Serum levels of vitamin D, vitamin D-binding protein and vitamin D receptor in migraine patients from central Anatolia region A. Celikbilek,1 A. Y. Gocmen,2 G. Zararsiz,3 N. Tanik,1 H. Ak,4 E. Borekci,5 N. Delibas2
Department of Neurology, Medical School, Bozok University, Yozgat, Turkey 2 Department of Biochemistry, Medical School, Bozok University, Yozgat, Turkey 3 Department of Biostatistics, Medical School, Hacettepe University, Ankara, Turkey 4 Department of Neurosurgery, Medical School, Bozok University, Yozgat, Turkey 5 Department of Internal Medicine, Medical School, Bozok University, Yozgat, Turkey Correspondence to: Asuman Celikbilek, Department of Neurology, Bozok University, 66200, Yozgat, Turkey Tel.: + 90 505 653 26 15 Fax: + 90 354 217 10 72 Email: [email protected]
Introduction Several studies support the role of inflammation in the pathogenesis of migraine in which the attacks are associated with neurovascular inflammation of the cerebral and extracerebral vessels (1). Increased inflammatory cytokines and interleukins have been reported during interictal periods and acute attacks of migraine (2–4). In recent years, vitamin D has attracted much attention (5). Beyond its role in calcium mobilisation and bone health, vitamin D deficiency is involved in numerous conditions, including muscle function, autoimmune diseases, cancer, cardiovascular diseases, diabetes, osteoarthritis, inflammatory and infectious diseases, mental and skin disorders (6–8). More recently, vitamin D deficiency is associated with a number of neurological disorders (9–12). Vitamin D has been suggested to play an important role in lots of physiological activities such as immune system
Objectives: Inflammation is proposed to be involved in the pathogenesis of both vitamin D deficiency and migraine. However, the data examining the relation of vitamin D with migraine are limited. We aimed to investigate the serum levels of vitamin D, vitamin D-binding protein (VDBP) and vitamin D receptor (VDR) in combination, in migraine patients from central Anatolia region. Methods: Fifty-two newly diagnosed migraine patients and age- and sex-matched 49 control subjects were enrolled in this cross-sectional prospective study. Migraine diagnosis was settled according to the International Classification of Headache Disorders-II diagnostic criteria. Serum samples were analysed for the measurement of vitamin D, VDBP and VDR levels by using commercial enzyme-linked immuno sorbent assay kits. Results: Serum vitamin D and VDR levels were found to be significantly lower in migraine patients than in controls (p = 0.012 and p = 0.038, respectively); whereas serum VDBP levels were similar between the groups (p > 0.05). There was no correlation between serum vitamin D, VDBP and VDR levels and headache characteristics including aura, attack severity, frequency and duration, and disease duration (p > 0.05). In terms of headache characteristics, no significant difference between migraineurs with vitamin D values < 25 and ≥ 25 ng/ml was observed (p > 0.05). Conclusions: The present findings may suggest that decreased serum vitamin D levels were associated with migraine.
Inflammation is involved in the pathogenesis of both vitamin D deficiency and migraine. The data examining the relation of vitamin D with migraine are limited.
Serum vitamin D and vitamin D receptor (VDR) levels were lower in migraineurs than in controls whereas serum vitamin D-binding protein (VDBP) levels were similar between the groups. Serum vitamin D, VDBP and VDR levels did not correlate with headache characteristics.
regulation and resolution of inflammation which are both proposed to be involved in the pathogenesis of migraine (8,13). However, the data examining the relation of vitamin D with migraine are limited. An earlier report by Thys-Jacobs showed alleviation of migraine with therapeutic vitamin D administration in a small study population (14). A study by Wheeler indicated that 40% of people with migraine had low vitamin D levels (15). In contrast, Kjaergaard et al. found no relation between serum level of vitamin D and migraine (16). More recently, Mottaghi et al. found a positive weak relationship between serum vitamin D and headache diary result that was defined as the multiple of headache duration and frequency, in his cross-sectional study conducted among only migraineurs in Iran (17). In this study, we aimed to investigate the serum levels of vitamin D, vitamin D-binding protein (VDBP) and vitamin D receptor (VDR) in combination, in migraine patients from central Anatolia region. ª 2014 John Wiley & Sons Ltd Int J Clin Pract, October 2014, 68, 10, 1272–1277. doi: 10.1111/ijcp.12456
Serum levels of vitamin D in migraine patients
Methods Study population Fifty-two newly diagnosed migraine patients and ageand sex-matched 49 control subjects of Caucasian origin, ranging 18–50 years, were enrolled in this cross-sectional prospective study, conducted in Yozgat region known as central Anatolia, Turkey, between 36° and 42° of latitude, in autumn 2012. Patients with malignancy; hepatic, renal or heart failure; endocrine disease such as diabetes, thyroid or parathyroid disease; inflammatory or autoimmune disease; osteoporosis; pregnancy; morbid obesity; medications (vitamin D supplements, anticonvulsants, rifampicin or antiretroviral drugs, etc.) known to interfere with the vitamin D metabolism; smoking habit and alcohol use were excluded from the study. Patients’ medical histories, physical and neurological examinations were performed by the same neurologist. Migraine diagnosis was settled according to the International Classification of Headache Disorders-II diagnostic criteria (18). Thirty-one patients had migraine with aura, while the rest had migraine without aura. The control subjects were enrolled as healthy individuals who had no headache of any kind. Migraine patients were evaluated according to the headache characteristics including aura, severity, frequency and duration of the migraine attack or the duration of the disease. Based on visual analogue scale, the headache was defined as mild (score 1–3), moderate (4–6), severe (score 7–8) or very severe (score 9–10) (19). Migraine headache attack frequency was noted as the number of attacks per month (20). Duration of the headache attack was defined as hours whereas disease duration as the year. All patients were studied during the headachefree period. These subjects were not on any medication. Dependent variables included systolic blood pressure, diastolic blood pressure and body mass index (BMI), which was calculated as weight in kilograms divided by the square of height in metres (21). Fasting venous blood samples were taken from all subjects in autumn (September and October) as a short timeframe to avoid seasonal variations for the serum vitamin D levels (5) and, routine haematological and biochemical analyses were performed by standard methods in our laboratory. The study protocol was approved by the Bozok University Research Ethics Committee, and written informed consent was obtained from all participants.
Biochemical analysis Blood samples were collected in vacutainer tubes without anticoagulant supplements. All blood samples were centrifuged for 10 min at 3000 rpm, after ª 2014 John Wiley & Sons Ltd Int J Clin Pract, October 2014, 68, 10, 1272–1277
which the supernatant was quickly removed and kept frozen at 80 °C until the assays were performed by an investigator blind to patient status. Commercially available enzyme-linked immunosorbent assay kits were used to measure the serum vitamin D (EIA5396, DRG GmbH, Marburg, Germany), VDBP (K2314, Immundiagnostik AG, Bensheim, Germany), and VDR (Cusabio, Wuhan, China) levels using appropriate wavelengths on a microplate reader (EL 9 800 TM, BioTek Instruments, Winooski, VT) following the assay instructions. Concentrations were calculated over the standard curves. The detectable ranges for vitamin D, VDBP and VDR were 30 100 ng/ml, 20 55 ng/ml and 6.25 400 pg/ml, respectively. Serum vitamin D and VDBP concentrations were expressed as ng/ml, whereas VDR concentrations were expressed as pg/ml.
Statistical analysis A Shapiro–Wilk’s test, histograms and q–q plots were used to test the normality of the data, and Levene’s test was used to assess variance homogeneity. Independent-sample t-tests and Mann–Whitney U-tests were used to compare differences between continuous variables, and v2 analyses were used to assess differences between categorical variables. Values are expressed as frequencies and percentages, means and standard deviations, or medians and interquartile ranges. To identify the risk factors of migraine, univariate and multiple binary logistic regression analysis were applied. For each variable, odds ratios (OR) are calculated with 95% confidence intervals (CI). Statistically significant variables at p < 0.15 in univariate analysis were included to multiple model and backward stepwise elimination was performed using Wald statistic at p < 0.05 stringency level to determine the independent risk factors. To assess the correlations between headache characteristics and laboratory data in migraine patients, eta and Pearson correlation coefficients were calculated. Analyses were conducted using R 3.0.1 software with considering a p < 0.05 statistically significant.
Results The demographic and laboratory data for the control group and for patients with migraine are summarised in Table 1. No significant differences were found in migraine patients compared with the controls in terms of age or sex (p > 0.05), and BMI was similar between the groups (p > 0.05). Routine laboratory results were also similar between the two groups (p > 0.05). However, serum vitamin D (p = 0.012) and VDR (p = 0.038) levels were found lower in migraineurs than in controls whereas VDBP (p > 0.05)
Serum levels of vitamin D in migraine patients
Table 1 Comparison of demographic and laboratory data between control and migraine patients
Logistic regression analysis
Control (n = 49)
Migraine (n = 52)
Univariate OR (95% CI)
Multiple OR (95% CI)
Age (years) Gender (female/male) Body mass index (kg/m2) WBC (103/mm3) Haemoglobin (mg/dl) Platelet (103/mm3)* Fasting glucose (mg/dl) Creatinine (mg/dl) AST (IU/l) ALT (IU/l) TSH (uIU/ml) Albumin (g/dl) LDH (IU/l) ALP (IU/l) Calcium (mg/dl) Phosphorus (mg/dl) Magnesium (mg/dl) Parathormone (pg/ml) 25-hydroxyvitamin D (ng/ml) VDBP (ng/ml) VDR (pg/ml)*
34.24 10.15 42 (85.7)/7 (14.3) 24.63 2.55
35.88 9.10 48 (92.3)/4 (7.7) 25.06 2.63
0.394 0.288 0.406
1.02 (0.98–1.06) 0.50 (0.14–1.83) 1.07 (0.92–1.24)
– – –
7.60 (6.50–8.90) 13.40 (12.80–14.60) 263.31 62.36 84.57 5.81
6.85 (6.25–8.50) 13.20 (12.25–13.90) 284.23 48.02 85.90 6.90
0.135 0.121 0.061 0.298
0.82 0.74 1.07 1.03
– – 1.12 (1.03–1.23) –
0.70 (0.60–0.80) 17.00 (12.00–22.00) 19.00 (16.00–26.00) 1.60 (1.10–2.50) 4.24 0.35 128.00 (117.00–143.00) 62.00 (55.00–71.00) 9.49 0.37 3.56 0.64 1.90 (1.80–2.00) 41.50 (34.20–55.10) 48.0321.53
0.70 (0.60–0.80) 16.00 (13.50–20.00) 17.50 (14.50–24.00) 1.90 (1.35–2.75) 4.33 0.35 118.00 (111.50–137.00) 59.00 (53.00–68.50) 9.34 0.42 3.48 0.66 1.90 (1.90–2.10) 48.70 (38.55–61.65) 38.08 17.28
0.054 0.447 0.221 0.226 0.186 0.091 0.132 0.067 0.568 0.070 0.071 0.012
0.06 (0.01–1.26) 0.97 (0.91–1.04) 0.97 (0.92–1.02) 1.34 (0.86–2.10) 2.18 (0.69–6.90) 0.99 (0.97–1.01) 0.97 (0.94–1.00) 0.39 (0.14–1.09) 0.84 (0.46–1.54) 11.62 (0.89–152.61) 1.02 (1.00–1.04) 0.97 (0.95–0.99)
– – – – – – 0.96 (0.92–1.00) 0.22 (0.06–0.81) – 34.95 (1.60–764.25) – 0.95 (0.93–0.98)
38.83 8.82 53.91 (48.96–86.92)
38.97 8.75 50.34 (43.19–85.54)
1.00 (0.96–1.05) 0.89 (0.76–0.99)
– 0.81 (0.66–0.99)
(0.62–1.07) (0.52–1.05) (0.99–1.15) (0.97–1.10)
OR (95% CI): Odds ratios and 95% confidence intervals. Values are expressed as n(%), mean SD or median(interquartile range). WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TSH, thyroid-stimulating hormone; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; VDBP, vitamin D-binding protein; VDR, vitamin D receptor. *Odds ratios are calculated for every 10 unit changes in the corresponding variable.
levels were similar between the groups (Figure 1). In multiple model; platelet, alkaline phosphatase, calcium, magnesium, vitamin D and VDR were independently associated with migraine [OR and 95% CI are 1.12 (1.03–1.23), 0.96 (0.92–1.00), 0.22 (0.06– 0.81), 34.95 (1.60–764.25), 0.95 (0.93–0.98) and 0.81 (0.66–0.99), respectively, Table 1]. There was no correlation between laboratory risk factors and headache characteristics in migraine patients except for alkaline phosphatase with a weak correlation (g = 0.292, p > 0.05) as presented in Table 2. Among the migraineurs, serum vitamin D levels were less than 20 ng/ml in 12 patients (vitamin D deficiency); between 20 and 30 ng/ml in one patient (vitamin D insufficiency); more than 30 ng/ ml in 39 patients (vitamin D sufficiency). In terms of headache characteristics, no significant difference between migraineurs with vitamin D values < 25 and ≥ 25 ng/ml was observed (p > 0.05, Table 3).
Discussion Three main findings emerged from this study. First, serum vitamin D and VDR levels were found lower in migraineurs than in controls, whereas VDBP levels were similar between the groups. Second, vitamin D and VDR were independently associated with migraine. Third, no correlation between serum vitamin D, VDBP and VDR levels, and headache characteristics was observed in migraine patients; as well as, headache characteristics did not differ according to the migraine subgroups categorised as vitamin D deficiency, sufficiency or insufficiency in migraineurs. 25-OHD is used to determine a patient’s vitamin D status owing to longer half-life in the plasma, and forms a circulating reservoir of vitamin D (7,22). There is no consensus on the optimal levels of 25OHD (7). Levels of more than 30 ng/ml are usually considered as vitamin D sufficiency. Between 20 and ª 2014 John Wiley & Sons Ltd Int J Clin Pract, October 2014, 68, 10, 1272–1277
Serum levels of vitamin D in migraine patients
Figure 1 Comparisons of vitamin D (A), vitamin D-binding protein (B) and vitamin D receptor (C) values between control and migraine patients
Table 2 Correlation coefficients between headache characteristics and laboratory risk factors in migraine patients
Laboratory risk factors Variables
Aura* Disease duration† Attack frequency† Attack severity† Attack duration†
0.080 0.016 0.025 0.139 0.116
0.292 0.121 0.083 0.252 0.088
0.170 0.062 0.015 0.043 0.055
0.074 0.124 0.043 0.059 0.073
0.032 0.207 0.070 0.018 0.182
0.016 0.190 0.033 0.159 0.206
0.168 0.101 0.117 0.026 0.159
Bold values indicate statistically significant correlation values at p < 0.05. ALP, alkaline phosphatase; VDBP, vitamin D-binding protein; VDR, vitamin D receptor. *Correlation values are eta coefficients (g), †correlation values are Pearson coefficients (r).
Table 3 Comparisons of headache characteristics between migraine patients with 25-hydroxyvitamin D values < 25
and ≥ 25 ng/ml Variables
25-hydroxyvitamin D < 25 ng/ml (n = 13)
25-hydroxyvitamin D ≥ 25 ng/ml (n = 39)
Aura Disease duration Attack frequency Attack severity Attack duration
9 (69.2) 5.0 (5.0–6.0) 4.0 (3.0–4.0) 8.0 (7.0–8.0) 48.0 (24.0–72.0)
22 (71.0) 8.0 (4.0–12.0) 4.0 (3.0–7.0) 8.0 (7.0–8.0) 24.0 (24.0–48.0)
0.415 0.269 0.923 0.839 0.184
Values are expressed as n(%) or median(interquartile range).
30 ng/ml of levels indicate an insufficiency state, while vitamin D deficiency is considered when the serum level is less than 20 ng/ml (5,7). In the present study, of the migraine patients, 12 had vitamin D deficiency, one had vitamin D insufficiency and 39 had vitamin D sufficiency. As a result, we found serum vitamin D lower in migraineurs than in controls and these lower levels were independently associated with migraine. Vitamin D has been involved in immune system regulation and resolution of inflammation which indicate anti-inflammatory and immunoregulatory effects through the regulation of interleukins and tumour necrosis factor, and the ª 2014 John Wiley & Sons Ltd Int J Clin Pract, October 2014, 68, 10, 1272–1277
activity of macrophages (8,13). Thus, vitamin D supplement might theoretically have a beneficial effect on inflammatory-induced pain (23). In contrast, this study failed to find any correlation between serum levels of vitamin D and the headache characteristics, including aura, severity, frequency and duration of the migraine attack or the disease duration. It is likely that larger cohorts are needed to produce more definitive results. Moreover, epidemiological data have shown an increasing frequency of headache attacks with increasing latitude which is possibly because of lower levels of vitamin D in the generation of recurrent headaches (5). Therefore, it can be
Serum levels of vitamin D in migraine patients
supposed that further studies at higher latitude might put forth positive associations between these variables. On the other hand, there is no clinical study yet investigating the serum VDBP and VDR levels in migraine in the literature. Jirikowski et al. showed that VDBP was observed in widespread axonal projections throughout the lateral hypothalamus in rat hypothalamus (24). Also, 1a-hydroxylase and VDR have been demonstrated in many areas of the central nervous system especially hypothalamus, which is a region for migraine pain sensation (25), in human brain (26). Considered together, demonstration of VDBP, 1 a-hydroxylase and VDR in the hypothalamus supports a hypothetical role of vitamin D deficiency in the generation of headache in migraineurs (5). This could be caused by the possible sensitisation of second and third neurons because of sustained stimulation of sensory receptors of periosteal coverage, possibly because of bone swelling in vitamin D deficiency (27). Under normal physiological conditions, most of the circulating vitamin D metabolites, which include 25-OHD and 1,25-OHD, are protein bound (28). One of the major functions of VDBP is the binding, solubilisation and serum transport of these two sterols into target cells (28). VDBP binds 88% of serum 25OHD and 85% of serum 1,25-OHD, leaving 0.40% ‘free’ and the remainder associated with other serum proteins (28). We found serum VDBP levels similar between controls and migraineurs, in agreement with more recent studies (22,29). Unlike the other plasma carriers of hormones, VDBP circulates in the plasma at higher concentrations than the total amount of vitamin D metabolites which might relate to the other functions of VDBP (28). Decreased serum vitamin D levels might cause an increase of other functions resulting in unaltered serum VDBP levels. Besides, VDBP affects the pharmacokinetics of vitamin D metabolites (30). Another hypothesis could be that these metabolites could be inactivating VDBP via feedback mechanisms. Indeed, no detailed information of the vitamin D-binding mechanism is available yet. Activated vitamin D leads to multiple biological responses and regulates cell differentiation by binding to intracellular nuclear receptors, the VDRs in several body tissues, such as cardiac tissue, vascular smooth muscle cells, endothelial cells, renal tissue and immune system (22,31). In the present study, similar to vitamin D levels, we found serum VDR levels lower in migraine patients than in controls. The binding of activated vitamin D to VDR activates the receptor to recruit cofactors to form a complex
that binds to vitamin D response elements in the promoter region of target genes to regulate gene transcription (32). If the serum vitamin D levels were decreased, then this could possibly lead to a similar decrease in this transcription. Also, vitamin D, as the other steroid hormones, influences a wide range of metabolic systems by transmitting signals that result in both genomic and non-genomic pathways which take place outside the cell nucleus (33). Decreased serum vitamin D levels may induce a decrement in the vitamin D-dependent non-genomic response that affects gene expression throughout cognate promoter DNA sequences, since the genomic and non-genomic pathways are closely linked to each other (31). This study has several potential limitations that should be considered. Despite the gender and racial homogeneity, it is clearly unrealistic to homogenise all environmental and demographic factors that significantly affect the serum vitamin D levels besides season and latitude, for all enrolled subjects; such as ethnic habits of covering the body, cultural food traditions, and the degree of skin pigmentation which represents the greatest limitation of these studies. The other drawbacks that may be attributed to our research were as follows: (i) we used a small sample, and it will be necessary to validate these findings with a larger cohort, (ii) this study is cross-sectional, hence, we cannot determine a causal link, (iii) this study investigated only serum samples, and cerebrospinal fluid analysis would probably provide additional clarification, (iv) data regarding the upper signalling pathways by which vitamin D is regulated are lacking and may help to clarify the exact mechanisms on this issue. In conclusion, despite the abovementioned limitations, for the first time in the literature, we have examined serum levels of vitamin D, VDBP and VDR in combination, in migraine patients. The literature is conflicting regarding this relation to which we investigated in central Anatolia region. Based on the present findings, we may suggest that decreased serum vitamin D levels were associated with migraine. Future large-scale longitudinal studies that overcome this study’s limitations are required to clarify the underlying mechanisms on this subject as well as to assess its role in the clinical evaluation and management of the migraine.
Acknowledgements This study was funded by the Bozok University Scientific Research Project Unit (2013 TF/A38) and was conducted at the Bozok University Hospital.
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, October 2014, 68, 10, 1272–1277
Serum levels of vitamin D in migraine patients
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Paper received December 2013, accepted April 2014