HFE-associated hereditary
hemochromatosis is characterized by imbalances of
iron homeostasis and alterations in intestinal
iron absorption. The identification of the HFE gene and the apical
iron transporter
divalent metal transporter-1, DMT-1, provide a direct method to address the mechanisms of
iron overload in this disease. The aim of this study was to evaluate the regulation of duodenal HFE and DMT-1 gene expression in HFE-associated hereditary
hemochromatosis. Small bowel biopsies and serum
iron indices were obtained from a total of 33 patients. The study population comprised 13 patients with hereditary
hemochromatosis (C282Y homozygous), 10 patients with
iron deficiency anemia, and 10 apparently healthy controls, all of whom were genotyped for the two common mutations in the HFE gene (C282Y and H63D). Total
RNA was isolated from tissue and amplified via RT-PCR for HFE, DMT-1, and the internal control GAPDH. DMT-1
protein expression was additionally assessed by immunohistochemistry. Levels of HFE
mRNA did not differ significantly between patient groups (P = 0.09), specifically between C282Y homozygotes and
iron deficiency anemic patients, when compared to controls (P = 0.09, P = 0.9, respectively). In contrast, DMT-1
mRNA levels were at least twofold greater in patients with hereditary
hemochromatosis and
iron deficiency anemia when compared to controls (P = 0.02, P = 0.01, respectively). Heightened DMT-1
protein expression correlated with
mRNA levels in all patients. Loss of HFE function in hereditary
hemochromatosis is not derived from inhibition of its gene expression. DMT-1 expression in C282Y homozygote subjects is consistent with the hypothesis of a "paradoxical" duodenal
iron deficiency in hereditary
hemochromatosis. The observed twofold upregulation of the DMT-1 is consistent with the slow but steady increase in body
iron stores observed in those presenting with clinical features of hereditary
hemochromatosis.