Aberrations of biochemical indicators in amyotrophic lateral sclerosis: a systematic review and meta-analysis

Abstract

Accumulating evidence has suggested that the pathological changes in amyotrophic lateral sclerosis (ALS) are not only confined to the central nervous system but also occur in the peripheral circulating system. Here, we performed a meta-analysis based on the PubMed, EMBASE, EBSCO, and CNKI databases, to find out biochemical indicators associated with energy metabolism, iron homeostasis, and muscle injury that are altered in ALS patients and their correlations with ALS phenotypes. Forty-six studies covering 17 biochemical indicators, representing 5454 ALS patients and 7986 control subjects, were included in this meta-analysis. Four indicators, including fasting blood glucose level (weighted mean difference [WMD] = 0.13, 95% CI [0.06-0.21], p = 0.001), serum ferritin level (WMD = 63.42, 95% CI [48.12-78.73], p < 0.001), transferrin saturation coefficient level (WMD = 2.79, 95% CI [1.52-4.05], p < 0.001), and creatine kinase level (WMD = 80.29, 95% CI [32.90-127.67], p < 0.001), were significantly higher in the ALS patients, whereas the total iron-binding capacity (WMD = - 2.42, 95% CI [- 3.93, - 0.90], p = 0.002) was significantly lower in ALS patients than in the control subjects. In contrast, the other 12 candidates did not show significant differences between ALS patients and controls. Moreover, pooled hazard ratios (HR) showed significantly reduced survival (HR = 1.38, 95% CI [1.02-1.88], p = 0.039) of ALS patients with elevated serum ferritin levels. These findings suggest that abnormalities in energy metabolism and disruption of iron homeostasis are involved in the pathogenesis of ALS. In addition, the serum ferritin level is negatively associated with the overall survival of ALS patients.

Keywords: Amyotrophic lateral sclerosis; Biochemical indicators; Creatinine kinase; Energy homeostasis; Iron metabolism.

Fig. 1

Flowchart of the literature search according to Preferred Reporting Items for Systematic Review and Meta-Analyses

Fig. 2

Forest plot showing the quantitative synthesis of fasting blood glucose (a), serum ferritin (b), creatine kinase (c), transferrin saturation coefficient (d) and total iron binding capacity (e) in amyotrophic lateral sclerosis patients and controls. Values and the corresponding 95% confidence intervals of individual studies are indicated by short solid lines. The weighted mean difference (WMD) and 95% confidence intervals are indicated by diamonds

Fig. 3

Forest plot showing separate analysis of serum transferrin based on control type (a) and high-density lipoprotein cholesterol based on ethnicity (b). Values and the corresponding 95% confidence intervals of individual studies are indicated by short solid lines. The weighted mean difference (WMD) and 95% confidence intervals are indicated by diamonds

Fig. 4

Forest plot showing subgroup analysis of serum ferritin (a) and creatine kinase (b) based on sex. M: male group, F: female group, Total: combined male and female patients. Values and the corresponding 95% confidence intervals of individual studies are indicated by short solid lines. The weighted mean difference (WMD) and 95% confidence intervals are indicated by diamonds

Fig. 5

Forest plot showing associations of serum ferritin (a) and creatine kinase (b) levels with the overall survival in ALS patients. Pooled hazard ratios (HR) suggest significantly reduced survival in ALS patients with elevated serum ferritin, whereas creatine kinase levels did not play a significant role in the survival of ALS patients. Ratios and the corresponding 95% confidence intervals of studies are indicated by short solid lines. The averaged ratios and 95% confidence intervals are indicated by diamonds