Ferritin, metabolic syndrome and NAFLD: Elective attractions and dangerous liaisons

Abstract

Accumulating evidence suggests a link between serum ferritin, insulin resistance, and non-alcoholic fatty liver disease (NAFLD). Several studies showed high ferritin levels and/or increased prevalence of hyperferritinemia in patients with the whole metabolic syndrome [1Bozzini 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, 2Jehn M. Clark J.M. Guallar E. Serum ferritin and risk of the metabolic syndrome in U.S. adults.Diabetes Care. 2004; 27: 2422-2428Crossref PubMed Scopus (317) Google Scholar] or its single components [3Tuomainen T.P. Nyyssonen K. Salonen R. Tervahauta A. Korpela H. Lakka T. et al.Body iron stores are associated with serum insulin and blood glucose concentrations. Population study in 1,013 eastern Finnish men.Diabetes Care. 1997; 20: 426-428Crossref PubMed Scopus (251) Google Scholar, 4Piperno A. Trombini P. Gelosa M. Mauri V. Pecci V. Vergani A. et al.Increased serum ferritin is common in men with essential hypertension.J Hypertens. 2002; 20: 1513-1518Crossref PubMed Scopus (138) Google Scholar, 5Williams M.J. Poulton R. Williams S. Relationship of serum ferritin with cardiovascular risk factors and inflammation in young men and women.Atherosclerosis. 2002; 165: 179-184Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 6Iwasaki T. Nakajima A. Yoneda M. Yamada Y. Mukasa K. Fujita K. et al.Serum ferritin is associated with visceral fat area and subcutaneous fat area.Diabetes Care. 2005; 28: 2486-2491Crossref PubMed Scopus (105) Google Scholar], with serum ferritin showing a linear increase with the increasing number of metabolic syndrome features [[1]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]. Epidemiologic studies have further supported this notion by suggesting that serum ferritin could be a marker of insulin resistance [[7]Fernandez-Real J.M. Ricart-Engel W. Arroyo E. Balanca R. Casamitjana-Abella R. Cabrero D. et al.Serum ferritin as a component of the insulin resistance syndrome.Diabetes Care. 1998; 21: 62-68Crossref PubMed Scopus (264) Google Scholar]. Fat accumulation in the liver seems to be a very early event in the course of insulin resistance and several studies demonstrated the strong association between NAFLD, insulin resistance and metabolic syndrome features [8Neuschwander-Tetri B.A. Nonalcoholic steatohepatitis and the metabolic syndrome.Am J Med Sci. 2005; 330: 326-335Crossref PubMed Scopus (165) Google Scholar, 9den Boer M. Voshol P.J. Kuipers F. Havekes L.M. Romijn J.A. Hepatic steatosis: a mediator of the metabolic syndrome. Lessons from animal models.Arterioscler Thromb Vasc Biol. 2004; 24: 644-649Crossref PubMed Scopus (221) Google Scholar, 10Reddy J.K. Rao M.S. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G852-G858Crossref PubMed Scopus (632) Google Scholar, 11Bradbury M.W. Lipid metabolism and liver inflammation. I. Hepatic fatty acid uptake: possible role in steatosis.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G194-G198Crossref PubMed Scopus (258) Google Scholar]. Serum ferritin is indeed frequently increased in NAFLD patients [12George D.K. Goldwurm S. MacDonald G.A. Cowley L.L. Walker N.I. Ward P.J. et al.Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.Gastroenterology. 1998; 114: 311-318Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar, 13Fargion S. Mattioli M. Fracanzani A.L. Sampietro M. Tavazzi D. Fociani P. et al.Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis.Am J Gastroenterol. 2001; 96: 2448-2455Crossref PubMed Google Scholar, 14Chitturi S. George J. Interaction of iron, insulin resistance, and nonalcoholic steatohepatitis.Curr Gastroenterol Rep. 2003; 5: 18-25Crossref PubMed Scopus (85) Google Scholar, 15Bugianesi 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 (377) Google Scholar] and related to disease progression [[15]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 (377) Google Scholar]. Finally, a common hepatic iron overload condition, characterised by hyperferritinemia with normal or slightly increased transferrin saturation, was described in non-C282Y homozygotes and named insulin-resistance hepatic iron overload [IR-HIO] syndrome due to frequent association with hepatic steatosis and metabolic abnormalities [[16]Mendler M.H. Turlin B. Moirand R. Jouanolle A.M. Sapey T. Guyader D. et al.Insulin resistance-associated hepatic iron overload.Gastroenterology. 1999; 117: 1155-1163Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar].Despite the substantial amount in support of an association between ferritin, iron overload, insulin resistance, and NAFLD the mechanisms underlying this intricate and intriguing relation are still unclear. Zelber-Sagi et al. in this issue of the Journal [[17]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] tried to fill one of these gaps. They showed that NAFLD was responsible for the association between serum ferritin and the metabolic syndrome and most of its components suggesting that the relation between serum ferritin and most of metabolic syndrome features might be mediated by the presence of NAFLD at population-based level. Expanding their conclusions, they also suggest that the association found in previous studies between ferritin and components of the metabolic syndrome may depend from undiagnosed NAFLD. Among metabolic features, insulin appeared to be the strongest predictor of increased serum ferritin levels, but the association between serum ferritin and insulin was much more evident in the NAFLD group. Accordingly, the interaction between NAFLD and hyperinsulinemia was the major determinant of serum ferritin levels in a linear multivariate analysis, besides gender.Despite the novelty of information, the cross-sectional design of the study prevents one from making inferences about the directionality of these associations. Two prospective studies provided evidence that increased ferritin levels precede the development of diabetes [18Salonen J.T. Tuomainen T.P. Nyyssonen K. Lakka H.M. Punnonen K. Relation between iron stores and non-insulin dependent diabetes in men: case-control study.BMJ. 1998; 317: 727Crossref PubMed Scopus (209) Google Scholar, 19Jiang R. Manson J.E. Meigs J.B. Ma J. Rifai N. Hu F.B. Body iron stores in relation to risk of type 2 diabetes in apparently healthy women.JAMA. 2004; 291: 711-717Crossref PubMed Scopus (452) Google Scholar]. However, it remains unanswered whether serum ferritin is a marker of insulin resistance or whether elevated serum ferritin may contribute, via iron accumulation, to the pathogenesis of altered metabolic states.An inherent problem in the study of this issue lies in the relation between serum ferritin and iron stores in patients with metabolic syndrome and NAFLD. Iron excess can induce hepatic damage and glucose intolerance or diabetes in hemochromatosis and thalassemia patients [20Niederau C. Berger M. Stremmel W. Starke A. Strohmeyer G. Ebert R. et al.Hyperinsulinaemia in non-cirrhotic haemochromatosis: impaired hepatic insulin degradation?.Diabetologia. 1984; 26: 441-444Crossref PubMed Scopus (153) Google Scholar, 21Merkel P.A. Simonson D.C. Amiel S.A. Plewe G. Sherwin R.S. Pearson H.A. et al.Insulin resistance and hyperinsulinemia in patients with thalassemia major treated by hypertransfusion.N Engl J Med. 1988; 318: 809-814Crossref PubMed Scopus (198) Google Scholar, 22Abraham D. Rogers J. Gault P. Kushner J.P. McClain D.A. Increased insulin secretory capacity but decreased insulin sensitivity after correction of iron overload by phlebotomy in hereditary haemochromatosis.Diabetologia. 2006; 49: 2546-2551Crossref PubMed Scopus (43) Google Scholar]. However, they represent severe iron overload conditions that can be hardly taken as models for disorders such as NAFLD and metabolic syndrome where liver iron stores are often normal or only slightly increased. In addition, recent data do not support insulin resistance as being a primary consequence of iron overload in hemochromatosis [[22]Abraham D. Rogers J. Gault P. Kushner J.P. McClain D.A. Increased insulin secretory capacity but decreased insulin sensitivity after correction of iron overload by phlebotomy in hereditary haemochromatosis.Diabetologia. 2006; 49: 2546-2551Crossref PubMed Scopus (43) Google Scholar]. On the other side, serum ferritin has several limitations as index of body iron stores and most aspects of its secretion remain unknown [[23]Ghosh S. Hevi S. Chuck S.L. Regulated secretion of glycosylated human ferritin from hepatocytes.Blood. 2004; 103: 2369-2376Crossref PubMed Scopus (106) Google Scholar]. Ferritin enters the circulation via a specific secretory pathway from its source tissues or is released from damaged cells [24Anderson G.J. Ramm G.A. Halliday J.W. Powell L.W. Ferritin metabolism in hemochromatosis.in: Barton J.C. Edwards C.Q. Hemochromatosis. Cambridge University Press, London2000: 145-156Crossref Google Scholar, 25Harrison P.M. Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation.Biochim Biophys Acta. 1996; 1275: 161-203Crossref PubMed Scopus (2217) Google Scholar]. In normal subjects secreted ferritin makes a major contribution to the serum ferritin pool, but in patients with chronic liver diseases high serum ferritin concentrations may reflect an increased release of tissue ferritin from injured hepatocytes into the circulation. Second, ferritin biosynthesis is stimulated at the transcriptional and translational levels by several factors other than iron. Cytokine-dependent control is particularly relevant to inflammation, because ferritin is an acute phase reactant and several pro-inflammatory cytokines stimulate ferritin synthesis [24Anderson G.J. Ramm G.A. Halliday J.W. Powell L.W. Ferritin metabolism in hemochromatosis.in: Barton J.C. Edwards C.Q. Hemochromatosis. Cambridge University Press, London2000: 145-156Crossref Google Scholar, 25Harrison P.M. Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation.Biochim Biophys Acta. 1996; 1275: 161-203Crossref PubMed Scopus (2217) Google Scholar]. Both hepatocellular necrosis and inflammation can occur in NAFLD and may lead to disproportionate serum ferritin levels. Indeed, almost all of the few studies that analysed both serum and tissue iron indices in patients with NAFLD or metabolic syndrome features showed that increased transferrin saturation and hepatic iron were far less common than hyperferritinemia (Table 1) [12George D.K. Goldwurm S. MacDonald G.A. Cowley L.L. Walker N.I. Ward P.J. et al.Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.Gastroenterology. 1998; 114: 311-318Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar, 13Fargion S. Mattioli M. Fracanzani A.L. Sampietro M. Tavazzi D. Fociani P. et al.Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis.Am J Gastroenterol. 2001; 96: 2448-2455Crossref PubMed Google Scholar, 14Chitturi S. George J. Interaction of iron, insulin resistance, and nonalcoholic steatohepatitis.Curr Gastroenterol Rep. 2003; 5: 18-25Crossref PubMed Scopus (85) Google Scholar, 15Bugianesi 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 (377) Google Scholar]. Moreover, serum ferritin and insulin resistance but not iron stores were significant predictors of severe fibrosis in NAFLD patients [[15]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 (377) Google Scholar]. Thus, it was suggested that high ferritin levels in NAFLD patients are more likely the expression of their metabolic state and/or hepatic damage [13Fargion S. Mattioli M. Fracanzani A.L. Sampietro M. Tavazzi D. Fociani P. et al.Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis.Am J Gastroenterol. 2001; 96: 2448-2455Crossref PubMed Google Scholar, 15Bugianesi 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 (377) Google Scholar] and that increase of serum ferritin levels can be induced either by the cause (insulin resistance) or the consequence (hepatocellular damage) of NAFLD, as also suggested by the present findings by Zelber-Sagi et al. [[17]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]. The known relationship between subclinical inflammation and metabolic syndrome does not seem to play a major role in determining serum ferritin concentrations in NAFLD or metabolic syndrome since CRP did not correlate with serum ferritin in the general population [3Tuomainen T.P. Nyyssonen K. Salonen R. Tervahauta A. Korpela H. Lakka T. et al.Body iron stores are associated with serum insulin and blood glucose concentrations. Population study in 1,013 eastern Finnish men.Diabetes Care. 1997; 20: 426-428Crossref PubMed Scopus (251) Google Scholar, 6Iwasaki T. Nakajima A. Yoneda M. Yamada Y. Mukasa K. Fujita K. et al.Serum ferritin is associated with visceral fat area and subcutaneous fat area.Diabetes Care. 2005; 28: 2486-2491Crossref PubMed Scopus (105) Google Scholar, 17Zelber-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] and in patients with the metabolic syndrome [1Bozzini 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, 2Jehn M. Clark J.M. Guallar E. Serum ferritin and risk of the metabolic syndrome in U.S. adults.Diabetes Care. 2004; 27: 2422-2428Crossref PubMed Scopus (317) Google Scholar]. However, more subtle inflammatory conditions, maybe at the local level in the liver or adipose tissue, cannot be excluded. Indeed, CRP expression is increased in liver and in adipose tissue of obese patients [[26]Anty R. Bekri S. Luciani N. Saint-Paul M.C. Dahman M. Iannelli A. et al.The inflammatory C-reactive protein is increased in both liver and adipose tissue in severely obese patients independently from metabolic syndrome, Type 2 diabetes, and NASH.Am J Gastroenterol. 2006; 101: 1824-1833Crossref PubMed Scopus (156) Google Scholar], adipose tissue contributes to the production of pro-inflammatory molecules, and the increase in their production participates in the metabolic syndrome [[27]Trayhurn P. Wood I.S. Adipokines: inflammation and the pleiotropic role of white adipose tissue.Br J Nutr. 2004; 92: 347-355Crossref PubMed Scopus (1693) Google Scholar]. In addition, it has been recently shown that adipose tissue expresses hepcidin, a key regulator of iron homeostasis, and that this expression is enhanced in massively obese patients and correlates with adipose tissue expression of CRP and interleukin-6 (IL-6) [[28]Bekri S. Gual P. Anty R. Luciani N. Dahman M. Ramesh B. et al.Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH.Gastroenterology. 2006; 131: 788-796Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]. This finding is intriguing if we consider that hepcidin decreases iron absorption and reduces iron mobilization from stores leading to decreased serum iron and hyperferritinemia [[29]Nemeth E. Ganz T. Hepcidin and iron loading anemias.Haematologica. 2006; 91: 727-732PubMed Google Scholar]. However, it should be taken with caution since the relative contribution of adipose tissue in circulating hepcidin is difficult to estimate, and all these findings seem to be more related to adiposity (through increased adipocyte IL-6 secretion) than to insulin resistance and NAFLD [26Anty R. Bekri S. Luciani N. Saint-Paul M.C. Dahman M. Iannelli A. et al.The inflammatory C-reactive protein is increased in both liver and adipose tissue in severely obese patients independently from metabolic syndrome, Type 2 diabetes, and NASH.Am J Gastroenterol. 2006; 101: 1824-1833Crossref PubMed Scopus (156) Google Scholar, 28Bekri S. Gual P. Anty R. Luciani N. Dahman M. Ramesh B. et al.Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH.Gastroenterology. 2006; 131: 788-796Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar].Table 1Number (%) of patients with NAFLD showing increased serum and hepatic iron indicesAuthor (ref.)PtsSerum iron indices reference valuePts with increased serum iron indicesHepatic iron indices reference valuePts with increased hepatic iron storesnTS n (%)SF n (%)n (%)George [12]George D.K. Goldwurm S. MacDonald G.A. Cowley L.L. Walker N.I. Ward P.J. et al.Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.Gastroenterology. 1998; 114: 311-318Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar51TS > 55%SF > 300 μg/l9/41 (22)26/42 (62)Perls’ stain > 121 (41)HIC > 40 μmol/g10/47 (21)Fargion [13]Fargion S. Mattioli M. Fracanzani A.L. Sampietro M. Tavazzi D. Fociani P. et al.Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis.Am J Gastroenterol. 2001; 96: 2448-2455Crossref PubMed Google Scholar90TS > 45%SF > 320 μg/l1 (1)24 (27)Perls’ stain > 13/20 (15)Chitturi [14]Chitturi S. George J. Interaction of iron, insulin resistance, and nonalcoholic steatohepatitis.Curr Gastroenterol Rep. 2003; 5: 18-25Crossref PubMed Scopus (85) Google Scholar93TS > 55%SF > 300 μg/l5 (6)37 (40)Perls’ stain > 19 (10)Bugianesi [15]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 (377) Google Scholar263TS > 55%SF > 350 μg/l19 (7)55 (21)HIC > 27 μmol/g7/80 (9)Only studies including both measures are reported. Open table in a new tab It can be argued that if ferritin, NAFLD and metabolic syndrome are linked together they should be modified in parallel by manoeuvres that affect either features. Phlebotomy-induced iron depletion improved insulin sensitivity in patients with NAFLD [30Facchini F.S. Hua N.W. Stoohs R.A. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease.Gastroenterology. 2002; 122: 931-939Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, 31Valenti L. Fracanzani A.L. Fargion S. Effect of iron depletion in patients with nonalcoholic fatty liver disease without carbohydrate intolerance.Gastroenterology. 2003; 124: 866Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar], some metabolic features in IR-HIO patients [[32]Piperno A. Vergani A. Salvioni A. Trombini P. Vigano M. Riva A. et al.Effects of venesections and restricted diet in patients with the insulin-resistance hepatic iron overload syndrome.Liver Int. 2004; 24: 471-476Crossref PubMed Scopus (45) Google Scholar] and serum ALT in both [30Facchini F.S. Hua N.W. Stoohs R.A. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease.Gastroenterology. 2002; 122: 931-939Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, 31Valenti L. Fracanzani A.L. Fargion S. Effect of iron depletion in patients with nonalcoholic fatty liver disease without carbohydrate intolerance.Gastroenterology. 2003; 124: 866Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 32Piperno A. Vergani A. Salvioni A. Trombini P. Vigano M. Riva A. et al.Effects of venesections and restricted diet in patients with the insulin-resistance hepatic iron overload syndrome.Liver Int. 2004; 24: 471-476Crossref PubMed Scopus (45) Google Scholar]. These findings could even occur in the absence of increased iron stores [30Facchini F.S. Hua N.W. Stoohs R.A. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease.Gastroenterology. 2002; 122: 931-939Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, 33Fernandez-Real J.M. Penarroja G. Castro A. Garcia-Bragado F. Hernandez-Aguado I. Ricart W. Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function.Diabetes. 2002; 51: 1000-1004Crossref PubMed Scopus (279) Google Scholar] suggesting that iron may exert its influence at a very subtle molecular level and that iron depletion may decrease hepatocellular injury and ALT activity either enhancing insulin sensitivity [[34]Fernandez-Real J.M. Lopez-Bermejo A. Ricart W. Cross-talk between iron metabolism and diabetes.Diabetes. 2002; 51: 2348-2354Crossref PubMed Scopus (455) Google Scholar] or reducing iron-mediated oxidative stress [35Templeton D.M. Liu Y. Genetic regulation of cell function in response to iron overload and chelation.Biochim Biophys Acta. 2003; 1619: 113-124Crossref PubMed Scopus (97) Google Scholar, 36Yano M. Hayashi H. Wakusawa S. Sanae F. Takikawa T. Shiono Y. et al.Long term effects of phlebotomy on biochemical and histological parameters of chronic hepatitis C.Am J Gastroenterol. 2002; 97: 133-137Crossref PubMed Google Scholar]. Moderate weight loss by diet and exercise is effective in reducing insulin resistance and is the first line therapy for NAFLD [[37]Adams L.A. Angulo P. Treatment of non-alcoholic fatty liver disease.Postgrad Med J. 2006; 82: 315-322Crossref PubMed Scopus (209) Google Scholar], but its effect on serum ferritin level is controversial [13Fargion S. Mattioli M. Fracanzani A.L. Sampietro M. Tavazzi D. Fociani P. et al.Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis.Am J Gastroenterol. 2001; 96: 2448-2455Crossref PubMed Google Scholar, 32Piperno A. Vergani A. Salvioni A. Trombini P. Vigano M. Riva A. et al.Effects of venesections and restricted diet in patients with the insulin-resistance hepatic iron overload syndrome.Liver Int. 2004; 24: 471-476Crossref PubMed Scopus (45) Google Scholar, 38Viganò M. Vergani A. Trombini P. Paleari F. Piperno A. Insulin resistance influence iron metabolism and hepatic steatosis in type II diabetes.Gastroenterology. 2000; 118: 986-987Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 39Guillygomarc’h A. Mendler M.H. Moirand R. Laine F. Quentin V. David V. et al.Venesection therapy of insulin resistance-associated hepatic iron overload.J Hepatol. 2001; 35: 344-349Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar]. Nevertheless, there is evidence that the diet-related decrease of serum ferritin depends on the relative proportion of the two components (iron overload and metabolic derangements) that influence ferritin changes in these patients. Further insights derive from IR-HIO patients. As compared to hemochromatosis patients with equal amounts of hepatic iron concentration (HIC) and iron removed, their serum ferritin concentrations are three times higher [[39]Guillygomarc’h A. Mendler M.H. Moirand R. Laine F. Quentin V. David V. et al.Venesection therapy of insulin resistance-associated hepatic iron overload.J Hepatol. 2001; 35: 344-349Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar]. Although this finding might simply suggest that serum ferritin overestimates the true amount of hepatic iron in IR-HIO, another explanation must be considered. Previous studies showed that relatively little ferritin is released from liver parenchymal cells in early hemochromatosis [[40]Beaumont C. Simon M. Smith P.M. Worwood M. Hepatic and serum ferritin concentrations in patients with idiopathic hemochromatosis.Gastroenterology. 1980; 79: 877-883PubMed Google Scholar] and that this may be because serum ferritin largely originates from cells of the reticuloendothelial system that are generally spared by iron accumulation in the early stage of disease. Accordingly, hyperferritinemia was more correlated with the mesenchymal than hepatocellular iron score in hemochromatosis [[41]Deugnier Y.M. Loreal O. Turlin B. Guyader D. Jouanolle H. Moirand R. et al.Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations.Gastroenterology. 1992; 102: 2050-2059Abstract PubMed Scopus (0) Google Scholar]. Thus, not only the total amount of hepatic iron, but also the relative distribution between different cellular compartments might be important in determining serum ferritin levels. This is not trivial if we consider that in IR-HIO hepatic iron deposition shows a particular distribution with large involvement of the sinusoidal compartment [[42]Turlin B. Mendler M.H. Moirand R. Guyader D. Guillygomarc’h A. Deugnier Y. Histologic features of the liver in insulin resistance-associated iron overload. A study of 139 patients.Am J Clin Pathol. 2001; 116: 263-270Crossref PubMed Scopus (119) Google Scholar] that can be undervalued by HIC and SQUID measurement and by Scheuer’s parenchymal iron grading.In Fig. 1 we try to summarize the links among ferritin (and iron), metabolic syndrome and NAFLD. Only a proportion of subjects with metabolic alterations appear at risk for iron overload [1Bozzini 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, 4Piperno A. Trombini P. Gelosa M. Mauri V. Pecci V. Vergani A. et al.Increased serum ferritin is common in men with essential hypertension.J Hypertens. 2002; 20: 1513-1518Crossref PubMed Scopus (138) Google Scholar] suggesting that other factors are involved. These patients have the IR-HIO. On the other side only a proportion of IR-HIO patients had features that suggest the presence of the metabolic syndrome [[16]Mendler M.H. Turlin B. Moirand R. Jouanolle A.M. Sapey T. Guyader D. et al.Insulin resistance-associated hepatic iron overload.Gastroenterology. 1999; 117: 1155-1163Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar]. It is not known whether metabolic alterations may lead to iron overload in susceptible individuals or iron accumulation precedes metabolic syndrome and NAFLD in IR-HIO. More accurate measurement of the amount and distribution of hepatic iron and a definition of IR-HIO according to the recent metabolic syndrome criteria [[43]National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–421.Google Scholar] are needed to clarify these relations. It is also needed to understand if and when the elective attraction among ferritin, metabolic syndrome and NAFLD turns into a dangerous iron-mediated liaison favouring hepatic damage. Studies on iron-related genes expression and genetic polymorphisms may help to clarify the alteration of iron homeostasis associated with metabolic syndrome and IR-HIO and to verify whether a genetic predisposition to iron overload exists in these patients. Accumulating evidence suggests a link between serum ferritin, insulin resistance, and non-alcoholic fatty liver disease (NAFLD). Several studies showed high ferritin levels and/or increased prevalence of hyperferritinemia in patients with the whole metabolic syndrome [1Bozzini 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, 2Jehn M. Clark J.M. Guallar E. Serum ferritin and risk of the metabolic syndrome in U.S. adults.Diabetes Care. 2004; 27: 2422-2428Crossref PubMed Scopus (317) Google Scholar] or its single components [3Tuomainen T.P. Nyyssonen K. Salonen R. Tervahauta A. Korpela H. La