Systematic review and meta-analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non-alcoholic fatty liver disease

Aims: Iron reduction has been proposed as treatment for dysmetabolic iron overload syndrome (DIOS) and non-alcoholic fatty liver disease (NAFLD), but results of published trials are conflicting. We undertook a systematic review and meta-analysis to determine the impact of phlebotomy in DIOS and NAFLD. Methods: We searched multiple databases systematically for studies evaluating the impact of phlebotomy in DIOS and NAFLD. We calculated weighted summary estimates using the inverse variance method. Study quality was assessed using the Cochrane collaboration tool. Results: We identified nine studies with 820 patients (427 had phlebotomy, 393 lifestyle changes alone). Iron depletion did not improve the Homeostasis Model Assessment (HOMA) index (mean difference [MD] -0.6; confidence interval (CI), -1.7, 0.5; P=0.3), insulin level (MD -0.8mU/L; CI, -5.3, 3.7; P=0.73), or aspartate aminotransferase (AST) (MD -0.7 IU/L; CI, -3.2, 1.8; P=0.6) in DIOS and/or NAFLD patients as compared to lifestyle changes alone (five studies, 626 patients). There was mild improvement in alanine aminotransferase (ALT) (MD -6.6 IU/L; CI, -11, -2.1); P<0.01), but the effect size was very small (Cohen's d, 0.15; r statistic, 0.07). Even in the subgroup of patients with NAFLD and hyperferritinemia, phlebotomy did not improve the HOMA index, insulin level, ALT, or AST. Additionally, no study showed significant improvement in liver inflammation or fibrosis with iron reduction. Conclusions: Phlebotomy does not bring about significant improvement in indices of insulin resistance, liver enzymes, or liver histology in patients with DIOS and/or NAFLD compared to lifestyle changes alone. Current evidence does not support the use of phlebotomy in patients with DIOS or NAFLD.