Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism

Hematology ◽  
2000 ◽  
Vol 2000 (1) ◽  
pp. 39-50 ◽  
Author(s):  
Gary M. Brittenham ◽  
Günter Weiss ◽  
Pierre Brissot ◽  
Fabrice Lainé ◽  
Anne Guillygomarc'h ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Full Range ◽  
Hereditary Hemochromatosis ◽  
Laboratory Evaluation ◽  
Hfe Gene ◽  
Iron Regulatory Proteins ◽  
Heme Metabolism ◽  
Clinical Consequences ◽  
And Storage

Abstract This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage—transferrin, transferrin receptor, and ferritin—have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the “Stimulator of Fe Transport” (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice. In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.

Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism

Hematology ◽  
2000 ◽  
Vol 2000 (1) ◽  
pp. 39-50
Author(s):  
Gary M. Brittenham ◽  
Günter Weiss ◽  
Pierre Brissot ◽  
Fabrice Lainé ◽  
Anne Guillygomarc'h ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Full Range ◽  
Hereditary Hemochromatosis ◽  
Laboratory Evaluation ◽  
Hfe Gene ◽  
Iron Regulatory Proteins ◽  
Heme Metabolism ◽  
Clinical Consequences ◽  
And Storage

This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage—transferrin, transferrin receptor, and ferritin—have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the “Stimulator of Fe Transport” (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice. In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.

Physiologic systemic iron metabolism in mice deficient for duodenal Hfe

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4511-4517 ◽  
Author(s):  
Maja Vujic Spasic ◽  
Judit Kiss ◽  
Thomas Herrmann ◽  
Regina Kessler ◽  
Jens Stolte ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Binding Capacity ◽  
Hereditary Hemochromatosis ◽  
Direct Interaction ◽  
Hfe Gene ◽  
Hepatic Iron ◽  
Primary Role ◽  
Genes Encoding

Abstract Mutations in the Hfe gene result in hereditary hemochromatosis (HH), a disorder characterized by increased duodenal iron absorption and tissue iron overload. Identification of a direct interaction between Hfe and transferrin receptor 1 in duodenal cells led to the hypothesis that the lack of functional Hfe in the duodenum affects TfR1-mediated serosal uptake of iron and misprogramming of the iron absorptive cells. Contrasting this view, Hfe deficiency causes inappropriately low expression of the hepatic iron hormone hepcidin, which causes increased duodenal iron absorption. We specifically ablated Hfe expression in mouse enterocytes using Cre/LoxP technology. Mice with efficient deletion of Hfe in crypt- and villi-enterocytes maintain physiologic iron metabolism with wild-type unsaturated iron binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters is unchanged in duodenal Hfe-deficient mice. Our data demonstrate that intestinal Hfe is dispensable for the physiologic control of systemic iron homeostasis under steady state conditions. These findings exclude a primary role for duodenal Hfe in the pathogenesis of HH and support the model according to which Hfe is required for appropriate expression of the “iron hormone” hepcidin which then controls intestinal iron absorption.

HFE Downregulates Iron Uptake From Transferrin and Induces Iron-Regulatory Protein Activity in Stably Transfected Cells

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3915-3921 ◽  
Author(s):  
H.D. Riedel ◽  
M.U. Muckenthaler ◽  
S.G. Gehrke ◽  
I. Mohr ◽  
K. Brennan ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular “labile iron pool.” The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

scholarly journals Hemochromatosis: one form of iron-overload diseases

2013 ◽  
Vol 154 (29) ◽  
pp. 1156-1164 ◽  
Author(s):  
Ferenc Szalay
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Clinical Symptoms ◽  
Fetal Liver ◽  
Hereditary Hemochromatosis ◽  
Gene Mutations ◽  
Organ Injury ◽  
Beta Thalassemia ◽  
Hfe Gene ◽  
Kinase Gene

Iron-overload diseases are typically insidious, causing progressive and irreversible organ injury before clinical symptoms develop. Some iron-overload diseases as HFE-associated hemochromatosis and beta-thalassemia are quite common, whereas others are very rare. Early diagnosis is important since iron toxicity can be attenuated or prevented. Significant progress of our knowledge on iron metabolism developed in the past years. We learned a lot about HFE gene mutations, function of ferroportin and hepcidin, the hypoferremia hormone produced by the liver. However, many questions are still open. Special forms of localized iron overload are the Hallervorden-Spatz syndrome and pantothenate kinase gene mutation associated neurodegeneration causing progressive extrapyramidal movement disorders. Neonatal hemochromatosis is a severe systemic iron-overload disorder due to gestational alloimmune liver disease caused by transplacental maternal IgG directed against the fetal liver. This review article gives an overview on iron metabolism and iron-overload disease. Pathomechanism, diagnosis and treatment of hereditary hemochromatosis are discussed. Orv. Hetil., 2013, 154, 1156–1164.

TFR2 BETA Isoform Is Differentially Produced Compared to ALFA and Has Specific Function at Young Age.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1856-1856
Author(s):  
Antonella Roetto ◽  
Rosa Maria Pellegrino ◽  
Ilaria Defilippi ◽  
Sonia Carturan ◽  
Enrico Bracco ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Functional Role ◽  
Transmembrane Protein ◽  
Hereditary Hemochromatosis ◽  
Life Time ◽  
Positive Control ◽  
Adult Age

Abstract The transferrin receptor 2 gene (TFR2) encodes for a transmembrane protein that plays a pivotal role in iron metabolism, since TFR2 mutations are responsible of type 3 Hereditary Hemochromatosis (HH). Together with other HH proteins (Hfe and Rgmc) Tfr2 participates to modulation of Hepcidin (Hepc) production, a small peptide able to regulate body iron availability through its negative effect on cellular iron exporter Ferroportin (Fpn1). Tfr2 protein is a member of the transferrin receptor family, showing moderate homology to transferrin receptor (Tfrc). It is able to bind transferrin even thought at lower affinity compared to TFRC. Two alternative transcripts of TFR2 have been reported, named alfa and beta. TFR2 alfa mRNA is highly expressed in the hepatocytes while TFR2 beta has a low ubiquitous expression (Kawabata et al, 1999). The beta isoform is identical to alfa but it lacks the transmembrane and cytoplasmic domains; it has been considered an alternative splicing form and its role is still poorly understood. Nevertheless, clinical observations support the hypothesis that TFR2 beta has an important functional role since HFE3 patients with mutations not compromising its production have a milder phenotype compared to those unable to synthesize both alfa and beta TFR2 isoforms (Roetto et al,2002; Le Gac et al, 2004). In order to elucidate whether TFR2 beta was differentially expressed and produced during life span its mRNA and translated protein were analyzed in C57BL/6 mice during their growth and adult age. Since Tfr2 beta protein has never been demonstrated to exist before, its cDNA has been cloned in an expression vector and transfected in HEK293T cells. Cells lysates have been electhrophoresed, transferred onto nitrocellulose membrane, decorated with Tfr2 Ab (Santa Cruz Biotechnoloy, Inc) and visualized on Western Blot. A 65 kDa band has been obtained from the transfection, consistent with the aminoacid sequence predicted molecular weight, and used as a positive control for further in vivo experiments. C57BL/6 mice livers from seven different ages, starting from birth until adult age (post natal days 0, 1, 3, 7, 14, 28, 40 and 60) have been analyzed in WB utilizing Tfr2 antibody. At least three mice per point have been analyzed. One band of a molecular weight of approximately 95 KDa has been detected during whole animal life, quantitatively increasing during life time, corresponding to Tfr2 alfa. Meanwhile, the beta isoform appeared to be consistently produced until the 7th day after birth and disappears starting from day 14. To evaluate the possible consequences of this result on iron metabolism, HH proteins (Hfe, Fpn1, Rgmc) mRNA expression pattern has been analyzed in real time PCR at the same points, as well as Hepcidin (Hepc) transcript, in order to evaluate whether TFR2 beta production could in some way influence Hepc modulation. HEPC transcription resulted to be significantly downmodulated from day 0 after birth until day 14 as compared to later stages in mice life (adulthood). HFE transcription resulted to be lower in young animals compared to adults while FPN1 increased significantly between day 3 and 7, according to HEPC decreasing. On the whole, these results suggest a functional role for the Tfr2 beta isoform in iron sensing, since this isoform resulted to be selectively produced during animal growth. At the same life period Hepc transcription resulted to be significantly downmodulated, allowing in this way increased iron absorption. These data are consistent with an higher iron requirement necessary for massive animal body growth.

Transferrin receptor 2 is emerging as a major player in the control of iron metabolism

2007 ◽  
Vol 2 (1) ◽  
pp. 34-55 ◽  
Author(s):  
Alessia Calzolari ◽  
Isabella Oliviero ◽  
Ugo Testa
Keyword(s):  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Cellular Localization ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Essential Element ◽  
Biological Properties ◽  
The Body ◽  
Major Player ◽  
Type 3

AbstractOur knowledge of mammalian iron metabolism has advanced dramatically over recent years. Iron is an essential element for virtually all living organisms. Its intestinal absorption and accurate cellular regulation is strictly required to ensure the coordinated synthesis of the numerous iron-containing proteins involved in key metabolic processes, while avoiding the uptake of excess iron that can lead to organ damage. A range of different proteins exist to ensure this fine control within the various tissues of the body. Among these proteins, transferrin receptor (TFR2) seems to play a key role in the regulation of iron homeostasis. Disabling mutations in TFR2 are responsible for type 3 hereditary hemochromatosis (Type 3 HH). This review describes the biological properties of this membrane receptor, with a particular emphasis paid to the structure, function and cellular localization. Although much information has been garnered on TFR2, further efforts are needed to elucidate its function in the context of the iron regulatory network.

scholarly journals SAT-354 Isolated Hypoparathyroidism: A Rare Initial Manifestation of Hereditary Hemochromatosis (HH)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Zainab Shaheen ◽  
Kevin McCann ◽  
Rodhan Abass Khthir
Keyword(s):  
Vitamin D ◽  
Hereditary Hemochromatosis ◽  
Organ Damage ◽  
Laboratory Evaluation ◽  
Hfe Gene ◽  
Iron Level ◽  
Initial Manifestation ◽  
Iron Saturation ◽  
History Of ◽  
Classic Form

Abstract Background: We present a case of hypoparathyroidism diagnosed in a patient as initial manifestation of hereditary hemochromatosis. As per our literature search, it is very rarely reported as an isolated abnormality in HH. Case: A 27 year old male with history of seizure disorder, well controlled on Oxcarbazepine, referred for evaluation of chronic hypocalcemia. His PMH includes cerebral palsy, with good functional capacity and mild cognitive impairment. He denied muscle spasm, perioral numbness, bone pain, muscle weakness or fracture. He was taking calcium carbonate 600mg bid and vitamin D 50,000 IU q2monthly. There was no family history of any Ca disorders. Physical exam was unremarkable. Laboratory evaluation revealed Ca levels ranging from 7.6 to 8.5mg/dl with intact PTH values ranging from 11 to 22pg/ml. His ionized calcium was also low. Patient’s 24 hr urinary Ca was 122mg/24hrs. In this case, he did initially have hypomagnesemia and vitamin d deficiency, which could potentially explain low calcium. But even after supplementing Vitamin D and Mg, patient’s Ca remained low. His kidney function was normal. Hemoglobin was in range of 14-15g/dl. To further evaluate the cause of hypoparathyroidism, iron saturation and iron levels were also sent. His iron saturation % was high at 89% with iron level of 286 ug/dl. His ferritin was 224 ng/ml and TIBC was 265 ug/dl. A sample was sent for genetic analysis to rule out hemochromatosis. Homozygous mutations in C282Y gene were found. A diagnosis of hereditary hemochromatosis was made. His other entire hormonal axis was intact. In this case, patient’s hypoparathyroidism is likely an initial manifestation of his HH. Discussion: Hereditary Hemochromatosis (HH) is a genetic disease characterized by an excessive (unregulated) entry of iron into the bloodstream with increased iron deposition in the parenchymal cells of a variety of organs leading to their failure. A defect in the hemochromatosis gene (HFE) is the most common form of HH, also known as the classic form or type 1 HH, where the principal mutation is represented by a substitution of tyrosine for cysteine at position 282 of the HFE gene (C282Y) as seen in our case. According to the genetic forms, the clinical manifestation usually ranges from simple biochemical abnormalities to severe organ damage and disease such as liver cirrhosis, arthritis, DM, cardiomyopathy and hypogonadism. There are reports of hypoparathyroidism from iron overload seen in thalassemia patients and patients who receive long term blood transfusions. In our literature review, this is the first documented case of HH initially manifesting as hypoparathyroidism. As HH is not uncommon in Caucasians, the work up for hemochromatosis as a possible cause of endocrinopathies should be kept in the differential diagnosis. It will help in early diagnosis & treatment which can reverse the effects of the disease leading to better outcomes.

Hepcidin is decreased in TFR2 hemochromatosis

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1803-1806 ◽  
Author(s):  
Elizabeta Nemeth ◽  
Antonella Roetto ◽  
Giovanni Garozzo ◽  
Tomas Ganz ◽  
Clara Camaschella
Keyword(s):  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Iron Loading ◽  
Inflammatory Conditions ◽  
Juvenile Hemochromatosis ◽  
The Relationship ◽  
Transferrin Receptor 2

Abstract The hepatic peptide hepcidin is the key regulator of iron metabolism in mammals. Recent evidence indicates that certain forms of hereditary hemochromatosis are caused by hepcidin deficiency. Juvenile hemochromatosis is associated with hepcidin or hemojuvelin mutations, and these patients have low or absent urinary hepcidin. Patients with C282Y HFE hemochromatosis also have inappropriately low hepcidin levels for the degree of iron loading. The relationship between the hemochromatosis due to transferrin receptor 2 (TFR2) mutations and hepcidin was unknown. We measured urinary hepcidin levels in 10 patients homozygous for TFR2 mutations, all with increased transferrin saturation. Urinary hepcidin was low or undetectable in 8 of 10 cases irrespective of the previous phlebotomy treatments. The only 2 cases with normal hepcidin values had concomitant inflammatory conditions. Our data indicate that TFR2 is a modulator of hepcidin production in response to iron. (Blood. 2005;105:1803-1806)

HFE Downregulates Iron Uptake From Transferrin and Induces Iron-Regulatory Protein Activity in Stably Transfected Cells

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3915-3921 ◽  
Author(s):  
H.D. Riedel ◽  
M.U. Muckenthaler ◽  
S.G. Gehrke ◽  
I. Mohr ◽  
K. Brennan ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron

Abstract Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular “labile iron pool.” The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

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