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Abstract

Background

Recent studies suggested a potential association between both overt and subclinical hypothyroidism and migraine. Aims of this study were to estimate the comorbidity of migraine in patients with subclinical hypothyroidism and to evaluate associated clinical characteristics.

Methods

Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine.

Results

The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs. 13%, p < 0.001; OR 5.80; 95% CI = 3.35–10.34). Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls (p < 0.001 and p = 0.010, respectively). Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine. Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine (p = 0.005).

Conclusions

Our data suggest that migraine is more frequent in patients with subclinical hypothyroidism in respect to controls. Further studies are needed in order to confirm this association.

Keywords

Subclinical hypothyroidism migraine migraine without aura migraine with aura autoimmune diseases

Introduction

Migraine is a common disorder in the general population and affects approximately 12% of adults in western countries, imposing a great burden on the patient, the family and society (1). In addition, migraine patients show important comorbidities with several diseases such as myocardial infarction, stroke, sub-clinical vascular brain lesions, patent foramen ovale, hypertension, epilepsy, asthma, and psychiatric disorders (2,3).

Recently, increased attention has been devoted to the potential association between migraine and thyroid function, with conflicting results. In 1991, the first report on this topic found that patients with chronic headache had a comorbid hyperthyroidism, while none had hypothyroidism (4). More recently, some studies showed that migraine is associated with an increased risk for the development of both overt and subclinical hypothyroidism (SCH) (5 –7). In patients with pediatric migraine, an increased risk of SCH has also been reported (8). At present, the underlying mechanisms of this potential association are unclear.

SCH is a condition characterized by mildly increased thyroid-stimulating hormone (TSH) concentrations, with normal values of free triiodothyronine (fT3) and free thyroxine (fT4). In population-based studies, the prevalence of SCH ranges from 4–15%, and the diagnosis is more common in women (9). In the adult population, SCH is associated with a risk of progression to overt hypothyroidism, lipid disorders, and higher mortality due to cardiovascular diseases, probably related to a mechanism of chronic inflammation and endothelial dysfunction (10,11). The clinical manifestations of SCH are generally minor, although affected patients may show symptoms of a neuropsychiatric nature such as depression, anxiety, and memory deficits (10).

At present, few data regarding the potential association of subclinical hypothyroidism and migraine are available. A recent clinical study in adults showed that headache in patients with both overt or subclinical hypothyroidism frequently fulfills the ICHD 3 beta criteria for migraine (12). Moreover, in patients with SCH, a significant decrease in headache frequency after levothyroxine treatment was observed (13).

The principal aim of this study was to investigate the potential association between subclinical hypothyroidism and migraine in adults. In addition, we evaluated the potential association of migraine with biological markers of thyroid function and with different comorbidities.

Methods

Subjects

One hundred and fifty-one consecutive patients with SCH (24 men and 127 women, mean age 48.36 ± 15.86 years) were enrolled at the Endocrinological Clinic of the Umberto I Hospital of Torino, Italy. After an endocrinologist's visit, patients were interviewed by a neurologist trained in headaches, using the Italian version of the Structured Migraine Interview (SMI) (14). Patients were asked about recurring headaches and age of onset, and to describe the headaches attacks in terms of frequency, duration and severity, pain characteristics, localization, presence of aura, nausea/vomiting, photophobia/phonophobia, number of medication intake, triggers and alleviating factors. All patients' headaches were diagnosed according to ICHD-III beta version criteria (12). Exclusion criteria included current or previous low fT4 levels that would be considered as an overt hypothyroidism and secondary subclinical hypothyroidism. Plasmatic levels of TSH, fT3, fT4, thyroglobulin (anti-TG) and anti-peroxidase (anti-TPO) antibodies titers were measured at the diagnosis of SCH.

One hundred and fifty subjects (37 men and 113 women, mean age 50.86 ± 9.19 years) were recruited among the relatives of the patients referring at the Endocrinological Clinic of the Umberto I Hospital of Torino, and were used as the control group. Exclusion criteria for control subjects were previous or current thyroid diseases and the presence of an increased TSH concentration. Presence or absence of migraine and other headaches and their clinical characteristics were collected.

All subjects involved in the study were of Caucasian origin. For all subjects involved in the study, age, sex, body mass index (BMI), smoking, hypothyroidism-inducing medications, hypertension, and further autoimmune diseases were also collected.

Laboratory assays

All blood specimens were drawn in the morning. Thyroid function tests (TSH, fT3 and fT4 serum levels) were performed using the chemiluminescent microparticle immunoassay method (15). The normal reference range for TSH, fT3 and fT4 was 0.35–3.6 μIU/ml, 2.0–4.0 pg/ml, and 8.0–15.0 pg/ml, respectively. The reference ranges for antithyroid antibodies were as follows: Anti-TPO less than 5.61 IU/mL, anti-TG less than 4.11 IU/mL, with a sensitivity of 0.16 and 0.07, respectively.

Statistics

Statistical analyses have been performed using SPSS – version 21 (SPSS Inc., Chicago, Illinois, USA). The statistical significance of differences among the groups was assessed by the chi-square test and Fisher's exact test to compare proportions, and Student's t-test and analysis of variance (ANOVA) to compare continuous variables. The association between thyroid function and migraine was assessed estimating prevalence odds ratios (OR) with 95% confidence intervals (CIs). The ANOVA Bonferroni test or Mann-Whitney U test were also used, as appropriate. Multiple linear logistic regression, and correlation analyses were done if necessary. A p value less than < 0.05 was considered as statistically significant in all the comparisons.

Results

The demographic and clinical characteristics are summarized in Table 1. No difference in age and sex was found between cases and controls. Patients with subclinical hypothyroidism showed a higher prevalence of migraine when compared to controls (46% vs. 13%, chi square = 39.679, p < 0.001; OR 5.80; 95% confidence interval = 3.35–10.34). For the clinical subtypes of migraine, patients with SCH showed a higher prevalence of both migraine without aura and with aura in respect to controls (38% vs. 9%, chi square = 36.163, p < 0.001, OR 6.64, 95% CI 3.41–12.91; 8% vs. 4%, chi square = 6.596, p = 0.010, OR 3.50, 95% CI 1.28–9.59, respectively).

Table 1.

Clinical characteristics of patients with subclinical hypothyroidism and controls.

	Subclinical hypothyroidism (n = 151)	Controls (n = 150)	p value
Age (yrs)	48.36 ± 15.86	50.46 ± 9.19	0.161
Gender
Males	24 (15.89%)	37 (24.67%)	0.058
Females	127 (84.11%)	113 (75.33%)

Diagnosis of migraine	70 (46.36%)	19 (12.66%)	<0.001
Migraine without aura	57 (37.75%)	13 (8.66%)	<0.001
Migraine with aura	13 (8.61%)	6 (4.00%)	0.010
Age at onset of migraine (yrs)	26.70 ± 15.50	23.82 ± 13.25	0.461
Duration of migraine (yrs)	23.03 ± 18.02	19.83 ± 12.38	0.469
Intensity of migraine
Mild	1 (1.43%)	2 (10.53%)	0.081
Moderate	35 (50.00%)	6 (31.58%)
Severe	34 (48.57%)	11 (57.89%)
Headache characteristics
Pulsating	37 (52.85%)	10 (52.63%)	0.986
Unilateral	55 (78.57%)	12 (63.16%)	0.167
Nausea/vomiting	51 (72.85%)	13 (69.42%)	0.703
Photo/phonophobia	53 (75.71%)	12 (63.16%)	0.274
Migraine days per month	5.03 ± 8.10	7.30 ± 5.13	0.250

Serum concentrations of TSH were not different between patients with subclinical hypothyroidism and migraine versus patients with subclinical hypothyroidism without migraine (6.41 ± 3.05 ng/mL vs. 5.82 ±2.64 ng/mL respectively, p = 0.246), also after adjusting for age (p = 0.74). Ft3 and ft4 concentrations also did not differ between patients with subclinical hypothyroidism and comorbid migraine when compared with patients with subclinical hypothyroidism without migraine (2.71 ± 0.76 ng/mL vs. 3.79 ± 2.67 ng/mL and 5.55 ± 4.81 ng/mL vs. 6.10 ± 4.97 ng/mL, p = 0.09 and 0.529, respectively), also when we adjusted for age (p = 0.053 and p = 0.592) in Table 2. Concentrations of anti-TPO and anti-TG antibodies did not differ within the two groups (p = 0.126 and p = 0.479, respectively), and 91.4% of SCH patients with migraine and 86.1% of SCH without migraine showed the presence of at least one anti-thyroid antibody, without a significant difference between the two groups (p = 0.798).

Table 2.

Clinical characteristics of patients with subclinical hypothyroidism with and without migraine.

	SCH patients with migraine (n = 70)	SCH patients without migraine (n = 81)	p value
Age (yrs)	49.73 ± 14.88	47.19 ± 16.65	0.328
Gender
Males	9 (12.86%)	15 (18.52%)	0.342
Females	61 (87.14%)	66 (81.48%)
Age at onset (yrs)	44.46 ± 16.26	43.10 ± 16.90	0.627
Duration of disease (yrs)	4.88 ± 6.11	3.68 ± 4.81	0.192
TSH at diagnosis (mUI/ml)	6.41 ± 3.05	5.82 ± 2.64	0.246
FT3 (pg/ml)	2.71 ± 0.76	3.79 ± 2.67	0.090
FT4 (pg/ml)	5.55 ± 4.81	6.10 ± 4.97	0.529
Anti-TPO antibodies (UI/ml)	702.99 ± 1601.08	360.41 ± 713.35	0.136
Anti-TG antibodies (UI/ml)	424.00 ± 841.00	296.58 ± 644.91	0.479
No comorbid autoimmune disease	51 (72.86%)	73 (90.12%)
Other autoimmune diseases	19 (27.14%)	8 (9.88%)	0.005
Organ-specific	12 (17.14%)	4 (4.94%)
Systemic	7 (10.00%)	4 (4.94%)

We also compared the clinical characteristics of headache between migraineurs in the SCH group and migraineurs in the control group. Duration of disease, frequency, severity of the headache attacks, presence of nausea/vomiting or phonophobia/photophobia were not significantly different between the two groups. In addition, we did not find significant correlations between TSH, fT3, fT4, antibody concentrations and frequency of migraine, severity of the disease, duration of the attacks, and presence of nausea/vomiting or phonophobia/photophobia.

Several comorbid autoimmune disorders were found in patients with subclinical hypothyroidism (celiac disease, type 1 diabetes mellitus, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis). Interestingly, patients with both subclinical hypothyroidism and migraine showed a higher prevalence of other autoimmune disorders (27.1%), both organ-specific and systemic, in comparison with patients with subclinical hypothyroidism without migraine (9.9%, chi square 7.624, p = 0.005).

Discussion

We investigated the prevalence of migraine in patients with SCH, and our data clearly suggested that these patients have a significantly higher lifetime risk of developing migraine in comparison with controls. This increased risk was observed both in migraine with aura and migraine without aura patients. No significant difference in the main biochemical parameters of thyroid function was observed between SCH patients with migraine and those without migraine headaches. Finally, we found that SCH patients in comorbidity with migraine showed an increased prevalence of both organ-specific and systemic autoimmune diseases.

To the best of our knowledge, this is the first study that investigated the comorbidity between subclinical hypothyroidism and migraine in an adult population, thence additional studies are needed in order to confirm our data. The observed prevalence of migraine in the control group was as expected in the Italian population (16). In addition, our data are in agreement with a recent study reporting a high frequency of migraine in patients with both overt and subclinical hypothyroidism (5). Furthermore, our findings are in accordance with the studies showing that in young migraineurs there is an increased risk of developing subclinical hypothyroidism (8) whereas, in adults, headache disorders may be associated with an increased risk for the development of new onset hypothyroidism (7). Taken together, these findings suggest a bidirectional comorbidity between migraine and hypothyroidism.

The biological mechanisms underlying the association between SCH and migraine are unknown. Autoimmune hypothyroidism is a complex disorder in which thyroid autoantigens develop on a specific genetic background after an exposure to environmental factors (17). Genetic factors play an important role in the pathogenesis of SCH and would contribute about 73% to the development of TPO and TG antibodies (18). Thyroid autoimmunity is facilitated by single nucleotide polymorphisms in genes regulating the immune system, such as human leukocyte antigen (HLA) genes, cytokines genes, and thyroid specific genes. Polymorphisms in some of these genes, such as TNFalpha and different HLA genes, have also been implicated in the pathogenesis of migraine (19 –21).

Recent studies suggested that thyroid hormones play a neuromodulatory role in the central nervous system, and that the hypothalamic–pituitary–thyroid axis is involved in pain mechanisms (22). Thyroid hormones influence several physiological functions in the brain, such as neurogenesis, neuronal and glial differentiation, myelination, and new synaptogenesis (23,24). Active thyroid hormones bind to specific receptors, TRalpha and TRbeta, that are expressed in the whole brain (25). TSH receptors have been found both in the cortical neurons and cerebral vasculature (26). TSH secretion after thyrotropin-releasing hormone (TRH) administration is altered in patients with chronic migraine and medication overuse headache (27). Conversely, patients with hypothyroidism showed a high frequency of both CNS and peripheral abnormalities in electrophysiological studies, even in the asymptomatic ones (28). Interestingly, opioids have been found to modulate TSH release, increasing TSH levels, whereas tricyclic antidepressants, glucocorticoids and dopamine reduce the response of TRH (29). However, further experimental and clinical studies are needed in order to investigate the role of TRH in the physiopathology of migraine.

In our study, we also found that patients with comorbid SCH and migraine have an increased risk of developing further autoimmune diseases when compared to patients with SCH without migraine. We could hypothesize that common autoimmune mechanisms may be involved in the comorbidity of SCH and migraine. Our findings are in accordance with previous studies that found a positive association between migraine and several autoimmune disorders such as systemic lupus erythematosus, multiple sclerosis, celiac and inflammatory bowel diseases, and type 1 diabetes (30,31). Interestingly, a recent study indicates an alteration of immunoregulation in the pathophysiology of migraine, with decreased levels of regulatory T-cells CD4+CD25 + in migraineurs, hypothesizing migraine as an autoimmune disorder (32). Intriguingly, the same T cell subset for self-immunotolerance, CD4+CD25+, influences the development of thyroiditis in experimental studies (33). Notwithstanding, further investigations are required to better elucidate the role of autoimmunity in the pathogenesis of migraine.

There are some limitations in this study that deserve mention and suggest caution in the interpretation of the results. First of all, this is a retrospective study performed in a group of patients referring at the tertiary Endocrinological Center, with a limited number of patients. Further population-based studies are needed in order to better investigate the co-occurrence of SCH and migraine. However, contrary to other studies, we personally examined all patients and controls and the diagnosis of migraine was performed using standardized criteria. However, we did not evaluate the effect of hormone replacement therapy on the presence and characteristics of migraine attacks in our patients. Moreau et al. showed that 30% of adult patients with hypothyroidism complain of headache attacks and 50% of these resolved within two weeks of treatment with l-tiroxine (34). Interestingly, Lima Carvalho et al. observed that hormone replacement therapy was effective in reducing migraine both in patients with subclinical hypothyroidism and with overt disease (6). Additional studies are therefore needed to evaluate the therapeutic perspectives of levothyroxine treatment in these comorbid patients.

In conclusion, our study showed that patients with subclinical hypothyroidism have an increased risk of developing both migraine with aura and migraine without aura in respect to controls. This comorbidity seems not to be directly related to thyroid hormones or to antithyroid antibody levels. Finally, in our population, SCH patients in comorbidity with migraine have an increased risk of additional autoimmune disease.

Footnotes

Clinical implications

Patients with subclinical hypothyroidism (SCH) have an increased risk of developing migraine

This increased risk has been observed both in migraine with aura and migraine without aura patients

There are no significant differences in thyroid hormones levels as well as anti-thyroid antibodies titers in SCH patients in comorbidity with migraine in respect to SCH patients without migraine comorbidity

SCH patients in comorbidity with migraine have an increased risk of additional autoimmune diseases

Patients with both overt and subclinical hypothyroidism could be investigated for migraine headaches

Acknowledgements

The authors thank the subjects who participated in the study.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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Subclinical hypothyroidism is associated with migraine: A case-control study

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Methods

Subjects

Laboratory assays

Statistics

Results

Discussion

Footnotes

Clinical implications

Acknowledgements

Declaration of conflicting interests

Funding

References