Reply

Abstract

We wish to make a few comments. First, a detailed analysis of hepatic transplantation patients has revealed that iron accumulation in patients with HFE-associated hemochromatosis can be abrogated by implanting a normal (wild-type) liver (Hepatology 2002;36:194A). Conversely, in a small number of genotypically normal individuals who inadvertently received a hemochromatotic liver, hepatic iron loading persists. These data further highlight the role of the liver in the regulation of intestinal iron absorption and support our evidence suggesting that this organ is the main site of HFE action (Lancet 2003;361:669–673).Second, the possibility that hepcidin is under the dual regulation of HFE and TfR2 pathways in the liver is consistent with earlier observations that iron absorption is only partly dysregulated in hemochromatosis and can still be modulated in response to changes in body iron levels (J Lab Clin Med 1991;117:390–401). Indeed, we observed a positive correlation between hepatic iron levels and hepcidin expression in hemochromatosis patients despite an overall lower hepcidin level. We would predict, therefore, that the signal for this residual regulation is being supplied by hepatic TfR2. Our model would also predict that patients with mutations in hepcidin (or in both HFE and TfR2) would have very limited capacity to regulate their body iron intake.Third, the demonstration that hepcidin levels are reduced in hemochromatosis has important implications for the diagnosis and treatment of this common disorder. Since a strong correlation has been found between hepcidin expression and iron absorption, measurements of plasma hepcidin levels could be of considerable value in predicting which individuals are likely to be at risk of iron loading. This is of particular interest given the variable nature of the penetrance of hemochromatosis. Furthermore, the administration of hepcidin or hepcidin agonists can potentially prevent the need for lifelong phlebotomy therapy in hemochromatosis patients. In addition, hepcidin (or its antagonists) has potential in the treatment of a range of other disorders in which iron absorption is perturbed. No doubt the elucidation of the pathways by which hepcidin is activated and how it exerts its effects on the intestinal epithelium will provide a number of key therapeutic targets. We wish to make a few comments. First, a detailed analysis of hepatic transplantation patients has revealed that iron accumulation in patients with HFE-associated hemochromatosis can be abrogated by implanting a normal (wild-type) liver (Hepatology 2002;36:194A). Conversely, in a small number of genotypically normal individuals who inadvertently received a hemochromatotic liver, hepatic iron loading persists. These data further highlight the role of the liver in the regulation of intestinal iron absorption and support our evidence suggesting that this organ is the main site of HFE action (Lancet 2003;361:669–673). Second, the possibility that hepcidin is under the dual regulation of HFE and TfR2 pathways in the liver is consistent with earlier observations that iron absorption is only partly dysregulated in hemochromatosis and can still be modulated in response to changes in body iron levels (J Lab Clin Med 1991;117:390–401). Indeed, we observed a positive correlation between hepatic iron levels and hepcidin expression in hemochromatosis patients despite an overall lower hepcidin level. We would predict, therefore, that the signal for this residual regulation is being supplied by hepatic TfR2. Our model would also predict that patients with mutations in hepcidin (or in both HFE and TfR2) would have very limited capacity to regulate their body iron intake. Third, the demonstration that hepcidin levels are reduced in hemochromatosis has important implications for the diagnosis and treatment of this common disorder. Since a strong correlation has been found between hepcidin expression and iron absorption, measurements of plasma hepcidin levels could be of considerable value in predicting which individuals are likely to be at risk of iron loading. This is of particular interest given the variable nature of the penetrance of hemochromatosis. Furthermore, the administration of hepcidin or hepcidin agonists can potentially prevent the need for lifelong phlebotomy therapy in hemochromatosis patients. In addition, hepcidin (or its antagonists) has potential in the treatment of a range of other disorders in which iron absorption is perturbed. No doubt the elucidation of the pathways by which hepcidin is activated and how it exerts its effects on the intestinal epithelium will provide a number of key therapeutic targets.