Status of Vitamin D and its Association with Stroke Risk Factors in Patients with Acute Ischemic Stroke in a Tertiary Care Hospital

Introduction: Vitamin D deficiency has been associated with many neurological illnesses. The status of Vitamin D in Nepalese ischemic stroke patients is still unknown. This study aims to assess the status of vitamin D and its association with stroke risk factors in patients with acute ischemic stroke from Central Nepal. Methods: A total of 60 patients with ischemic stroke were included in the study. Their clinical profile and Vitamin D status were assessed. Frequency distribution, Pearson χ2test and Kruskal-Wallis test were performed for statistical analysis using SPSS-IBM 20. results: The median (IQR) age of the patient was 65 (53.25, 70.75) years, ranging from 18-87 years. Thirty-four (56.7%) were males. Fourty-eight (80%) patients had hypertension and 34 (56.7%) were smoker. Previous stroke was present in six (10%) cases. Thirty-seven (61.6%) patients had low levels of Vitamin D out of which 26 (43.3%) had vitamin D insufficiency and 11 (18.3%) had vitamin D deficiency. Vitamin D level was significantly associated with previous history of stroke (P=0.043). conclusions: Vitamin D deficiency occurs in patients with ischemic stroke. Previous episodes of stroke with low vitamin D levels could be a cause of recurrent strokes. Further studies are necessary to establish the role of vitamin D in acute ischemic stroke in Nepalese population. _______________________________________________________________________________________


IntroductIon
Vitamin D has roles in immunity, cardiovascular and cerebrovascular physiology 1 and its deficiency might be involved in the development of several diseases, including arterial hypertension, diabetes mellitus, heart failure, 2 acute myocardial infarction 3 and stroke. 4 Its antitumor property has been studied in breast, 5 prostate, 6 and colon cancers. 7 The overall health importance of vitamin D is further supported by a meta-analysis that found a significant reduction of total mortality in patients who received vitamin D. 8 research on the role of supplementary vitamin D in acute ischemic stroke patients. Therefore, this study was conducted to assess the status of vitamin D and its association with stroke risk factors in patients with acute ischemic stroke from Central Nepal.

Methods
This was a cross sectional study conducted from Jan 2013 to May 2013 in patients admitted to the Neurology Department of College of Medical Sciences-Teaching Hospital with the diagnosis of ischemic stroke. An informed consent was obtained from all the patients and those refusing to investigate their vitamin D levels were excluded from the study. Demographic profile, blood pressure, risk factors of stroke and vitamin D level were recorded.
Hypertension was defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, or use of antihypertensive therapy. 12 Diabetes mellitus was diagnosed when fasting plasma glucose ≥ 126mg/ dl or two hr post-prandial plasma glucose ≥ 200 mg/ dl or random plasma glucose ≥ 200mg/dl or HBA1c ≥ 6.5% or patient already diagnosed and on treatment, based on American Diabetes Association Guidelines. 13 Dyslipidemia was defined as total cholesterol ≥ 240 mg/dl or LDL ≥ 160 mg/dl, or patient on lipid lowering drugs. 14 Vitamin D levels ≥ 30 ng/ml was taken as normal in our study. Low vitamin D levels (< 30 ng/ ml) were classified into insufficiency (20 -29ng/ml) and deficiency (<20 ng/ml) states. 2,15 The association between risk factors and vitamin-D level was determined using Pearson χ 2 test whereas the association between the continuous variables and vitamin-D level was determined using Kruskal-Wallis test. All the analysis was done using SPSS-IBM-20 and P<0.05 was taken as significant.

results
A total of 60 patients were included in this study. The median (IQR) age of the patient was 65 (53. 25 The one sample chi-square test for vitamin D level showed that there is statistically significant differences in the various categories of vitamin D level with previous history of stroke (P=0.043). There were six patients who had a previous history of stroke and none of these patients had a normal level of vitamin D, instead 50% of these patients had insufficient vitamin D level and remaining 50% had deficient level (Table 2).

dIscussIon
The association of gender with vitamin D level showed that more females (5%) had lower vitamin D levels as compared to males though males in our study were higher (13.4%) than the females. Though this relationship is not statistically significant (P=0.078) this might suggest that taking vitamin D deficient state into consideration, females are at more risk of having stroke than males.
Most of our patients were elderly (median age 65yrs) and there was no significant difference in the median age of patients at various levels of vitamin D. Low levels of 25-OH-vitamin D are present in at least half of the elderly population. 2,10,16 Also, this age group is more prone to cerebrovascular diseases such as stroke. 17 Studies have been done to find out whether the vitamin D deficiency observed in elderly is associated to stroke. A study done by Poole et al observed reduced vitamin D levels (77%) in acute stroke showing vitamin D deficiency as a potential risk marker for stroke. 4 Low vitamin D levels were seen in 61.6% of our ischemic stroke patients (18.3% in deficiency and 43.3% in insufficiency levels). A study done by Pilz et al have showed that low levels of 25(OH)D and 1,25(OH)2 D were independently predictive of fatal stroke, thus explaining vitamin D supplementation as a promising approach in prevention of stroke. 10 Stepwise decrease in 25-OH-D levels were associated with stepwise increase in risk of symptomatic ischemic stroke in a large population-based prospective study. 18 Several theories and mechanisms have been explained to describe how vitamin D deficiency can lead to stroke. Vitamin D receptors have a broad tissue distribution including vascular smooth muscle 19 and endothelium. 20 Furthermore, vitamin D deficiency influences vascular remodeling through modulation of smooth muscle cell proliferation, 21 inflammation 22 and thrombosis. 23 Also, vitamin D deficiency leads to secondary hyperparathyroidism, and the increase in parathyroid hormone promotes myocyte hypertrophy 24 and vascular remodeling. 25 Parathyroid hormone related protein (PTHrP) acts as a proinflammatory cytokine and may contribute to the instability of the atherosclerotic plaques. 26 These vascular changes are eventually responsible to cause stroke.
Deficiency of vitamin D has been associated with hypertension, 27 diabetes mellitus,28 and hyperlipidemia, 29 which are the known risk factors for stroke. 30 In our study, most of the patients who had risk factors for stroke such as hypertension, diabetes mellitus, dyslipidemia, smoking, alcohol intake, atrial fibrillation and previous history of stroke had low levels of vitamin D, suggesting role of vitamin D in these risk factors leading to stroke.
Vitamin D deficiency is associated with increase in renin expression and angiotensin II production, leading to hypertension. 31 In a prospective cohort study, plasma 25-OH-D has been inversely associated with risk of incident hypertension. 27 Hypertension was the most common (48, 80%) modifiable risk factor in our study, and 62.5 % of those hypertensives had low vitamin D levels suggesting clinical significance. However, there was no statistically significant association between hypertension and vitamin D level.
All the patients with previous history of stroke had either insufficient (20-29 ng/ml) or deficient (<20 ng/ ml) vitamin D levels, suggesting vitamin D insufficiency or deficiency as a risk factor for recurrent stroke. On the other hand, stroke patients are elderly with some neurological deficit or bed-bound, with poor exposure to sunlight and low dietary intake, which predispose them to suffer from vitamin D deficiency and its further consequences, stroke probably being one of them. 32 This necessitates follow up of these patients, and monitoring of any vascular events in the future correlating with their changing vitamin D status. The statistically significant relationship of previous history of stroke with vitamin D level along with its clinical relevance suggests that vitamin D supplement might be essential for patients who had first ever stroke to prevent recurrent stroke.
Despite of their proved and possible clinical significance, as none of the modifiable and non-modifiable risk factors except previous history of stroke showed statistically significant relationship with vitamin D level in our study, further study in larger population is suggestive.

conclusIons
Majority of stroke patients have low level of vitamin D. Previous episodes of stroke with low vitamin D levels could be a good predictor of recurrent strokes. Linking vitamin D deficiency with increased strokes suggests role of vitamin D supplementation as a promising strategy to prevent strokes. But there are no enough studies to advocate vitamin D supplementation to prevent strokes in high risk individuals; or to prevent recurrent strokes in patients with past history of such vascular events.
Further studies are recommended to show indirect or direct causal relationship between vitamin D deficiency and stroke, and vitamin D supplementation in preventing strokes and its recurrences.