Oxidative stress marker aberrations in children with autism spectrum disorder: a systematic review and meta-analysis of 87 studies (N = 9109)

Abstract

There is increasing awareness that oxidative stress may be implicated in the pathophysiology of autism spectrum disorder (ASD). Here we aimed to investigate blood oxidative stress marker profile in ASD children by a meta-analysis. Two independent investigators systematically searched Web of Science, PubMed, and Cochrane Library and extracted data from 87 studies with 4928 ASD children and 4181 healthy control (HC) children. The meta-analysis showed that blood concentrations of oxidative glutathione (GSSG), malondialdehyde, homocysteine, S-adenosylhomocysteine, nitric oxide, and copper were higher in children with ASD than that of HC children. In contrast, blood reduced glutathione (GSH), total glutathione (tGSH), GSH/GSSG, tGSH/GSSG, methionine, cysteine, vitamin B9, vitamin D, vitamin B12, vitamin E, S-adenosylmethionine/S-adenosylhomocysteine, and calcium concentrations were significantly reduced in children with ASD relative to HC children. However, there were no significance differences between ASD children and HC children for the other 17 potential markers. Heterogeneities among studies were found for most markers, and meta-regressions indicated that age and publication year may influence the meta-analysis results. These results therefore clarified blood oxidative stress profile in children with ASD, strengthening clinical evidence of increased oxidative stress implicating in pathogenesis of ASD. Additionally, given the consistent and large effective size, glutathione metabolism biomarkers have the potential to inform early diagnosis of ASD.

Fig. 1. Forest plots of effect sizes for glutathione metabolism.

Meta-analysis of pooled data from the included studies showing the association between GSH (A), GSSG (B), tGSH (C), GSH/GSSG (D), tGSH/GSSG (E), and ASD. GSH reduced glutathione, GSSG oxidative glutathione, tGSH total glutathione, ASD autism spectrum disorder.

Fig. 2. Forest plots of effect sizes for transmethylation cycle and transsulfuration pathways.

Meta-analysis of pooled data from the included studies showing the association between homocysteine (A), methionine (B), cysteine (C), SAH (D), SAM/SAH (E), and ASD. SAH S-adenosylhomocysteine, SAM/SAH S-adenosylmethionine/S-adenosylhomocysteine, ASD autism spectrum disorder.

Fig. 3. Forest plots of effect sizes for vitamins.

Meta-analysis of pooled data from the included studies showing the association between vitamin B9 (A), vitamin B12 (B), vitamin D (C), vitamin E (D), and ASD. ASD autism spectrum disorder.

Fig. 4. Forest plots of effect sizes for trace elements, NO, and MDA.

Meta-analysis of pooled data from the included studies showing the association between Ca (A), Cu (B), NO (C), MDA (D), and ASD. Ca calcium, Cu copper, NO nitric oxide, MDA malondialdehyde, ASD autism spectrum disorder.

Fig. 5. Biomarker performance rating for autism spectrum disorder.

Head-to-head biomarker performance in blood oxidative stress markers based on effective size (95% CI). Highlighted oxidative stress markers with red indicate high priority for potential diagnosis of autism spectrum disorder.