Reduced Iron Absorption Research Articles

Circulating Human Hepcidin-25 Concentrations Display a Diurnal Rhythm, Increase with Prolonged Fasting, and Are Reduced by Growth Hormone Administration

Hepcidin-25 reduces iron absorption by binding to the intestinal iron transporter ferroportin and causing its degradation. Currently, little is known about the basal regulation of circulating hepcidin-25. In addition, although erythropoietin administration has been reported to decrease the circulating hepcidin concentration, information is limited regarding how other stimulators of erythropoiesis, such as growth hormone (GH), might alter hepcidin-25 concentrations. We used a sensitive and specific hepcidin-25 dual-monoclonal antibody sandwich immunoassay to measure hepcidin-25 in healthy human volunteers at various time points throughout the day and during 3 days of fasting and subsequent refeeding. We also measured hepcidin-25 concentrations in healthy volunteers after GH administration. In healthy individuals, hepcidin-25 concentrations displayed a diurnal variation, with concentrations being lowest in the early morning and steadily increasing throughout the day before declining during the evening hours, a pattern that was not influenced by food intake. Prolonged fasting produced statistically significant increases in hepcidin-25 concentrations. Refeeding reversed this process, and GH administration markedly decreased hepcidin-25 concentrations. Our results indicate that in humans, hepcidin-25 exhibits diurnal changes that can be altered by prolonged fasting, which increases hepcidin-25 concentrations approximately 3-fold after 3 days of fasting, possibly owing to a suppression of erythropoiesis that may occur during the fasting state to preserve tissue iron concentrations. In contrast, GH administration decreased hepcidin-25 concentrations by approximately 65%, presumably by stimulating erythropoiesis. These results indicate that circulating hepcidin-25 concentrations display much more dynamic and rapid variation than might have been anticipated previously.

Management of renal anemia in patients with chronic kidney disease: the role of the general practitioner

The prevalence of chronic kidney disease (CKD) is high and diabetic nephropathy is a leading cause of CKD. One of the most common complications of CKD is anemia, the frequency and severity of which increase as kidney failure progresses. Renal anemia is primarily caused by reduced renal erythropoietin production. It can also be associated with iron deficiency caused by reduced iron absorption, occult blood loss and impaired iron mobilization. This work provides an overview of the management of renal anemia with focus on intravenous iron therapy, which is more effective than oral iron administration in CKD due to reduced iron absorption.

Hepcidin and HFE protein: Iron metabolism as a target for the anemia of chronic kidney disease

The anemia of chronic kidney disease and hemodialysis is characterized by chronic inflammation and release of cytokines, resulting in the upregulation of the iron hormone hepcidin, also increased by iron therapy and reduced glomerular filtration, with consequent reduction in iron absorption, recycling, and availability to the erythron. This response proves advantageous in the short-term to restrain iron availability to pathogens, but ultimately leads to severe anemia, and impairs the response to erythropoietin (Epo) and iron. Homozygosity for the common C282Y and H63D HFE polymorphisms influence iron metabolism by hampering hepcidin release by hepatocytes in response to increased iron stores, thereby resulting in inadequate inhibition of the activity of Ferroportin-1, inappropriately high iron absorption and recycling, and iron overload. However, in hemodialysis patients, carriage of HFE mutations may confer an adaptive benefit by decreasing hepcidin release in response to iron infusion and inflammation, thereby improving iron availability to erythropoiesis, anemia control, the response to Epo, and possibly survival. Therefore, anti-hepcidin therapies may improve anemia management in hemodialysis. However, HFE mutations directly favor hemoglobinization independently of hepcidin, and reduce macrophages activation in response to inflammation, whereas hepcidin might also play a beneficial anti-inflammatory and anti-microbic action during sepsis, so that direct inhibition of HFE-mediated regulation of iron metabolism may represent a valuable alternative therapeutic target. Genetic studies may offer a valuable tool to test these hypotheses and guide the research of new therapies.

The Control of Iron Homeostasis: microRNAS Join the Party

Castoldi M, Spasic MV, Altamura S, et al. (Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany; others). The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice. J Clin Invest 2011;121:1386–1396. Our understanding of the regulation of iron homeostasis has increased rapidly in the last decade. The identification of the iron regulatory hormone hepcidin, and the genes underlying iron disorders such as hereditary hemochromatosis have been instrumental in identifying the molecules necessary for the control of iron balance....

Hepcidin: clinical utility as a diagnostic tool and therapeutic target

Iron is essential for life, yet excessive iron can damage tissues and organs. To prevent iron deficiency and overload, iron balance is regulated by the hormone hepcidin. Hepcidin levels increase in response to iron sufficiency, decreasing intestinal iron absorption and inhibiting release of iron from stores and macrophages. Iron deficiency lowers hepcidin, leading to enhanced iron absorption and mobilization of iron from stores. Hepcidin is also increased by inflammation, and has a major role in the anemia of chronic disease. Chronic kidney disease (CKD) is associated with increased hepcidin levels, and this likely contributes to the incidence and severity of anemia, and resistance to erythropoiesis-stimulating agents (ESAs). Elevated hepcidin contributes to the dysregulation of iron homeostasis in CKD. In patients with CKD, although parenteral iron in CKD can bypass some of the iron-blocking effects of hepcidin, free iron and iron stores increase, anemia is only partially corrected, and ESA dose requirements remain significantly higher than physiological replacement. Agents that lower hepcidin or inhibit its actions may be effective strategies to restore normal iron homeostasis, and overcome anemia of chronic kidney disease. We review the regulation of hepcidin, its role in CKD-related anemia, and discuss the potential for hepcidin as a clinical marker, and several investigational methods to lower hepcidin for treatment of anemia in CKD.

Diagnostic Yield of Upper Gastrointestinal Endoscopy in the Evaluation of Iron Deficiency Anemia in Older Children and Adolescents

Iron deficiency anemia (IDA) is frequent in childhood. Inadequate nutrition and gastrointestinal malabsorption are the frequent causes of IDA in children. But reduced iron absorption and insidious blood loss from the gastrointestinal tract has been identified as the most frequent causes of IDA in older children and adolescents. Therefore the authors evaluated the frequency and etiologies of the upper gastrointestinal system pathologies causing IDA in older pediatric population. Patients with known hematological or chronic diseases, heavy menstrual flow, and obvious blood loss were excluded from the study. Forty-four children between the ages of 9.5 and 17.5 years and diagnosed with IDA were enrolled. They underwent upper gastrointestinal endoscopy and biopsy from esophagus, stomach, and duodenum. Mean age and hemoglobin (Hb) levels of study group (32 boys, and 12 girls) were 14.6 ± 2.0 years and 7.9 ± 1.8 g/dL, respectively. Only 1 patient had a positive serology testing with anti-tissue transglutaminase and small bowel biopsy correlating with celiac disease. Endoscopy revealed abnormal findings in 25 (56.8%) patients (21 endoscopic antral gastritis, 2 active duodenal ulcers, and 2 duodenal polyps). Helicobacter pylori (HP) infection was identified by using antral histopathological evaluation in 19 of 44 children (43.2%). In 2 of duodenal samples, one patient had celiac disease, and the other one was diagnosed as giardiasis. In conclusion, there are different etiologies resulting in IDA in older children and adolescents. When older children and adolescents are found to have iron deficiency, HP infection and other gastrointestinal pathologies should be ruled out before iron deficiency treatment.

Establishment of a simple test for iron absorption from the gastrointestinal tract

Recent studies on iron metabolism have begun to reveal the molecular mechanisms underlying iron absorption, which is dramatically affected in several disorders. In the clinical setting, the ability to determine the status of iron absorption would aid in the diagnosis of pathological conditions. Efforts to develop an oral iron absorption test (OIAT) date back to at least 60 years. However, previous procedures were associated with a number of problems, such as radiation exposure and low reproducibility. In an attempt to resolve these issues, we employed sodium ferrous citrate (SFC), by which the influence of various nutrients and drugs on iron absorption was markedly reduced. We found that OIAT using SFC was simple to perform in both hospitalized patients and outpatients. The increment of serum iron and % transferrin saturation at 120 min after SFC administration was useful in distinguishing iron absorption between healthy volunteers, patients with iron-deficiency anemia, and patients with anemia secondary to chronic disorders, which are respectively characterized by normal, enhanced, and reduced iron absorption. Thus, the SFC-based OIAT may represent a viable screening test for the evaluation of gastrointestinal iron absorption.

Helicobacter pylori and Effects on Iron Status in Children: Delineating Causality

<i>Helicobacter pylori</i> and Effects on Iron Status in Children: Delineating Causality

Reduced Expression of Ferroportin-1 Mediates Hyporesponsiveness of Suckling Rats to Stimuli That Reduce Iron Absorption

Suckling mammals absorb high levels of iron to support their rapid growth. In adults, iron absorption is controlled by systemic signals that alter expression of the iron-regulatory hormone hepcidin. We investigated whether hepcidin and absorption respond appropriately to systemic stimuli during suckling. In Sprague-Dawley rats, iron levels increased following administration of iron dextran, and inflammation was induced with lipopolysaccharide. Gene expression was measured by quantitative reverse-transcription polymerase chain reaction; protein levels were measured by immunoblot analyses. Iron absorption was determined based on retention of an oral dose of 59Fe. Iron absorption was high during suckling and reduced to adult levels upon weaning. In response to iron dextran or lipopolysaccharide, iron absorption in adults decreased substantially, but, in suckling animals, the changes were minimal. Despite this, expression of hepcidin messenger RNA was strongly induced by each agent, before and after weaning. The hyporesponsiveness of iron absorption to increased levels of hepcidin during suckling correlated with reduced or absent duodenal expression of ferroportin 1 (Fpn1), normally a hepcidin target. Fpn1 expression was robust in adults. Predominance of the Fpn1A splice variant, which is under iron-dependent translational control, accounts for the low level of Fpn1 in the iron-deficient intestine of suckling rats. Iron absorption during suckling is largely refractory to changes in expression of the systemic iron regulator hepcidin, and this in turn reflects limited expression of Fpn1 protein in the small intestine. Iron absorption is therefore not always controlled by hepcidin.

The Wide Spectrum of Hepatic Iron Overload σ

We would like to thank Manco and colleagues for their interest in our article.1 We agree that stratification of our study cohort according the presence of diabetes and HFE (hereditary hemochromatosis) genotype status could be of interest. We have conducted additional analyses with regard to diabetes status in our cohort. HFE genotyping was not routinely performed as part of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Database study; this is currently in progress in an ancillary study. Among the 849 adult subjects in our study, 221 were enrolled in the PIVENS (Pioglitazone or Vitamin E for NASH Study) clinical trial,2 which excluded diabetic patients; therefore, to prevent any potential bias, we report here the relationship of diabetes and iron deposition in the remaining 628 subjects. As shown in Table 1, diabetic NASH CRN subjects were less likely to have hepatic iron deposition. In particular, diabetic patients had significantly less hepatocellular but not reticuloendothelial system iron deposition. There are several possible explanations for these findings. The iron regulatory hormone hepcidin is expressed in adipose tissue and has been shown to correlate to body mass index.3 It is possible that increased visceral fat in our diabetic subjects could lead to greater circulating hepcidin levels, reduced iron absorption, and less hepatocellular iron deposition. Recently, alcohol has been shown to down-regulate hepcidin gene expression.4 Because diabetic subjects in our study consumed less alcohol than subjects without diabetes, this could also contribute to higher hepcidin levels in these patients. Diabetic subjects were also more likely to be women, and physiologic blood loss through menstruation and childbirth may have resulted in decreased body iron stores. Additional studies are warranted to define the mechanism for decreased hepatocellular iron content in diabetic patients with NAFLD. In contrast to Manco et al.,5 who have reported hepatic iron deposition in 29% of their Italian pediatric subjects, which was not associated with measurements of insulin resistance, the prevalence of iron deposition in the NASH CRN pediatric subjects was only 4%. It is likely that, as in adults, differences in the Italian and U.S. cohorts, including body mass index (25.2 in Manco et al. versus 33.0 in the NASH CRN pediatric subjects) account for the observed differences.6 James Nelson Ph.D.*, Kris Kowdley M.D.*, * Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA.

White tea consumption slightly reduces iron absorption but not growth, food efficiency, protein utilization, or calcium, phosphorus, magnesium, and zinc absorption in rats

We investigated the antinutritional effect of white tea extract (0, 15, and 45 mg of the tea solid extract per kilogram body weight) incorporated in the drinking water of rats for 3 and 30 days. Gender-based differences were found for all these variables, except apparent protein digestibility and the apparent absorption of calcium, phosphorus, and iron. White tea extract consumption did not significantly change body weight gain, food intake, food efficiency, protein efficiency ratio, apparent protein digestibility, nitrogen balance, or the apparent absorption of calcium, phosphorus, magnesium, and zinc. Nevertheless, the apparent absorption of iron was slightly (15-18%) but significantly (P<0.05) lower in rats that consumed white tea at the highest dose compared with the control groups at both 3 and 30 days. Our results suggest that the usual consumption of white tea is safe, although its effect on long-term iron absorption at high doses warrants more detailed investigation.

Does Obesity Increase Risk for Iron Deficiency? A Review of the Literature and the Potential Mechanisms

Increasing obesity is a major global health concern while at the same time iron-deficiency anemia remains common worldwide. Although these two conditions represent opposite ends of the spectrum of over- and under-nutrition, they appear to be linked: overweight individuals are at higher risk of iron deficiency than normal-weight individuals. Potential explanations for this association include dilutional hypoferremia, poor dietary iron intake, increased iron requirements, and/or impaired iron absorption in obese individuals. Recent evidence suggests obesity-related inflammation may play a central role through its regulation of hepcidin. Hepcidin levels are higher in obese individuals and are linked to subclinical inflammation; this may reduce iron absorption and blunt the effects of iron fortification. Thus, low iron status in overweight individuals may result from a combination of nutritional (reduced absorption) and functional (increased sequestration) iron deficiency. In this review, we focus on subclinical inflammation in obesity, and its effect on hepcidin levels, as the most plausible explanation for the link between iron deficiency and obesity.

Suppression of SLC11A2 Expression Is Essential to Maintain Duodenal Integrity During Dietary Iron Overload

Iron is essential for the survival of mammals, but iron overload causes fibrosis and carcinogenesis. Reduced iron absorption and regulated release into circulation in duodenal mucosa constitute two major mechanisms of protection against dietary iron overload; however, their relative contribution remains elusive. To study the significance of the former process, we generated SLC11A2 transgenic mice (TGs) under the control of the chicken beta-actin promoter. TGs were viable and fertile, and displayed no overt abnormalities up to 20 months. No significant difference in iron concentration was observed in major solid organs between TGs and their wild-type littermates, suggesting that increased number of iron transporters does not lead to increased iron absorption. To test the sensitivity to iron overload, TGs and wild-type mice were fed with an iron-rich diet containing 2% ferric citrate. Iron supplementation caused suppression of endogenous duodenal SLC11A2 expression, down-regulation of duodenal ferroportin, and overexpression of hepatic hepcidin, precluding excessive iron uptake both in the TGs and wild-type mice. However, iron-treated TGs revealed increased mortality, resulting from oxidative mucosal damage leading to hemorrhagic erosion throughout the whole intestinal area. These findings suggest that reduced iron release from duodenal cells into circulation plays a role in mitigating excessive iron uptake from the diet and that finely regulated duodenal absorption is essential to protect intestinal mucosa from iron-induced oxidative damage.

How I treat hemochromatosis

AbstractHemochromatosis is a common genetic disorder in which iron may progressively accumulate in the liver, heart, and other organs. The primary goal of therapy is iron depletion to normalize body iron stores and to prevent or decrease organ dysfunction. The primary therapy to normalize iron stores is phlebotomy. In this opinion article, we discuss the indications for and monitoring of phlebotomy therapy to achieve iron depletion, maintenance therapy, dietary and pharmacologic maneuvers that could reduce iron absorption, and the role of voluntary blood donation.

The iron-chelating potential of silybin in patients with hereditary haemochromatosis

Milk thistle contains silybin, which is a potential iron chelator. We aimed to determine whether silybin reduced iron absorption in patients with hereditary haemochromatosis. In this crossover study, on three separate occasions, 10 patients who were homozygous for the C282Y mutation in the HFE gene (and fully treated) consumed a vegetarian meal containing 13.9 mg iron with: 200 ml water; 200 ml water and 140 mg silybin (Legalon Forte); or 200 ml tea. Blood was drawn once before, then 0.5, 1, 2, 3 and 4 h after the meal. Consumption of silybin with a meal resulted in a reduction in the postprandial increase in serum iron (AUC±s.e.) compared with water (silybin 1726.6±346.8 versus water 2988.8±167; P<0.05) and tea (silybin 1726.6±346.8 versus tea 2099.3±223.3; P<0.05). In conclusion, silybin has the potential to reduce iron absorption, and this deserves further investigation, as silybin could be an adjunct in the treatment of haemochromatosis.

Inhibitory Effect of Calcium on Non-heme Iron Absorption May Be Related to Translocation of DMT-1 at the Apical Membrane of Enterocytes

Many studies show that calcium reduces iron absorption from single meals, but the underlying mechanism is not known. We tested the hypothesis that calcium alters the expression and/or functionality of iron transport proteins. Differentiated Caco-2 cells were treated with ferric ammonium citrate and calcium chloride, and ferritin, DMT-1, and ferroportin were quantified in whole-cell lysate and cell-membrane fractions. Calcium attenuated the iron-induced increase in cell ferritin levels in a dose-dependent manner; a significant decrease was seen at calcium concentrations of 1.25 and 2.5 mM but was only evident after a 16-24 h incubation period. Calcium and iron treatments decreased DMT-1 protein in Caco-2 cell membranes, although total DMT-1 in whole cell lysates was unchanged by either iron or calcium. No change was seen in ferroportin expression. Our data suggest that calcium reduces iron bioavailability by decreasing DMT-1 expression at the apical cell membrane, thereby downregulating iron transport into the cell.

Prohepcidin concentrations and erythroid progenitors in cord blood of appropriate versus small for gestational age neonates

Prohepcidin (Pro-Hep), synthesized in the liver, is the prohormone of hepcidin (Hep), which reduces iron absorption in the gut; its synthesis is enhanced by inflammation and is reduced during hypoxia. We aimed to study the hypothesis that infants born small for gestational age (SGA) have reduced cord blood concentrations of Pro-Hep. Cord blood was collected from 20 SGA (term and near term >35 week gestation) infants and 20 appropriate for gestational age (AGA) controls. We excluded infants exposed to maternal chronic diseases, smoking, diabetes, alcohol or drug use. Both groups had a 1 min Apgar score above or equal to 7 and had normal cord blood pH (above 7.25). ELISA was used to determine serum concentrations of Pro-Hep and erythropoietin (EPO). Circulating CD71(+)/CD45(-)/SSC(low) cells were measured by flow cytometry as an index of erythroid progenitors. There were no significant differences between groups in terms of hemoglobin concentrations, and Pro-Hep. In contrast, EPO levels and circulating CD71(+)/CD45(-)/SSC(low) erythroid progenitors were significantly higher in the SGA group. These differences remained significant even after controlling for gestational age and gravidity. Contrary to EPO upregulation during intrauterine growth restriction (IUGR), and higher concentrations of circulating erythroid progenitors, Pro-Hep concentration is not affected by IUGR.

Overweight children have higher circulating hepcidin concentrations and lower iron status but have dietary iron intakes and bioavailability comparable with normal weight children

Obesity increases the risk for iron deficiency, but the underlying mechanism is unclear. It is possible that overweight individuals may have lower dietary iron intake and/or bioavailability. Alternatively, obesity-related inflammation may increase hepcidin concentrations and reduce iron availability. Circulating hepcidin levels have not been compared in normal weight vs overweight individuals. The objective of this study was to compare iron status, dietary iron intake and bioavailability, as well as circulating levels of hepcidin, leptin and interleukin-6 (IL-6), in overweight vs normal weight children. In 6-14-year-old normal and overweight children (n=121), we measured dietary iron intake, estimated iron bioavailability and determined body mass index s.d. scores (BMI-SDS). In all children (n=121), we measured fasting serum ferritin, soluble transferrin receptor (sTfR), C-reactive protein (CRP) and leptin; in a subsample, we measured IL-6 (n=68) and serum hepcidin (n=30). There were no significant differences in dietary iron intake or bioavailability comparing normal and overweight children. The prevalence of iron-deficient erythropoiesis (an increased sTfR concentration) was significantly higher in the overweight than in the normal weight children (20 vs 6%, P=0.022, with sTfR concentrations of 4.40+/-0.77 and 3.94+/-0.88 mg l(-1), respectively, P=0.010). Serum hepcidin levels were significantly higher in the overweight children (P=0.001). BMI-SDS significantly correlated with sTfR (P=0.009), serum hepcidin (P=0.005) and the three measures of subclinical inflammation, namely CRP (P<0.001), IL-6 (P<0.001) and leptin (P<0.001). In a multiple regression model, serum hepcidin was correlated with BMI-SDS (P=0.020) and body iron (P=0.029), but not with the inflammatory markers. Our findings indicate that there is reduced iron availability for erythropoiesis in overweight children and that this is unlikely due to low dietary iron supply but rather due to hepcidin-mediated reduced iron absorption and/or increased iron sequestration.

Effect of tannic acid on iron absorption in straw‐colored fruit bats (Eidolon helvum)

Excessive absorption and subsequent storage of dietary iron has been found in a variety of captively held birds and mammals, including fruit bats. It is thought that feeding a diet that is low in iron can prevent the onset of this disease; however, manufacturing a diet with commonly available foodstuffs that contains a sufficiently low iron concentration is difficult. An alternative is to feed captive animals that may be susceptible to this disease potential iron chelators such as tannins that may bind to iron and block its absorption. Using stable isotope methods established in humans, we measured iron bioavailability in straw-colored fruit bats (Eidolon helvum) and tested whether tannic acid significantly reduced the extent of iron absorption. Regardless of dose, tannic acid significantly reduced iron absorption (by 40%) and in the absence of tannic acid, iron absorption was extensive in this species (up to 30%), more so than in humans. Species susceptible to iron storage disease may efficiently absorb iron in the gut regardless of iron status, and supplementing these species with tannic acid in captivity may provide an alternative or additional means of preventing the development of this disease.

Mechanism of action of metformin in nonalcoholic steatohepatitis: authors’ reply

Sirs, Mascitelli and colleagues1 speculate that metformin acts by reducing iron overload causing decreases in serum ferritin and improved insulin resistance. Current evidence suggests that metformin leads to improvement in insulin resistance not by altering iron metabolism but by activating the LKB1 receptor in liver leading to upregulation of AMP kinase, a master regulator of glucose metabolism.2 There is scant evidence to suggest that metformin reduces iron absorption or hepatic iron content. Persons with insulin resistance and nonalcoholic steatohepatitis often have high serum ferritin levels,3, 4 but this association does not prove causality. To address these issues, we have analysed results of iron staining from the 26 patients who were treated with metformin in this study.5 Liver biopsy tissue was stained using Perl’s iron stain and graded from 0 to 4 with 0 = no iron seen; trace = rare speck of iron staining; 1+ to 4+ according to published criteria.6 No patient had more than 2+ iron staining and a majority (60%) had no stainable iron (Table 1). The distribution of iron staining scores did not change with therapy, the average being 0.40 before and 0.42 at the end of 48 weeks of metformin treatment. Among 18 nonresponders, the average iron score decreased slightly from 0.39 to 0.32; among the eight responders, the average increased slightly, from 0.43 to 0.63, but no patient increased by more than 1 point and the changes were not statistically significant. Iron staining is only a semi-quantitative means of assessing hepatic iron, but these results suggest that metformin had little or no effect on iron absorption or liver iron accumulation. Declaration of personal interests: None. Declaration of funding interests: This paper was supported by the intramural research program of National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.