Reply to: “Might some of the beneficial effects of the Mediterranean diet on non-alcoholic fatty liver disease be mediated by reduced iron stores?”
Authors: Marno C. Ryan, Paul Desmond, Andrew Wilson
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 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 3PreviewRyan and colleagues [1] 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]. Full-Text PDF Open Access We thank Mascitelli et al. for their comments regarding our study on the effects of the Mediterranean diet on hepatic steatosis and insulin sensitivity [[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 (468) Google Scholar]. 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. Firstly, Mascitelli and colleagues state that serum ferritin is a good marker of iron stores in NAFLD. We suggest that whilst in healthy non-diabetic subjects, serum ferritin is strongly associated with hepatic iron stores, in NAFLD this is not the case. In fact, dysmetabolic subjects often have high serum ferritin levels, being the so-called dysmetabolic hyperferritinaemia (DHF) the commonest cause of mild to moderate hyperferritinaemia in clinical practice [[2]Adams P.C. Barton J.C. A diagnostic approach to hyperferritinemia with a non-elevated transferrin saturation.J Hepatol. 2011; 55: 453-458Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. As non-alcoholic fatty liver disease (NAFLD) is associated with systemic inflammation, increased adipokine release and oxidative and endoplasmic reticulum stress, the assessment of iron status is particularly challenging in these patients. However, we agree that hyperferritinaemia has been associated with hepatic histological damage in NAFLD [[3]Bugianesi E. Manzini P. D’Antico S. Vanni E. Longo F. Leone N. et al.Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver.Hepatology. 2004; 39: 179-187Crossref PubMed Scopus (397) Google Scholar]. A recent paper published by the Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN) demonstrated that in subjects with NASH, a serum ferritin >1.5 × ULN was associated with increased iron deposition, but was also independently associated with a higher NAFLD activity score (NAS) and was a predictor of advanced fibrosis regardless of iron deposition [[4]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 nonalcoholic fatty liver disease.Hepatology. 2012; 55: 77-85Crossref PubMed Scopus (362) Google Scholar]. Hyperferritinaemia is also known to be associated with reduced insulin sensitivity. It is a predictor of development of type 2 diabetes, as well as more rapid progression of cardiovascular disease [[5]Forouhi N.G. Harding A.H. Allison M. Sandhu M.S. Welch A. Luben R. et al.Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study.Diabetologia. 2007; 50: 949-956Crossref PubMed Scopus (204) Google Scholar]. In another study, both serum ferritin and hepcidin levels increased linearly with the number of metabolic syndrome features [[6]Martinelli N. Traglia M. Campostrini N. Biino G. Corbella M. Sala C. et al.Increased serum hepcidin levels in subjects with the metabolic syndrome: a population study.PLoS One. 2012; 7: e48250Crossref PubMed Scopus (71) Google Scholar]. Therefore, it is likely that the hyperferritinaemia seen in NASH is reflective of reduced insulin sensitivity and the presence of the metabolic syndrome rather than of iron overload. However, it is still unclear which is the nature of the relationship between iron and insulin sensitivity: is ferritin reflective of pathological iron levels that affect IGF-1/insulin signaling [[7]Ackerman D. Gems D. Insulin/IGF-1 and hypoxia signaling act in concert to regulate iron homeostasis in Caenorhabditis elegans.PLoS Genet. 2012; 8: e1002498Crossref PubMed Scopus (46) Google Scholar], or is it simply a marker of the subsequent inflammation and cytokine release that accompanies insulin resistance? Our subjects underwent baseline ferritin estimations but not follow-up assays, so we can only provide cross-sectional data. Overall, there was no significant association between serum iron and hepatic fibrosis or NAS score, however, this may be because of the small numbers involved. In our dietary intervention, subjects were exposed to four-week diets. We doubt that this would provide sufficient time for the iron stores to be altered to a sufficient degree as to make any difference to insulin sensitivity or steatosis. However, we also noted that in a recent paper by Kowdley et al. [[8]Messner D.J. Rhieu B.H. Kowdley K.V. Iron overload causes oxidative stress and impaired insulin signaling in AML-12 hepatocytes.Dig Dis Sci. 2013; PubMed Google Scholar], the negative effects of iron in an animal model were ameliorated by oleic acid, which was abundant in the diet studied in our paper, providing an additional potential mechanism by which our diet could have reduced insulin sensitivity and steatosis. Overall, we agree that Mascitelli and colleagues provide evidence for an intriguing alternative benefit of the Mediterranean diet in NAFLD. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.