Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia; evidence from a case control study

Objectives and Aims: Hyperferritinemia is frequently observed in NAFLD, the hepatic manifestation of the metabolic syndrome characterized by hepatic insulin resistance and considered at high cardiovascular risk. Iron depletion by phlebotomy has been reported to decrease insulin resistance in NAFLD in small, uncontrolled studies. Aims of this study with NAFLD, the effect of iron depletion on insulin resistance, and whether basal ferritin levels influence treatment outcome. Methods: Subjects were included if ferritin and/or ALT were persistently elevated after 4 months of standard therapy. Sixty-four phlebotomized subjects were matched 1:l for age, sex, ferritin, obesity, and ALT levels with patients who underwent lifestyle modifications only. Insulin resistance was evaluated by insulin levels, determined by RIA, and the HOMA-R index, at baseline and after 8 months. Results: Baseline ferritin levels were associated with body iron stores (p=0.006). Iron depletion resulted in a significantly larger decrease in insulin resistance (p = 0.0002 for insulin, p = 0.0007 for HOMA-R) compared with nutritional counseling alone, independently of changes in BMI, baseline HOMA-R, and the presence of the metabolic syndrome. Iron depletion was more effective in reducing HOMA-R in patients in the top two tertiles offerritin concentrations (p 0.05 vs. controls), but not in the first tertile, and in carriers of mutations in the HFE gene of hereditary hemochromatosis vs. non-carriers (p < 0.05). Conclusions: Given that phlebotomy reduces insulin resistance, which correlates with tissue damage, future studies should evaluate the effect of iron depletion on liver histology and cardiovascular endpoints.