Primary iron overload with inappropriate hepcidin expression in V162del ferroportin disease

Clinical Division of Gastroenterology and Hepatology, Innsbruck Medical University, Innsbruck, Austria.
Hepatology (Impact Factor: 11.06). 08/2005; 42(2):466-72. DOI: 10.1002/hep.20775
Source: PubMed


Ferroportin disease (hemochromatosis type 4) is a recently recognized disorder of human iron metabolism, characterized by iron deposition in macrophages, including Kupffer cells. Mutations in the gene encoding ferroportin 1, a cellular iron exporter, are responsible for this iron storage disease, inherited as an autosomal dominant trait. We present clinical, histopathological, and radiological findings in a family with the most common ferroportin mutation, V162del. In the index case, the disorder is characterized by abundant deposition of hemosiderin in all tissues investigated (mesenteric lymph node, liver, gastric and duodenal mucosa, and also in squamous cell carcinoma of the lung). The radiological findings indicated the presence of excess iron in bone marrow and spleen. Despite a significant burden of iron, no features of chronic liver disease were found in affected members of the family, including individuals aged up to 80 years. Hyperferritinemia greater than 1,000 microg/L was a penetrant biochemical finding before the second decade in life and was associated with significantly increased serum concentrations of pro-hepcidin that correlated positively with urinary hepcidin concentrations. In conclusion, the systemic iron burden in ferroportin disease is not a sufficient cause for chronic liver disease. In patients with most, but not all, ferroportin mutations, retention of iron in macrophages of the liver and other organs may protect against damage to parenchymal cells. Finally, macrophage iron storage in ferroportin disease is associated with elevated serum pro-hepcidin levels.

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    • "Of the transporter genes listed in Table 2, ''solute carrier family 39 (iron-regulated transporter), member 1'' (Slc40a1) encodes a multiple transmembrane domain protein, known as ferroportin 1, which acts as a cellular iron exporter in the liver (Anderson and Frazer, 2005). In humans, functional loss of Slc40a1 by mutation is reported to cause impaired iron homeostasis, resulting in iron overload and hemosiderin deposition in Kupffer cells (Zoller et al., 2005). Accordingly, the induction of Slc40a1 that we found may reflect a cellular effort to decrease the enhanced levels of intracellular iron, which was confirmed as hemosiderin deposition by histopathological analysis (Table 1) and was probably derived from heme degradation by Hmox1 (Fig. 5). "
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