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Novel scientific insights in iron metabolism


Krayenbühl, Pierre‐Alexandre. Novel scientific insights in iron metabolism. 2011, University of Zurich, Faculty of Medicine.

Abstract

Summary: Introduction: My scientific work focuses on iron metabolism of the human body. Specifically iron overload (in patients with hereditary hemochromatosis), iron deficiency (in non‐anaemic menstruating women), and iron regulation mechanisms have been under investigation. Moreover, a large Swiss cohort of actually 180 patients with hereditary hemochromatosis has been assembled, and a well frequented homepage for these patients and further interested people has been created (www.haemochromatose.ch). The five cited papers provide an overview about my research work on the field of iron metabolism at the Division of Internal Medicine at the University Hospital of Zurich: A. IRON OVERLOAD ‐ Phenotypic modulators in hereditary hemochromatosis (1, 2) Hereditary hemochromatosis is an inherited disease characterised by progressive iron overload of parenchymal tissues. More than 90% (in Switzerland) of patients with typical clinical features of this metabolic disease are homozygous for a G>A mutation at nucleotide 845 of the HFE gene, resulting in a substitution of tyrosine for cysteine at amino acid 282 (C282Y). Main clinical manifestations in patients with hereditary hemochromatosis due to the homozygous HFE C282Y mutation are hepatic fibrosis/cirrhosis, arthropathy, diabetes mellitus, cardiopathy, and hypogonadism. Phenotypic expression of the disease, however, is highly variable suggesting other additional modifying genetic or environmental factors. Studies in animal models have supported the theory that the control of iron absorption is associated with secretion of TNF‐alpha, probably by lymphocytes in the small intestinal epithelium. We have therefore studied the influence of tumor necrosis factor‐alpha allelic variants in patients with hereditary HFE hemochromatosis. Patients with the allelic TNFalpha ‐308G>A variant had increased intestinal iron absorption, i.e., total body iron overload at diagnosis, higher hepatic iron index and need of phlebotomies to prevent iron reaccumulation. Other genes such as toll‐like receptor 4 (TLR4), 9 (TLR9) and nucleotide oligomerization domain protein (NOD2) known to be involved in the cellular response of inflammatory stimuli (like reactive oxygen species due to the tissue iron overloaded) were analyzed. Carriers of TLR4 Asp299Gly polymorphism as compared with noncarriers showed significantly more often the two main manifestations of hereditary hemochromatosis, i.e., liver disease and arthropathy of the metacarpophalangeal joints. We have proposed that TLR4 is involved in the signalling of inflammatory processes arising from the toxic effects of accumulated iron in tissues of the body in clinical hemochromatosis. Outlook (ongoing and planned projects): • Further research of the phenotypic expression of hereditary hemochromatosis with microarray studies of macrophages from patients in collaboration with the Functional Genomics Center Zurich (ETH Zurich and the University of Zurich) • Determination of the prevalence of hepatic cellular carcinoma in hereditary hemochromatosis in Switzerland • Study of liver biopsies in patients with iron overload other than hereditary hemochromatosis Krayenbühl Pierre‐Alexandre: Novel scientific insights in iron metabolism 2 B. IRON DEFICIENCY ‐ Effect of iron treatment on fatigue in non‐anemic women (3) Iron deficiency is a frequent disorder in menstruating women. Similarly, fatigue is a common complaint in general practice and especially in woman often associated to iron deficiency. Whereas fatigue is comprehensible in the anemic state of iron deficiency, sparse information in non‐anemic patients with fatigue and low body iron stores are available. In a randomised, double‐blinded, placebo‐controlled study, 90 premenopausal women presenting with fatigue, serum ferritin ≤50 ng/mL, and haemoglobin ≥120 g/L were randomised to receive either 800 mg intravenous iron (III)‐hydroxide sucrose or intravenous placebo. Fatigue and serum iron status were assessed at baseline, after 6 and 12 weeks using the Brief Fatigue Inventory (BFI) and Short Performance Inventory (SPI) questionnaire. Replenishing iron stores by intravenous iron therapy significantly ameliorated fatigue in non‐anaemic women with low serum ferritin concentrations. The significant effect of iron (compared to placebo) on fatigue was however observed exclusively in patients with substantially depleted iron stores – as indicated by a serum ferritin concentration ≤15 ng/mL at baseline. Iron administration did not influence haemoglobin concentration which was in the normal range at baseline and throughout the study in both iron‐treated and placebo‐treated patients. Thus, the fatigue‐reducing effects of iron therapy seem to be haemoglobin independent and reflect the non‐haematological functions of iron. Indeed, iron itself is an essential component of a large numbers of human metabolic enzymes which catalyse important biochemical reactions such as the formation of deoxyribonucleotides and mitochondrial adenosintriphosphat (ATP) generation. Refilling depleted iron store might therefore affect theses processes. Outlook (ongoing and planned projects): • Effects on iron supplementation on mitochondrial capacity (phosphocreatine recovery rate assessed by 31P‐MR‐spectroscopy of the lower leg muscle) and physical performance in non‐anemic premenopausal women with iron deficiency in Collaboration with Institute for Biomedical Engineering, ETH and Exercise Physiology ETH Zurich and University of Zurich. • Effects on iron supplementation on cerebral dopamine receptor density (assessed by brain positron emission tomography) and neuropsychological function in non‐anemic premenopausal women with iron deficiency. C. IRON REGULATION ‐ Markers of intestinal iron absorption and iron regulation (4,5) In a collaborative project with the Institute of Food, Nutrition and Health from the Swiss Federal Institute of Technology we analysed the iron isotopic composition of blood of patients with hereditary hemochromatosis. All iron in nature consists of 4 stable isotopes that differ in their masses and natural abundances: 54Fe (5.8%), 56Fe (91.8%), 57Fe (2.1%), and 58Fe (0.3%). Each individual bears a distinct 56Fe/54Fe isotope ratio in the blood that is, on average, lower in males than in females. Hypothetically iron isotopic composition may be altered during intestinal absorption. In our study, we found that blood of patients with hemochromatosis is characterized by a higher 56Fe/54Fe isotope ratio than blood of healthy individuals and that 56Fe/54Fe isotope ratio of blood significantly correlates with total‐body iron accumulation, severity of clinical disease, and the need for regular phlebotomies to prevent iron reaccumulation. We concluded that blood of patients with hereditary hemochromatosis contains more of the heavier iron isotopes than blood of healthy Krayenbühl Pierre‐Alexandre: Novel scientific insights in iron metabolism 3 individuals. The primary determinant of the iron isotopic composition of blood appears to be isotope‐sensitive iron absorption in the intestine. Prior to this work, there was no satisfactory technique available to measure regulation of intestinal iron absorption. With the recently identified peptide hepcidin the starting signal for a new research area in hereditary hemochromatosis has been given. Hepcidin is small 25‐amino‐acid peptide, synthesized in the liver, which seems to be the central regulator of iron homeostasis. Hepcidin originally secreted by hepatocytes to the plasma binds to ferroportin present in the basolateral membrane of enterocytes and macrophages. Binding of hepcidin to ferroportin mediates the internalization of this complex in the cell and, by that, to the inhibition of duodenal iron absorption respectively the release of iron from macrophages. In a collaborative project with the Department of Internal Medicine, University Hospital Ulm, we have developed the first monoclonal competitive enzyme‐linked immunosorbent assay (ELISA) to determine hepcidin concentrations in sera of patients with hereditary hemochromatosis. Patients with homozygous C282Y HFE mutation showed significant lower serum hepcidin levels compared to healthy controls indicating disturbed hepcidin regulation in these patients. Our results support the theory of defective HFE mediated iron sensing in the liver of patients with homozygous C282Y HFE mutations, leading to inadequate liver hepcidin synthesis with uncontrolled iron absorption and progressive iron overload of the body. Outlook (ongoing and planned projects): • Determination of changes in blood iron isotope ratios in response to phlebotomy treatment in patients with hereditary hemochromatosis • Development of a new mass spectrometry based hepcidin assay in collaboration with the Functional Genomics Center Zurich (ETH Zurich and the University of Zurich)

Summary: Introduction: My scientific work focuses on iron metabolism of the human body. Specifically iron overload (in patients with hereditary hemochromatosis), iron deficiency (in non‐anaemic menstruating women), and iron regulation mechanisms have been under investigation. Moreover, a large Swiss cohort of actually 180 patients with hereditary hemochromatosis has been assembled, and a well frequented homepage for these patients and further interested people has been created (www.haemochromatose.ch). The five cited papers provide an overview about my research work on the field of iron metabolism at the Division of Internal Medicine at the University Hospital of Zurich: A. IRON OVERLOAD ‐ Phenotypic modulators in hereditary hemochromatosis (1, 2) Hereditary hemochromatosis is an inherited disease characterised by progressive iron overload of parenchymal tissues. More than 90% (in Switzerland) of patients with typical clinical features of this metabolic disease are homozygous for a G>A mutation at nucleotide 845 of the HFE gene, resulting in a substitution of tyrosine for cysteine at amino acid 282 (C282Y). Main clinical manifestations in patients with hereditary hemochromatosis due to the homozygous HFE C282Y mutation are hepatic fibrosis/cirrhosis, arthropathy, diabetes mellitus, cardiopathy, and hypogonadism. Phenotypic expression of the disease, however, is highly variable suggesting other additional modifying genetic or environmental factors. Studies in animal models have supported the theory that the control of iron absorption is associated with secretion of TNF‐alpha, probably by lymphocytes in the small intestinal epithelium. We have therefore studied the influence of tumor necrosis factor‐alpha allelic variants in patients with hereditary HFE hemochromatosis. Patients with the allelic TNFalpha ‐308G>A variant had increased intestinal iron absorption, i.e., total body iron overload at diagnosis, higher hepatic iron index and need of phlebotomies to prevent iron reaccumulation. Other genes such as toll‐like receptor 4 (TLR4), 9 (TLR9) and nucleotide oligomerization domain protein (NOD2) known to be involved in the cellular response of inflammatory stimuli (like reactive oxygen species due to the tissue iron overloaded) were analyzed. Carriers of TLR4 Asp299Gly polymorphism as compared with noncarriers showed significantly more often the two main manifestations of hereditary hemochromatosis, i.e., liver disease and arthropathy of the metacarpophalangeal joints. We have proposed that TLR4 is involved in the signalling of inflammatory processes arising from the toxic effects of accumulated iron in tissues of the body in clinical hemochromatosis. Outlook (ongoing and planned projects): • Further research of the phenotypic expression of hereditary hemochromatosis with microarray studies of macrophages from patients in collaboration with the Functional Genomics Center Zurich (ETH Zurich and the University of Zurich) • Determination of the prevalence of hepatic cellular carcinoma in hereditary hemochromatosis in Switzerland • Study of liver biopsies in patients with iron overload other than hereditary hemochromatosis Krayenbühl Pierre‐Alexandre: Novel scientific insights in iron metabolism 2 B. IRON DEFICIENCY ‐ Effect of iron treatment on fatigue in non‐anemic women (3) Iron deficiency is a frequent disorder in menstruating women. Similarly, fatigue is a common complaint in general practice and especially in woman often associated to iron deficiency. Whereas fatigue is comprehensible in the anemic state of iron deficiency, sparse information in non‐anemic patients with fatigue and low body iron stores are available. In a randomised, double‐blinded, placebo‐controlled study, 90 premenopausal women presenting with fatigue, serum ferritin ≤50 ng/mL, and haemoglobin ≥120 g/L were randomised to receive either 800 mg intravenous iron (III)‐hydroxide sucrose or intravenous placebo. Fatigue and serum iron status were assessed at baseline, after 6 and 12 weeks using the Brief Fatigue Inventory (BFI) and Short Performance Inventory (SPI) questionnaire. Replenishing iron stores by intravenous iron therapy significantly ameliorated fatigue in non‐anaemic women with low serum ferritin concentrations. The significant effect of iron (compared to placebo) on fatigue was however observed exclusively in patients with substantially depleted iron stores – as indicated by a serum ferritin concentration ≤15 ng/mL at baseline. Iron administration did not influence haemoglobin concentration which was in the normal range at baseline and throughout the study in both iron‐treated and placebo‐treated patients. Thus, the fatigue‐reducing effects of iron therapy seem to be haemoglobin independent and reflect the non‐haematological functions of iron. Indeed, iron itself is an essential component of a large numbers of human metabolic enzymes which catalyse important biochemical reactions such as the formation of deoxyribonucleotides and mitochondrial adenosintriphosphat (ATP) generation. Refilling depleted iron store might therefore affect theses processes. Outlook (ongoing and planned projects): • Effects on iron supplementation on mitochondrial capacity (phosphocreatine recovery rate assessed by 31P‐MR‐spectroscopy of the lower leg muscle) and physical performance in non‐anemic premenopausal women with iron deficiency in Collaboration with Institute for Biomedical Engineering, ETH and Exercise Physiology ETH Zurich and University of Zurich. • Effects on iron supplementation on cerebral dopamine receptor density (assessed by brain positron emission tomography) and neuropsychological function in non‐anemic premenopausal women with iron deficiency. C. IRON REGULATION ‐ Markers of intestinal iron absorption and iron regulation (4,5) In a collaborative project with the Institute of Food, Nutrition and Health from the Swiss Federal Institute of Technology we analysed the iron isotopic composition of blood of patients with hereditary hemochromatosis. All iron in nature consists of 4 stable isotopes that differ in their masses and natural abundances: 54Fe (5.8%), 56Fe (91.8%), 57Fe (2.1%), and 58Fe (0.3%). Each individual bears a distinct 56Fe/54Fe isotope ratio in the blood that is, on average, lower in males than in females. Hypothetically iron isotopic composition may be altered during intestinal absorption. In our study, we found that blood of patients with hemochromatosis is characterized by a higher 56Fe/54Fe isotope ratio than blood of healthy individuals and that 56Fe/54Fe isotope ratio of blood significantly correlates with total‐body iron accumulation, severity of clinical disease, and the need for regular phlebotomies to prevent iron reaccumulation. We concluded that blood of patients with hereditary hemochromatosis contains more of the heavier iron isotopes than blood of healthy Krayenbühl Pierre‐Alexandre: Novel scientific insights in iron metabolism 3 individuals. The primary determinant of the iron isotopic composition of blood appears to be isotope‐sensitive iron absorption in the intestine. Prior to this work, there was no satisfactory technique available to measure regulation of intestinal iron absorption. With the recently identified peptide hepcidin the starting signal for a new research area in hereditary hemochromatosis has been given. Hepcidin is small 25‐amino‐acid peptide, synthesized in the liver, which seems to be the central regulator of iron homeostasis. Hepcidin originally secreted by hepatocytes to the plasma binds to ferroportin present in the basolateral membrane of enterocytes and macrophages. Binding of hepcidin to ferroportin mediates the internalization of this complex in the cell and, by that, to the inhibition of duodenal iron absorption respectively the release of iron from macrophages. In a collaborative project with the Department of Internal Medicine, University Hospital Ulm, we have developed the first monoclonal competitive enzyme‐linked immunosorbent assay (ELISA) to determine hepcidin concentrations in sera of patients with hereditary hemochromatosis. Patients with homozygous C282Y HFE mutation showed significant lower serum hepcidin levels compared to healthy controls indicating disturbed hepcidin regulation in these patients. Our results support the theory of defective HFE mediated iron sensing in the liver of patients with homozygous C282Y HFE mutations, leading to inadequate liver hepcidin synthesis with uncontrolled iron absorption and progressive iron overload of the body. Outlook (ongoing and planned projects): • Determination of changes in blood iron isotope ratios in response to phlebotomy treatment in patients with hereditary hemochromatosis • Development of a new mass spectrometry based hepcidin assay in collaboration with the Functional Genomics Center Zurich (ETH Zurich and the University of Zurich)

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Item Type:Habilitation
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic and Policlinic for Internal Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:August 2011
Deposited On:30 Nov 2012 10:43
Last Modified:05 Apr 2016 16:08
Number of Pages:67
Permanent URL: https://doi.org/10.5167/uzh-67503

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