Health Study of Nord-Trondelag (HUNT) Eur. J. Endocrinol. 2000;143:639–647. doi: 10.1530/eje.0.1430639. [DOI] [PubMed] [Google Scholar]
- 15.Pedersen I.B., Knudsen N., Jørgensen T., Perrild H., Ovesen L., Laurberg P. Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency. Clin. Endocrinol. (Oxf). 2003;58:36–42. doi: 10.1046/j.1365-2265.2003.01633.x. [DOI] [PubMed] [Google Scholar]
- 16.Tunbridge W.M., Evered D.C., Hall R., Appleton D., Brewis M., Clark F., Evans J.G., Young E., Bird T., Smith P.A. The spectrum of thyroid disease in a community: the Whickham survey. Clin. Endocrinol. (Oxf). 1977;7:481–493. doi: 10.1111/j.1365-2265.1977.tb01340.x. [DOI] [PubMed] [Google Scholar]
- 17.Li Y., Teng D., Shan Z., Teng X., Guan H., Yu X., Fan C., Chong W., Yang F., Dai H., Gu X., Yu Y., Mao J., Zhao D., Li J., Chen Y., Yang R., Li C., Teng W. Antithyroperoxidase and antithyroglobulin antibodies in a five-year follow-up survey of populations with different iodine intakes. J. Clin. Endocrinol. Metab. 2008;93:1751–1757. doi: 10.1210/jc.2007-2368. [DOI] [PubMed] [Google Scholar]
- 18.Sheu J.-J., Kang J.-H., Lin H.-C., Lin H.-C. Hyperthyroidism and risk of ischemic stroke in young adults: a 5-year follow-up study. Stroke. 2010;41:961–966. doi: 10.1161/STROKEAHA.109.577742. [DOI] [PubMed] [Google Scholar]
- 19.Ross D.S., Neer R.M., Ridgway E.C., Daniels G.H. Subclinical hyperthyroidism and reduced bone density as a possible result of prolonged suppression of the pituitary-thyroid axis with L-thyroxine. Am. J. Med. 1987;82:1167–1170. doi: 10.1016/0002-9343(87)90219-1. [DOI] [PubMed] [Google Scholar]
- 20.Franco J.-S., Amaya-Amaya J., Molano-González N., Caro-Moreno J., Rodríguez-Jiménez M., Acosta-Ampudia Y., Mantilla R.D., Rojas-Villarraga A., Anaya J.-M. Autoimmune thyroid disease in Colombian patients with systemic lupus erythematosus. Clin. Endocrinol. (Oxf). 2015;83:943–950. doi: 10.1111/cen.12662. [DOI] [PubMed] [Google Scholar]
- 21.Anaya J.-M. The autoimmune tautology. A summary of evidence. Jt. Bone Spine. 2017;84:251–253. doi: 10.1016/j.jbspin.2016.11.012. [DOI] [PubMed] [Google Scholar]
- 22.Mariotti S., Sansoni P., Barbesino G., Caturegli P., Monti D., Cossarizza A., Giacomelli T., Passeri G., Fagiolo U., Pinchera A. Thyroid and other organ-specific autoantibodies in healthy centenarians. Lancet (London, England) 1992;339:1506–1508. doi: 10.1016/0140-6736(92)91265-a. [DOI] [PubMed] [Google Scholar]
- 23.Brent G.A. Environmental exposures and autoimmune thyroid disease. Thyroid. 2010;20:755–761. doi: 10.1089/thy.2010.1636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Franco J.-S., Molano-González N., Rodríguez-Jiménez M., Acosta-Ampudia Y., Mantilla R.D., Amaya-Amaya J., Rojas-Villarraga A., Anaya J.-M. The coexistence of antiphospholipid syndrome and systemic lupus erythematosus in Colombians. PLoS One. 2014;9 doi: 10.1371/journal.pone.0110242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Vásquez-Awad D., Cano-Gutiérrez C.A., Gómez-Ortiz A., González M. Ángel, Guzmán-Moreno R., Martínez-Reyes J.I., Rosero-Olarte O., Rueda-Beltz C., Acosta-Reyes J.L. Vitamina D. Consenso colombiano de expertos. Rev. Med. 2017;39:140–157. [Google Scholar]
- 26.Anaya J.-M., Restrepo-Jiménez P., Rodríguez Y., Rodríguez-Jiménez M., Acosta-Ampudia Y., Monsalve D.M., Pacheco Y., Ramírez-Santana C., Molano-González N., Mantilla R.D. Sjögren’s syndrome and autoimmune thyroid disease: two sides of the same coin. Clin. Rev. Allergy Immunol. 2019;56:362–374. doi: 10.1007/s12016-018-8709-9. [DOI] [PubMed] [Google Scholar]
- 27.Rojas M., Rodriguez Y., Pacheco Y., Zapata E., Monsalve D.M., Mantilla R.D., Rodríguez-Jimenez M., Ramírez-Santana C., Molano-González N., Anaya J.-M. Resilience in women with autoimmune rheumatic diseases. Jt. Bone Spine. 2018;85:715–720. doi: 10.1016/j.jbspin.2017.12.012. [DOI] [PubMed] [Google Scholar]
- 28.Tunbridge W.M., Brewis M., French J.M., Appleton D., Bird T., Clark F., Evered D.C., Evans J.G., Hall R., Smith P., Stephenson J., Young E. Natural history of autoimmune thyroiditis. Br. Med. J. 1981;282:258–262. doi: 10.1136/bmj.282.6260.258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Roos A., Links T.P., de Jong-van den Berg L.T.W., Gans R.O.B., Wolffenbuttel B.H.R., Bakker S.J.L. Thyroid peroxidase antibodies, levels of thyroid stimulating hormone and development of hypothyroidism in euthyroid subjects. Eur. J. Intern. Med. 2010;21:555–559. doi: 10.1016/j.ejim.2010.09.001. [DOI] [PubMed] [Google Scholar]
- 30.Burek C.L., Rose N.R., Guire K.E., Hoffman W.H. Thyroid autoantibodies in black and in white children and adolescents with type 1 diabetes mellitus and their first degree relatives. Autoimmunity. 1990;7:157–167. doi: 10.3109/08916939008993388. [DOI] [PubMed] [Google Scholar]
- 31.McLeod D.S.A., Caturegli P., Cooper D.S., Matos P.G., Hutfless S. Variation in rates of autoimmune thyroid disease by race/ethnicity in US military personnel. J. Am. Med. Assoc. 2014;311:1563–1565. doi: 10.1001/jama.2013.285606. [DOI] [PubMed] [Google Scholar]
- 32.Tomer Y., Ban Y., Concepcion E., Barbesino G., Villanueva R., Greenberg D.A., Davies T.F. Common and unique susceptibility loci in Graves and Hashimoto diseases: results of whole-genome screening in a data set of 102 multiplex families. Am. J. Hum. Genet. 2003;73:736–747. doi: 10.1086/378588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Sakai K., Shirasawa S., Ishikawa N., Ito K., Tamai H., Kuma K., Akamizu T., Tanimura M., Furugaki K., Yamamoto K., Sasazuki T. Identification of susceptibility loci for autoimmune thyroid disease to 5q31-q33 and Hashimoto’s thyroiditis to 8q23-q24 by multipoint affected sib-pair linkage analysis in Japanese. Hum. Mol. Genet. 2001;10:1379–1386. doi: 10.1093/hmg/10.13.1379. [DOI] [PubMed] [Google Scholar]
- 34.Tomer Y., Greenberg D.A., Concepcion E., Ban Y., Davies T.F. Thyroglobulin is a thyroid specific gene for the familial autoimmune thyroid diseases. J. Clin. Endocrinol. Metab. 2002;87:404–407. doi: 10.1210/jcem.87.1.8291. [DOI] [PubMed] [Google Scholar]
- 35.Vestergaard P. Smoking and thyroid disorders-a meta-analysis. Eur. J. Endocrinol. 2002;146:153–161. doi: 10.1530/eje.0.1460153. [DOI] [PubMed] [Google Scholar]
- 36.Carlé A., Bülow Pedersen I., Knudsen N., Perrild H., Ovesen L., Banke Rasmussen L., Jørgensen T., Laurberg P. Smoking cessation is followed by a sharp but transient rise in the incidence of overt autoimmune hypothyroidism - a population-based, case-control study. Clin. Endocrinol. (Oxf). 2012;77:764–772. doi: 10.1111/j.1365-2265.2012.04455.x. [DOI] [PubMed] [Google Scholar]
- 37.Belin R.M., Astor B.C., Powe N.R., Ladenson P.W. Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Surve. J. Clin. Endocrinol. Metab. 2004;89:6077–6086. doi: 10.1210/jc.2004-0431. [DOI] [PubMed] [Google Scholar]
- 38.Tracey K.J. Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Investig. 2007;117:289–296. doi: 10.1172/JCI30555. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Bencherif M., Lippiello P.M., Lucas R., Marrero M.B. Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell. Mol. Life Sci. 2011;68:931–949. doi: 10.1007/s00018-010-0525-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Karaconji I.B. Facts about nicotine toxicity. Arh. Hig. Rada. Toksikol. 2005;56:363–371. http://www.ncbi.nlm.nih.gov/pubmed/16370520 [PubMed] [Google Scholar]
- 41.Benowitz N.L. Nicotine addiction. N. Engl. J. Med. 2010;362:2295–2303. doi: 10.1056/NEJMra0809890. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Caturegli P., De Remigis A., Ferlito M., Landek-Salgado M.A., Iwama S., Tzou S.-C., Ladenson P.W. Anatabine ameliorates experimental autoimmune thyroiditis. Endocrinology. 2012;153:4580–4587. doi: 10.1210/en.2012-1452. [DOI] [PubMed] [Google Scholar]
- 43.Schmeltz L.R., Blevins T.C., Aronoff S.L., Ozer K., Leffert J.D., Goldberg M.A., Horowitz B.S., Bertenshaw R.H., Troya P., Cohen A.E., Lanier R.K., Wright C. Anatabine supplementation decreases thyroglobulin antibodies in patients with chronic lymphocytic autoimmune (Hashimoto’s) thyroiditis: a randomized controlled clinical trial. J. Clin. Endocrinol. Metab. 2014;99:E137–E142. doi: 10.1210/jc.2013-2951. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Pearce E.N., Braverman L.E. Environmental pollutants and the thyroid. Best Pract. Res. Clin. Endocrinol. Metabol. 2009;23:801–813. doi: 10.1016/j.beem.2009.06.003. [DOI] [PubMed] [Google Scholar]
- 45.Dankers W., Colin E.M., van Hamburg J.P., Lubberts E. Vitamin D in autoimmunity: molecular mechanisms and therapeutic potential. Front. Immunol. 2016;7:697. doi: 10.3389/fimmu.2016.00697. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Mazokopakis E.E., Kotsiris D.A. Hashimoto’s autoimmune thyroiditis and vitamin D deficiency. Current aspects. Hellenic J. Nucl. Med. 2014;17:37–40. doi: 10.1967/s002449910120. [DOI] [PubMed] [Google Scholar]
- 47.Misharin A., Hewison M., Chen C.-R., Lagishetty V., Aliesky H.A., Mizutori Y., Rapoport B., McLachlan S.M. Vitamin D deficiency modulates Graves’ hyperthyroidism induced in BALB/c mice by thyrotropin receptor immunization. Endocrinology. 2009;150:1051–1060. doi: 10.1210/en.2008-1191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Welsh P., Peters M.J.L., Sattar N. Vitamin D insufficiency. N. Engl. J. Med. 2011;364 doi: 10.1056/NEJMc1101911. 1378–9; author reply 1380. [DOI] [PubMed] [Google Scholar]
- 49.Clozel M., Branchaud C.L., Tannenbaum G.S., Dussault J.H., Aranda J.V. Effect of caffeine on thyroid and pituitary function in newborn rats. Pediatr. Res. 1983;17:592–595. doi: 10.1203/00006450-198307000-00015. [DOI] [PubMed] [Google Scholar]
- 50.Spindel E., Arnold M., Cusack B., Wurtman R.J. Effects of caffeine on anterior pituitary and thyroid function in the rat. J. Pharmacol. Exp. Ther. 1980;214:58–62. http://www.ncbi.nlm.nih.gov/pubmed/6104718 [PubMed] [Google Scholar]
- 51.Medici M., Porcu E., Pistis G., Teumer A., Brown S.J., Jensen R.A., Rawal R., Roef G.L., Plantinga T.S., Vermeulen S.H., Lahti J., Simmonds M.J., Husemoen L.L.N., Freathy R.M., Shields B.M., Pietzner D., Nagy R., Broer L., Chaker L., Korevaar T.I.M., Plia M.G., Sala C., Völker U., Richards J.B., Sweep F.C., Gieger C., Corre T., Kajantie E., Thuesen B., Taes Y.E., Visser W.E., Hattersley A.T., Kratzsch J., Hamilton A., Li W., Homuth G., Lobina M., Mariotti S., Soranzo N., Cocca M., Nauck M., Spielhagen C., Ross A., Arnold A., van de Bunt M., Liyanarachchi S., Heier M., Grabe H.J., Masciullo C., Galesloot T.E., Lim E.M., Reischl E., Leedman P.J., Lai S., Delitala A., Bremner A.P., Philips D.I.W., Beilby J.P., Mulas A., Vocale M., Abecasis G., Forsen T., James A., Widen E., Hui J., Prokisch H., Rietzschel E.E., Palotie A., Feddema P., Fletcher S.J., Schramm K., Rotter J.I., Kluttig A., Radke D., Traglia M., Surdulescu G.L., He H., Franklyn J.A., Tiller D., Vaidya B., de Meyer T., Jørgensen T., Eriksson J.G., O’Leary P.C., Wichmann E., Hermus A.R., Psaty B.M., Ittermann T., Hofman A., Bosi E., Schlessinger D., Wallaschofski H., Pirastu N., Aulchenko Y.S., de la Chapelle A., Netea-Maier R.T., Gough S.C.L., Meyer Zu Schwabedissen H., Frayling T.M., Kaufman J.-M., Linneberg A., Räikkönen K., Smit J.W.A., Kiemeney L.A., Rivadeneira F., Uitterlinden A.G., Walsh J.P., Meisinger C., den Heijer M., Visser T.J., Spector T.D., Wilson S.G., Völzke H., Cappola A., Toniolo D., Sanna S., Naitza S., Peeters R.P. Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genet. 2014;10 doi: 10.1371/journal.pgen.1004123. [DOI] [PMC free article] [PubMed] [Google Scholar]