Serum Homocysteine and NAFLD risk have a positive correlation, whereas serum Folate and NAFLD risk have an inverse correlation.

A systematic review and meta-analysis investigated the link between circulating levels of Homocysteine and Folate and risk of NAFLD development.

A meta-analysis of observational studies collected from three databases was conducted to assess the correlations. In order to strengthen the causal inference, Mendelian randomization analysis was executed. From two meta-analyses of genome-wide association studies (GWASs) of 44,147 and 37,645 people with European ancestry, independent single-nucleotide polymorphisms without linkage disequilibrium that were actively linked with serum Homocysteine and Folate levels were chosen as instrumental variables, respectively.

A GWAS of 8434 NAFLD-affected patients and 770,180 controls with European ancestry provided information on NAFLD. From a GWAS of 361,194 people with European descent, four liver enzymes as secondary endpoints were included.

The meta-analysis included 22 observational studies (30,368 volunteers). NAFLD risk and serum Homocysteine were positively correlated (odds ratio [OR]: 1.96; n = 20), but NAFLD risk and serum Folate were inversely correlated (OR: 0.75; n = 12).

The ORs of NAFLD in the MR analysis were 0.75 and 1.17 per 1-SD increase of genetically predicted circulating Folate and Homocysteine concentrations, respectively. Each 1-SD elevation in circulating Folate and Homocysteine levels genetically predicted was associated with alterations in ALT concentrations of -0.84 U/L and 0.62 U/L, respectively.

Future clinical research on the possibility of reducing Homocysteine concentrations for prophylaxis of NAFLD is necessary given the probable role of circulating Homocysteine and possibly Folate in the disease.