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ARTICLES: Peter F. Whitington and Susan Kelly Outcome of Pregnancies at Risk for Neonatal Hemochromatosis Is Improved by Treatment With High-Dose Intravenous Immunoglobulin Pediatrics 2008; 121: e1615-e1621 [Abstract] [Full text] [PDF]

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Is iron toxic for fetal hepatocytes?

Julien Baruteau, Dominique Debray, Vincent Guigonis, Pierre Broué   (26 March 2009)

Is iron toxic for fetal hepatocytes? 26 March 2009
Julien Baruteau, MD APHP, Hôpital Robert Debré, Pediatric neurology and metabolic unit, Dominique Debray, Vincent Guigonis, Pierre Broué Send letter to journal: Re: Is iron toxic for fetal hepatocytes? jbaruteau{at}yahoo.fr Julien Baruteau, et al.	Dear Editor, The very elegant article by Whitington et al, that investigated survival improvement of at-risk pregnancies with antenatal immunoglobulin perfusions (1) in perinatal hemochromatosis (PH) (OMIM 231100), encouraged us to write this commentary letter. We would like to highlight disease causing physiopathological mechanisms through new insights about transplacental iron flux. PH is an interesting pathogenic model regarding iron-induced injury in the human liver. PH is a rare gestational disease with intra- and extrahepatic iron overload sparing the reticuloendothelial system, causing in utero fetal death or neonatal liver failure associated with antenatal cirrhosis (2). An alloimmune etiology was recently strengthened by improved survival. However, little is known about physiopathological mechanisms concerning iron overload and liver toxicity. The liver could be relatively tolerant to iron overload compared with other organs like heart and antehypophysis, which are also involved in hereditary hemochromatosis type 2 or juvenile hemochromatosis (OMIM 602390) with late-onset liver failure (3). Similarly, the murine model Usf 2 -/-, a knockout for hepcidin synthesis that leads to tissue iron overload mimicking hereditary hemochromatosis, develops liver failure after many years (4). In PH, siderosis involves all organs but spares the reticuloendothelial system (especially the spleen and bone marrow). Apart from the liver, no other neonatal organ failure resulting from iron overload has been reported, except for multi-organ failure resulting from end-stage liver failure. Therefore, it seems unlikely that life- threatening liver failure in PH results only from iron overload contracted in few weeks. Fetal liver plays a key role in iron homeostasis and placental iron transport. Liver hepcidin controls intestinal iron uptake by modulating the degradation of ferroportin, an enterocyte iron transporter (5). Hepcidin expression in fetal liver is correlated with the level of fetal liver iron. Fetal hepcidin regulates placental expression of the transferrin receptor (TfR) and at least partially influences placental iron flow in an unclear way (6). Placental ferroportin expression increases during the third trimester of pregnancy, a period during which iron flux from mother to fetus is maximal, thus suggesting the involvement of ferroportin in materno-fetal iron flow. But no modulation of ferroportin expression is reported whatever the maternal iron status, raising the possibility of a different mechanism (7). Iron does not seem to be the initial cause of liver injury such as in hereditary hemochromatosis (8), but only the result of primary severe liver dysfunction leading to iron homeostasis dysregulation. Previous observations of PH demonstrated the onset of liver injury before the demonstration of iron overload corroborate this view. Whitington’s theory emphasizes these findings. Maternal alloantibodies cross the materno- placental barrier and react with a fetal liver antigen. This hepatocyte immune injury leads to hepatocyte dysfunction, liver failure and secondary iron balance disruption. Siderosis would only play an accessory role in fetal hepatotoxicity by strengthening oxidant injury. A potential pathway of iron homeostasis dysregulation could involve hepcidin and ferroportin. The decreased liver synthesis of hepcidin in the fetus would remove its negative retrocontrol on placental iron flux. As iron hepatotoxicity was assumed to be due to an oxidant/antioxidant imbalance, this was the justification of a controversial antioxidant therapy in PH (9). If hepatocyte oxidant injury is not the primum movens of liver disease, this could explain in part its mild efficiency. Bibliography 1. Whitington PF, Hibbard JU. High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis. Lancet 2004;364(9446):1690-8. 2. Knisely AS, Mieli-Vergani G, Whitington PF. Neonatal hemochromatosis. Gastroenterol Clin North Am 2003;32(3):877-89, vi-vii. 3. Brissot P, Jouanolle AM, Le Lan C, Loreal O, Deugnier Y, David V. [Non- HFE related hereditary iron overload]. Gastroenterol Clin Biol 2005;29(5):565-8. 4. Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A 2001;98(15):8780-5. 5. Ganz T. Hepcidin and its role in regulating systemic iron metabolism. Hematology Am Soc Hematol Educ Program 2006:29-35, 507. 6. Gambling L, Czopek A, Andersen HS, Holtrop G, Srai SK, Krejpcio Z, et al. Fetal Iron Status Regulates Maternal Iron Metabolism During Pregnancy in the Rat. Am J Physiol Regul Integr Comp Physiol 2009. 7. Li YQ, Yan H, Bai B. Change in iron transporter expression in human term placenta with different maternal iron status. Eur J Obstet Gynecol Reprod Biol 2008;140(1):48-54. 8. Whitington PF. Fetal and infantile hemochromatosis. Hepatology 2006;43(4):654-60. 9. Shamieh I KP, Suchy FJ, Freese DK. Anti-oxidant therapy for neonatal iron storage disease (NISD) (abstract). Pediatr Res 1993;33:109A. Conflict of Interest: None declared