Serum levels of Homocysteine, Vitamin B12 and Folate in Patients with Multiple Sclerosis: an Updated Meta-Analysis

Int J Med Sci. 2020 Mar 5;17(6):751-761. doi: 10.7150/ijms.42058. eCollection 2020.


Background: Multiple sclerosis (MS) is a demyelinating and disabling inflammatory disease of the central nervous system. MS is triggered by complex environmental factors which mostly affect genetically the susceptible young people. Emerging data has suggested that changes of homocysteine (Hcy), Vitamin B12 and folate serum levels may be associated with MS. However, previous findings are not always consistent. Methods: In this study, we aimed to investigate the relationships between MS and Hcy, Vitamin B12 and folate with updated available data (until September, 2019). The diagnosis of MS was performed based on international criteria for the diagnosis of MS, including magnetic resonance imaging and cerebrospinal fluid tests. We searched the databases including PubMed, EMBASE, Cochrane Library and ScienceDirect. After data collection, separate analyses based on random-effect models were used to test for relationships between MS and Hcy, Vitamin B12 or folate blood levels. The effective sizes were estimated by the combined standardized mean difference (SMD) and associated 95% confidence interval (CI). Results: Based on the inclusion criteria, a total of 21 original studies with 1738 MS patients and 1424 controls were included in this study. There were 17 studies for measuring Hcy, 16 studies for measuring Vitamin B12 and 13 studies for measuring folate in patients with MS, respectively. Specifically, patients with MS had higher serum levels of Hcy (SMD: 0.64; 95% CI:0.33, 0.95; P <0.0001) compared with control groups. There were no significant differences of SMD for Vitamin B12 (SMD: -0.08; 95% CI: -0.35, 0.20; P=0.58) or folate (SMD: 0.07; 95% CI: -0.14, 0.28; P=0.52) between MS and controls. Subgroup analysis demonstrated that there was statistically significant difference for Hcy between relapsing-remitting MS (RRMS) patients and controls with a SMD of 0.67 (95% CI: 0.21, 1.13; P=0.004). However, no significant difference of Hcy serum levels between secondary progressive MS patients or primary progressive MS patients and controls was noted in this study. In addition, there was no significant difference of Hcy levels in females (SMD: 0.22; 95% CI: -0.16, 0.60; P=0.25) or males (SMD: 0.56; 95% CI: -0.13, 1.26; P=0.11) between MS patients and controls. Conclusions: Higher serum levels of Hcy were noted in patients with MS when compared with control groups. And the difference was especially significant between RRMS patients and controls. Hcy may play an important role in the pathogenesis of MS. Functional studies are required to assess the effects of Hcy on patients with MS at the molecular level.

Keywords: Folate; Homocysteine; Meta-analysis; Multiple sclerosis; Vitamin B12.

Publication types

  • Meta-Analysis

MeSH terms

  • Adult
  • Case-Control Studies
  • Disease Progression
  • Female
  • Folic Acid / blood*
  • Homocysteine / blood*
  • Humans
  • Male
  • Middle Aged
  • Multiple Sclerosis / blood*
  • Multiple Sclerosis / epidemiology
  • Multiple Sclerosis / pathology
  • Vitamin B 12 / blood*


  • Homocysteine
  • Folic Acid
  • Vitamin B 12