Changes of Target Essential Trace Elements in Multiple Sclerosis: A Systematic Review and Meta-Analysis

Abstract

(1) Background: Multiple sclerosis (MS) is a chronic, complex, and demyelinating disease closely associated with altered levels of trace elements. Although the first studies into the role of trace elements in MS were published in the 1970s, for five decades it has remained unknown whether trace elements can be part of this heterogeneous neurological disease. (2) Materials and methods: To drive toward at a potential solution, we conducted a systematic review and meta-analysis to elucidate whether there were differences in circulating levels of neurologically important essential trace elements (Zn, Fe, Co, Cu, Mn, and Se) between MS cases and controls. (3) Results: This study revealed significantly lower serum/plasma Zn and Fe levels and higher Cu levels in MS-affected individuals compared to controls. At the same time, no significant differences were found between the MS cases and controls regarding their serum/plasma levels of Co, Mn, or Se. Thus, the loss of Fe and Zn should be considered in supplementation/nutrition strategies for MS patients. On the other hand, since high serum Cu levels indicate a burden on the bloodstreams of MS patients, Cu should be excluded from mineral supplement strategies. Furthermore, all three trace elements (Fe, Zn, and Cu) should be considered from an etiological point of view, and, most importantly, their levels in the bloodstreams of MS patients should be monitored. (4) Conclusions: This study highlights the way for personalized and targeted strategies in the management of MS.

Keywords: deficiency; essential trace elements; monitoring; multiple sclerosis (MS); supplementation.

Figure 1

Focused Comprehensive Network Visualization of: (A). a total of 5051 registered multiple-sclerosis-related author keywords in scholarly literature; (B). 672 detected multiple sclerosis and trace-element-related author keywords in scholarly literature; (C). 27 most commonly used multiple-sclerosis- and trace-element-related author keywords in scholarly literature.

Figure 2

PRISMA flow diagram illustrating literature search, study identification, inclusion, and exclusion process. Abbreviation: n (number of studies).

Figure 3

Forest plot for random-effects meta-analysis. Differences in serum/plasma Zn levels between controls and cases are shown. The size of each square is proportional to the weight of the study. The diamond symbol indicates the pooled total effect size for the set of studies included in the meta-analysis. Abbreviation: CI = confidence interval [37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59].

Figure 4

Funnel plots to assess publication bias in observed studies comparing Zn levels in the serum/plasma of controls and cases. The figure shows the effect size (Hedges’s g) of the studies against their precision (inverse of SE). The circles represent observed studies. The diamond symbol indicates the pooled overall effect size based on the observed studies. Egger’s regression test: t₂₂ = −3.231, p = 0.313; Begg and Mazumdar rank correlation: Kendall’s τ = −0.095, p = 0.526.

Figure 5

Forest plot for random-effects meta-analysis. Differences in serum/plasma Fe levels between controls and cases are shown. The size of each square is proportional to the weight of the study. The diamond symbol indicates the pooled total effect size for the set of studies included in the meta-analysis. Abbreviation: CI = confidence interval [44,50,51,56,57,58,60,61,62,63,64,65,66,67,68].

Figure 6

Funnel plots to assess publication bias in observed studies comparing Fe levels in the serum/plasma of controls and cases. The figure shows the effect size (Hedges’s g) of the studies against their precision (inverse of SE). The circles represent observed studies. The diamond symbol indicates the pooled overall effect size based on the observed studies. Egger’s regression test: t₁₅ = 5.273, p = 0.323; Begg and Mazumdar rank correlation: Kendall’s τ = 0.235, p = 0.207.

Figure 7

Forest plot for random-effects meta-analysis. Differences in serum/plasma Co levels between controls and cases are shown. The size of each square is proportional to the weight of the study. The diamond symbol indicates the pooled total effect size for the set of studies included in the meta-analysis. Abbreviation: CI = confidence interval [37,44,45,46,47,48,49,50,56,57,69].

Figure 8

Funnel plots to assess publication bias in observed studies comparing Co levels in the serum/plasma of controls and cases. The figure shows the effect size (Hedges’s g) of the studies against their precision (inverse of SE). The circles represent observed studies. The diamond symbol indicates the pooled overall effect size based on the observed studies. Egger’s regression test: t₅ = 0.583, p = 0.944; Begg and Mazumdar rank correlation: Kendall’s τ = 0.200, p = 0.707.

Figure 9

Forest plot for random-effects meta-analysis. Differences in serum/plasma Cu levels between controls and cases are shown. The size of each square is proportional to the weight of the study. The diamond symbol indicates the pooled total effect size for the set of studies included in the meta-analysis. Abbreviation: CI = confidence interval [37,38,41,46,48,49,50,55,56,57,58,59,60,65,66,67,68,69,70,71,72,73].

Figure 10

Funnel plots to assess publication bias in observed studies comparing Cu levels in the serum/plasma of controls and cases. The figure shows the effect size (Hedges’s g) of the studies against their precision (inverse of SE). The circles represent observed studies. The diamond symbol indicates the pooled overall effect size based on the observed studies. Egger’s regression test: t₂₁ = −7.244, p = 0.021; Begg and Mazumdar rank correlation: Kendall’s τ = −0.363, p = 0.018.

Figure 11

Forest plot for random-effects meta-analysis. Differences in serum/plasma Mn levels between controls and cases are shown. The size of each square is proportional to the weight of the study. The diamond symbol indicates the pooled total effect size for the set of studies included in the meta-analysis. Abbreviation: CI = confidence interval [37,44,50,56,57,69,72].

Figure 12

Funnel plots to assess publication bias in observed studies comparing Mn levels in the serum/plasma of controls and cases. The figure shows the effect size (Hedges’s g) of the studies against their precision (inverse of SE). The circles represent observed studies. The diamond symbol indicates the pooled overall effect size based on the observed studies. Egger’s regression test: t₆ = −3.218, p = 0.769; Begg and Mazumdar rank correlation: Kendall’s τ = −0.000, p = 1.000.

Figure 13

Forest plot for random-effects meta-analysis. Differences in serum/plasma Se levels between controls and cases are shown. The size of each square is proportional to the weight of the study. The diamond symbol indicates the pooled total effect size for the set of studies included in the meta-analysis. Abbreviation: CI = confidence interval [37,42,44,48,74,75,76,77,78,79].

Figure 14

Funnel plots to assess publication bias in observed studies comparing Se levels in the serum/plasma of controls and cases. The figure shows the effect size (Hedges’s g) of the studies against their precision (inverse of SE). The circles represent observed studies. The diamond symbol indicates the pooled overall effect size based on the observed studies. Egger’s regression test: t₉ = −4.292, p = 0.089; Begg and Mazumdar rank correlation: Kendall’s τ = −0.400, p = 0.107.