Might some of the beneficial effects of the Mediterranean diet on non-alcoholic fatty liver disease be mediated by reduced iron stores?
Authors: Luca Mascitelli, Mark R. Goldstein
Journal: Journal of Hepatology (2013)

The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver diseaseJournal of HepatologyVol. 59Issue 1PreviewNon-alcoholic fatty liver disease (NAFLD) affects up to 30% of the population and signifies increased risk of liver fibrosis and cirrhosis, type 2 diabetes, and cardiovascular disease. Therapies are limited. Weight loss is of benefit but is difficult to maintain. We aimed at examining the effect of the Mediterranean diet (MD), a diet high in monounsaturated fatty acids, on steatosis and insulin sensitivity, using gold standard techniques. Full-Text PDF Reply to: “Might some of the beneficial effects of the Mediterranean diet on non-alcoholic fatty liver disease be mediated by reduced iron stores?”Journal of HepatologyVol. 59Issue 3PreviewWe thank Mascitelli et al. for their comments regarding our study on the effects of the Mediterranean diet on hepatic steatosis and insulin sensitivity [1]. Mascitelli suggests that because of the relatively low red meat content of the Mediterranean diet (MD), there is a relatively reduced intake of iron, which may be a potential mechanism improving insulin sensitivity and steatosis. We believe that although there is merit in the comments, we would like to dispute some of the statements made. Full-Text PDF Open Access Ryan and colleagues [[1]Ryan M.C. Itsiopoulos C. Thodis T. Ward G. Trost N. Hofferberth S. et al.The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.J Hepatol. 2013; 59: 138-143Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar] found that a Mediterranean diet pattern reduced liver steatosis and improved insulin sensitivity in an insulin resistant population with non-alcoholic fatty liver disease (NAFLD), compared to current dietary advice. We suggest that lower body iron stores induced by components of the Mediterranean diet may be involved in this beneficial effect. In this setting, it has been proposed that the balance between the average bio-availability of dietary iron and the overall effects of inhibitors and enhancers of iron absorption may lead to lower iron stores in people consuming a Mediterranean dietary pattern [[2]Mascitelli L. Goldstein M.R. Mediterranean diet, lower body iron stores and metabolic syndrome.Int J Clin Pract. 2011; 65: 1110Crossref PubMed Scopus (9) Google Scholar]. In fact, it has been reported that elderly men from Crete, in the Mediterranean south of Europe had consistently lower levels of indicators of oxidative stress and iron status than elderly men from Zutphen in the north of Europe [[3]Buijsse B. Feskens E.J. Moschandreas J. Jansen E.H. Jacobs Jr., D.R. Kafatos A. et al.Oxidative stress, and iron and antioxidant status in elderly men: differences between the Mediterranean south (Crete) and northern Europe (Zutphen).Eur J Cardiovasc Prev Rehabil. 2007; 14: 495-500Crossref PubMed Scopus (44) Google Scholar]. In particular, serum ferritin, a good marker of the iron stored in the body, were 2-fold lower in men from Crete than in men from Zutphen (69.8 μg/L and 134.2 μg/L, respectively). Mounting evidence suggests a link between serum ferritin, insulin resistance, and NAFLD [[4]Trombini P. Piperno A. Ferritin, metabolic syndrome and NAFLD: elective attractions and dangerous liaisons.J Hepatol. 2007; 46: 549-552Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. Body iron excess has frequently been found in patients with metabolic syndrome [[5]Bozzini C. Girelli D. Olivieri O. Martinelli N. Bassi A. De Matteis G. et al.Prevalence of body iron excess in the metabolic syndrome.Diabetes Care. 2005; 28: 2061-2063Crossref PubMed Scopus (144) Google Scholar], with serum ferritin showing a linear increase with the increasing number of metabolic syndrome features [[5]Bozzini C. Girelli D. Olivieri O. Martinelli N. Bassi A. De Matteis G. et al.Prevalence of body iron excess in the metabolic syndrome.Diabetes Care. 2005; 28: 2061-2063Crossref PubMed Scopus (144) Google Scholar]. Moreover, it has been suggested that the relation between serum ferritin and most of metabolic syndrome features might be mediated by the presence of NAFLD at population-based level [[6]Zelber-Sagi S. Nitzan-Kaluski D. Halpern Z. Oren R. NAFLD and hyperinsulinemia are major determinants of serum ferritin levels.J Hepatol. 2007; 46: 700-707Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar]. Excessive hepatic iron accumulation in NAFLD can be one of the potential cofactors involved in the enhanced oxidative stress, which triggers liver cell necrosis and activation of hepatic stellate cells, both leading to fibrosis [[7]George D.K. Goldwurm S. MacDonald G.A. Cowley L.L. Walker N.I. Ward P.J. et al.Increased hepatic iron concentration in non-alcoholic steatohepatitis is associated with increased fibrosis.Gastroenterology. 1998; 114: 311-318Abstract Full Text Full Text PDF PubMed Scopus (626) Google Scholar]. One of the largest studies evaluating iron and liver histology in NAFLD demonstrated that elevated serum ferritin identified NAFLD patients with more advanced disease [[8]Kowdley K.V. Belt P. Wilson L.A. Yeh M.M. Neuschwander-Tetri B.A. Chalasani N. et al.Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with non-alcoholic fatty liver disease.Hepatology. 2012; 55: 77-85Crossref PubMed Scopus (334) Google Scholar]. Previous studies have shown a benefit of iron reduction therapy on NAFLD severity and insulin sensitivity [[9]Valenti L. Moscatiello S. Vanni E. Fracanzani A.L. Bugianesi E. Fargion S. et al.Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling – a propensity score-adjusted observational study.QJM. 2011; 104: 141-149Crossref PubMed Scopus (55) Google Scholar]. Furthermore, iron depletion by phlebotomy has been recently found to impact liver histology, which is considered the gold standard for evaluating the efficacy of liver disease treatment. A small phase II study of phlebotomy carried out to achieve near-iron depletion (serum ferritin ⩽50 μg/L) demonstrated statistically significant reductions in the NAFLD activity score (NAS), transaminases, serum ferritin, and hepatic iron concentration [[10]Beaton M.D. Chakrabarti S. Levstik M. Speechley M. Marotta P. Adams P. Phase II clinical trial of phlebotomy for non-alcoholic fatty liver disease.Aliment Pharmacol Ther. 2013; 37: 720-729Crossref PubMed Scopus (66) Google Scholar]. Although not statistically significant, improvements in steatosis, lobular inflammation, hepatocyte ballooning, and fibrosis were all in the predicted direction. Of note, these beneficial effects were reached in patients with a relatively mild overall degree of iron overload and liver disease at baseline (mean NAS = 3.8). Therefore, lower body iron stores induced by dietary components of Mediterranean diet could be involved in the beneficial action of this dietary pattern. It is important in future studies to include assessment of the dietary intervention on iron status and also to investigate the particular effects of iron depletion. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.