Increase In Intestinal Iron Absorption Research Articles

Haemochromatosis revisited.

Haemochromatosis is a genetic disease caused by hepcidin deficiency, responsible for an increase in intestinal iron absorption. Haemochromatosis is associated with homozygosity for the HFE p.Cys282Tyr mutation. However, rare cases of haemochromatosis (non-HFE haemochromatosis) can also be caused by pathogenic variants in other genes (such as HJV, HAMP, TFR2 and SLC40A1). A working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) has concluded that the classification based in different molecular subtypes is difficult to be adopted in clinical practice and has proposed a new classification approaching clinical questions and molecular complexity. The aim of the present review is to provide an update on classification, pathophysiology and therapeutic recommendations.

Systemic iron reduction by venesection alters the gut microbiome in patients with haemochromatosis.

Background & AimsIron reduction by venesection has been the cornerstone of treatment for haemochromatosis for decades, and its reported health benefits are many. Repeated phlebotomy can lead to a compensatory increase in intestinal iron absorption, reducing intestinal iron availability. Given that most gut bacteria are highly dependent on iron for survival, we postulated that, by reducing gut iron levels, venesection could alter the gut microbiota.MethodsClinical parameters, faecal bacterial composition and metabolomes were assessed before and during treatment in a group of patients with haemochromatosis undergoing iron reduction therapy.ResultsSystemic iron reduction was associated with an alteration of the gut microbiome, with changes evident in those who experienced reduced faecal iron availability with venesection. For example, levels of Faecalibacterium prausnitzii, a bacterium associated with improved colonic health, were increased in response to faecal iron reduction. Similarly, metabolomic changes were seen in association with reduced faecal iron levels.ConclusionThese findings highlight a significant shift in the gut microbiome of patients who experience reduced colonic iron during venesection. Targeted depletion of faecal iron could represent a novel therapy for metabolic and inflammatory diseases, meriting further investigation.Lay summaryIron depletion by repeated venesection is the mainstay of treatment for haemochromatosis, an iron-overload disorder. Venesection has been associated with several health benefits, including improvements in liver function tests, reversal of liver scarring, and reduced risk of liver cancer. During iron depletion, iron absorption from the gastrointestinal (GI) tract increases to compensate for iron lost with treatment. Iron availability is limited in the GI tract and is crucial to the growth and function of many gut bacteria. In this study we show that reduced iron availability in the colon following venesection treatment leads to a change in the composition of the gut bacteria, a finding that, to date, has not been studied in patients with haemochromatosis.

Haemochromatosis: a clinical update for the practising physician

Haemochromatosis is most commonly due to the autosomal recessive inheritance of a C282Y substitution in the HFE protein, whereby both alleles of the corresponding gene are affected. The disease is characterised by an inappropriate increase in intestinal iron absorption due to reduced expression of the iron regulatory protein, hepcidin. Progressive iron deposition in parenchymal tissues may ultimately lead to liver and other organ toxicity. The characteristic biochemical abnormalities are raised serum ferritin and transferrin saturation, which can be used in conjunction with genetic tests and emerging magnetic resonance imaging-based techniques to diagnose patients with the disorder. Progressive iron overload can manifest clinically as advanced fibrosis, cirrhosis and hepatocellular carcinoma. Enigmatically, the penetrance of both raised iron indices and clinically significant disease is incomplete in patients with hereditary haemochromatosis. Regardless, advanced clinical presentations of the disease have become less common due to increased awareness and earlier diagnosis. On the other hand, obesity and alcohol have been identified as major risk factors that can compound the risk of liver injury in people with hereditary (HFE) haemochromatosis. The prospect of modifying genes that may contribute to the clinical expression of the disease is the subject of ongoing research. Treatment with phlebotomy remains the first-line therapy, and if instigated early leads to a normal life expectancy. A healthy, well-balanced diet is recommended to be incorporated as part of the ongoing management of the disease.

SAT-005 - Iron reduction by venesection alters the gut microbiome in Haemochromatosis patients

Background & Aims: Iron reduction by venesection has been the cornerstone of treatment of Hemochromatosis for decades; its reported health benefits are many. Repeated phlebotomy can lead to a compensatory increase in intestinal iron absorption, reducing intestinal iron availability. As most gut bacteria are highly dependent on iron for survival, we postulated that by reducing gut iron levels, venesection could alter the gut microbiota. Methods: Clinical parameters, faecal bacterial composition and metabolomes were assessed before and during treatment in a group of Haemochromatosis patients undergoing iron reduction therapy. Results: Here we show that systemic iron reduction is associated with an alteration of the gut microbiome, with changes evident in those who experienced reduced faecal iron availability with venesection. For example, levels of F. prausnitzii, a bacteria associated with improved colonic health, were increased by faecal iron reduction. Similarly, metabolomic changes were seen in association with reduced faecal iron levels. Conclusion: These findings highlight a significant shift in the gut microbiome of patients who experience reduced colonic iron during venesection. Targeted depletion of faecal iron may represent a novel therapy for metabolic and inflammatory diseases, meriting further investigation.

Pentraxin-3 Levels in Beta Thalassemia Major and Minor Patients and Its Relationship With Antioxidant Capacity and Total Oxidant Stress

Thalassemia major (TM) results in hemolytic anemia, an increase in intestinal iron absorption, and occurrence of iron loading due to erythrocyte transfusion; the disease is characterized by oxidative damage in major organs. Oxidative stress leads to vascular endothelial damage and forms the basis for serious cardiovascular diseases. Pentraxin-3 (PTX-3) is one of the markers of vascular endothelial damage that increases in response to the oxidative stress, which can be used as an early diagnostic marker for inflammation. This study's purpose is to define the relation between PTX-3 and the vascular endothelial damage that increases with oxidative stress in thalassemia patients. Our study included 35 TM patients, 30 β-thalassemia minor patients, and 30 healthy children. As a result of our study, in TM patients, a positive relation was detected between the PTX-3 levels and the total oxidative stress, triglyceride, and very low-density lipoprotein values, whereas a negative relation was detected with the total antioxidant capacity and high-density lipoprotein values. This result shows that as oxidant stress increases, PTX-3 levels also increase; very low-density lipoprotein and triglyceride contribute to the endothelial damage occurring with oxidative stress. As a result, it was concluded that vascular endothelial damage in thalassemia patients can be evaluated through the serum PTX-3 level.

FRI0237 Diagnosing Hereditary Hemochromatosis in the Rheumatology Practice

BackgroundHereditary Hemochromatosis (HH) is a genetic disorder in which mutations of the HFE gene, and less frequently in the transferring receptor 2 (TFR2) gene, result in an increase in intestinal...

Hepcidin Is Directly Regulated by Insulin and Plays an Important Role in Iron Overload in Streptozotocin-Induced Diabetic Rats

Iron overload is frequently observed in type 2 diabetes mellitus (DM2), but the underlying mechanisms remain unclear. We hypothesize that hepcidin may be directly regulated by insulin and play an important role in iron overload in DM2. We therefore examined the hepatic iron content, serum iron parameters, intestinal iron absorption, and liver hepcidin expression in rats treated with streptozotocin (STZ), which was given alone or after insulin resistance induced by a high-fat diet. The direct effect of insulin on hepcidin and its molecular mechanisms were furthermore determined in vitro in HepG2 cells. STZ administration caused a significant reduction in liver hepcidin level and a marked increase in intestinal iron absorption and serum and hepatic iron content. Insulin obviously upregulated hepcidin expression in HepG2 cells and enhanced signal transducer and activator of transcription 3 protein synthesis and DNA binding activity. The effect of insulin on hepcidin disappeared when the signal transducer and activator of transcription 3 pathway was blocked and could be partially inhibited by U0126. In conclusion, the current study suggests that hepcidin can be directly regulated by insulin, and the suppressed liver hepcidin synthesis may be an important reason for the iron overload in DM2.

Iron Metabolism in the Mice with Targeted Mutations of the DMT1 Gene.

Divalent metal transporter 1 (DMT1) was shown to be important for iron metabolism through studies of the mk/mk mouse, which carries a spontaneous mutation (G185R) resulting in defective intestinal iron absorption and anemia. To further investigate the importance of this transporter in vivo, we inactivated the DMT1 gene through targeted deletion of transmembrane domains 3, 4 and 5. We obtained mice carrying a universally inactivated DMT1 allele (DMT1−/−) and mice carrying a floxed DMT1 allele that could be selectively inactivated by breeding to mice expressing a Cre recombinase transgene. We crossed the floxed mice to mice expressing Cre under the control of the Villin promoter to inactivate DMT1 exclusively in the intestine. All mutations were made on a 129S6/SvEvTac background. For comparison, we backcrossed the mk mutation onto the same background. We noted that, in this context, the mk/mk phenotype was much less severe.DMT1−/− mice were born with substantial liver iron stores, indicating that fetal DMT1 is not required for placental iron transfer or hepatic iron loading. However, DMT1−/− mice invariably died of anemia by day 7, suggesting that DMT1 is important for erythroid iron acquisition but not absolutely required. Transfusions improved survival. The DMT1−/− phenotype was much more severe than the mk/mk phenotype, and compound heterozygous DMT1-/mk mice survived to adulthood. These results confirm that the mk mutation does not result in total loss of protein function.Intestine-specific inactivation of DMT1 caused no abnormalities at birth, but progressive anemia developed thereafter. At 12 weeks, mice lacking intestinal DMT1 were more anemic than mk/mk mice. To investigate the importance of DMT1 in hematopoietic cells, we transferred fetal liver hematopoietic stem cells (HSC) from DMT1−/− animals to irradiated wild type adult mice. Twelve weeks after transfer, DMT1−/− HSC recipients were anemic, but less so than singly transfused DMT1−/− mice or mice lacking intestinal DMT1. DMT1−/− HSC recipients accumulated more liver iron than wild type HSC recipients, suggesting a compensatory increase in intestinal iron absorption and/or altered iron distribution.Surprisingly, though DMT1−/− mice died as neonates, heterozygosity for a null Hfe mutation allowed some DMT1−/−;Hfe+/−animals to survive without transfusions. The effect was more pronounced in animals homozygous for Hfe null mutations. We took advantage of this to compare untransfused DMT1−/− mice with mk/mk mice on an Hfe−/− background. Liver iron content and hemoglobin levels of both mk/mk;Hfe−/− and DMT1−/−;Hfe−/− mice were significantly lower than DMT1+/+;Hfe−/− mice, as expected. Again, mk/mk mice were less severely affected than DMT1−/− mice.We have confirmed that DMT1 plays primary roles in intestinal iron absorption and erythroid iron acquisition but it is likely that there are minor, alternative iron uptake mechanisms. The mk mutation allows for considerable residual iron transport activity. Inactivation of Hfe ameliorates the effects of DMT1 deficiency through an as yet unknown mechanism.

Hepcidin in HFE-associated hemochromatosis: Another piece of the “iron” puzzle

Hepcidin in HFE-associated hemochromatosis: Another piece of the “iron” puzzle

Decreased mucosal iron induces an increase in intestinal iron absorption in the early stage of iron-deficiency

To investigate the contribution of non-heme iron and ferritin in the intestinal mucosa in regulating intestinal iron absorption during the early stage of iron-deficiency, we performed an in vivo study using rats fed an iron-deficient diet. Intestinal iron absorption was measured using the ligated intestine method. Rats fed the iron-deficient diet for 2 days showed no change in hematological parameter values (blood hemoglobin, plasma iron, the total iron binding capacity) and no change in the content of non-heme iron and ferritin in the liver. However, uptake of iron into the mucosa (mucosal uptake) and transfer of iron from mucosal cells to blood (serosal transfer) was significantly increased compared with the initial levels. At that time, the content of non-heme iron in the mucosa significantly decreased, however, no significant change in mucosal ferritin was observed. Extending the period of feeding the iron-deficient diet resulted in a small additional decrease in the level of mucosal non-heme iron, but led to no significant increase in mucosal uptake and serosal transfer. These findings suggest that a decrease in non-heme iron content in the intestinal mucosa may induce an increase in intestinal iron absorption during the early stage of iron-deficiency. In addition, it was evident that there is an upper limit in intestinal iron absorption. This limit in iron absorption may play a role in preventing iron-overload in the body.

Decreased Mucosal Iron Induces an Increase in Intestinal Iron absorption in the Early Stage of Iron-Deficiency

Decreased Mucosal Iron Induces an Increase in Intestinal Iron absorption in the Early Stage of Iron-Deficiency

Of metals, mice, and men: what animal models can teach us about body iron loading.

Of metals, mice, and men: what animal models can teach us about body iron loading.

The influence of the Gyne-T 380S IUD on menstrual blood loss and iron status

The influence of the Gyne-T 380S intrauterine contraceptive device (IUD) on menstrual blood loss (MBL) and iron status (hemoglobin, hematocrit, red cell count and indices, and serum ferritin) was evaluated. MBL was determined objectively by the alkaline hematin method in 18 women (mean age 37.1 ± 1.6 yr, range 22–46 yr) before and 3,6 and 12 months after insertion of a Gyne-T 380S IUD. MBL prior to IUD insertion was 59 ± 8 ml and increased to 91 ± 11 ml (p<0.01) 3 months after insertion. MBL then remained largely unchanged during the remainder of the observation period (6 months, 94 ± 12 ml; 12 months, 92 ± 13 ml). The percentage increase in MBL at the respective measurement points ranged between 54 and 59% which is comparable with previous reports regarding the increase in MBL associated with the use of a copper IUD. There were no significant changes recorded in iron status parameters during the 12-month observation period following IUD insertion. Based on the results of the present study, women from developed countries apparently tolerate an increased MBL of approximately 55% without developing iron deficiency anemia. Iron stores were unchanged indicating an adequate adaptive increase in intestinal iron absorption.

The long-term effects of copper surface area on menstrual blood loss and iron status in women fitted with an IUD

The long-term effects of copper surface area on menstrual blood loss (MBL) and iron status (hemoglobin, hematocrit, red cell count and indices, and serum ferritin) were evaluated in 25 healthy women who were observed for a period of 3 years following insertion of an intrauterine device. MBL was determined objectively by the alkaline hematin method. The women (mean age 37.2 ± 1.6 yr, range 27–46 yr) were fitted with a Multiload intrauterine device (IUD) with a copper surface area of either 250 mm 2 (MLCu-250, n = 13) or 375 mm 2 (MLCu-375, n = 12). MBL prior to IUD insertion was 55 ± 8 ml for women subsequently fitted with a MLCu-250 and 59 ± 9 ml for women fitted with a MLCu-375. An increase in MBL was recorded at all measurement points following IUD insertion ( MLCu-250 MLCu-375 : 3 months: 55 49% ; 6 months: 58 49% ; 12 months: 64 41% ; 24 months: 55 49% ; 36 months: 47 39% , NS). There were no significant differences in iron status parameters before IUD insertion between groups nor were there any significant changes recorded in any of these parameters after IUD insertion. Our findings that the increase in copper surface area from 250 mm 2 to 375 mm 2 had no effect on MBL were thus substantiated by the hematological findings. Based on the results of the present study, women from developed countries apparently tolerate an increased MBL of approximately 45% without developing anemia. Iron stores were unchanged indicating an adequate adaptive increase in intestinal iron absorption.

INTESTINAL IRON ABSORPTION IN CHRONIC ALCOHOLICS

Chronic alcohol misusers frequently accumulate significant amounts of excess iron, but the mechanism of this loading is unknown. In vivo whole-body retention studies demonstrated, on average, a two-fold increase in intestinal iron absorption in six male chronic alcoholics. Degrees of iron loading as assessed by serum ferritin or hepatic iron levels did not correlate with alcohol consumption or liver function tests. In vitro studies of iron uptake at varying medium iron concentrations by duodenal mucosa biopsies showed increased iron uptake by tissue from the chronic alcoholics, particularly at the highest medium iron concentration used. Analysis of the uptake data showed similar Michaelis-Menten kinetic constants for uptake by tissue from control subjects and alcoholics. The analysis showed, in addition, a linear component for 59Fe uptake. This component was five-fold greater for the tissue from the chronic alcoholics compared to the controls at the highest medium iron concentration. 57Co-cyanocobalamin was included in the incubation medium as a tissue extracellular fluid marker (ECF). It was found that the apparent distribution volume of the ECF marker, reflecting tissue permeability, was 75% higher for the biopsies from the alcoholics compared to control subjects. These results, together with the previous reports of enhanced in vitro and in vivo intestinal permeability to 51Cr-EDTA in chronic alcoholics, indicate that unregulated increased iron absorption via the non-carrier-mediated paracellular route contributes to the iron overload in chronic alcoholics.

Rheumatic manifestations of haemochromatosis

Haemochromatosis (HC) is a group of phenotypically heterogeneous clinical syndromes, which may have a common molecular basis. Classical genetic haemochromatosis (GHC) is one of these syndromes and is a disorder of iron storage due to an increase in intestinal iron absorption, which results in progressive and massive iron deposition leading to fibrosis and organ malfunction. The liver, pancreas, heart and pituitary are commonly involved. There is a specific arthropathy and an association with osteoporosis. Clinically, the arthropathy may resemble rheumatoid arthritis, with acute attacks of inflammation associated with bilateral destruction of the metacarpophalangeal joints. However, bony joint swelling may occur, suggestive of osteoarthritis. Hip arthritis may be unduly severe and disabling. Haemochromatosis arthritis is composed of three radiographic categories: isolated chondrocalcinosis, hypertrophic osteoarthritis which is indistinguishable from pyrophosphate associated arthropathy, and disease specific changes such as subchondral radiolucency of the femoral head, hook-like osteophytes on the metacarpal heads and a degenerative predilection for the metacarpophalangeal joint rather than the scapholunate. The characteristic histological changes are: abnormal amounts of iron deposits, little or no signs of synovial inflammation and CPPD deposition. Subchondral radiolucency of the femoral head and atypical stripping of the cartilage from the subchondral bone are thought to be specific radiographic and histological changes of HC. The pathogenesis of HC arthritis has been associated with the presence of iron in joint tissue, a defect in cartilage metabolism and immunological dysfunction. Treatment has little effect on clinical, radiological or histological progression.

Immunohistochemical evidence for a lack of ferritin in duodenal absorptive epithelial cells in idiopathic hemochromatosis

Patients with idiopathic hemochromatosis exhibit an unexplained increase in intestinal iron absorption. The aim of this work was to study immunohistochemical H- and L-ferritin distribution in duodenal mucosal cells of patients with idiopathic hemochromatosis, and of subjects with various degrees of iron loading. Biopsy sections of gastrointestinal mucosa from 24 patients with idiopathic hemochromatosis, 10 patients with secondary iron overload, 6 normal subjects, and 13 iron-deficient subjects were analyzed with monoclonal antibodies for the presence of immunohistochemical H and L ferritin types, and with Perls' stain for hemosiderin. Ferritin content of duodenal homogenates was evaluated in 5 cases. The absorptive duodenal cells were found to contain ferritin, mostly of the L type, in apical granules; these ferritin granules were present in all normal, iron-deficient, and iron-over-loaded subjects, but were absent in 21 (87%) of the patients with established idiopathic hemochromatosis. In cells other than those of the duodenal epithelium, such as lamina propria or antral mucosa, ferritin and hemosiderin contents were related to iron loading and no difference was evident between primary and secondary iron overload. These findings indicate that (a) idiopathic hemochromatosis is associated with an altered ferritin expression in the duodenal absorptive epithelial cells, (b) this alteration cannot be detected by analysis of duodenal homogenates, (c) idiopathic hemochromatosis does not affect ferritin accumulation in the other cell types analyzed, and (d) ferritin in absorptive duodenal cells may have a regulatory role in iron absorption.