The wide spectrum of hepatic iron overload
Authors: Melania Manco, Anna Alisi, Antonella Mosca, Valerio Nobili
Journal: Hepatology (2011)

To the Editor: We read with great interest the article by Nelson et al.1 The authors elegantly described the association between patterns of intrahepatic iron deposition (within the hepatocytes [HC]; in the reticular endothelial cells [RES]; or both, HC/RES), liver histology, and metabolic abnormalities, including dyslipidemia and insulin resistance in the large cohort of adult patients from the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CNR). Intrahepatic iron deposition was found in 34.5% of patients. Most of them (44.7%) showed a mixed pattern, while the RES pattern was significantly associated with more severe histological damage and, particularly, with fibrosis.1 These findings seem to support the concept that differences may exist in patients with fatty liver based on different genetic background, inclination to inflammation, and co-occurrence of metabolic abnormalities such as diabetes. In this context, hepatic iron overload would represent a complex phenotype resulting from the maladaptation to environmental cues, mainly nutrients, and nurtured by metabolic abnormalities such as altered glucose metabolism (Fig. 1).2 Interactions between HFE and non-HFE gene with environmental cues (nutrients and poor physical activity) and metabolic abnormalities (i.e., altered glucose metabolism) leading to intrahepatic iron accumulation. C282Y homozygous individuals were excluded from the NASH-CNR survey, as, by far, this mutation is the commonest form of hereditary hemochromatosis. Nevertheless, it should be useful to know how many individuals in the cohort carry any HFE and non-HFE mutation among those causing iron overload syndrome.2 By categorizing patients according to their genetic background and/or prevalence of metabolic disorders (mainly diabetes), probably a more clear overview of the complex picture of the iron overload syndrome would emerge. Moreover, information on the genetic background would also be informative for explaining the difference in pattern of iron staining observed in this cohort respect with European series.1, 3 In this regard, differences may also involve children with fatty liver. Different from the low prevalence of hepatic siderosis observed in patients younger than 18 years by the authors, in our series of 66 youths of European ancestry with fatty liver we observed low to mild intrahepatic iron deposition in 15 patients (23%). Two of them showed an RES pattern, five an HC pattern and eight patients had a mixed pattern of iron deposition.4 Accordingly, the prevalence of positive iron staining in youth, even though of low-medium grade, seems to be not as negligible as observed from the authors in their cohort. The last concern is for the presence of diabetic patients in this cohort. Diabetes entered regression models as a covariate, but it should be of interest to know how many diabetic patients had hepatic siderosis and what was their prevalent pattern of iron deposition. Indeed, diabetes might represent a different pathogenic category in the heterogeneous sets of iron overload syndromes. Categorizations of patients with fatty liver and iron overload syndrome may be particularly important, in terms of therapeutic procedures, to discriminate patients who can benefit from blood letting, which has been demonstrated to be useful in most of these syndromes.5-7 We congratulate the authors on their excellent work; however, by adding the above information important insights may be provided. Melania Manco M.D., Ph.D., F.A.C.N.*, Anna Alisi Ph.D.*, Antonella Mosca M.D.*, Valerio Nobili M.D.*, * Laboratorio di Malattie Epatiche Auto-Immuni e Metaboliche Ospedale Pediatrico Bambino Gesù IRCCS, Centro di Nutrizione e Dietetica Dipartimento di Pediatria Università La Sapienza Roma, Italia.