Pathophysiology and classification of iron overload diseases; update 2018

doi:10.1016/j.tracli.2018.08.006

Transfusion Clinique et Biologique

Volume 26, Issue 1, February 2019, Pages 80-88

https://doi.org/10.1016/j.tracli.2018.08.006 Get rights and content

Abstract

Iron overload pathophysiology has benefited from significant advances in the knowledge of iron metabolism and in molecular genetics. As a consequence, iron overload nosology has been revisited. The hematologist may be confronted to a number of iron overload syndromes, from genetic or acquired origin. Hemochromatoses, mostly but not exclusively related to the HFE gene, correspond to systemic iron overload of genetic origin in which iron excess is the consequence of hepcidin deficiency, hepcidin being the hormone regulating negatively plasma iron. Iron excess develops following hypersideremia and the formation of non-transferrin-bound iron, which targets preferentially parenchymal cells (hepatocytes). The ferroportin disease has a totally different iron overload mechanism consisting of defective egress of cellular iron into the plasma, iron deposition taking place mostly within the macrophages (spleen). Hereditary aceruloplasminemia is peculiar since systemic iron overload involves the brain. Two main types of acquired iron overload can be seen by the hematologist, one related to dyserythropoiesis (involving hypohepcidinemia ), the other related to multiple transfusions (thalassemias, myelodysplasia, hematopoietic stem cell transplantation). Congenital sideroblastic anemias, either monosyndromic (anemia) or polysyndromic (anemia plus extra-hematological syndromes), develop both compartimental iron excess within the erythroblast mitochondria, and systemic iron overload (through dyserythropoiesis and/or transfusions).

Résumé

La physiopathologie des surcharges en fer a connu de grandes avancées grâce à une meilleure connaissance du métabolisme du fer et aux apports de la génétique moléculaire. Il s’en est suivi un recadrage nosologique de ces surcharges. L’hématologiste pourra ainsi être confronté à de nombreuses situations d’excès en fer, héréditaires ou acquises. Les hémochromatoses, surtout – mais non exclusivement – liées au gène HFE, sont des surcharges en fer d’origine génétique développées du fait d’une déficience en hepcidine, l’hepcidine étant l’hormone régulant négativement le taux plasmatique en fer. Cette hypohepcidinémie génère une hypersidérémie, avec apparition secondaire de fer non lié à la transferrine qui cible préférentiellement les cellules parenchymateuses (hépatocytes). La maladie de la ferroportine présente un mécanisme de surcharge en fer différent puisque associé à un défaut de sortie cellulaire du fer, avec une localisation du fer surtout macrophagique (et donc splénique). L’acéruloplasminémie héréditaire présente la particularité de développer une surcharge en fer systémique incluant le cerveau. Deux grands types de surcharges en fer acquises peuvent concerner plus particulièrement l’hématologiste, la surcharge liée à la dysérythropoïèse qui implique une hypohepcidinémie, et la surcharge transfusionnelle notamment des thalassémies, myélodysplasies et greffes de cellules souches hématopoïétiques. Les anémies sidéroblastiques congénitales, qu’elles soient « monosyndromiques » (anémie) ou polysyndromiques (anémie associée à des atteintes extra-hématologiques), ont en commun de développer une surcharge en fer compartimentale mitochondriale érythroblastique, associée à une surcharge systémique (par dysérythropoïèse et/ou transfusions).

Introduction

Iron overload, either of genetic or of acquired origin, represents an important field in hematology. Major advances in the knowledge of iron metabolism have provided the pathophysiological bases for revisiting the nosology of iron-related diseases.

Section snippets

Circulating iron

Considering the hematologist viewpoint, let's start with circulating iron…

Acknowledgements

The authors thank for their support Inserm, CNRS, AHO (Association hémochromatose Ouest), FFAMH (Fédération française des associations de malades de l’hémochromatose), and AFeMERS (Association fer – métaux essentiels – recherche – santé).

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^☆: Congress (where this work was presented): Journée SFTS (Société française de transfusion sanguine) – SFVTT (Société française de vigilance et de thérapeutique transfusionnelle); May 18 2018; Paris (France).

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EducationPathophysiology and classification of iron overload diseases; update 2018Bases physiopathologiques et classification des surcharges en fer ; mise au point 2018☆

Abstract

Résumé

Introduction

Section snippets

Circulating iron

Acknowledgements

J Hepatol

J Biol Chem

Blood

Biochim Biophys Acta

Mutat Res

Blood

Blood

Hematol Oncol Clin North Am

Semin Hematol

Presse Med

Mutat Res

Blood Cells Mol Dis

J Pediatr

Blood

Blood Cells Mol Dis

Eur J Paediatr Neurol

Am J Hum Genet

Blood

Blood

Education
Pathophysiology and classification of iron overload diseases; update 2018Bases physiopathologiques et classification des surcharges en fer ; mise au point 2018☆