Hereditary hemochromatosis usually results from C282Y homozygosity in the HFE gene on chromosome 6p. Recently, a new type of hemochromatosis (HFE3) has been characterized in 2 unrelated Italian families with a disorder linked to 7q. Patients with HFE3 have transferrin receptor 2 (TFR2) inactivated by a homozygous nonsense mutation (Y250X). Here the identification of 2 newTFR2 mutations is reported. In a large inbred family from Campania, a frameshift mutation (84-88 insC) in exon 2 that causes a premature stop codon (E60X) is identified. In a single patient with nonfamilial hemochromatosis, a T→A transversion (T515A), which causes a Methionine→Lysine substitution at position 172 of the protein (M172K), has been characterized. TFR2 gene gives origin to 2 alternatively spliced transcripts—the α-transcript, which may encode a transmembrane protein, and the β-transcript, a shorter, possibly intracellular variant. Based on their positions, the effects of the identified mutations on the 2 TFR2 forms are expected to differ. Y250X inactivates both transcripts, whereas E60X inactivates only the α-form. M172K has a complex effect: it causes a missense in the α-form, but it may also prevent the β-form production because it affects its putative initiation codon. Analysis of the clinical phenotype of 13 HFE3 homozygotes characterized at the molecular level has shown a variable severity, from nonexpressing patients to severe clinical complications. The identification of new mutations of TFR2 confirms that this gene is associated with iron overload and offers a tool for molecular diagnosis in patients without HFE mutations.

Insulin-resistance-associated hepatic iron overload syndrome (IRHIO) is characterized by high serum ferritin and presence of metabolic alterations that are part of insulin-resistance syndrome (IRS). Thus, clinical conditions characterized by a high prevalence of IRS may also be characterized by a high prevalence of IRHIO. We studied 88 consecutive patients with essential hypertension, 62 patients with IRHIO and 102 healthy normotensive controls. Hemochromatosis, other conditions able to induce secondary iron overload or serum ferritin increase unrelated to body iron stores were excluded. Iron indices, metabolic profiles and hepatic tests in hypertensive with or without increased serum ferritin and in IRHIO with and without hypertension were studied. Metabolic variables, serum iron indices, liver function tests and hepatic ultrasound data were analysed. Data were compared by non-parametric tests. In men with hypertension, increased serum ferritin was more frequent than in controls (21 versus 0%, P = 0.001). Hypertensive men with increased serum ferritin had more frequent and pronounced metabolic alterations than those with normal serum ferritin, the metabolic abnormalities and serum ferritin being frequently positively correlated. In hypertensive men with increased serum ferritin, metabolic and iron data were similar to those of IRHIO patients with hypertension. In males, hypertension is characterized by a higher prevalence of increased iron stores and metabolic abnormalities that are part of the IRHIO syndrome. This finding may have clinical implications due to the increased risk of IRHIO patients to develop hepatic cirrhosis and also for the role of iron in early atherogenesis.

Sporadic porphyria cutanea tarda (PCT) is caused by a reduced activity of uroporphyrinogen decarboxylase (URO-D) in the liver. Mild to moderate iron overload is common in PCT, as iron is one of the factors which trigger the clinical manifestations of the disease through the inactivation of URO-D. A role for genetic hemochromatosis in the development of iron overload in sporadic PCT has been hypothesized in the past. The aim of this work was to investigate whether mutations of HFE, which is a candidate gene for hemochromatosis, play the role of genetic susceptibility factors for PCT in Italian patients, who have a high prevalence of acquired triggering factors, such as hepatitis C virus (HCV) chronic infection and alcohol. We determined HFE genotypes of 68 male patients with PCT. Our data do not confirm an association of PCT with the Cys282Tyr HFE mutation, strongly associated with hemochromatosis in Northern European countries. A second mutation of HFE, His63Asp, however, had a significantly increased frequency as it was present in half of the patients. Surprisingly, the presence of the His63Asp mutation was not related to the iron status of patients, suggesting that a subtle abnormality of iron metabolism induced by this mutation could escape detection by the standard parameters of iron status. In PCT patients with liver disease, the presence of the mutation could contribute to the inactivation of URO-D, either directly or through a synergistic action with other factors that cause liver damage.