We studied ethnic differences in terms of iron status during pregnancy between Dutch women and other ethnicities and explore to what extent these differences can be explained by environmental factors. This cross-sectional population-based study (2002–2006) was embedded in the Generation R study and included a total of 4737 pregnant women from seven ethnic groups (Dutch, Turkish, Moroccan, Cape Verdean, Surinamese-Hindustani, Surinamese-Creole and Antillean). Ethnicity was defined according to the Dutch classification of ethnic background. Ferritin, iron and transferrin were measured in early pregnancy. The overall prevalence of iron deficiency was 7 %, ranging from 4 % in both Dutch and Surinamese-Creoles, to 18 % in Turkish, Moroccan and Surinamese-Hindustani women. Iron overload was most prevalent in Surinamese-Creole (11 %) and Dutch (9 %) women. Socioeconomic factors accounted for 5–36 % of the differences. Income was the strongest socioeconomic factor in the Cape Verdean and Surinamese-Hindustani groups and parity for the Turkish and Moroccan groups. Lifestyle determinants accounted for 8–14 % of the differences. In all groups, the strongest lifestyle factor was folic acid use, being associated with higher iron status. In conclusion, in our population, both iron deficiency and iron overload were common in early pregnancy. Our data suggest that ethnic differences in terms of socioeconomic and lifestyle factors only partly drive the large ethnic differences in iron status. Our data support the development of more specific prevention programmes based on further exploration of socioeconomic inequities, modifiable risk and genetic factors in specific ethnic subgroups, as well as the need for individual screening of iron status before supplementation.

Iron overload is associated with an increased risk of atrial and ventricular arrhythmias. Data regarding the relationship between electrocardiographic parameters of atrial depolarisation and ventricular repolarisation with cardiac T2* MRI are scarce. Therefore, we aimed to investigate these electrocardiographic parameters and their relationship with cardiac T2* value in patients with β-thalassemia major. In this prospective study, 52 patients with β-thalassemia major and 52 age- and gender-matched healthy patients were included. Electrocardiographic measurements of QT, T peak to end interval, and P wave intervals were performed by one cardiologist who was blind to patients’ data. All patients underwent MRI for cardiac T2* evaluation. Cardiac T2* scores less than 20 ms were considered as iron overload. P wave dispersion, QTc interval, and the dispersions of QT and QTc were significantly prolonged in β-thalassemia major patients compared to controls. Interestingly, we found prolonged P waves, QT and T peak to end dispersions, T peak to end intervals, and increased T peak to end/QT ratios in patients with T2* greater than 20 ms. No significant correlation was observed between electrocardiographic parameters and cardiac T2* values and plasma ferritin levels. In conclusion, our study demonstrated that atrial depolarisation and ventricular repolarisation parameters are affected in β-thalassemia major patients and that these parameters are not correlated with cardiac iron load.

There are limited data on the association between Fe overload and leucocyte telomere length (LTL), known as a useful biomarker of the replicative ageing of cells. The aim of the study was to evaluate associations between Fe-status biomarkers and LTL. A cross-sectional study included 1174 men and women aged 50–79 years who provided blood samples for assays of Fe-status biomarkers including ferritin, transferrin saturation (TSAT), total Fe-binding capacity (TIBC) and relative LTL. They were free of hepatitis, potential infection or Fe deficiency. In multiple linear regression analysis adjusted for potential confounding variables, log-transformed LTL was positively associated with TIBC (adjusted coefficient estimate for its highest quartile: 0·17 (se 0·03), P<0·001) and inversely associated with TSAT (adjusted coefficient estimate for its third and fourth quartiles: −0·09 (se 0·03), P<0·01). These associations were consistent after additional adjustment for serum concentrations of high-sensitivity C-reactive protein, alanine transaminase and aspartate transaminase. In particular, participants with not only abnormally high concentrations (>45 %) but also with high-normal concentrations (35–45 %) of TSAT had shorter LTL compared with those with low-normal concentrations (<30 %) (P<0·05). We also observed that less-active or obese persons with high TSAT concentrations had shorter LTL than others. Our findings that cellular ageing is influenced not only by Fe overload but also by high-normal concentrations of TSAT support the hypothesis regarding the detrimental effects of labile Fe, which has a potent pro-oxidant activity in the body.

The peptide hormone hepcidin functions as a negative regulator of intestinal Fe absorption and Fe recycling. Since its discovery as a systemic negative regulator of Fe metabolism, hepcidin has attracted enormous interest as a potential drug for the treatment and/or prevention of several forms of Fe overload. We therefore tested whether multiple doses of intraperitoneally administered synthetic renatured hepcidin can prevent hepatic Fe loading in mice concurrently fed an Fe-rich diet, and whether the same treatment affects hepatic Fe stores in mice fed a normal diet. Cohorts of male mice were fed either a normal defined diet (180 parts per million Fe) or an Fe-rich diet (the same diet supplemented with 2 % carbonyl iron for 2 weeks). Concurrently, half of the animals in each diet group received 100 μg of renatured hepcidin intraperitoneally every 12 h, for the same 2-week period. The second half of the animals received PBS only. The renatured synthetic hepcidin demonstrated biological activity by significantly decreasing transferrin saturation, which lasted for up to 24 h after a single hepcidin dose. However, the 14 d intraperitoneal hepcidin therapy did not prevent hepatic Fe overload in mice fed the Fe-rich diet, nor did it affect hepatic Fe stores in mice fed the normal diet. Both hepcidin agonists and antagonists are expected to have broad therapeutic potential. The absence of an effect of biologically active hepcidin on hepatic Fe loading shows the need for thorough future studies on the hepcidin regulation of Fe absorption and tissue distribution.

Like most essential nutrients, Fe needs to be maintained in the body at a defined level for optimal health, with appropriate adaptation to varying Fe needs and supply. The primary mechanism for controlling Fe level is the regulation of Fe absorption. Several different proteins have been identified as contributors to the process. Despite a complex regulatory system, Fe disorders (both Fe deficiency and Fe overload) occur. Fe deficiency is a common problem worldwide, resulting from inadequate dietary Fe and blood loss. Complications include pre-term labour, developmental delay, and impaired work efficiency. No specific genetic syndromes causing isolated Fe deficiency have been described, but animal studies and clinical observations suggest that such a relationship may be a possibility. Conversely, the known causes of Fe overload are genetic. Fe overload is less common than Fe deficiency, but can result in serious medical complications, including cirrhosis, primary liver cancer, diabetes, cardiomyopathy and arthritis. The most common and best characterized syndrome of Fe overload is hereditary haemochromatosis (HHC), an autosomal recessive disorder. Mutations in the HFE protein cause HHC, but the clinical presentation is variable. Of particular interest is the factor that some HFE genotypes appear to be associated with protection from Fe deficiency. Other genetic variants in the regulatory pathway may influence the likelihood of Fe deficiency and Fe overload. Studies of genetic variants in HFE and other regulatory proteins provide important tools for studying the biological processes in Fe regulation. This work is likely to lead to new insights into Fe disorders and potentially to new therapeutic approaches. It will not be complete, however, until coordinated study of both genetic and nutritional factors is undertaken.

Fe homeostasis is maintained by regulation of Fe absorption to balance largely unregulated body Fe losses. The majority of human subjects maintain relatively constant Fe stores; however, Fe deficiency and Fe overload are common conditions. Fe overload is frequently associated with mutations in genes of Fe metabolism. The present paper summarises present knowledge of these mutations as well as indicating other genes that animal studies have implicated as candidates for influencing body Fe stores.

A 71-year-old man with Stage II gastric cancer developed rapid onset radiation induced liver disease after ceasing adjuvant chemotherapy and radiotherapy. Autopsy revealed moderate hepatocellular iron overload. Posthumously, he was found to be a compound heterozygote for hereditary haemochromatosis. Since both radiation and iron overload may induce liver damage through the activation of hepatic stellate cells, it is possible that hepatocellular iron overload may potentiate the effects of irradiation and predispose the patient to radiation induced liver disease.

The UK Food Standards Agency convened a group of expert scientists to review current research investigating diet and carriers of genetic mutations associated with hereditary haemochromatosis. The workshop concluded that individuals who are heterozygous for the C282Y mutation of the HFE gene do not appear to respond abnormally to dietary Fe and therefore do not need to change their diet to prevent accumulation of body Fe.

Excessive deposition of Fe in the organs and tissues of Sub-Saharan Africans was first described in South Africa in 1929. Fe overload, or siderosis, was initially attributed to infections and to metallic poisoning (Cu, Sn, Zn), and then to malnutrition. In 1953 it was hypothesized that it was due primarily to excessive Fe intake derived from foods and drinks prepared in Fe vessels. Recently, in 1992 it was advanced that a gene distinct from any HLA-linked locus may also play a role. As to sequelae, in early research on series of hospital patients, the condition was linked to scurvy, osteoporosis, diabetes, cirrhosis, and latterly, to hepatocellular cancer and tuberculosis. Accordingly, many have concluded that Fe overload is responsible for considerable morbidity and mortality, that adventitious Fe intake should be reduced, and that phlebotomy be recommended for those severely affected. However, there are numerous limitations in the evidence. There are also problems in interpretation, since levels of Fe in the serum are affected additionally by a variety of factors: infection, inflammation, certain cancers and alcohol intake. These considerations complicate attempts to assess to what extent the associations described denote causation, and whether Fe overload has significant ramifications for ill in the general African population. While the adverse sequelae of overload may be less of significance than many believe, the precise pathogenicity of the phenomenon will remain uncertain until further investigations, including prospective studies, are undertaken.

The influence of Fe status on cell-mediated immunity was studied in weanling mice fed on Fe-deficient (7 mg Fe/kg), Fe-sufficient (120 mg Fe/kg) and high-Fe (3000 or 5000 mg Fe/kg) diets for 7 weeks. The contact sensitivity (CS) response to dinitrofluorobenzene (DNFB), the in vivo delayed-type hypersensitivity (DTH) response to sheep erythrocytes (SRBC) and the ability of primed spleen cells to transfer DTH response to naive normal mice were suppressed in mice consuming the Fe-deficient diet. High-Fe diets (3000 or 5000 mg Fe/kg) selectively suppressed the CS response to DNFB, but the DTH response to SRBC or the transfer of DTH response by primed spleen cells to naive normal mice remained normal. Spleen cell functions associated with the expression of class II major histocompatibility (MHC) surface antigens, concanavalin A-induced interleukin-2 (IL-2) secretion or the antigen-presenting cell (APC) ability to stimulate antigen-dependent proliferation of an SRBC-specific helper T-lymphocyte clone were not altered by Fe status. However, consistent with the suppressed DTH response in the Fe- deficient mice was the suppressed concanavalin A-induced T-lymphocyte blastogenesis and the interferon-γ (INF-γ) production by spleen cells from mice fed on the Fe-deficient diet. Spleen cells from mice fed on excess levels of Fe in the diet secreted less INF-γ than the control mice, although T- lymphocyte proliferation remained unaffected. Suppression of the cellular immune response associated with Fe deficiency may be related in part to impaired T-lymphocyte proliferation and INF-γ secretion rather than to deficits in IL-2 secretion or APC function.