Iron absorption in nonalcoholic steatohepatitis and dysmetabolic iron overload syndrome
Authors: Marc Ruivard, Fabrice Laine, Yves Deugnier
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: We read with interest the article of Hoki et al.1 The authors showed an increased duodenal absorption of iron through up‐regulation of divalent metal transporter 1 (DMT1) in patients with nonalcoholic steatohepatitis (NASH), despite high serum hepcidin levels. Duodenal absorption of iron from the gut was measured using an iron absorption test established in their laboratory, with natural, nonisotopic iron. We agree that up‐regulation of DMT1 could account for increased iron absorption, but it is difficult to understand how iron was exported from duodenal cells in the presence of high serum hepcidin levels and the absence of increased ferroportin messenger RNA expression. The authors also validated their model in vitro, demonstrating the induction of DMT1, but not of ferroportin, in cells cultured with sera from NASH patients. Dysmetabolic iron overload syndrome (DIOS) is another common condition characterized by increased body iron stores. In half of the cases, DIOS is associated with nonalcoholic fatty liver or NASH. These three conditions share the same etiology, i.e., the metabolic syndrome. Using a stable isotope of iron (58Fe), we have demonstrated that iron absorption, estimated as the area under the curve of 58Fe, was significantly lower in patients with DIOS than in lean and overweight controls without iron overload (Fig. 1).2 As expected, we found an inverse correlation between intestinal iron absorption and plasma hepcidin (r = −0.61, P < 0.001), ultrasensitive C‐reactive protein levels (r = −0.52, P < 0.001), and serum ferritin (r = −0.51, P < 0.001). These results indicate that regulation of iron absorption through hepcidin is preserved in DIOS.Figure 1: Intestinal iron absorption evaluated by the area under the curve of 58Fe given orally in patients with insulin‐resistance iron overload (DIOS), overweight controls, and lean controls. Results are expressed in mean ± standard deviation. Differences between DIOS patients and controls were significant (P < 0.01 for DIOS versus lean controls and P < 0.05 for DIOS versus overweight controls). Abbreviations: AUC, area under the curve; L, lean controls; OW, overweight controls. (Adapted from Ruivard et al., J Hepatol 2009;50:1219‐1225.2)The study of Hoki et al.1 raises several issues: (1) the time elapsed between the oral absorption test and the duodenal biopsy was not indicated (a long time could explain the lack of correlation between the oral iron absorption test, serum hepcidin, and expression of ferroportin); (2) the authors did not compare results of the iron absorption test according to the absence or presence of hepatic iron accumulation; (3) the expression of DMT1 in duodenal cells depending on local hypoxia through induction of hypoxia inducible factor‐2α,3 the hypothesis of a serum factor regulating DMT1 expression needs further investigation; and (4) the results are difficult to reconcile with the demonstration that a 6‐week regimen of a high‐fat/high‐energy diet4 induced hepcidin down‐regulation in an animal model. It is likely that iron metabolism varies along the long story of the metabolic syndrome: in the constitutive phase of overweight, hepcidin down‐regulation allows iron accumulation, probably to supply the increase of erythropoiesis, as has been demonstrated in rats4; and in the steady overweight phase, hepcidin is up‐regulated, which is related to iron excess. Interpretation of future studies of iron metabolism in DIOS or/and NASH should take such a dynamic view into account.