Effects of Selenium Supplementation on Serum C Reactive Protein Level: Asystematic review and meta-analysis of randomized controlled clinical trials

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Effects of Selenium Supplementation on Serum C Reactive Protein Level: A systematic review and meta-analysis of randomized controlled clinical trials

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DOI: 10.1016/j.obmed.2020.100182

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Obesity Medicine

journal homepage:www.elsevier.com/locate/obmed

Review

E ff ects of selenium supplementation on serum C reactive protein level: A systematic review and meta-analysis of randomized controlled clinical trials

Omid Asbaghi

^a

, Somayeh Saboori

^b

, Azita Hekmatdoost

^c,d

, Foad Abdollahpour

^b

, Esmaeil Youse fi Rad

^b,∗

, Shadab Salehpour

^e

aStudent Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran

bNutritional Health Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran

cDepartment of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology, Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran

dDivision of Gastroenterology, Hepatology and Nutrition, British Columbia's Children's Hospital and Child and Family Research Institute, The University of British Columbia, British Columbia, Canada

eDepartment of Pediatrics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

A R T I C L E I N F O

Keywords:

Selenium CRP Inflammation meta-Analysis

A B S T R A C T

Aims: This meta-analysis study aimed to assess effects of selenium supplementation on serum C-reactive protein (CRP) levels in randomized controlled clinical trial studies.

Methods:A systematic literature search on clinical trial studies was performed in PubMed, Embase, Scopus, Cochrane's Library and ISI Web of Science databases up to June 2018, which was completed by manual searching of the reference lists of all included studies. From 533 articles retrieved in thefirst step of the search after excluding duplicatefindings, only 14 trials with 22 effect sizes were included for pooling the effects of selenium supplementation on serum CRP level with 1082 and 1080 participants in the intervention and control groups, respectively.

Results:Results of random effects model meta-analysis showed a non-significant reducing effect of selenium supplementation on serum CRP levels (WMD:−0.31 mg/l; 95% CI:−0.63, 0.01; P = 0.06). The results of subgroup analysis showed that selenium supplementation could only decrease significantly serum CRP levels, when the dosage of selenium supplementation is 200μg/day (WMD:−0.52 mg/l; 95% CI =−1.04,−0.01;

P = 0.043), when the trial duration is > 8 weeks (WMD:−1.01 mg/l; 95% CI =−1.88,−0.15; P = 0.021), and when the baseline level of CRP is > 3 mg/l (WMD:−2.02 mg/l; 95% CI =−2.87,−1.18; P < 0.001).

Conclusion:In conclusion, results of this meta-analysis study showed that selenium supplementation can reduce significantly serum CRP level especially in patients with elevated CRP levels.

1. Introduction

Inflammation is defined as immune system response to injury and infection. When the inflammation is short-term and acute, it can re- move pathogenic compounds from the body and have beneficial effects for the host. However, it can be considered as risk factor for several chronic diseases including cardiovascular disease, obesity, gastro- intestinal disorders, cancer and diabetes, when it persist for a long time (Hotamisligil and Erbay, 2008;Libby, 2006;Trinchieri, 2012). Pro-in- flammatory cytokines including tumor necrosis factor-α(TNF-α), In- terleukin-1β)IL-1β(and C-reactive protein (CRP) could induce the ex- pression of adhesion molecules, which result in endothelial dysfunction and subsequent atherosclerosis (Verma et al., 2002; Kaplanski et al.,

1998). CRP is a member of pentraxin family and it is an acute phase reactant protein. CRP level increases greatly during initial stages of inflammation and stress responses (Pepys and Hirschfield, 2003). Be- cause it has constant plasma half-life, it can predict strongly future occurrence of cardiovascular disease. It is relatively a low cost test and clinical studies usually measuring this factor for detecting the in- flammatory processes (Vigushin et al., 1993;Cesari et al., 2004;Tonelli et al., 2005).

Selenium is an essential trace-element for the human health with proved antioxidant properties, as it is a component of selenium-con- taining antioxidant enzymes including glutathioneperoxidase (GPX) and thioredoxin reductase (TrR) (Rayman, 2000). It is also essential for normal thyroid function (Schomburg and Köhrle, 2008). Dietary intake

https://doi.org/10.1016/j.obmed.2020.100182

Received 19 December 2019; Received in revised form 30 December 2019; Accepted 1 January 2020

∗Corresponding author. Nutritional Health Research Center, Lorestan University of Medical Sciences, Khorram-abad, Iran.

E-mail address:esyussefirad2@yahoo.com(E. YousefiRad).

2451-8476/ © 2020 Elsevier Ltd. All rights reserved.

T

of selenium had been linked inversely with cancer mortality and it can protect human against cardiovascular diseases (Amaral et al., 2010;

Flores-Mateo et al., 2006). Selenium may has anti-inflammatory prop- erties and serum level of it was inversely associated with acute and chronic inflammation in observational studies (Maehira et al., 2002).

This anti-inflammatory role is probably linked to increasing the CD4⁺T cells differentiation into T-helper-1 (Th1) effector cells (Hoffmann et al., 2010). Anti-inflammatory effects of selenium had been studied in several clinical trial studies by determining its effect on serum CRP levels. In a recent study, supplementation with 200μg/day selenium yeast for 12 weeks resulted in significant reduction in high-sensitivity C-reactive protein(hs-CRP) level in diabetic nephropathy patients (Bahmani et al., 2016). Another study on pregnant women with in- creased risk for intrauterine growth restriction (IUGR) showed that consuming only 100 μg/day selenium for 10 weeks could decrease significantly hs-CRP level (Mesdaghinia et al., 2017). However, 12 weeks supplementation with 500 μg/day sodium selenite in another clinical trial did not reduce CRP level significantly in coronary artery disease (CAD) patients (Schnabel et al., 2008). Two previous clinical

trials on hemodialysis patients also showed that 3 months supple- mentation with 200μg/day selenium could not affect CRP levels sig- nificantly (Omrani et al., 2015;Salehi et al., 2012). Because of these conflicting results, this meta-analysis study was performed to assess the pooled effects of selenium supplementation on CRP levels in clinical trial studies. Another aim of this study is to determine other possible influencing factors which can affect the net effect of selenium supple- mentation on serum CRP level including dose and type of selenium, trial duration, baseline levels of CRP and mean age and BMI of the participants.

2. Materials and methods 2.1. Search strategy

The Preferred Reporting Items of Systematic Reviews and Meta- Analysis (PRISMA) statement guideline was followed for performing this meta-analysis.

PubMed, Embase, Scopus, Cochrane's Library and ISI Web of Science Fig. 1.Flowchart of the study selection for inclusion trials in the systematic review.

O. Asbaghi, et al. Obesity Medicine 17 (2020) 100182

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were searched up to June 2018 with the use of following keywords:

("selenium"[Title/Abstract]) OR "selenite"[Title/Abstract]) OR

"selenate"[Title/Abstract]) AND ("CRP"[Title/Abstract]) OR "c reactive protein"[Title/Abstract]) OR "c-reactive protein" [Title/Abstract]) OR

"high-sensitivity CRP"[Title/Abstract]) OR "hs-CRP"[Title/Abstract]) OR "hsCRP"[Title/Abstract]) OR "high sensitivity CRP"[Title/

Abstract]). No limitation in language or time of publication were im- posed. The reference list of all included studies was manually searched to supplement the search process.

2.2. Inclusion and exclusion criteria

Trials were included in this systematic review and meta-analysis if they had following criteria: 1) randomized clinical trials that in- vestigated the effect of selenium supplementation on serum/plasma C- reactive protein levels. 2) State the mean or median values of C-reactive protein concentrations in baseline and at the end of supplementation in both intervention and control groups with SD, SEM or 95% CI. The articles were excluded if they were 1) observational studies; 2) ex- amined the effect of selenium co-administration with other nutrient supplements; 3) trials without control or placebo group; 4) studies with not enough data about plasma/serum levels of CRP at baseline and after intervention.

2.3. Data extraction and quality assessment

After removing of duplicated references, titles and abstracts of ar- ticles were screened independently by two authors (SS, OA). The full texts of more relevant articles to the topic were retrieved and assessed for eligibility. Any disagreement between two authors were resolved by discussion and the help of third author (EY). The quality of included studies were assessed using Cochrane collaboration modified tool. This tool assess risk of biases in the trials based on randomization and al- location concealment, blinding of the participants and researchers, at- trition bias, selective reporting and other biases (Higgins et al., 2011).

The following characteristics of included studies were extracted in a spreadsheet:first author's name, year of publication, origin of country, study design, sex, mean body mass index, mean age, study sample size in intervention and control groups, subjects' health condition, dosage and duration of selenium supplementation, type of selenium and mean ± SD of CRP in study groups.

2.4. Data synthesis and statistical analysis

For estimation of pooled effect size, the mean changes and SD for CRP levels in the intervention and control groups were used. Estimates of effect sizes were expressed on the basis of the weighted mean dif- ference (WMD) and 95% CI from the random-effects model. Assessment of between-study heterogeneity was performed using Cochran's Q-test at P < 0.05 level of significance and the percent of heterogeneity among studies calculated by I-square (I²) test (Cochran, 1954). Sub- group analyses based on selenium dosage, type of selenium, trial duration, baseline CRP level, mean age and BMI of participants were carried out for discovering possible sources of heterogeneity. The sen- sitivity analysis was conducted by the one-study removing (leave-one- out) approach, to estimate the impact of each trial on the pooled effect size. Publication bias was evaluated by begg test and egger's regression asymmetry test and visually assessed by funnel plot. All statistical analyses were carried out using STATA software version 12 (StataCorp.

College Station, Texas, USA) and P < 0.05 was considered as statis- tically significant.

Table1 Characteristicofincludedstudiesinthemeta-analysis. Samplesize(intervention/ control)TypeofseleniumDailydoseof selenium(μg)Trialduration (week)MeanBMI(intervention/ control)Meanage(intervention/ control)sexparticipantsStudy designcountryyearAuthor 19/18selenomethionine2004nr/nr31.26/31.69F/MPsoriasisvulgarisDB/R/PLPoland2006A.B.Serwin 20/20Seyeast3001/423.4/23.426.8/26.8MHealthyDB/R/PLDenmark2008G.Ravn-Haren 20/20selenium3001/423.4/23.426.8/26.8 148/144Sodiumselenite2006/1228.4/28.166/66F/MCoronaryarterydiseaseDB/R/PLGermany2008R.Schnabel 141/144Sodiumselenite5006/1227.8/28.166/66F/M 61/62Seyeast1002423.8/2321.6/21.6F/MPreeclampsiaDB/R/PLIran2010F.Tara 21/21Seyeast2003/6>25/>2536.7/36.6FCardiovasculardiseaseDB/R/PLIran2011M.Alizadeh 40/40Seyeast2001222.86/22.3750/55F/MHemodialysisDB/R/PLIran2013M.Salehi 35/35selenium200627.3/28.527.6/29.6FGestationaldiabetesDB/R/PLIran2015Z.Asemi 32/32selenium2001223.78/24.4657.34/59.53F/MHemodialysisDB/R/PLIran2015H.Omrani 32/32Seyeast200824.7/25.325.1/25.4FPolycysticovarysyndromeDB/R/PLIran2015M.Razavi 30/30selenium2008nr/nr40-85/40-85F/MType2DiabetesandCoronary HeartDiseaseDB/R/PLIran2015A.Farrokhian 28/28Seyeast2002428.6/28.738.3/38.3FCervicalintraepithelialneoplasiaDB/R/PLIran2015M.Karamali 3030Seyeast1001021.2/22.518-40/18-40FPregnantDB/R/PLIran2016E.Mesdaghinia 30/30Seyeast20012nr/nr40-85/40-80F/MDiabeticnephropathyDB/R/PLIran2016F.Bahmani 26/27Seyeast2001225.7/26.268.5/68.5F/MCongestiveheartfailureDB/R/PLIran2018F.Raygan

Table 2

Risk of bias assessment of studies included to the meta-analysis.

Author Random Sequence Generation

Allocation Concealment

Blinding of Participants and Personnel

Blinding of Outcome Assessment

Incomplete Outcome Data (Attrition bias)

Reporting bias Other sources of bias

A.B. Serwin L U L L U U U

G. Ravn-Haren L U U U L U L

R. Schnabel L U U U L U U

F. Tara L U L L L U L

M. Alizadeh L U L L L U L

M. Salehi L H L L L U L

Z. Asemi L L L L L U L

H.Omrani L U U U U U L

M. Razavi L L L L L U L

A. Farrokhian L L L L L U L

M. Karamali L L L L L U L

E.Mesdaghinia L L L L L U L

F. Bahmani L U U U U U L

F. Raygan L L L L L U L

Abbreviations: H, high risk of bias; L, low risk of bias; U, unclear risk of bias.

Fig. 2.Pooled effect size of selenium supplementation on C-reactive protein (mg/l).

O. Asbaghi, et al. Obesity Medicine 17 (2020) 100182

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3. Results

3.1. Search results and study selection

In the primary literature search of PubMed, Embase, Scopus, Cochrane's Library and ISI Web of Science and after removing duplicate findings, a total of 533 articles remained for titles and abstracts screening. Subsequently, 514 irrelevant articles were excluded and 19 relevant articles were remained for eligibility assessment. Of these ar- ticles, 5 studies were excluded because they have no sufficient data or placebo/control group. Therefore, 14 eligible articles were included in thefinal meta-analysis. Theflow diagram of the study selection is dis- played inFig. 1.

3.2. Study characteristics

Generally, 14 articles with 22 effects sizes are included in this meta- analysis. All publications were randomized clinical trials which had been published between years of 2006–2018. Duration of interventions varied from 4 to 24 weeks and the dosage of selenium in included trials ranged between 100 and 500μg/day. The number of participants in the intervention and control groups were 1082 and 1080 subjects, respec- tively with following health status: healthy subjects (Ravn-Haren et al., 2008), patient with psoriasis vulgaris (Serwin et al., 2006), coronary artery disease (Schnabel et al., 2008), preeclampsia (Tara et al., 2010), cardiovascular disease (Alizadeh et al., 2012), hemodialysis (Omrani et al., 2015; Salehi et al., 2012), gestational diabetes (Asemi et al., 2015), cervical intraepithelial neoplasia (Karamali et al., 2015), poly- cystic ovary syndrome (Razavi et al., 2016), diabetic nephropathy Table 3

Subgroup analyses of Selenium supplementation on CRP level.

NO WMD (95% CI) P within group P heterogeneity I²

Baseline serum CRP (mg/l)

< 3 12 0.15 (−0.01, 0.32) 0.072 0.153 29.9%

> 3 10 −2.02 (−2.87,−1.18) < 0.001 0.030 51.3%

Trial Duration (week)

≤8 13 −0.08 (−0.39, 0.22) 0.603 < 0.001 66.1%

> 8 9 −1.01 (−1.88,−0.15) 0.021 < 0.001 84.2%

Selenium Dose (μg)

< 200 2 −9.49 (−23.26, 4.27) 0.177 0.069 69.8%

= 200 14 −0.52 (−1.04,−0.01) 0.043 < 0.001 75.8%

> 200 6 0.14 (−0.03, 0.31) 0.108 0.464 0.0%

Selenium Type

Selenium yeast 11 −0.60 (−1.32, 0.10) 0.095 < 0.001 83.5%

other types 11 −0.08 (−0.37, 0.21) 0.587 0.005 60.0%

Age (year)

< 40 13 −0.32 (−0.80, 0.16) 0.199 < 0.001 77.1%

> 40 9 −0.34 (−0.80, 0.11) 0.138 < 0.001 76.8%

BMI (kg/m²)

< 25 9 −0.55 (−1.20, 0.10) 0.097 < 0.001 79.3%

≥25 9 0.03 (−0.32, 0.39) 0.862 < 0.001 72.8%

Abbreviations: CI, confidence interval; CRP, C-reactive protein; WMD, weighted mean difference.

Fig. 3.Sensitivity analysis of selenium supplementation on CRP level.

(Bahmani et al., 2016), type 2 Diabetes and Coronary Heart Disease (Farrokhian et al., 2016), pregnant (Mesdaghinia et al., 2017), and congestive heart failure (Raygan et al., 2018). Characteristics and quality assessment of included studies are summarized inTable 1and Table 2, respectively.

3.3. Meta-analysis and subgroup analyses

Results of random effects model meta-analysis of 14 studies with 22 effect sizes showed a non-significant reducing effect of selenium sup- plementation on serum CRP levels (WMD:−0.31 mg/l; 95% CI:−0.63, 0.01; P = 0.06; test for heterogeneity: P < 0.001 and I²= 75.8%, Fig. 2). Because of the significant heterogeneity seen between studies, subgroup analysis based on selenium dose and type, trial duration, mean age and BMI of the participants and baseline level of CRP were carried out. The results showed that selenium supplementation could decrease significantly serum CRP levels, when the dosage of supple- mented selenium is equal to 200 μg/day (WMD: −0.52 mg/l; 95%

CI =−1.04,−0.01; P = 0.043), when the trial duration is > 8 weeks (WMD:−1.01 mg/l; 95% CI =−1.88,−0.15; P = 0.021), and when the baseline level of CRP is > 3 mg/l(WMD: −2.02 mg/l; 95%

CI =−2.87,−1.18; P < 0.001). Type of selenium, age and BMI of the participants did not influence significantly selenium supplementation results. The subgroup analyses results are summarized inTable 3.

3.4. Sensitivity analysis

Sensitivity analysis was carried out to estimate the impact of each trial on the pooled effect size. Results of leave-one-out study on the effect size ranged from −0.18 mg/l (95% CI = −0.47, 0.1) to

−0.38 mg/l (95%CI =−0.70,−0.05) (Fig. 3).

3.5. Publication bias

Evaluation of publication bias by visual detection of the funnel plot indicated evidence of bias in the meta-analysis of selenium supple- mentation on plasma CRP levels (Fig. 4). Egger's linear regression test (P < 0.001) and Begg tests (p = 0.001) also showed evidence of publication bias. However, the significance of results were remained unchanged after trim-and-fill adjustment (WMD: 0.09 mg/l; 95% CI:

−0.04, 0.23; P = 0.16) (Duval and Tweedie, 2000).

4. Discussion

This meta-analysis study was carried out to assess the effects of selenium supplementation on serum CRP levels of patients in clinical trial studies. The Results showed a non-significant decreasing effect of selenium supplementation on serum CRP level. Because of the existence of significant heterogeneity between studies, sub-group analysis was performed. The results showed that when the baseline level of CRP is > 3 mg/l, selenium supplementation can reduce CRP levels around 2 mg/l. Thisfinding is in accordance with the results of other meta- analysis studies which showed that vitamin E or alpha-lipoic acid supplementation could affect significantly serum CRP levels only in patients with serum CRP > 3 mg/l (Saboori et al., 2015,2018). Serum CRP level greater than 3 mg/l is associated with a substantial 58% in- creased risk of coronary heart diseases (Danesh et al., 2004).Therefore, the net effect of selenium supplementation on serum CRP level in pa- tients at greater risk of coronary disease seems to be clinically sig- nificant.

It seems that selenium supplementation can increase the gene ex- pression of seleno-proteins including SELR, SELW and SELS in the peripheral blood mononuclear cells (PBMCs) which are necessary for immune cells activation (Goldson et al., 2011). Selenium administra- tion also can inhibit gene expressions of adhesion molecules including vascular cell adhesion molecule 1 (VCAM-1) and Intercellular adhesion molecule (ICAM)-1 in the endothelial cells, when these cells had been stimulated by high glucose levels (Zheng et al., 2008). Results of one study on HuH-7 cells cultured with selenite showed that selenium can suppress NFkB activation and regulate the gene expression of in- flammatory cytokines (Maehira et al., 2003). Cell-culture studies on RAW 264.7 mouse macrophages also revealed that high selenium content in these cell-types could inhibit NFkB activation mediated by Lipopolysaccharides (LPS) (Zamamiri-Davis et al., 2002). NFkB acti- vation triggers inflammation process by increasing the expression of various genes especially tumor necrosis factor (TNF) and inducible ni- tric oxide synthase (iNos) which can regulate CRP synthesis and se- cretion from the liver (Puglisi and Fernandez, 2008). Ebselen is seleno- organic compound with anti-inflammatory properties and its adminis- tration has been linked to decreased gene expressions of Fig. 4.Funnel plot.

O. Asbaghi, et al. Obesity Medicine 17 (2020) 100182

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cyclooxygenase-2 (Cox-2), nitric oxide synthase (Nos), and TNF-a in rat Kupffer cells (Shimohashi et al., 2000).

Another interestingfinding of this study is that the duration of se- lenium supplementation should be more than 8 weeks so that it can show its reducing effects on serum CRP level. The recommended intake for dietary selenium is approximately 1μg/kg of body weight (Kipp et al., 2015). Four months supplementation with 150μg/day selenite was not successful for increasing serum selenium level in coronary ar- tery disease patients (Sena-Evangelista et al., 2015) while in another study on CAD patients, supplementation with 200 and 500μg/day so- dium selenite for 12 weeks resulted in significant elevation in serum selenium level (Schnabel et al., 2008). Although increasing intake of selenium from supplements at doses of greater than 200μg/day could elevate its serum levels in favor of antioxidant defense, there are studies which showing that increasing selenium intake especially at doses of equal or greater than 200μg/day can worsen hyper-glycemia in dia- betic patients or increase the risk of diabetes type-2 development (Faghihi et al., 2014;Wei et al., 2015). One explanation for these ad- verse effects is that increased levels of seleno-protein P after selenium supplementation could decrease the activation of AMPK signaling pathway, which can results in insulin resistance (Misu et al., 2010;Yang et al., 2011). For these reasons, it seems prudent for advising selenium supplementation at the maximum dose of 200 μg/day for seeking its anti-inflammatory effects.

One limitation of this study is significant heterogeneity seen be- tween studies, because various patients with different pathologic con- ditions were included in the meta-analysis. Another limitation of the study is the lack of any information about dietary intake of selenium in studied populations, which can influence thefinal results. Moreover, we observed evidences of publication bias in this meta-analysis, although the results were not changed after adjustment.

5. Conclusions

In conclusion, the results of this systematic review and meta-ana- lysis study showed that selenium supplementation could successfully decrease serum CRP especially at dosage of 200 μg/day when the duration of intervention is greater than 8 weeks or when the baseline CRP level is greater than 3 mg/l. So, its consumption can be used as probable strategy for control of elevated CRP level.

Funding

This work had no source of funding.

Author contributions

SS and EY designed and searched systematically for the study. OA and SS reviewed and selected the articles and extracted data from ar- ticles under the supervision of EY. EY: performed quality assessment of the trials. SS performed data analysis and interpretation. OA, EY and SS drafted the manuscript. MM, SSP and AH revised the article for im- portant intellectual content.

Declaration of competing interest

The authors declare no conflicts of interest.

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