C-reactive protein (CRP), a marker of chronic inflammation, has a major role in the etiology of chronic disease. Vitamin E may have anti-inflammatory effects. However, there is no consensus on the effects of vitamin E supplementation on CRP levels in clinical trials. The aim of this study was to systematically review randomized controlled trials (RCTs) that report on the effects of vitamin E supplementation (α- and γ-tocopherols) on CRP levels. A systematic search of RCTs was conducted on Medline and EMBASE through PubMed, Scopus, Ovid and Science Direct, and completed by a manual review of the literature up to May 2014. Pooled effects were estimated by using random-effects models and heterogeneity was assessed by Cochran’s Q and I2 tests. Subgroup analyses and meta-regression analyses were also performed according to intervention duration, dose of supplementation and baseline level of CRP. Of 4734 potentially relevant studies, only 12 trials met the inclusion criteria with 246 participants in the intervention arms and 249 participants in control arms. Pooled analysis showed a significant reduction in CRP levels of 0.62 mg/l (95% confidence interval=−0.92, −0.31; P<0.001) in vitamin E-treated individuals, with the evidence of heterogeneity across studies. This significant effect was maintained in all subgroups, although the univariate meta-regression analysis showed that the vitamin E supplementation dose, baseline level of CRP and duration of intervention were not the sources of the observed heterogeneity. The results of this meta-analysis suggest that supplementation with vitamin E in the form of either α-tocopherol or γ-tocopherol would reduce serum CRP levels.
Chronic inflammation is an important aspect of the development of cardiovascular disease, and is related to the pathogenesis of many diseases such as atherosclerosis, diabetes and metabolic syndrome.1, 2, 3 C-reactive protein (CRP) is an acute phase reactant protein and a biomarker for inflammation status. Its serum level increases during inflammatory conditions or any stresses such as infection, surgery lesions and trauma.1, 4 This 115 kDa protein belongs to the pentraxin family and is composed of five identical subunits, which are synthesized in the liver.4, 5 Many previous studies have shown that CRP levels are a strong predictor of future cardiovascular disease.6, 7, 8
There are two main forms of vitamin E in the human body, α-tocopherol and γ-tocopherol, which are different from each other in degree of methylation and position of methyl groups on the chromanol ring. The vitamin E found in nature contains three chiral centers with a configuration of ‘R’ at three positions, so is known as RRR-α-tocopherol. Synthetic vitamin E, commonly referred to as all rac-α-tocopherol, is a mixture of eight possible α-tocopherol stereoisomers in equal amounts. The biological activity of natural RRR-α-tocopherol is higher than that of the synthetic all rac-α-tocopherol and other natural forms of vitamin E.9 Several studies have shown that vitamin E has antioxidant properties and can break the chain formation of free radicals.10, 11, 12 Recently, much evidence has supported the idea that this vitamin also can acts as an anti-inflammatory agent by suppressing the release of inflammatory cytokines such as interleukin 6 (IL-6).13, 14, 15 Vitamin E, especially α-tocopherol, isoforms are used as a common supplement in clinical practice, and there are some studies showing that this vitamin can reduce circulating CRP concentration as a result of its anti-inflammatory effects, mainly due to lowering pro-inflammatory cytokines such as IL-1β. However, there is little consistency in the significance and magnitude of the effect of vitamin E on CRP levels. For example, Aryaeian et al. showed that 400 IU/day vitamin E supplementation for 3 months did not significantly decrease serum levels of CRP in adults with active rheumatoid arthritis.16 In contrast, Bhattacharya et al. showed that 3 months supplementation with 200 IU/day vitamin E significantly decreased the serum level of CRP in patients with knee osteoarthritis.17 Because of these conflicting reports in the literature, we conducted this meta-analysis to assess the effect of vitamin E supplementation on CRP levels in randomized controlled trials.
Materials and Methods
Search strategy and study selection
We conducted our search in PubMed, Scopus, Ovid and Science Direct up until 10 May 2014. Publications with the following search words in the titles, abstracts or keywords of the original studies were included: 'Tocopherols’[Mesh] or ‘Vitamin E’[Mesh] and ‘CRP’ or ‘C-Reactive Protein’[Mesh]. The search was limited to publications in English.
Only published articles were searched for this meta-analysis. The following criteria were used for a publication to be included in the meta-analysis: (1) any published clinical trials on supplementation with tocopherol isoforms of vitamin E, including either α- or γ-tocopherol, (2) dose equal to or exceeding 100 IU/day administered orally, (3) reported serum or plasma CRP levels in intervention and control groups, separately.
We excluded (1) studies with combined supplementation of vitamin E and lifestyle change or dietary modification and co-supplementation of vitamin E with multivitamins or other antioxidants; (2) studies in which vitamin E was administered as fortified food; (3) randomized controlled trials that used cluster randomizations and cross-over studies; (4) trials without control or placebo groups; (5) repeated studies, the results of the trials which were published in more than one article; (6) abstracts, because of insufficient information; and (7) dissertations, because the full text was rarely available.
Data extraction and quality assessment
Two independent researchers reviewed all identified studies for titles and abstracts of articles for relevance to the topic, and then retrieved the full-text articles for those that were potentially relevant. A screening form was used to select eligible articles. The quality control of the articles was performed independently by two authors (SS and EY) and any disagreement solved by discussion or help of third author (SSH).
Characteristics of studies were abstracted including first author, publication year, country of origin, journal name; study design, trial duration; number of participants in control and intervention groups; type and dose of daily vitamin E. Participant characteristics consisted of sex, mean age, mean body mass index, number of smokers, baseline and after intervention level of serum CRP. Studies with two independent strata were considered as two studies. All CRP levels recorded as mg/l.
The quality of studies was assessed by Jadad scales that assigns scores for reported randomization, blinding and withdrawals.18
Data synthesis and statistical analysis
Mean difference and s.d. of CRP level in baseline and end of study in intervention and control groups were considered. If a confidence interval was reported in place of s.d., we converted it to s.d. for analyses. Existence of heterogeneity was tested by Cochran’s Q-test at P<0.05 level of significance. The I2 test also used for calculating percent heterogeneity.19 A fixed effects model was used for estimating pooled effect sizes. To investigate the source of heterogeneity, pre-defined subgroup analyses were performed. We assessed dose of vitamin E, trial duration, baseline CRP level and the isoform of vitamin E used. Using meta-regression, we analyzed the contribution of dose of vitamin E, intervention duration, baseline CRP level and mean difference of CRP level. Publication bias was analyzed by funnel plot analysis and Egger’s regression asymmetry test.20 All of the analyses were performed using STATA version 12.0 (Stata Corporation, College Station, TX, USA) and P<0.05 was considered as significant.
Search results and study selection
The flowchart of the selection process in meta-analysis is shown in Figure 1. Of 4374 studies identified, 2121 articles were excluded because they were duplicated records. In all, 2613 articles were included for title and abstract screening. A total of 2560 articles were excluded because they did not meet the inclusion criteria and 53 articles were chosen for assessing full-text eligibility and in this step, 22 were excluded because they used vitamin E in forms other than α- and γ-tocopherols or used vitamin E-coated membrane dialyzers, and hence 31 studies were retained for qualitative synthesis. Of these, 19 studies with no exact CRP value, no control group, lack of baseline value for CRP in each groups were excluded. Finally 1216, 21, 22, 23, 24, 25, 26, 27, 28, 29 studies were included for meta-analysis, which were all randomized, controlled trials.
The characteristics of the included studies and participants are presented in Table 1. Publication year of these studies were from 2000 to 2013; of 12 studies, 11 were conducted on both male and female participants16, 21, 22, 23, 24, 25, 26, 27, 28, 29 and a single study was conducted only on males.30 Sample size of participants varied from 25 to 110 with a total sample size of 495. All trials involved parallel, placebo-controlled designs, but only eight of them were double blinded,16, 22, 23, 24, 25, 27, 28 and four of them did not clearly mention the blinding of the study.21, 26, 29, 30 Trial duration was from 1 to 26 weeks with a median of 6 weeks. Nine trials used the α-tocopherol isoform of vitamin E for intervention16, 21, 22, 24, 26, 27, 28, 29, 30 and three used the γ-tocopherol isoform for supplementation.23, 25 Dosage of supplementation varied from 100 to 536 IU/day with the median of 334IU/day. Mean age of participants in the intervention groups were in the range 21.6–65 years and in the control group were in the range of 22.3–66 years. Three trials were conducted on healthy subjects,25, 27 three on hemodialysis patients,21, 22, 29 two trials on type 2 diabetes patients26, 28 and the others were conducted on smokers,23 smokers with acute coronary syndrome,24 patients with erectile dysfunction30 and patients with active rheumatoid arthritis.16 Baseline serum CRP levels were in the range of 1.1–23.85 mg/l with a median of 3.44 mg/l in the intervention group and 1.01–20.45 mg/l with the median of 2.67 mg/l in the control group.
Of 12 trials included in this meta-analysis, 8 trials showed a significant reduction in the CRP level after supplementation. The forest plot with mean differences (MD) in post-trial CRP concentration between intervention and placebo groups and their 95% confidence intervals (CIs) are shown in Figure 2. As there was significant heterogeneity between studies (test for heterogeneity: P<0.001 and I2=55.3%), we used a random-effects model to estimate the pooled MD in the serum CRP level. Using the random-effects model, the pooled effect size of vitamin E supplementation on CRP level versus control was calculated at −0.62 mg/l (95% CI=−0.92, −0.31; P<0.001).
Subgroup analyses showed that serum CRP level decreased more significantly after vitamin E supplementation in participants with baseline CRP level <3 mg/l (−0.75 (95% CI=−0.88, −0.63)) compared with participants with baseline CRP level >3 mg/l (−0.43 (95% CI=−0.71, −0.14); Table 2). However, the reduction of CRP level in both groups was significant. There was a greater reduction in the serum CRP level following supplementation with α-tocopherol (-0.73 mg/l) compared with γ-tocopherol (−0.62 mg/l). Serum CRP level decreased more when trial duration was ⩾6 weeks (−0.73) compared with trial duration of <6 weeks (−0.63). Each of the pre-specified factors significantly affected the pooled effect size but analyses of between-group heterogeneity showed that the only significant source of heterogeneity between studies was the variation in the baseline level of CRP (P=0.041).
Influence and cumulative analysis
Influence analysis also showed that none of trials had significant effect on pooled effect size and they were in a range from -0.63 (95% CI=−0.93, −0.32) to −0.61(95% CI=−0.93, −0.30; Figure 3). We conducted cumulative analysis to see the consistency of the studies and consistency was observed between 2000 and 2011 (Figure 4).
We used univariate meta-regression analysis to examine the variation in treatment effect attributed to some pre-specified covariates. The univariate meta-regression analysis suggested that type of vitamin E, supplementation dose, baseline CRP concentration and trial duration were not significant sources of trial heterogeneity (Table 3).
The Begg’s (P=0.78) and Egger’s (P=0.28) tests did not show any publication bias (Figure 5).
In this meta-analysis of the effect of vitamin E supplementation on CRP level including 12 trials with 495 participants between 2000 and 2013, we found that vitamin E can exert a reduction effect around 0.62 mg/l on serum CRP levels. Some of the heterogeneity between studies was accounted for by variation in the baseline levels of CRP.
CRP can activate the complement system and induces tissue factor release from monocytes and mediates its thrombotic effects.31 The mechanism by which vitamin E exerts its anti-inflammatory role is not completely known, but may be related to protein kinase C (PKC) dephosphorylation. α-Tocopherol can activate activation protein 1 (AP-1), which can dephosphorylate PKC(α) and inhibit smooth muscle cell proliferation.32 This inhibition can reduce reactive oxygen species (especially superoxide anion) release from monocytes.33 In vitro administration of RRR-α-tocopherol (natural), but not all rac-α-tocopherol (synthetic) can significantly decrease PKC activity as well as platelet aggregation.34 However, the studies we examined generally did not distinguish if the source of the α-tocopherol was natural or synthetic.
Another mechanism is that vitamin E may suppress the ability of pro-inflammatory cytokines such as IL-6 to induce the synthesis of CRP in the liver. Devaraj et al. concluded that vitamin E supplementation can decrease the release of IL-1β from monocytes. IL-1β in turn may elevate the IL-6 level and in this way increase serum levels of CRP.14 Moreover, several studies showed that vitamin E has an ability to activate protein phosphatase 2A, which leads to dephosphorilation and therefore inactivation of PKCα. So, IKK remains dephosphorelated and cannot activate nuclear factor-κB via IκB phosphorylation. Therefore, this vitamin can have anti-inflammatory properties in this way.35, 36
Previously, it was reported that there was a positive association between plasma levels of CRP and γ-tocopherol, but a negative association between plasma levels of CRP and α-tocopherol.37 Moreover, one study showed that only α-tocopherol in combination with γ-tocopherol had a significant effect in reducing CRP compared with placebo, and either α-tocopherol or γ-tocopherol alone.38 In contrast, the present meta-analysis showed that both α-tocopherol and γ-tocopherol supplements taken alone can significantly decrease the serum level of CRP. The results of some clinical trials showed that supplementation with α-tocopherol isoform of vitamin E at high doses (for example, 1200 IU/day) can decrease serum levels of γ-tocopherol, the isoform that has been shown to be very protective against some types of oxidative stress.39 However, there are several studies reporting that only the serum level of γ-tocopherol, and not α-tocopherol, has an inverse association with the incidence of coronary heart disease.40, 41
The recommended dietary allowance and tolerable upper intake level (UL) of vitamin E for adults are 15 mg α-tocopherol (22.4 IU) and 1000 mg α-tocopherol (1500 IU), respectively.42 Previous studies have also shown that supplementation with vitamin E at doses ⩽400 IU/day had no effect in reducing inflammatory markers.43 Some studies showed that vitamin E at doses between 600 and 1200 IU/day can significantly reduce serum levels of inflammatory markers, such as IL-6, tumor-necrosis factor-α and CRP.44, 45 One study reported that the minimum needed dose of α-tocopherol for reducing low-density lipoprotein oxidation is 400 IU/day.15 But, subgroup analysis in this meta-analysis showed that vitamin E supplementation at doses lower than 400 IU/day also can significantly reduce serum levels of CRP. Previously, Miller et al. in one meta-analysis study showed that high doses of vitamin E (⩾400 IU/day) may increase all-cause mortality and should be used cautiously.46 So, it is reasonable that doses less than 400 IU/day should be used for lowering serum CRP level.
Previous work has suggested that serum CRP concentrations of >3 mg/l were associated with 58% increased risk of coronary heart disease compared with CRP concentrations <1 mg/l.47 The results of this meta-analysis showed that vitamin E was more effective in lowering CRP levels, when the baseline CRP concentration was lower than 3 mg/l, compared with when it was higher than 3 mg/l. The exact reason is not clear but may be related to the concentration of the antioxidants in the blood. One plausible explanation is that inflammation may affect antioxidant status by decreasing their concentrations in the serum and in this way it can mask the possible protective effects of antioxidants on CRP level.48
In conclusion, the results of this meta-analysis demonstrated the significant beneficial effects of vitamin E supplements in both α and γ isoforms of tocopherol on the serum level of CRP, with slightly greater reductions achieved when the serum level of CRP was <3 mg/l. It seems that vitamin E supplementation may be a good strategy for decreasing inflammatory conditions in susceptible people, although large well-designed randomized controlled trials are needed to confirm these results, which are based on a total sample of less than 500 subjects.
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The authors declare no conflict of interest.
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Saboori, S., Shab-Bidar, S., Speakman, J. et al. Effect of vitamin E supplementation on serum C-reactive protein level: a meta-analysis of randomized controlled trials. Eur J Clin Nutr 69, 867–873 (2015). https://doi.org/10.1038/ejcn.2014.296
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