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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 11  |  Issue : 3  |  Page : 228-233

Hyperhomocysteinemia and Vitamin B12 deficiency as a risk factor for ischemic stroke: A case–control study from Northwestern India


Department of Neurology, SMS Medical College, Jaipur, Rajasthan, India

Date of Web Publication25-Sep-2018

Correspondence Address:
Dr. Maulik A Panchal
Department of Neurology, SMS Medical College and Hospital, Jaipur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kleuhsj.kleuhsj_9_18

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  Abstract 


BACKGROUND: Vitamin B12 (B12) deficiency, by virtue of causing hyperhomocysteinemia (HHC), may be implicated as an acquired risk factor of ischemic stroke (IS), which is also easily modifiable. There is a scarcity of data from India regarding the prevalence of B12 deficiency in IS patients.
OBJECTIVES: The objective of this study is to explore the relationship between B12 and folate deficiency, HHC, and IS.
DESIGN: The study was a case–control study.
MATERIALS AND METHODS: Eighty cases of IS were compared with equal number of age- and sex-matched controls. Plasma total homocysteine (tHcy) level, serum B12, and folate levels were analyzed as continuous data (Student's t-test) as well as categorical data (Chi-square test). Odds ratio (OR) for the occurrence of IS was calculated for each variable. Correlation of tHcy with serum B12 and folate was studied using Pearson's coefficient.
RESULTS: Mean homocysteine was higher in cases compared to controls (20.49 ± 12.64 vs. 13.09 ± 6.96 μmol/L, P < 0.001, while B12 (282.46 ± 161.52 vs. 480 ± 248.92 pg/ml, P < 0.001) and folate (10.49 ± 6.86 vs. 17.00 ± 5.52 ng/ml, P < 0.001) were lower. Both HHC (OR 4.48, 95% confidence interval: 1.99–10.07, P + 0.0003) and B12 deficiency emerged as significant risk factors for occurrence of IS. Negative correlation of homocysteine with B12 (r = 0.457, P < 0.0001) and folate (r = 0.337, P = 0.0001) was observed.
CONCLUSIONS: HHC appears to be an important risk factor for IS in Indian population. B12 deficiency is a major acquired cause for the same while folate deficiency is relatively rare.

Keywords: Folate, hyperhomocysteinemia, ischemic stroke, Vitamin B12 deficiency


How to cite this article:
Kumawat BL, Sharma CM, Shah MJ, Panchal MA. Hyperhomocysteinemia and Vitamin B12 deficiency as a risk factor for ischemic stroke: A case–control study from Northwestern India. Indian J Health Sci Biomed Res 2018;11:228-33

How to cite this URL:
Kumawat BL, Sharma CM, Shah MJ, Panchal MA. Hyperhomocysteinemia and Vitamin B12 deficiency as a risk factor for ischemic stroke: A case–control study from Northwestern India. Indian J Health Sci Biomed Res [serial online] 2018 [cited 2018 Dec 15];11:228-33. Available from: http://www.ijournalhs.org/text.asp?2018/11/3/228/242051




  Introduction Top


Stroke is a major cause of morbidity and mortality worldwide. Apart from the traditionally recognized risk factors for ischemic stroke (IS), several potential novel risk factors have emerged over the last two decades. Among these, hyperhomocysteinemia (HHC) has been shown to be associated with IS in systematic reviews of various case–control and cohort studies.[1],[2],[3],[4],[5] The evidence for a causal link between HHC and stroke has also been strengthened by a meta-analytic study based on the principle of Mendelian randomization.[6] HHC has a multifactorial origin including genetic, nutritional, and metabolic factors.[7] Genetic causes include methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and cystathionine beta synthase, but these remain inherently nonmodifiable, at least in the current era. Nutritional factors of HHC include mainly the deficiency of Vitamin B12 (B12) and also of folate and pyridoxine. B12 deficiency, by virtue of causing an increase in serum homocysteine levels, may thus also be implicated as a risk factor for IS. This potentially holds significance as an acquired risk factor for stroke, which is also easily modifiable.

B12 deficiency may hold even more significance in the Indian scenario where a major bulk of the population is vegetarian and the diet is often lacking in milk and dairy products. Besides malnutrition as well as malabsorption is also rampant, especially in the underprivileged sections of the society. Folate deficiency in Indian population is also related to cooking methods like cooking vegetables at high temperature for prolonged period of time which causes destruction of folate. Some hospital- or community-based studies from India have also shown a high prevalence of B12 deficiency in both rural and urban population.[8],[9],[10],[11],[12] There are few studies from India regarding homocysteine levels in IS patients which have shown an association between HHC and stroke.[13],[14],[15],[16],[17] There are fewer studies which in addition to HHC have also looked for B12 or folate deficiency in IS patients.[13],[18]

More data are needed from the Indian subcontinent, and from different parts of the country, to explore the relationship between B12 deficiency, HHC, and risk of IS. Our study was planned in this context and is the first such study from the Northwestern part of the country.


  Materials and Methods Top


A case–control study was done to measure plasma total homocysteine (tHcy), serum B12, and folate levels in patients of acute IS and compare it with age- and sex-matched controls. Sample size was calculated using the power of study 80% and alpha error 0.5%. Minimum difference to be detected between measured values of homocysteine was 2 μmol/L and expected standard deviation was 4 μmol/L (with reference to a previous study from North India by Modi et al.).[14] The cases were selected from the patients of either sex, admitted in neurology ward or within 1 month of the acute event, irrespective of their socioeconomic status or dietary habits. Acute IS was diagnosed on the basis of sudden onset of focal neurological deficit along with a compatible CT scan or MR imaging of the brain.

Exclusion criteria were patients <18 or >60 years of age (patient >60 years were excluded to avoid confounding effect of comorbidities); patients with hemorrhagic stroke, venous infarcts, cardioembolic stroke, strokes due to arterial dissection, nonatherosclerotic vasculopathies, or hypercoagulable states; and patients with coronary artery disease, peripheral vascular disease, chronic kidney or liver disease, hypothyroidism, pregnancy, or collagen vascular diseases. Patients with more than two other well-established risk factors for stroke including diabetes (known case or those with fasting blood sugar >126 or postprandial sugar >200 mg/dl), hypertension(>140/90 mmHg), smoking, dyslipidemia (those with total cholesterol >200, low-density lipoprotein >130, high-density lipoprotein <40 or triglycerides >150 mg/dl), carotid stenosis, and atrial fibrillation were also excluded; and hence were the patients who had taken any B12 injections or oral B12/folate supplements in the preceding 2 years, or those who were on anti-epileptics or other drugs known to increase homocysteine levels. An equal number of sex- and age-matched (age difference <5 years from the cases) controls were taken from among the other patients admitted to neurology ward who did not have stroke and who did not have a neurological illness of the nature or severity that would lead to a nonambulatory state or alteration of dietary habits. The various exclusion criteria for cases applied to the controls as well.

Detailed history (including diabetes, hypertension, previous stroke or transient ischemic attacks, smoking, dietary habits, and drug history) and examination were recorded in all patients. Computed tomography (CT)/magnetic resonance imaging scan of the brain was done to confirm the diagnosis of IS in cases. A carotid Doppler study or CT angiogram of the neck and cerebral vessels, along with a transthoracic echo study was done to look for etiology of stroke in all cases. The cases were then categorized into large artery disease, small artery occlusion, or of undetermined etiology using the TOAST classification system.[19]

Fasting blood samples for plasma tHcy, B12, and folate were withdrawn in all patients. Plasma tHcy was measured by chemiluminescent assay technique (Beckter–Coulman analyzer). B12 and folate were also measured by chemiluminescent enzyme immunoassay technique (Seimens IMMULITE 2000 system). Since it could be debatable whether a definite threshold for HHC and B12 and folate deficiency can be defined, above which the cerebrovascular risks associated with them would appear, and also which would be applicable to different populations, we decided to analyze them both as continuous as well as categorical data.

Statistical analysis

The three main variables under consideration, that is, homocysteine, B12, and folate were analyzed both as continuous data (summarized as mean ± standard deviation and median values), as well as categorical data (summarized as proportions) among cases and controls. For categorical data, HHC was defined as homocysteine >15 μmol/L, B12 deficiency as B12 <200 pg/ml, and folate deficiency as levels <4 ng/ml, all as per internationally accepted values. Homocysteine was studied further among various predefined subgroups based on age, sex, history of diabetes, hypertension, smoking, and dietary habits. Continuous variables were compared using two-tailed unpaired t-test, while categorical/nominal variables were compared using Chi-square test. Adjusted odds ratios (ORs) were calculated to assess degree of risk for individual risk factors under study. All statistical analysis was done using Epi Info software (Centers for Disease Control and Prevention(CDC), Atlanta, Georgia). P < 0.05 was considered as statistically significant.

Ethical considerations

The study was approved by the institutional ethics committee. The study required a simple venepuncture procedure in all patients for sample collection.


  Results Top


An equal number (n = 80) of cases and controls were taken, with equal number of males and females and equal number of patients <40/>40 years of age in both the groups. The mean age was 40.71 ± 9.46 years in cases and 40.77 ± 10.09 years in controls. The proportion of hypertensives was much higher among cases, whereas the proportions of smokers, patients with diabetes, and vegetarians were comparable [Table 1].
Table 1: Baseline sociodemographic and stroke risk factors of the study population

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[Table 2] compares the mean and median values of homocysteine, folate, and B12 levels in the two groups. Mean homocysteine level was significantly higher, whereas mean levels of B12 and folate were significantly lower in cases compared to controls. Alternatively, the proportion of patients with HHC (>15 μmol/L) and B12 deficiency (<200 pg/ml) was significantly higher in cases (P < 0.001). Folate deficiency (<4 ng/ml) was found in 5 cases only and in none of the controls [Figure 1]. There were 52 cases of large artery disease, 23 cases of small artery occlusion, and 5 cases of undetermined etiology. The mean homocysteine level was higher in cases with small artery occlusion than those with large artery disease (25.31 ± 13.72 vs. 18.63 ± 11.92 μmol/L), but the difference did not achieve statistical significance (P = 0.089). Subgroup analysis revealed higher mean values of homocysteine in males, smokers, hypertensives, and vegetarians in both cases and controls, but the differences achieved statistical significance only in two subgroups: males versus females and smokers versus nonsmokers, among the cases. Median values also followed a similar trend in the above subgroups. No specific pattern was observed between patients <40 and >40 years of age and in patients with diabetes versus nondiabetics.
Table 2: Mean and median values of different variables among cases and controls

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Figure 1: Hyperhomocysteinemia, Vitamin B12 deficiency, and folate deficiency among cases versus controls

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The mean levels of B12 were lower in vegetarians compared to nonvegetarians in both cases (261.77 ± 160.41 vs. 367.86 ± 147.44 pg/ml) and controls (444.09 ± 255.79 vs. 562.20 ± 210.96 pg/ml), but the differences did not reach statistical significance. The comparison was done for the homocysteine levels in vegetarians and nonvegetarians among cases and controls, and the homocysteine was significantly (P < 0.0001) high among vegetarians who developed stroke than who did not develop stroke. Moreover, homocysteine levels were high (P = 0.0216) also among the nonvegetarians, although not as high as vegetarians [Figure 2]. No specific pattern was found in the difference of folate levels between vegetarians and nonvegetarians.
Figure 2: Mean homocysteine levels according to dietary habits in cases and controls

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Adjusted OR for the occurrence of stroke for individual risk factors is shown in [Table 3]. HHC (>15 μmol/L) and B12 deficiency (<200 pg/ml) emerged as significant risk factors for the occurrence of stroke in the present study in addition to hypertension.
Table 3: Adjusted odds ratio for occurrence of stroke for individual risk factors

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  Discussion Top


The present study revealed a statistically significant higher mean homocysteine level in cases of IS as compared to controls. Three previous studies from North India have also shown a similar difference in mean homocysteine levels in cases versus controls (Modi et al. – 9.9 vs. 8.0 μmol/L, Narang et al. – 16.8 vs. 12.3 μmol/L, and Biswas et al. – 12 vs. 11.2 μmol/L.[14],[16],[17] But in contrast to these studies, relatively higher values of homocysteine was observed in both cases and controls in our study. These findings might be reflective of a higher prevalence of HHC in the population our hospital caters to. This assumption can however only be confirmed by a large-scale community-based study in this particular part of the country. In a large community-based study by Yajnik et al. from Pune compromising both rural and urban population, HHC was found in 58% of the participants.[12] Another study from Maharashtra with participants from urban higher socioeconomic strata showed mean homocysteine levels to be as high as 21.96 μmol/L in males and 15.9 μmol/L in females.[20] A smaller study from Delhi found the mean homocysteine levels to be 23.2 and 20.8 μmol/L in the urban nonslum-dwelling and slum-dwelling population, respectively, with HHC present in 84% of the participants overall.[11],[21]

The subgroup analysis in the present study revealed a statistically significant difference in mean homocysteine levels only in males versus females and smokers versus nonsmokers among the cases. Previous Indian studies in IS patients have shown higher levels among hypertensives as well.[14],[16] The Hordland homocysteine study had shown increasing age, male sex, and smoking among the strongest determinants of plasma homocysteine concentration in a multivariate analysis, while a weaker positive association with blood pressure was observed.[22],[23] The European Concerted Action project had also concluded that the vascular risk factor of homocysteine got amplified in the presence of either smoking or hypertension.[24] The discrepancy observed on statistical analysis from previous studies could be the result of smaller sample size as well as skewed data resulting in a greater standard deviation in the present study. We found a statistically insignificant difference in the mean homocysteine values among patients with small artery occlusion compared to those with large artery disease. Similar observations have been made by Modi et al. and Lindgren et al. who did not find an independent association of HHC with any particular stroke type.[14],[25] Parnetti et al. also found HHC to be associated with all stroke types including large vessel, small vessel, and cardioembolic disease.[26]

Indeed looking at the multitude of mechanisms of vascular damage with homocysteine, which includes endothelial dysfunction, proliferation of vascular smooth muscle cells, increased oxidative stress, alteration of lipid metabolism, and induction of thrombosis, it seems unlikely that the cerebrovascular risk associated with HHC would be limited to any specific stroke subtype only.

HHC (and B12 deficiency) emerged as significant risk factors for occurrence of stroke in the present study. As noted earlier, the etiology of HHC can be multifactorial. In an attempt to minimize confounding factors, we had excluded patients with renal failure, hypothyroidism, other major systemic illnesses, and also those taking drugs known to cause HHC, at the outset. A significantly higher proportion of HHC as well as B12 deficiency in our cases compared to controls, along with good degree of negative correlation between the two variables, suggest that B12 deficiency was one of the major contributors to HHC in our patients and hence can be regarded as a potential risk factor for IS. A previous study from Maharashtra by Wadia et al. examining the association of E312 deficiency with IS, had also suggested that nutritional B12 deficiency was the major cause of HHC in their patients of IS, both arterial and venous.[13] The problem of B12 deficiency in the Indian population and its varied ramifications are rather underappreciated by the medical fraternity. There have been only few large studies in India so far studying the prevalence of B12 and folate deficiency. Refsum et al. found B12 deficiency in nearly half of their participants and also noted a strong negative correlation between homocysteine and B12 (r = 0:59). The mean serum B12 was 154 pg/ml, even though 62% of participants were nonvegetarians.[9] Similarly, Yajnik et al. found B12 deficiency in 67% of their community-based participants, and a strong inverse relationship between B12 and homocysteine (r = 0.41).[12] Both the authors did a detailed analysis of dietary habits of their participants and concluded that though B12 deficiency was more commonly associated with vegetarianism, the food habits could only partly explain the high prevalence of B12 deficiency.

The proportion of vegetarians in our cases and controls are almost comparable, but a larger difference in the proportion of B12 deficient in the two groups have been obtained, again suggesting that other factors like impaired intestinal absorption of B12 must be at play in the population group our participants came from. In addition, B12 deficiency could be prevalent in nonvegetarians as well due to expense and scarcity of meat ingestion.

Only 5% of participants of Refsum et al. were deficient in folate, and the mean folate was 12 ng/ml.[9] Folate deficiency was uncommon in participants of Yajnik et al. as well as varying from 5% to 12% in different subgroups.[12] In the NNNB survey, the average folate intake in Indian diet was 150 pg/day which appeared to meet the recommended daily allowance of 100 pg/day for a healthy Indian adult. About 60% of this intake came from cereals or millets along with pulses, which in some form or another are a part of staple diet of most of the Indian population.[27],[28] The staple diet of an average Rajasthan household consist of wheat, millet, and maize, and the dietary adequacy of folate appears to be the reason why folate deficiency was found in only 5 of the 160 participants. There are several limitations to our study. We could not do an MTHFR gene polymorphism analysis, and hence, we are unable to comment on what role genetic polymorphism had to play in causing HHC in our study participants. MTHFR gene polymorphism associated with HHC in IS patients has been found in some studies from other parts of India and could be a significant risk factor in our population group as well.[17],[29],[30] Second, the measurement and interpretation of levels of homocysteine and other analytes in the days following the acute stroke event may also be debatable.[30],[31] Raised homocysteine could be an epiphenomenon of the acute stressful event rather than an actual risk factor for stroke.[32] Furthermore, there can be factors such as hydration status and nutritional status of the patient that can affect the overall laboratory results.

Finally, the present study does show an association between B12 deficiency, HHC, and IS, but like any other observational study, it falls way short of proving an epidemiological causation. Causation can only be proven if treating the presumed risk factor; B12 deficiency in this case, results in a subsequent reduction of cerebrovascular risk.

Over the last decade, some very large, international trials including HOPE-2, VISP, and VITATOPS have attempted to answer the question whether homocysteine-lowering therapy with multivitamin supplementation has a role to play in decreasing cardiovascular risk, but the initially published results were largely disappointing. However, questions have been raised about the interpretation of their results or presence of factors confounding the analysis.[33] There was indeed a significant relative risk reduction in nonfatal stroke in the HOPE-2 trial, even though no reduction in the composite primary outcome was seen.[34] In a subsequent efficacy analysis of the VISP trial, after excluding patients in either arm who had received B12 injections, and also patients of renal failure, high-dose oral vitamin therapy was indeed found to reduce the stroke and coronary events risk significantly.[35] Also in VITATOPS, there was a significant reduction in the primary outcome among patients with normal creatinine levels but not in their counterparts, raising a question whether the final results have been confounded by inclusion of patients with renal dysfunction.[36] Needless to say, proving or disproving a role of homocysteine-lowering therapy with multivitamins in stroke prevention remains a herculean task in the near future.


  Conclusions Top


We emphasize that HHC appears to be an important risk factor for IS in our population group, and B12 deficiency has a major role to play in its causation, while folate deficiency is relatively rare. Both prevention and treatment of B12 deficiency may thus have important implications in primary as well as secondary prevention of IS. More studies are needed to further explore the relationship between B12 deficiency and IS and also to assess the relative contributions of nutritional deficiencies and genetic polymorphism in the causation of HHC in the Indian population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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