Concept: Human iron metabolism
There is increasing evidence from clinical and population studies for a role of H. pylori infection in the aetiology of iron deficiency. Rodent models of Helicobacter infection are helpful for investigating any causal links and mechanisms of iron deficiency in the host. The aim of this study was to investigate the effects of gastric Helicobacter infection on iron deficiency and host iron metabolism/transport gene expression in hypergastrinemic INS-GAS mice. INS-GAS mice were infected with Helicobacter felis for 3, 6 and 9 months. At post mortem, blood was taken for assessment of iron status and gastric mucosa for pathology, immunohistology and analysis of gene expression. Chronic Helicobacter infection of INS- GAS mice resulted in decreased serum iron, transferrin saturation and hypoferritinemia and increased Total iron binding capacity (TIBC). Decreased serum iron concentrations were associated with a concomitant reduction in the number of parietal cells, strengthening the association between hypochlorhydria and gastric Helicobacter-induced iron deficiency. Infection with H. felis for nine months was associated with decreased gastric expression of iron metabolism regulators hepcidin, Bmp4 and Bmp6 but increased expression of Ferroportin 1, the iron efflux protein, iron absorption genes such as Divalent metal transporter 1, Transferrin receptor 1 and also Lcn2 a siderophore-binding protein. The INS-GAS mouse is therefore a useful model for studying Helicobacter-induced iron deficiency. Furthermore, the marked changes in expression of gastric iron transporters following Helicobacter infection may be relevant to the more rapid development of carcinogenesis in the Helicobacter infected INS-GAS model.
There has been no evidence for the necessity of endoscopy in asymptomatic young men with iron deficiency anemia (IDA). To determine whether endoscopy should be recommended in asymptomatic young men with IDA, we compared the prevalence of gastrointestinal (GI) lesions between young men (< 50 years) with IDA and those without IDA.
Tea interferes with iron absorption and can lead to iron deficiency anemia when consumed in large quantities. The rechallenge effect of green tea on anemia in a middle-aged man emphasizes the potential causal role of this beverage. Lifestyle and dietary habits are important diagnostic considerations in diseases of this type.
The iron regulatory hormone hepcidin responds to both oral and parenteral iron. Here, we hypothesized that the diverse iron trafficking routes may affect the dynamics and kinetics of the hepcidin activation pathway. To address this, C57BL/6 mice were administered an iron-enriched diet or injected i.p. with iron dextran and analyzed over time. After 1 week of dietary loading with carbonyl iron, mice exhibited significant increases in serum iron and transferrin saturation, as well as in hepatic iron, Smad1/5/8 phosphorylation and bone morphogenetic protein 6 (BMP6), and hepcidin mRNAs. Nevertheless, hepcidin expression reached a plateau afterward, possibly due to upregulation of inhibitory Smad7, Id1, and matriptase-2 mRNAs, while hepatic and splenic iron continued to accumulate over 9 weeks. One day following parenteral administration of iron dextran, mice manifested elevated serum and hepatic iron levels and Smad1/5/8 phosphorylation, but no increases in transferrin saturation or BMP6 mRNA. Surprisingly, hepcidin failed to appropriately respond to acute overload with iron dextran, and a delayed (after 5-7 days) hepcidin upregulation correlated with increased transferrin saturation, partial relocation of iron from macrophages to hepatocytes, and induction of BMP6 mRNA. Our data suggest that the physiological hepcidin response is saturable and are consistent with the idea that hepcidin senses exclusively iron compartmentalized within circulating transferrin and/or hepatocytes.
The relation between Lead (Pb) and iron (Fe) becomes increasingly concerned because they are both divalent metals that are absorbed by the same intestinal mechanism, and Pb exposure and Fe deficiency in the developmental brain, as well as Fe overload in the aged brain, can cause cognitive deficits. However, the interaction between Pb exposure and Fe status in the brain has not been established. Therefore, in the current study, we examined the effects of maternal ingestion of Pb in drinking water during gestation and lactation on the Fe status and the expression of divalent metal transporter 1 (DMT1) and ferroportin 1 (FP1) in the brain of offspring. The offspring were followed through old age, with measurements taken at postnatal week 3, 41 and 70. Pb exposure increases the Fe content in the old-aged rats' brain, Which might be not subjected to DMT1 mediating, but may be associated with the decrease expression of FP1. Furthermore, the effect of Pb on FP1 expression is regulated at transcriptional and posttranscriptional levels. The perturbation in Fe homeostasis may contribute to the neurotoxicology consequences induced by Pb exposure, and FP1 may play a role in Pb-induced Fe cumulation in the brain.
Abstract Anemia is a global health issue with disproportionately high prevalence in women. In addition to being an independent risk factor for decreased quality of life and increased morbidity and mortality, anemia in women has been linked to unfavorable outcomes of pregnancy and other issues for children born to anemic women. Iron deficiency is the leading cause of anemia in many populations. Guidelines recommend proactive screening for anemia, particularly in the preoperative setting. Once anemia is diagnosed, treatment should be based on etiology (most commonly, iron deficiency followed, in order of prevalence, by inflammation or chronic disease). Iron supplementation (oral and intravenous) offers safe and effective treatment for anemia associated with iron deficiency. Anemia of chronic disease may be more challenging to treat, and attention must be given to the underlying disease, along with use of hematinic agents. Given its enormous impact on the health and well-being of women and the availability of simple and effective treatment options, anemia should never be left unmanaged.
Ferroportin exports iron into plasma from absorptive enterocytes, erythrophagocytosing macrophages, and hepatic stores. The hormone hepcidin controls cellular iron export and plasma iron concentrations by binding to ferroportin and causing its internalization and degradation. We explored the mechanism of hepcidin-induced endocytosis of ferroportin, the key molecular event in systemic iron homeostasis. Hepcidin binding caused rapid ubiquitination of ferroportin in cell lines overexpressing ferroportin and in murine bone marrow-derived macrophages. No hepcidin-dependent ubiquitination was observed in C326S ferroportin mutant which does not bind hepcidin. Substitutions of lysines between residues 229 and 269 in the third cytoplasmic loop of ferroportin prevented hepcidin-dependent ubiquitination and endocytosis of ferroportin, and promoted cellular iron export even in the presence of hepcidin. The human ferroportin mutation K240E, previously associated with clinical iron overload, caused hepcidin resistance in vitro by interfering with ferroportin ubiquitination. Our study demonstrates that ubiquitination is the functionally relevant signal for hepcidin-induced ferroportin endocytosis.
Aims: Free iron plays an important role in the pathogenesis of acute kidney injury (AKI) via the formation of hydroxyl radicals. Systemic iron homeostasis is controlled by the hemojuvelin-hepcidin-ferroportin axis in the liver, but less is known about this role in AKI. Results: By proteomics, we identified a 42 kDa soluble hemojuvelin (sHJV), processed by furin protease from membrane-bound hemojuvelin (mHJV), in the urine during AKI after cardiac surgery. Biopsies from human and mouse specimens with AKI confirm that HJV is extensively increased in renal tubules. Iron overload enhanced the expression of hemojuvelin-hepcidin signaling pathway. The furin inhibitor decreases furin mediated proteolytic cleavage of mHJV into sHJV and augments the mHJV/sHJV ratio after iron overload with hypoxia condition. The furin inhibitor could reduce renal tubule apoptosis, stabilize hypoxic induced factor-1 (HIF-1), prevent the accumulation of iron in the kidney and further ameliorate ischemic-reperfusion injury. mHJV is associated with decreasing total kidney iron, secreting hepcidin, and promoting the degradation of ferroportin at AKI, whereas sHJV does the opposite. Innovation: This study suggests the ratio of mHJV/sHJV affects the iron deposition during acute kidney injury and sHJV could be an early biomarker of AKI. Conclusion: Our findings link endogenous HJV inextricably with renal iron homeostasis for the first time, add new significance to early predict AKI, and identify novel therapeutic targets to reduce the severity of AKI using the furin inhibitor.
OBJECTIVE: To describe the prevalence of iron depletion (ID), iron-deficiency anaemia (IDA) and risk of haemoconcentration during pregnancy and at delivery and to assess the influence of initial Fe stores and Fe supplementation on that prevalence. DESIGN: Longitudinal study. SETTING: Hospital Universitari Sant Joan de Reus (Catalonia, Spain). SUBJECTS: Two hundred and eighty-five pregnant women. Serum ferritin and Hb were measured in the first, second and third trimesters and at delivery. Women were classified according to initial Fe stores as ID or no ID (serum ferritin ≥12 μg/l) and according to Fe supplement use as supplemented or non-supplemented. RESULTS: Initial ID was 16·2 %. At delivery, 45·7 % had ID, 13·5 % IDA and 13·3 % had risk of haemoconcentration. Initial ID and non-supplemented groups had significantly higher prevalences of ID and IDA and lower risk of haemoconcentration at delivery than the other groups. In the multiple logistic models, no initial ID and Fe supplementation exerted a protective effect against ID at delivery (adjusted OR = 0·28; 95 % CI 0·13, 0·58 and adjusted OR = 0·39; 95 % CI 0·22, 0·69, respectively). Moderate Fe supplementation did not seem to clearly prevent IDA (adjusted OR = 0·91; 95 % CI 0·42, 1·96) or to enhance the haemoconcentration (adjusted OR = 1·42; 95 % CI 0·58, 3·50). CONCLUSIONS: The prevalence of ID and IDA was high in late pregnancy in healthy pregnant women, particularly in those with initial ID and/or those not taking supplements. Starting pregnancy with no ID and/or taking moderate Fe supplementation decreased the likelihood of ID at delivery. The risk of haemoconcentration was high at delivery, but did not seem to be promoted by Fe supplementation. Further research is necessary to determine the most appropriate nutritional advice for pregnant women.
BACKGROUND & AIMS: Celiac disease is an increasingly recognized disorder in Caucasian populations of European origin. Little is known about its prevalence in non-Caucasians. Although it is thought to be a cause of iron deficiency anemia, little is known about the extent to which celiac disease contributes to iron deficiency in Caucasians, and especially non-Caucasians. We analyzed samples collected from participants in the Hemochromatosis and Iron Overload Screening (HEIRS) study to identify individuals with iron deficiency and assess the frequency of celiac disease. METHODS: We analyzed serum samples from white men (25 y old or older) and women (50 y old or older) who participated the HEIRS study; cases were defined as individuals with iron deficiency (serum level of ferritin ≤12 mg/L) and controls were those without (serum level of ferritin >100 mg/L in men and >50 mg/L in women). All samples were also analyzed for human recombinant tissue transglutaminase immunoglobulin A; positive results were confirmed by an assay for endomysial antibodies. Patients with positive results from both celiac disease tests were presumed to have untreated celiac disease, and those with a positive result from only 1 test were excluded from analysis. We analyzed HLA genotypes and frequencies of celiac disease between Caucasians and non-Caucasians with iron deficiency. RESULTS: Celiac disease occurred in 14 of 567 of cases (2.5%) and in only 1 of 1136 controls (0.1%; Fisher’s exact test, P=1.92 10(-6)). Celiac disease was more common in Caucasian cases (14/363, 4%) than non-Caucasian cases (0/204; P=.003). Only 1 Caucasian control and no non-Caucasian controls had celiac disease. The odds of celiac disease in individuals with iron deficiency was 28-fold (95% confidence interval, 3.7-212.8) that of controls; 13/14 cases with celiac disease carried the DQ2.5 variant of the HLA genotype. CONCLUSIONS: Celiac disease is associated with iron deficiency of Caucasians. Celiac disease is rare among non-Caucasians-even among individuals with features of celiac disease, such as iron deficiency. Celiac disease is also rare among individuals without iron deficiency. Men and post-menopausal women with iron deficiency should be tested for celiac disease.