Effect of alpha lipoic acid on Iron metabolism parameters: A systematic review and meta- analysis of randomized controlled clinical trials

doi:10.21203/rs.3.rs-2482935/v1

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Effect of alpha lipoic acid on Iron metabolism parameters: A systematic review and meta- analysis of randomized controlled clinical trials

https://doi.org/10.21203/rs.3.rs-2482935/v1

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Background

Alpha-lipoic acid (ALA) exhibits antioxidant and iron chelator properties and may have regulating effects on factors related to Iron metabolism. However, findings from clinical trials are equivocal. This systematic review and meta-analysis aimed to evaluate the effect of ALA supplementation on iron metabolism parameters including serum iron, total iron binding capacity, hemoglobin and ferritin.

Methodology

We searched online databases, including PubMed, Scopus, and Web of Science, up to 29 May 2022, to obtain relevant publications.

Results

A total of 1901 records were identified in the systematic search; from these, 10 were included in the systematic review and meta-analysis. The pooled analysis of the studies showed no effects of ALA on ferritin (WMD= -11.01 ng/ml; 95% CI: -40.07, 18.05 ng/ml; I² = 0.0%, P = 0.670), serum Iron (WMD=-0.47 µ/dL; 95% CI: -24.48, 23.54 µ/dl; I² = 94.7%, P < 0.001), hemoglobin (WMD = 0.49 g/dl; 95% CI: -0.54, 1.52 g/dl; I² = 95.7%, P < 0.001), and TIBC (WMD = 3.95 µ/dL; 95% CI: -21.3, 29.2 µ/dl; I² = 53.1%, P = 0.094). In subgroups analysis ALA significantly increased hemoglobin in patients with hematological disorders (WMD = 1.23 g/dl; 95% CI: 1.00, 1.45 g/dl; I² = 96.6%, P < 0.001) and in durations > 8 weeks (WMD = 1.03 g/dl; 95% CI: 0.82, 1.25 g/dl; I² = 96.5%, P = 0.02).

Conclusion

ALA supplementation yielded no significant effect on Iron related parameters. Subgroup analysis revealed a significant increasing effect of ALA on hemoglobin in patients with hematological disorders and durations > 8 weeks. More consistent clinical trials, with larger sample size, and consideration more strength inclusion criteria, are required.

Thioctic acid

Ferritin

Hemoglobin

Iron overload

systematic review

Alpha lipoic acid (ALA) is an endogenous short chain fatty acid which acts as a cofactor for mitochondrial dehydrogenase complexes(1). In addition to endogenous synthesis, this organosulfur compound is supplied exogenously in human diet(2). Alpha-lipoic acid exhibits antioxidant, anti inflammatory and iron chelator properties and has attracted considerable clinical interest as a therapeutic agent for several diseases, such as cardiovascular diseases, hypertension, renal diseases and diabetes(3–6). The therapeutic effects of ALA in the humans seems to be at the doses ranged from 200 to 1800 mg/d and at the doses up to 1800–2400 mg/day it can be tolerated safely without significant adverse effects(7). ALA is reduced to dihydrolipoic acid (DHLA) after taken up by cells and tissues. Both ALA and DHLA exert iron chelating activities and have the ability of scavenging reactive oxygen species (ROS)(8). Nevertheless, there is some evidence of the prooxidant activity of redox couple ALA/DHLA specially in the presence of iron(9, 10). Iron is a redox active element, which can enhance oxidative stress by generation of oxygen free radicals via Fenton reaction(11, 12). Therefore, in order to ameliorate the toxic effects of iron, it is usually bonded with proteins such as transferrin, as it occurs in serum, or ferritin in intracellular section(13). However, extensive oxidative stress enhances proteins needed for iron uptake, which causes excessive catalytic iron with consequent iron induced tissue damage(14, 15). Given the potential of ALA in reduction of iron in cells and tissues, it may be considered as a treatment for ameliorating oxidative damage(16). So far, several studies have evaluated the effects of ALA on iron related factors including, ferritin, hemoglobin and total iron binding capacity (TIBC) (2, 5, 17). Findings from primary studies indicated the protective role of ALA on iron overload and related oxidative stress(8, 17). Nevertheless, results from clinical trials are controversial. El-Nakib et al in a study that was conducted on end stage renal disease patients undergoing hemodialysis reported that supplementation with 600 mg/d ALA for 3 months had no significant effects on hemoglobin and iron store indices, although the required doses of erythropoietin (EPO) was reduced(18). Conversely, in a study by Mendes et al. daily intake of 600 mg ALA for 12 weeks, significantly reduced serum levels of iron and TSI (Transferrin Saturation Index) in hypertensive patients(19). Considering the controversies among studies, this systematic review and meta-analysis aimed to evaluate and quantify the effect of ALA supplementation on iron metabolism parameters including serum iron, total iron binding capacity (TIBC), hemoglobin (Hgb) and ferritin.

Search Strategy

This systematic review was performed according to the Preferred Reporting Items in Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive and systematic literature search was performed in online literature databases including PubMed, Scopus, and Web of Science from inception up to 29 May 2022 to determine relevant publication. Relevant MeSH (Medical Subject Headings) terms related to alpha lipoic acid were searched in combination with parameters related to Iron metabolism (supplementary table 1). In addition, the first 4 pages of Google Scholar and the references list of relevant studies and recent reviews were assessed to find other, potentially, eligible studies. The publication search was not limited by language or date set on databases.

Eligibility Criteria

One researcher (ESZ) searched the mentioned online databases to retrieve potentially related studies. Titles, abstracts, and full texts of the retrieved studies were screened independently by the two authors according to the following inclusion criteria: 1) all RCTs that considered ALA as an intervention 2) studies in which the comparator was no treatment, a placebo or standard treatment, 3) those that considered the serum level of Iron, TIBC, ferritin and Hgb as outcomes, and 4) publications in which mean ± standard deviation (SD), mean ± standard error (SE), or mean (95% CI) were used to report the related effect sizes. In this review publications were excluded if the effect of ALA was not independently examined, there was no appropriate control group or no randomization process, the information for the dosage and duration of the intervention, was not provided, RCTs involving pregnant or lactating women, and studies in languages other than English. Nonclinical studies, reviews, meta-analyses, and publications with no available full-text. were also excluded.

Data Extraction

After screening and reading the selected articles, all data were independently extracted by the two researchers using a predefined form. Extracted data for each included study were as follows: first author name, year of study publication, country or region, study design, sample size, subjects’ characteristic, dose and type of intervention, follow-up duration and outcome. Any disagreement regarding data extraction was resolved by discussion.

Quality Assessment

Quality and risk of bias for included studies were evaluated by the Cochrane Risk of bias assessment tool(20). Assessment was performed based on the following criteria: selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and researcher), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective outcome reporting), and any other bias (adjustment for baseline variables and dietary intake). The quality of studies was identified as poor (low risk for less than four domains), fair (low risk for four domain), and good (low risk for more than four domain), respectively. Any disagreements regarding risk of bias were discussed and resolved by consultation.

Data synthesis and analysis

Mean differences (MD) for ferritin, serum Iron, Hgb and TIBC with their corresponding standard deviations between intervention and control groups (SDs), in each study were used to calculate the effect size for ferritin, serum Iron, Hgb and TIBC. The weighted mean difference (WMD) and its corresponding SD for each variable was determined and pooled using the DerSimonian and Laird method (21), taking between-study heterogeneity into account. Between-study heterogeneity was assessed using Cochrane’s Q statistic and I-squared statistic (22). Subgroup analyses, according to

Dose of ALA (< 600 mg/d ad ≥ 600 mg/d), participant’s heath status (Hematological and Non-Hematological disorders) and study duration (≤ 8 weeks and > 8 weeks) were conducted to determine heterogeneity between studies. Sensitivity analysis to evaluate the impact of a single study on the results was carried out by removing studies from the analysis, one by one. We also performed sensitivity analysis to detect the effect of methodological differences in relation to dosing and administration of ALA. Publication bias was examined through visual inspection of funnel plots as well as Egger’s regression test. Stata software (version 14.0; Stata Corporation) was used to conduct the meta-analysis; whilst statistical significance was accepted at P < 0.05.

Study characteristics

Figure 1 shows the detailed processes of study selection. Overall, 1901 publications were initially retrieved from the online databases search, of which, 456 duplicate and 1416 irrelevant articles were excluded based on title and abstract screening. Of the remaining 29 articles, an additional 19 articles were removed due to the reasons mentioned in Fig. 1. Finally, 10 RCTs were included in this systematic review and meta-analysis. Table 1 summarizes the main characteristics of the included studies. Of the 10 included studies, eight had a parallel design and two had a cross over design. The duration of intervention varied from 8 weeks to 24 weeks, and ALA doses ranged from 200 mg/d to 1200 mg/d. Five studies were conducted on patients undergoing hemodialysis(4, 18, 23–25), one on hypertensive subjects(19), one on obese patients with NAFLD (non-alcoholic fatty liver)(26) and two on β-TM patients(27, 28). The study by Abdel Hamid et al(4) had a different protocol for ALA supplementation (600mg/d, three times per week), hence the daily dose of ALA was calculated and used in subgroup analysis. In addition, the study by Martins et al, that enrolled three different population, was considered as three separate studies. Geographically, these 10 studies originated from Korea (n = 1), Brazil (n = 2) Egypt (n = 3) and Iran(n = 4).

Assessment risk of bias

Of the ten included studies four studies had a good quality based on Cochrane Collaboration’s tool, five were classified as poor and one study received a fair score. Five studies for the method of random sequence generation and six for process to conceal the allocation of participants had unclear risk of bias. Four studies did not indicate the blinding of participants and outcome assessment. Three studies had selective reporting bias and six studies had other bias. (Fig. 2).

Ala And Ferritin

Six studies with eight effect sizes assessed the effect of ALA on ferritin level. The overall analysis showed no significant changes in ferritin levels in subjects treated with ALA compared to control (WMD= -11.01 ng/ml; 95% CI: -40.07, 18.05 ng/ml), and the heterogeneity was low (I² = 0.0%, P = 0.670) (Fig. 3). This result was also observed across all subgroups (P > 0.05) Table 2. Although visual inspection of funnel plot showed evidence of asymmetry, there was no publication bias among studies based on Egger’s test (P = 0.354)

Table1. Main characteristics of studies examining the effect of ALA on Hematological indices
Author. date	Country	Study design	Subjects, n, T/C	Subject characteristic	Dose and Type intervention	Duration (week)	Results	Total score
Chang et al. 2007(25)	Korea	Parallel RCT	25/25	End-Stage Renal Disease Patients on Hemodialysis	600 mg/d ALA Vs placebo	12	No significant effects on Hgb	2
Mendes et al. 2009(19)	Brazil	DB Parallel RCT	32/28	Hypertensive subjects	600 mg/d ALA Vs placebo	12	Significant reduction in serum Iron. No significant effects on TIBC, Hgb and ferritin.	4
AEl-Nakib et al. 2013(18)	Egypt	Parallel RCT	22/22	End stage renal disease patients undergoing hemodialysis	EPO+ ALA 600 mg/d Vs EPO	12	No significant effects on Hgb, TIBC, serum iron and ferritin	2
Martins et al. 2015(9)	Brazil	Parallel RCT	30/30	-Normal subjects -Sickle cell trait subjects -Sickle cell patients	200 mg/d ALA Vs placebo	12	No significant effects on hematological indices	2
Hosseinpour‐Arjmand et al.2019(26)	Iran	DB Parallel RCT	23/22	Obese patients with NAFLD	vitamin E+1200 mg/d ALA Vs Vitamin E+placebo	12	No significant effects on ferritin	7
Mahdavi et al. 2019(24)	Iran	DB Parallel RCT	24/28	Hemodialysis patients	600 mg/d ALA Vs placebo	8	No significant effects on Hgb	7
Sharifi Zahabi et al. 2020(28)	Iran	Cross-over DB RCT	22/22	β-TM patients	600 mg/d ALA Vs placebo	8	No significant effects on TIBC, Hgb and serum Iron	6
Elewa et al.2020(23)	Egypt	DB Parallel RCT	35/35	Hemodialysis patients	600 mg/d ALA Vs placebo	12	Significant elevations in Hgb concentration and serum iron	3
Sharifi Zahabi et al.2021(27)	Iran	Cross-over DB RCT	22/22	β-TM patients	600 mg/d ALA Vs placebo	8	Significant reduction in ferritin	6
Abdel Hamid et al. 2022(4)	Egypt	Parallel RCT	30/30	Diabetic patients on hemodialysis	257mg/d ALA+EPO+insulin therapy Vs EPO+insulin therapy	24	Significant elevations in Hgb concentration and serum iron	3
Abbreviation: AlA, alpha lipoic acid; n, number; T, treatment; C, control; DB, RCT, randomized controled trial; double blinded; NAFLD, non-alcoholic fatty liver; β-TM, β-thalassemia major; EPO, erythropoietin; Hgb, hemoglobin; TIBC, total binding capacity.

Table 2. Subgroup analysis for the effects of alpha lipoic acid on hematologic indices
Variables	Number of effect measures	I²	Effect measures (95% CI)	P_between
Ferritin
Overall	8	0.0	-11.0 (-40.07, 18.05)	-
Dose of ALA
<600 mg/d	4	0.0	-3.22 ( -79.66, 73.22)	0.829
≥600 mg/d	4	0.0	-12.32 ( -43.74, 19.10)
Health status
Hematological disorders	4	18.6	-39.26 (-103.8, 25.32)	0.337
Non-Hematological disorders	4	0.0	-3.83 ( -36.38, 28.71)
Hgb
Overall	9	75.1	0.38 (0.16, 0.6)	-
Dose of ALA
<600 mg/d	4	77.8	0.85 (0.54, 1.17)	0.43
≥600 mg/d	6	97.4	1.02 (0.76, 1.28)
Health status
Hematological disorders	7	96.6	1.23 (1.00, 1.45)	<0.001
Non-Hematological disorders	3	0.0	-0.24( -0.7, 0.23)
Follow-up duration (wk)
≤ 8	2	0.0	0.25 (-0.38, 0.87)	0.02
> 8	8	96.5	1.03 (0.82, 1.25)

Abbreviation: AlA, alpha lipoic acid; Hgb, hemoglobin

Ala And Tibc

Four studies evaluated the effect of ALA on TIBC and combining the effect sizes of these studies revealed no significant differences in TIBC level in subjects treated with ALA compared to control (WMD = 3.95 µ/dL; 95% CI: -21.3, 29.2 µ/dL), and the heterogeneity was high (I² = 53.1% P = 0.094) (Fig. 6). Subgroup analysis for TIBC was not possible due to the limited number of studies. Visual inspection of funnel plot showed evidence of asymmetry, However Egger’s test showed no publication bias among studies (P = 0.294).

Sensitivity Analysis

We sequentially removed each trial from the analysis in order to perform sensitivity analysis. Since one of the included studies(4) had a different protocol for ALA supplementation (600mg/d, three times weekly) we conducted the sensitivity analysis in the absence of this study, and found that no study had noticeable impact on the overall effect size.

To the best our knowledge, this systematic review and meta-analysis is the first one that assessed the quantitative effect of ALA on Iron metabolism parameters. The results of this study revealed no significant effects of ALA on serum Iron, Hgb, ferritin and TIBC as compared to control groups. Subgroup analysis, based on the participants health status, and duration of the intervention showed a significant increase in Hgb in patients with hematological disorders and in studies with durations > 8 weeks. Our sensitivity analysis Also, revealed that excluding a single study had no significant effects on the overall result. Iron plays an important role in various metabolic pathways, and acts as a cofactor for several enzymes, including nonheme iron-containing proteins or hemoproteins(29, 30). However, it may also exert toxic effects when present in its free form and when the related regulating mechanisms are compromised(11). As a metal chelator agent, ALA may have regulating effects on factors related to Iron metabolism(2, 8, 17). In this regard, several studies have evaluated the effects of ALA on iron status and protein involved in iron metabolism. Goralska et al in a study on human lens epithelial cells indicated that supplementation with lipoic acid decreases the concentration of free iron, reduces the iron uptake from transferrin and increases iron deposition into ferritin, leading to increase in the concentration of this protein(8). Mendes et al showed that supplementation with 600 mg/d ALA for 12 weeks in hypertensive patients significantly reduced transferrin saturation index, TIBC and serum levels of iron(19). However, findings of this systematic review yielded no significant effect of ALA on serum Iron. This may be due to the small number of the studies on the role of ALA on serum Iron and also the high heterogeneity between the included studies. In contrast to that reported by Goralska et al, ALA had no such increasing effect on ferritin level. This discrepancy may be related to the differences in the health status of studies participants. Ferritin is an acute phase protein which its levels can rise in response to the inflammatory process independent of iron status (31, 32). Inflammation usually decreases the predictive values of ferritin for iron stores status(33). As most studies assessing the effect of ALA on Iron metabolism parameters, enrolled participants with a pathological condition or chronic inflammation state, the reduction effects of ALA on ferritin might be related to its anti-inflammatory and antioxidant activity(34). Hence assessment of serum levels of C-reactive protein (CRP) was required to better discern the effect of ALA on Iron stores(35). However, this issue was not considered in most of the studies evaluated.

In El-Nakib et al study, administration of ALA in the dose of 600 mg/d resulted no significant effect on Hgb and iron store indices in patients undergoing hemodialysis and receiving EPO. Generally, patients in this study were considered non-anemic, with few Hgb values below 10.5 g/dL (18). Therefore, the effect of ALA on Iron related parameter might be dependent on the baseline values of these parameters. In this regard and consistent with our subgroup analysis, Abdell Hamid et al in a study on anemic diabetic patients on hemodialysis revealed that ALA had a significant increasing effect on Hgb. Same results were also observed in a study by Elewa et al on anemic hemodialysis patients(23). Inflammatory cytokines may have a significant role in the development of anemia in patients with chronic condition such as end stage renal diseases(4), fatty liver(26) and sickle cell disease(9). As all the studies in the first subgroup of Hgb were conducted on patients with inflammatory conditions, the increasing effect of ALA on hemoglobin can be related to its reduction effect on inflammatory factors which consequently protect red blood cell membrane from oxidative damage(9).

However, as the baseline hematological indices were not considered as an inclusion criterion in the most of the studies included, interpreting the effect of ALA on hematological indices based on the baseline values are difficult. Therefore, it seems, for assessing the effect of ALA on iron related parameters more strength inclusion criteria are needed.

In the blood, iron is mainly bound to transferrin, and TIBC depends on the transferrin concentration. The fraction of transferrin to which iron is not bound is called “unsaturated iron-binding capacity” (UIBC). The TIBC is equal to the sum of serum iron concentration and the UIBC. TIBC can be used as a diagnostic test for both iron deficiency and iron overload (36). Moreover, TIBC has been reported as a negative acute phase reactant, also diurnal variation in plasma iron, can reduce TIBC diagnostic value (37). Combining the results of the four studies revealed no significant effect of ALA on TIBC. More evaluation of the studies revealed that our study on thalassemia patients account for the major weight of the included studies(28). Compared to the other studies, the baseline level of TIBC in in thalassemia patients were lower, this may be related to the pathologic condition of the patients. As these patients are at higher risk for oxidative stress and inflammation, mainly due to the iron overload and blood transfusion, the increasing effect of ALA on TIBC might be related to the lower baseline values of TIBC and also ALA anti-inflammatory effect, as previously noted. However, considering the small number of the studies and the heterogeneity between studies in regard to participants health status this finding may not be conclusive.

The current study has some strengths. The first of which is inclusion of RCTs assessing the role of ALA supplementation on iron metabolism parameters allowing to achieve more coherent and conclusive results. Adopting a comprehensive and robust methodology to identify available studies that assessed the effect of ALA on iron metabolism parameters, performing sensitivity and subgroup analysis to determine the source of heterogeneity, and evaluating the effects of a single study on the overall result represent additional strengths. However, there are some limitations that should be taken into account when interpreting our findings. According to our risk of bias assessment, three of the eight included studies had a poor quality, which may affect the results for overall and subgroup analysis. Additionally, the effect of ALA on iron metabolism parameters may depend on the baseline values, health status of participants, duration of the intervention, dose of ALA and dietary intake. As most of the included studies did not consider these variables, it is difficult to discern a clear conclusion.

The overall results of this systematic review indicated that ALA treatment had no significant effect on Iron metabolism parameters levels. The results of subgroup analysis revealed a significant increasing effect of ALA on Hgb in patients with hematological disorders and durations > 8 weeks. However due to the limited number of available studies, heterogeneity regarding participant’s health status, baseline values of variables and dietary intake caution should be taken when interpreting the current results. More consistent clinical trials, with larger sample size, and consideration more strength inclusion criteria, are required to better discern the actual effect of ALA supplementation on Iron metabolism parameters.

Guidelines

We confirm that all methods were carried out in accordance with relevant guidelines and regulations (PRISMA).

Funding: This research was supported by Kermanshah University of Medical Sciences.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The dataset applied and analyzed for the present study is available from the corresponding author on a reasonable request.

Conflicts of interest

Authors declare that there is no conflict of interest.

Acknowledgements

This research was supported by Kermanshah University of Medical Sciences.

Author contributions:

ESZ: Contributed to the study design and data collection, and interpretation and drafting the manuscript. HA: Participated in the study conception, revising the paper critically and approving the version of the manuscript being submitted. All authors read the final content of the manuscript before submission.

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No competing interests reported.

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Effect of alpha lipoic acid on Iron metabolism parameters: A systematic review and meta- analysis of randomized controlled clinical trials

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Abstract

Background

Methodology

Results

Conclusion

Figures

Introduction

Methods

Search Strategy

Eligibility Criteria

Data Extraction

Quality Assessment

Data synthesis and analysis

Results

Study characteristics

Assessment risk of bias

Ala And Ferritin

Ala And Tibc

Sensitivity Analysis

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

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