ABSTRACT
Aim:
Migraine is a common neurovascular inflammatory disease that causes disability and is characterized by recurrent headache attacks. The role of thyroid regulation in migraine is poorly understood, and data are conflicting. The aim of this study is to evaluate the association of thyroid hormone levels and migraine types and headache severity.
Materials and Methods:
One hundred-fifty migraine patients enrolled in this retrospective study. Demographic and clinical characteristics of the patients, migraine subtypes, frequency and severity, serum thyrothytropine (TSH), and free thyroxin levels were evaluated from records. The Migraine Disability Assessment Questionnaire (MIDAS) and Visual Analog Scale (VAS) were used to assess the severity of migraine. Data analysis was performed.
Results:
The mean age was 40.40±10.84 years, and the female to male ratio was 5.1: 1. No significant relationship was found between thyroid hormone levels and headache characteristics of migraine patients and migraine severity (p>0.05). There was no significant relationship between VAS and MIDAS values and TSH levels (p=0.973).
Conclusion:
Migraine and thyroid diseases are common diseases in the society. Thyroid diseases and thyroid function tests should be evaluated together when determining the characteristics of migraine and the headache severity. Our data suggest that there is no relationship between thyroid hormone levels and migraine subtypes and severity. Further studies are needed in order to confirm this association.
INTRODUCTION
Migraine is a chronic, widespread neurovascular inflammatory disease characterized by recurrent moderate and severe headache attacks1. Photophobia, phonophobia, nausea, and vomiting are often accompanied by unilateral, throbbing, repetitive headache pain experienced for 4 to 72 hours by the patients2. Migraine pain not only affects the work or school performance of patients, but also causes a decrease in their quality of life, family time, and social activities. This condition, which completely or partially affects people’s normal activities and lives, has been evaluated as a disability by the World Health Organization. Migraine Disability Assessment Questionnaire (MIDAS) is one of the widely used scales developed to measure disability in migraine patients3,4. Migraine can cause disability as well as showing significant co-morbidities with various diseases such as myocardial infarction, stroke, subclinical vascular brain lesions, patent foramen ovale, hypertension, epilepsy, asthma and psychiatric disorders5,6. Recently, the relationship between migraine and thyroid functions has been attempted to be established.
Subclinical hypothyroidism (SCH) is a condition characterized by normal free triiodothyronine (fT3) and free thyroxin (fT4) values and slightly increased thyrotropin (TSH) concentrations. Some studies have shown that migraine is associated with an increased risk in the development of both overt and SCH7,8. However, the underlying mechanisms of this relationship are still unclear. Although clinical symptoms are very few in SCH, some patients may show neuropsychiatric symptoms such as depression, anxiety, and memory disorders. There are studies that explain hormonal levels related to thyroid function, TSH, T3 and T4 blood concentrations, and migraine pathogenesis7. In a previous meta-analysis, serum TSH levels were found to be higher in patients with migraine compared to control groups without migraine, which was statistically significant9. However, when we look at the literature, the number of studies investigating the difference between serum TSH and fT4 levels and loss of working days together with pain severity are very scarce. The aim of the present study is to determine whether there is a difference between thyroid function tests (TFT) in patients diagnosed with migraine, defined migraine type and difference between TFT according to loss of working days and pain severity.
GİRİŞ
Migren, tekrarlayan orta ve şiddetli baş ağrısı atakları ile karakterize kronik, yaygın nörovasküler enflamatuvar bir hastalıktır1. Baş ağrısı migren hastalarında genel olarak 4 ila 72 saat süren tek taraflı, zonklayıcı, tekrarlar ve ağrıya sıklıkla fotofobi, fonofobi, bulantı ve kusma eşlik eder2. Migren ağrısı hastaların iş veya okul performansını etkilemesinin yanında yaşam kalitesinde, aile içi ve sosyal aktivitelerinde de azalmaya neden olduğu bilinmektedir. İnsanların normal aktivite ve yaşamlarını tamamen veya kısmen etkileyen bu durum Dünya Sağlık Örgütü tarafından dizabilite olarak değerlendirilmiştir. Migren hastalarında dizabiliteyi ölçmek amacıyla geliştirilen ve yaygın olarak kullanılmakta olan ölçeklerden biri olan Migren Dizabilite Değerlendirme Anketi’dir (MIDAS)3,4. Migren dizabiliteye neden olabildiği gibi miyokard enfarktüsü, inme, subklinik vasküler beyin lezyonları, patent foramen ovale, hipertansiyon, epilepsi, astım ve psikiyatrik bozukluklar gibi çeşitli hastalıklarla önemli komorbiditeler göstermektedir5,6. Son zamanlarda migren ile tiroid fonksiyonları arasındaki ilişki gösterilmeye çalışılmıştır.
Subklinik hipotiroidizm (SKH), normal serbest triiyodotironin (sT3) ve serbest tiroksin (sT4) değerleri ile hafif derecede artan tirotiropin (TSH) konsantrasyonları ile karakterize bir durumdur. Bazı çalışmalarda migrenin hem aşikar hem de SKH gelişiminde artan risk ile ilişkili olduğunu göstermiştir7,8. Fakat bu ilişkinin altında yatan mekanizmalar halen belirsizdir. SKH’de klinik belirtiler çok az olmasına rağmen bazı hastalarda depresyon, anksiyete ve hafıza bozuklukları gibi nöropsikiyatrik nitelikte semptomlar gösterebilmektedir. Tiroid fonksiyonu ile ilgili hormonal seviyeleri TSH, T3 ve T4 kan konsantrasyonlarını ve migren patogenezi açısından açıklayan araştırmalar bulunmaktadır7. Daha önce yapılan bir metaanalizde de migrenli hastalarda serum TSH düzeyi migrenli olmayan kontrol gruplarına göre istatiksel olarak anlamlı yüksek bulunmuştur9. Fakat literatüre baktığımızda iş gün kaybı ve ağrı şiddetine göre serum TSH ve sT4 düzeyleri arasında fark olup olmadığını araştıran çalışma çok fazla görmemekteyiz. Çalışmamızdaki amaç migren tanısı almış, migren tipi belirlenmiş hastalarda tiroid fonksiyon testleri (TFT) arasında fark olup olmadığını, ayrıca iş günü kaybına ve ağrı şiddetine göre hastaların TFT arasında fark olup olmadığını belirlemektir.
MATERIALS AND METHODS
One hundred-fifty patients admitted to Necmettin Erbakan University, Meram Faculty of Medicine, Neurology Outpatient Clinic between January 2021 and July 2022 and diagnosed with migraine (according to International Headache Society) were included in the present study. The study was approved by Necmettin Erbakan University, Meram Medical Faculty Ethics Committee (decision no: 2022/3969, date: 16.09.2022). Patients’ files were analyzed retrospectively. Sixteen patients with a history of thyroid disease and using drugs related to thyroid disease, according to their records, were excluded from the present study. Patients’ age, gender, biochemical serum TSH and fT4 levels, migraine type, presence of aura, frequency of attacks, duration and severity of attacks were recorded. Serum TSH and fT4 levels were studied by using standard electrochemiluminescence methods. The frequency of attacks refers to the total number of migraine attacks in the last 3 months; yet, whether the patients received treatment or not during the attacks was disregarded. Headache severity was evaluated with VAS. According to VAS 100 mL line 0-4 mL was evaluated as no pain, 5-44 mL as mild pain, 45-74 mL as moderate pain, and 75-100 mL as severe pain depending on the mark on the line10. MIDAS Turkish version was obtained by questioning the days on which the patients were unable to work due to the pain and the days when patients’ performance decreased by at least 50%11. According to MIDAS, little or no disability was defined with a loss of 0-5 days, mild disability with a loss of 6-10 days, moderate disability with a loss of 11-20 days, and severe disability with a loss of 21 days or more4. The difference between serum TSH and fT4 values according to migraine type, the presence of aura, and the presence of a relationship with TFT in these patients, whose VAS and MIDAS values were calculated, were all taken into consideration.
Statistical Analysis
In the present study, the data obtained were analyzed using Statistical Package for Social Sciences for Windows 20.0 package program. Categorical variables were expressed as numbers (n) and the chi-square test (and/or Fisher’s exact test) was used for the analysis. The Pearson correlation test was also applied to determine the correlations between serum TSH levels and migraine characteristics. Numerical variables were expressed as mean±standard deviation, and the Student’s t-test was used to analyze the comparison of the means of two independent groups. A threshold level of <0.05 was considered for statistical significance in all results obtained.
RESULTS
The files of 150 migraine patients were reviewed retrospectively. Sixteen patients with a history of thyroid disease and relevant use of drugs were excluded from the present study. Out of the patients, 112 (83.6%) were female and 22 (16.4%) were male, with an age range between 18 and 65 years. The mean age was 40.40±10.84 years. The type of migraine (chronic, episodic), the presence of aura, headache severity according to VAS, disability score and demographic characteristics according to MIDAS are presented in Table 1. FT4 levels of the patients whose serum TSH level were found to be above 4.2 mU/L were reevaluated. Eleven (8.2%) subclinical hypothyroid patients with TSH levels above 4.2 mU/L, fT4 levels within the normal range of 0.93-1.7 ng/dL, and no thyroid medication use were determined. Out of the 11 patients diagnosed with SCH, 10 were female and 1 was male.
Out of 134 migraine patients, 36 (26.9%) had migraine with aura and 98 (73.1%) had migraine without aura. The mean TSH value of patients diagnosed with migraine with aura was 2.10±1.46 mU/L, and fT4 was 1.25±0.32 ng/dL. The mean TSH value of patients with migraine but without aura was 2.24±1.58 mU/L, fT4 value was 1.16±0.17 nd/dL. However, no statistically significant differences could be determined in the TSH and fT4 values between the groups. There was no statistically significant difference between them (p=0.761, p=0.097).
Out of the migraine patients, 87 (64.9%) had episodic and 47 (35.1%) chronic migraine episodes. The mean TSH value of patients with chronic migraine was 2.33±1.61 mU/L, fT4 value was 1.19±0.29 ng/dL. The mean TSH value of patients with episodic migraine was 2.14±1.51 mU/L, fT4 value was 1.18±0.19 nd/dL. In terms of TSH and fT4 values, there was no statistically significant difference between the groups (p=0.490, p=0.887).
According to VAS, 2 patients (1.5%) had mild headache, 27 (20.1%) had moderate headache, and 105 patients (78.4%) had severe headache. Considering TSH and fT4 levels of the patients according to the severity of pain, the mean TSH value was 1.10±0.14 mU/L, fT4 value was 1.21±0.16 ng/dL in mild pain; the mean TSH value was 2.41±1.54 mU/L, fT4 value was 1.18±0.22 ng/dL in moderate pain; the meanTSH value was 2.17±1.56 mU/L, fT4 was determined as 1.18±0.23 ng/dL in severe pain, and there was no statistically significant difference among the groups (p=0.248, p=0.836).
Considering the working day loss of the patients, there were 21 patients (15.7%) with little or no disability, 43 (32.1%) with mild disability, 42 (31.3%) with moderate disability, and 28 (20.9%) with severe disability. The mean TSH value of patients with very low disability was 1.98±1.08 and fT4 value was 1.15±0.15. For those with mild disability, the mean TSH value was 2.28±1.81 and fT4 value was 1.16±0.19. For those with moderate disability, the mean TSH level was 2.06±1.27 and fT4 value was 1.21±0.17, and for those with severe disability, the mean TSH value was 2.48±1.79, and fT4 level was 1.21±0.36. There was no statistically significant difference between the groups (p=0.843, p=0.414).
TSH and fT4 levels of the patients are presented in Table 2.
DISCUSSION
In the present study investigating TFT values in migraine patients, TSH level was above 4.2 mU/L in 134 migraine patients and fT4 level was between 0.93 and 1.7 ng/dL. We identified 11 (8.2%) patients diagnosed with SCH, who were in the normal range and did not use thyroid medication. Of the 11 patients diagnosed with SCH, 10 were female and 1 was male. In population-based studies, the prevalence of SCH varies between 4% and 15% and the diagnosis is more common in women12. We did not have a control group in our study, but the prevalence of SCH was similar to that in community-based studies. Our female patients with SCH were more in numbers compared to male patients.
Hormones synthesized in the thyroid glands are vital for normal development and growth as well as for the development of the central nervous system. Severe deficiency of thyroid hormones results in mental retardation and ataxia during fetal and neonatal periods13. Basic evidence has been provided that thyroid hormones are involved in pain processing through the anterior cingulate cortex in mice with experimentally formed hypothyroidism. There are indications that thyroid hormones affect the development of pain/migraine. While hypothyroidism has been found to cause hypersensitivity to noxious thermal, but not mechanical, stimulus in mice, interestingly, pain intensity has been shown to be alleviated by T3 or T4 replacement. The mechanism underlying the effect of hormone therapy was thought to result from an improvement in the balance of glutamatergic and gamma aminobutyric acidergic transmission in the anterior cingulate cortex of hypothyroid mice14.
In the study conducted by Bhattacharjee et al.15, investigating the rate of SCH in patients with migraine, they determined the rate of SCH to be significantly higher in patients with migraine compared to the group without. Another study performed by Rubino et al.16 reported a higher prevalence of migraine in patients with SCH compared to controls (46% vs. 13%, respectively). In their study, they also reported that they did not determine a statistically significant difference in serum TSH levels between SCH patients with and without migraine. The biological mechanisms underlying the relationship between SCH and migraine are unknown. Autoimmune hypothyroidism is a complex disease in which thyroid autoantigens develop on a certain genetic background after exposure to environmental factors. Thyroid autoimmunity is facilitated by single nucleotide polymorphisms in genes that regulate the immune system, such as human leucocyte antigen (HLA) genes, cytokine genes, and thyroid-specific genes. In the pathogenesis of migraine, polymorphisms play a role in some of these genes, such as tumor necrosis factor-alpha and different HLA genes17-19.
In another study within the relevant literature, the meta-analysis results of Seidkhani-Nahal et al.20 demonstrated statistically significantly higher TSH concentrations in patients with migraine and in controls without migraine. Based on this meta-analysis, the aim of the present study was to investigate whether there was a difference between serum TSH levels and fT4 levels in patients having migraine with or without the presence of aura, according to the severity of the headache, and type of migraine. The present study could not determine a statistically significant difference between TSH and fT4 levels of 134 migraine patients. The findings presented in the relevant literature were mostly in line with the findings of the present study. In a randomized case-control study, Bigal et al.21 evaluated the factors associated with the transition from episodic migraine to chronic migraine. Among these factors, hypothyroidism has been found to contribute to the emergence of chronic migraine. In another study, it was shown that the rate of hypothyroidism in patients with migraine was higher than in community-based studies7. In addition, in the study of Rubino et al.16, conducted with clinical subtypes of migraine, it was determined that the prevalence of migraine with and without aura was higher in patients with SCH than in the controls. In a retrospective cohort of consecutive migraine patients, which investigated the presence of migraine co-morbidities, Tietjen et al.22 defined a subgroup with a high incidence of metabolic co-morbidities (such as hypertension, hyperlipidemia, diabetes mellitus) and hypothyroidism. Spanou et al.23 could not determine a statistically significant relationship between headache types and thyroid hormone disorders. In terms of headache subtypes and thyroid dysfunctions, no statistically significant relationship could be determined in their study. However, a higher prevalence of thyroid dysfunction in general (20.7%) and a higher prevalence of hypothyroidism specifically (6.3%) in patients with primary headache were reported.
In a study conducted in Russia, only 5% of the migraine patients in the study were reported to have abnormal TSH levels (lower or higher than normal). Nevertheless, lower TSH values were associated with longer-term migraine attacks and had a greater impact on quality of life. Based on these findings, it was suggested that TSH levels should be confirmed in patients with severe migraine24.
Study Limitations
The lack of a control group and the limited number of patients are the inherent limitations of the present study.
TARTIŞMA
Migren hastalarında TFT değerlerini araştırdığımız çalışmamızda; 134 tane migren hastasında TSH düzeyi 4,2 mU/L üzerinde olup ve sT4 0,93-1,7 ng/dL arasında yani; normal aralıklarda olan tiroid ilaç kullanımı olmayan SKH tanısı alan 11 (%8,2) tane hasta saptandı. On bir SKH tanısı alan hastanın 10’u kadın 1 tanesi erkekti. Toplum temelli çalışmalarda SKH prevalansı %4-15 arasında değişmektedir ve tanı kadınlarda daha sık görülmektedir12. Çalışmamızda kontrol grubumuz yoktu fakat SKH görülme prevalansı toplum kökenli çalışmalar ile benzerdi. SKH kadın hasta sayılarımız erkek hastalardan daha fazlaydı.
Tiroid bezinde sentezlenen hormonlar, normal gelişim ve büyüme için hayati öneme sahiptir ve merkezi sinir sisteminin gelişimi için gereklidir. Tiroid hormonlarının ciddi eksikliği, fetal ve neonatal dönemlerde zeka geriliği ve ataksi ile sonuçlanmaktadır13. Deneysel olarak hipotiroidizm geliştirilmiş farelerde tiroid hormonların, anterior singulat korteks yoluyla ağrı işlemeye dahil olduğuna dair temel kanıtlar sağlanmıştır. Tiroid hormonların ağrı/migren gelişimini etkilediğine dair göstergeler sunulmuştur. Hipotiroidizm, farelerde zararlı termal, ancak mekanik olmayan uyarana karşı aşırı duyarlılığa neden olduğu saptanırken, ilginç bir şekilde, ağrı şiddetinin T3 veya T4 replasmanı ile hafiflediği gösterilmiştir. Hormon tedavisinin etkisinin altında yatan mekanizmanın, hipotiroidik farelerin anterior singulat korteksindeki glutamaterjik ve gama aminobütirik asiterjik aktarım dengesinde bir iyileşmeden kaynaklandığı düşünülmüştür14.
Migreni olan hastalarda SKH oranını araştıran Bhattacharjee ve ark.’nın15 yaptıkları çalışmada migrenli hastalarda SKH oranını migrenli olmayan gruba göre anlamlı olarak daha yüksek saptamışlardır. Başka bir çalışmaya tersten baktığımızda Rubino ve ark.’nın16 çalışmasında, kontrollere kıyasla SKH olan hastalarda migren prevalansının daha yüksek olduğu bildirilmiştir (sırasıyla %46’ya karşı %13). Bu çalışmada ayrıca migreni olan ve migreni olmayan SKH hastaları arasında serum TSH düzeyleri arasında anlamlı bir fark saptamadıklarını bildirmişlerdir. SKH ve migren arasındaki ilişkinin altında yatan biyolojik mekanizmalar bilinmemektedir. Otoimmün hipotiroidizm; çevresel faktörlere maruz kaldıktan sonra tiroid otoantijenlerinin belirli bir genetik arka plan üzerinde geliştiği karmaşık bir hastalıktır. Tiroid otoimmünitesi, insan lökosit antijeni (HLA) genleri, sitokin genleri, tiroide özgü genler gibi bağışıklık sistemini düzenleyen genlerdeki tek nükleotid polimorfizmleri ile kolaylaştırılmaktadır. Migren patogenezinde ise tümör nekrozis faktör-alfa ve farklı HLA genleri gibi bu genlerin bazılarında polimorfizmler rol oynamaktadır17-19.
Literatüre baktığımız başka bir çalışmada Seidkhani-Nahal ve ark.’nın20 meta-analiz sonuçlarında ise; migrenliler ve migreni olmayan kontroller arasında migrenli hastalarda istatistiksel olarak anlamlı daha yüksek TSH kontsantrasyonları kaydedildiğini bildirmişlerdir. Bu meta-analizden yola çıkarak migrenli hastalarında serum TSH düzeyleri ve sT4 düzeyleri arasında migrenin auralı, aurasız oluşuna göre, baş ağrısının şiddetine göre, migrenin tipine göre fark olup olmadığını araştırmayı planladık. Çalışmamızda 134 migrenli hastaların sonuçlarında TSH ve sT4 düzeyleri arasında anlamlı bir fark saptamadık. Literatüre baktığımızda çalışmamıza benzer çok fazla çalışma saptamadık. Bir randomize olgu kontrol çalışmasında, Bigal ve ark.21 epizodik migrenden kronik migrene geçişle ilgili faktörleri değerlendirmişler. Bunlar arasında hipotiroidizmin migrenin kronikleşmesine katkıda bulunduğu gösterilmiştir. Yapılan başka bir çalışmada migrenli hastalarda hipotiroidizm oranının toplum kökenli çalışmalardan daha yüksek olduğu gösterilmiştir7. Ayrıca Rubino ve ark.’nın16 yaptığı çalışmada migrenin klinik alt tipleri için, SKH’li hastalarda kontrollere göre hem aurasız hem de auralı migren prevalansının daha yüksek olduğunu tespit etmişlerdir.
Tietjen ve ark.22 migren komorbiditelerinin varlığını araştıran, ardışık migren hastalarından oluşan retrospektif bir kohortta, metabolik komorbiditeler (hipertansiyon, hiperlipidemi, diabetes mellitus gibi) ve hipotiroidizm insidansının yüksek olduğu bir alt grup tanımlamışlardır. Spanou ve ark.’nın23 baş ağrısı tipleri ve tiroid hormon bozuklukları ile ilgili yaptıkları çalışmada baş ağrısı alt tipleri ile tiroid fonksiyon bozukluğu arasında anlamlı bir ilişki gösterememişlerdir. Bununla birlikte bu çalışmada birincil baş ağrısı olan hastalarda genel olarak tiroid disfonksiyonu (%20,7) ve spesifik olarak hipotiroidizm (%6,3) prevalansını daha yüksek bulmuşlardır. Rusya’da yapılan bir araştırmada ise, incelenen migren hastalarının yalnızca %5’inde anormal TSH düzeyleri (normalden düşük veya yüksek) bulunduğunu bildirmişlerdir. Bununla birlikte, daha düşük TSH değerlerinin daha uzun süreli migren atakları ile ilişkili olduğunu ve yaşam kalitesi üzerinde daha büyük bir etkiye sahip olduğunu saptamışlardır bundan yola çıkarak şiddetli migreni olan hastalarda TSH düzeylerinin doğrulanması gerektiğini önermişlerdir24.
Çalışmanın Kısıtlılıkları
Çalışmamızın kontrol grubunun olmaması ve hasta sayımızın kısıtlı olması eksik yönümüzdür.
CONCLUSION
In the present study, however, no statistically significant difference could be determined between TSH and fT4 levels and the severity of headache, loss of working days, chronic and episodic migraine. The group with chronic migraine had a higher TSH value than the group with episodic migraine but there was no statistically significant difference between the groups. The pathogenesis of this association requires further research and studies with larger numbers of patients. In the present study, in 8,2% of the migraine patients, SCH was determined. As there was not a control group, comparisons with community-based studies could be made.
