In
genetic hemochromatosis (GH), excess
iron is deposited in parenchymal cells, whereas little
iron is found in reticuloendothelial (RE) cells until the later stages of the disease. As
iron absorption is inversely related to RE cells stores, a failure of RE to retain
iron has been proposed as the basic defect in GH. In RE cells of GH subjects, we examined the activity of
iron regulatory protein (IRP), a reliable
indicator of the elusive regulatory labile
iron pool, which modulates cellular
iron homeostasis through control of
ferritin (Ft) and
transferrin receptor gene expression.
RNA-bandshift assays showed a significant increase in IRP activity in monocytes from 16 patients with untreated GH compared with 28 control subjects (1.5-fold) and five patients with secondary
hemochromatosis (SH) with similar
iron burden (fourfold). In 17 phlebotomy-treated GH patients, IRP activity did not differ from that of control subjects. In both GH and SH monocyte-macrophages, Ft content increased by twofold and the L subunit-rich
isoferritin profile was unchanged as compared with controls. IRP activity was still upregulated in vitro in monocyte-derived macrophages of GH subjects but, following manipulations of
iron levels, was modulated normally. Therefore, the sustained activity of monocyte IRP found in vivo in monocytes of GH patients is not due to an inherent defect of its control, but is rather the expression of a critical abnormality of
iron metabolism, eg, a paradoxical contraction of the regulatory
iron pool. By preventing Ft mRNA translation, high IRP activity in monocytes may represent a molecular mechanism contributing to the inadequate Ft accumulation and insufficient RE
iron storage in GH.