Ernest Beutler

The report by Allen et al. (Jan. 17 issue)¹ on iron-overload–related disease in patients with HFE hereditary hemochromatosis states that among men, the clinical penetrance among HFE C282Y homozygotes was 28.4%. Our study showed that only about 2% of male C282Y homozygotes had full-blown clinical disease.² We are disappointed that the authors still suggest that our results were biased because we excluded patients with a prior diagnosis of hemochromatosis, even after we showed them that the results were unaltered without this exclusion.³ Moreover, contrary to their assertion, all our patients were examined by a physician.

Because the penetrance of HFE hemochromatosis is low, traditional population screening measuring the transferrin saturation is unlikely to be cost-effective because the majority of subjects detected neither have clinical disease nor are likely to develop it. Three independent studies show that only patients with serum ferritin concentrations more than 1000 μg/L are at risk for cirrhosis, one of the main morbidities of hemochromatosis. Among 29 699 white subjects participating in the Scripps/Kaiser hemochromatosis study, only 59 had serum ferritin levels more than 1000 μg/L; 24 had homozygous mutant or compound heterozygous mutant HFE genotypes. In all but 5 of the other subjects, the causes of elevated ferritin were excessive alcohol intake, cancer, or liver disease. Screening for hemochromatosis with serum ferritin levels will detect the majority of patients who will be clinically affected and may detect other clinically significant disease in patients who do not have hemochromatosis genotypes. Because the ferritin level of the majority of adult homozygotes for HFE mutations does not rise over long periods of time, excluding subjects with serum ferritin levels less than or equal to 1000 μg/L should not result in missed opportunities for early treatment of patients who could benefit.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is relatively common in populations exposed to malaria. This deficiency appears to provide some protection from this infection, but it can also cause hemolysis after administration of some antimalarial drugs, especially primaquine. The risk of drug-induced G6PD deficiency-related hemolysis depends on a number of factors including the G6PD variant, the drug and drug dosage schedule, patient status, and disease factors. Although a great deal is known about the molecular biology of G6PD, determining the potential for drug-induced hemolysis in the clinical setting is still challenging. This report discusses the potential strategies for assessing drug-induced G6PD deficiency-related hemolytic risk preclinically and in early clinical trials. Additionally, the issues important for conducting larger clinical trials in populations in which G6PD deficiency is prevalent are examined, with a particular focus on antimalarial drug development.

Summary: Hepcidin is a major regulator of iron homeostasis. Hepcidin expression is upregulated by inflammatory cytokines, particularly interleukin (IL)‐6 and even more potently by the bone morphogenetic proteins 2, 4 and 9 (BMP‐2, BMP‐4 and BMP‐9). This study showed that the regulation of hepcidin expression by IL‐6 and BMPs occurs through distinct regulatory elements. The induction of hepcidin by BMPs requires at least two regions of the Hamp1 promoter, one between 140–260 bp and the other between 1·6–2·0 kb upstream of the start of translation. Reporter constructs including 1·6–2·0 kb of the Hamp1 promoter were induced >16‐fold by BMPs whereas a 260 bp reporter Hamp1 promoter construct was induced only two‐ to threefold. The distal 1·6–2·0 kb region appeared to contain several different BMP‐responsive elements, as incremental lengthening of the promoter construct in this region produced gradual escalation of BMP‐responsiveness. In contrast, the IL‐6 response required only the proximal 260 bp Hamp1 promoter region. Furthermore, there were no regulatory elements located in the non‐coding or coding regions of Hamp1 and activation of the Hamp1 promoter was absent or markedly reduced in cells of non‐hepatic origin.