Clinical Study
Meta-analysis of the relationship between homocysteine, vitamin B12, folate, and multiple sclerosis

https://doi.org/10.1016/j.jocn.2010.12.022Get rights and content

Abstract

A meta-analysis was conducted to assess the relationship between serum homocysteine, vitamin B12, and folate levels in patients with multiple sclerosis (MS). The DerSimonian and Laird Q test was used to evaluate the degree of heterogeneity between studies and a funnel plot was used to assess publication bias. The pooled effect size (standardized mean difference [SMD]) between patients with MS and control patients) from a random effects model was 0.84 (95% confidence interval: 0.18, 1.49) for homocysteine and –0.25 (–0.45, –0.04) for vitamin B12, and from a fixed effects model was 0.98 (0.80, 1.16) for homocysteine and –0.25 (–0.41, –0.09) for vitamin B12. Both nutrients were statistically significant, but the SMD for folate was not. Patients with MS were found to have raised homocysteine levels but low B12 levels, which might contribute to the pathogenesis of MS.

Introduction

Multiple sclerosis (MS) is a neurological disease characterized by inflammation and demyelination of the central nervous system (CNS).1 The cause of MS is unknown but complex interacting genetic and environmental factors are thought to be involved.[2], [3] In particular, the relationship between the immune and neurohormonal systems is important.4

Homocysteine is a neurotoxic amino acid that accumulates in patients with neurodegenerative disorders including Alzheimer’s disease,5 Parkinson’s disease,6 Huntington’s disease,7 and primary dystonia.8 Large epidemiological studies indicate that high homocysteine levels may be a risk factor for neurodegenerative conditions.[9], [10] The presence of elevated blood homocysteine levels in disorders of the CNS, and identification of vitamin B12 or folate deficiencies in patients with MS, has prompted investigation of homocysteine levels in MS.11 Homocysteine is produced during methionine metabolism, and is removed either by conversion to cysteine or by remethylation to methionine. Methylation processes are vital for normal cell function because of their key role in protein, lipid, and DNA metabolism, gene expression, and myelination. Homocysteine can also directly damage CNS cells or influence macrophage activation, both of which are important aspects of MS pathology.[12], [13], [14] Increased serum homocysteine levels may therefore have a neurodegenerative effect and may be a risk factor for neurological decline in MS.[15], [16] Certain nutritional deficiencies are important as are common determinants of elevated homocysteine levels, particularly vitamin B12 and folate, which relate inversely to serum homocysteine levels.17 Interestingly, homocysteine levels may increase in patients with MS compared with healthy patients, while vitamin B12 or folate levels remain unaffected.[18], [19], [20], [21] However, not all studies have demonstrated a relationship between elevated serum homocysteine and MS.[22], [23]

The association between B-vitamin deficiency and elevated homocysteine levels in MS might indicate that higher levels of homocysteine play a role in the etiology of MS. This study aimed to examine the relationship between homocysteine, vitamin B12, folate and MS by conducting a meta-analysis of case–control studies. This is the first meta-analysis on this subject, although other work has summarized existing knowledge.[18], [19], [20], [21], [22], [23]

Section snippets

Literature search

Eligible studies were identified by searching the electronic literature (MEDLINE and EMBASE) for relevant reports published before May 2009, using the search terms “homocysteine”, “hyperhomocysteinemia”, “vitamin B12” or “folate”, and “multiple sclerosis”. In addition, we performed a manual search of reference lists for original articles. We also studied special meeting issues of journals to identify abstracts not usually included in computer indices. We identified 31 studies for homocysteine

Identified studies

Thirty-one reports on the role of homocysteine levels in MS were identified in the literature. We excluded 20 studies for the following reasons: homocysteine was measured in cerebrospinal fluid (CSF), the publications dealt with other topics, or they were not available as full text articles. The primary search identified 11 potentially relevant studies, of which eight met the selection criteria.[19], [20], [22], [23], [29], [30], [31], [32] Of the three articles excluded, one was a duplication

Discussion

This is the first meta-analysis to evaluate the association between serum homocysteine, vitamin B12, folate levels, and MS. The principal observation is that MS is moderately associated with elevated serum homocysteine levels, with an SMD of 0.84 (0.18, 1.49), which is statistically and perhaps clinically significant. This finding must be interpreted with some caution because of the significant observed heterogeneity among the homocysteine studies in this meta-analysis. Similarly, serum vitamin

Conclusion

The cause of MS, an inflammatory demyelinating disease, is unknown. The condition cannot be fully explained by genetic factors and other risk factors are unclear. Elevated homocysteine levels and lower vitamin B12 levels are related to MS, indicating a role for the transmethylation pathway in MS. Although the results of this meta-analysis on homocysteine and vitamin B12 are robust and stable (that is, not substantially altered by excluding any individual study), its effect size was moderate.

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