Reversible atransferrinemia in a patient with chronic enteropathy: is transferrin mandatory for iron transport?

Herein, we report the case of a 42-year-old woman, hospitalized in a French tertiary hospital for a relapse of a chronic enteropathy, who was found on admission to have no detectable serum transferrin. Surprisingly, she only exhibited mild anaemia. This atransferrinemia persisted for two months throughout her hospitalization, during which her haemoglobin concentration remained broadly stable. Based on her clinical history and evolution, we concluded to an acquired atransferrinemia secondary to chronic undernutrition, inflammation and liver failure. We discuss the investigations performed in this patient, and hypotheses regarding the relative stability of her haemoglobin concentration despite the absence of detectable transferrin

Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria

Loss-of-function mutations in genes for heme biosynthetic enzymes can give rise to congenital porphyrias, eight forms of which have been described. The genetic penetrance of the porphyrias is clinically variable, underscoring the role of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of δ-aminolevulinate synthase (ALAS), which catalyzes the first step of heme synthesis. CLPX has also been reported to mediate heme-induced turnover of ALAS. Here we report a dominant mutation in the ATPase active site of human CLPX, p.Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family. The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. Our results thus identify an additional molecular mechanism underlying the development of EPP and further our understanding of the multiple mechanisms by which CLPX controls heme metabolism. Keywords: heme biosynthesis; porphyria; ALAS; protein unfoldases; AAA+ ATPaseNational Institutes of Health (U.S.) (Grant F32 DK095726)National Institutes of Health (U.S.) (Grant R01 GM049224

The Relevancy of Data Regarding the Metabolism of Iron to Our Understanding of Deregulated Mechanisms in ALS; Hypotheses and Pitfalls

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the loss of motor neurons. Its etiology remains unknown, but several pathophysiological mechanisms are beginning to explain motor neuronal death, as well as oxidative stress. Iron accumulation has been observed in both sporadic and familial forms of ALS, including mouse models. Therefore, the dysregulation of iron metabolism could play a role in the pathological oxidative stress in ALS. Several studies have been undertaken to describe iron-related metabolic markers, in most cases focusing on metabolites in the bloodstream due to few available data in the central nervous system. Reports of accumulation of iron, high serum ferritin, and low serum transferrin levels in ALS patients have encouraged researchers to consider dysregulated iron metabolism as an integral part of ALS pathophysiology. However, it appears complicated to suggest a general mechanism due to the diversity of models and iron markers studied, including the lack of consensus among all of the studies. Regarding clinical study reports, most of them do not take into account confusion biases such as inflammation, renal dysfunction, and nutritional status. Furthermore, the iron regulatory pathways, particularly involving hepcidin, have not been thoroughly explored yet within the pathogenesis of iron overload in ALS. In this sense, it is also essential to explore the relation between iron overload and other ALS-related events, such as neuro-inflammation, protein aggregation, and iron-driven cell death, termed ferroptosis. In this review, we point out limits of the designs of certain studies that may prevent the understanding of the role of iron in ALS and discuss the relevance of the published data regarding the pathogenic impact of iron metabolism deregulation in this disease and the therapeutics targeting this pathway

Erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is an inherited disorder of the haem metabolic pathway characterised by accumulation of protoporphyrin in blood, erythrocytes and tissues, and cutaneous manifestations of photosensitivity. EPP has been reported worldwide, with prevalence between 1:75,000 and 1:200,000. It usually manifests in early infancy upon the first sun exposures. EPP is characterised by cutaneous manifestations of acute painful photosensitivity with erythema and oedema, sometimes with petechiae, together with stinging and burning sensations upon exposure to sunlight, without blisters. These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule that is excreted by the liver, EPP patients are at risk of cholelithiasis with obstructive episodes, and chronic liver disease that might evolve to rapid acute liver failure. In most patients, EPP results from a partial deficiency of the last enzyme of the haem biosynthetic pathway, ferrochelatase, EC 4.99.1.1/FECH (encoded by the FECH gene). EPP appears to be inherited as an autosomal dominant disease, the clinical expression of which is modulated by the presence of the hypomorphic FECH IVS3-48C allele trans, but recessive inheritance with two mutated FECH alleles has also been described. In about 2% of patients, overt disease was recently shown to be caused by gain-of-function mutations in the erythroid-specific aminolevulinic acid synthase 2 (ALAS2/ALAS, EC 2.3.1.27) gene and named X-linked dominant protoporphyria. Diagnosis is established by finding increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 634 nm. Investigations for hepatic involvement, ferrochelatase activity level, genetic analysis (FECH mutations, presence of the hypomorphic FECH IVS3-48C allele trans and ALAS2 mutations) and family studies are advisable. Differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angio-oedema and, in some cases, other types of porphyria. Management includes avoidance of exposure to light, reduction of protoporphyrin levels and prevention of progression of possible liver disease to liver failure. As the major risk in EPP patients is liver disease, a regular follow-up of hepatic involvement is essential. Sequential hepatic and bone marrow transplantation should be considered as a suitable treatment for most severe cases of EPP with hepatic involvement. EPP is a lifelong disorder whose prognosis depends on the evolution of the hepatic disease. However, photosensitivity may have a significant impact on quality of life of EPP patients

Identification de(s) gène(s) et des mécanismes pathogéniques responsables d'une nouvelle forme de Protoporphyrie Erythropoïétique Humaine

La protoporphyrie érythropoïétique (PPE) est une maladie métabolique héréditaire rare résultant d un déficit en ferrochélatase (FECH), dernière enzyme de la voie de biosynthèse de l hème. Ce déficit entraîne l accumulation anormale de protoporphyrine IX (PP) libre, produit phototoxique déclenchant chez le patient une photodermatose algique et rarement des incidents hépatiques graves. Le mode de transmission original de cette maladie repose sur la cotransmission d une mutation FECH délétère et de l allèle FECH hypomorphe IVS3-48C, présent dans la population générale. Quatre familles atypiques sans atteinte FECH ont été identifiées, suggérant l existence d un variant de PPE. Les objectifs de cette thèse ont donc été d affiner la description clinique du phénotype de ces patients, d identifier l anomalie moléculaire et de comprendre le mécanisme physiopathologique responsable de l accumulation de PP. Cette thèse a permis : -1) d identifier des mutations activatrices de l acide -aminolévulinique synthase isoforme érythroïde spécifique (ALAS2), responsables d une surproduction d acide -aminolévulinique (ALA). La FECH, bien que fonctionnelle, devient limitante, entraînant l accumulation de PP libre et PP complexée au zinc. Les mutations responsables de protoporphyrie érythropoïétique dominante liée à l X (XLDPP) sont limitées à un domaine défini du domaine C-terminal de l ALAS2 causant sa délétion ou son remplacement, ce qui permet une libération plus rapide de l ALA. - 2) de démontrer l existence d un troisième variant de PPE/XLDPP. Une analyse de liaison pan génomique couplée à un séquençage exomique du cas index a permis de restreindre la liste des gènes candidatsPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Contribution des bases moléculaires à la physiopathologie d'une porphyrie hépatique aiguë (la coproporphyrie héréditaire et son variant phénotypique l'hardéroporphyrie)

Chez l homme, les mutations du gène CPO codant pour la coproporphyrinogène III oxydase, sixième enzyme de la voie de biosynthèse de l hème sont à l origine de deux pathologies différentes. La majorité des mutations est responsable du phénotype de coproporphyrie héréditaire, porphyrie hépatique aiguë, autosomique dominante. Seule la mutation faux sens K404E, codée par l exon 6 du gène CPO est responsable du phénotype hardéroporphyrie , caractérisé par une symptomatologie hématologique de transmission autosomique récessive. Nous avons analysé les caractéristiques enzymatiques de mutants produits par mutagenèse dirigée en système procaryote. Les résultats obtenus montrent que cinq acides aminés (D400-K404) jouent un rôle dans la rétention de l hardéroporphyrinogène au niveau du site actif de l enzyme et que leur mutation est responsable du phénotype hardéroporphyrie . Nous avons réalisé d autre part l étude exhaustive clinique, biologique et moléculaire de 56 patients coproporphyriques suivis au Centre Français des Porphyries.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Extrahepatic hepcidin production: The intriguing outcomes of recent years

International audienceHepcidin is the hyposideremic hormone regulating iron metabolism. It is a defensin-like disulfide-bonded peptide with antimicrobial activity. The main site of hepcidin production is the liver where its synthesis is modulated by iron, inflammation and erythropoietic signaling. However, hepcidin locally produced in several peripheral organs seems to be an important actor for the maintenance of iron homeostasis in these organs. This review highlights the presence of peripheral hepcidin and its potential functions. Understanding the role of extrahepatic hepcidin could be of great physiological and therapeutic importance for several specific pathologies

Ferroptosis in Liver Diseases: An Overview

Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and redox imbalance. Ferroptosis shows specific biological and morphological features when compared to the other cell death patterns. The loss of lipid peroxide repair activity by glutathione peroxidase 4 (GPX4), the presence of redox-active iron and the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are considered as distinct fingerprints of ferroptosis. Several pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion, p53, Keap1/Nrf2 and phospholipid biosynthesis, can modify susceptibility to ferroptosis. Through the decades, various diseases, including acute kidney injury; cancer; ischemia–reperfusion injury; and cardiovascular, neurodegenerative and hepatic disorders, have been associated with ferroptosis. In this review, we provide a comprehensive analysis of the main biological and biochemical mechanisms of ferroptosis and an overview of chemicals used as inducers and inhibitors. Then, we report the contribution of ferroptosis to the spectrum of liver diseases, acute or chronic. Finally, we discuss the use of ferroptosis as a therapeutic approach against hepatocellular carcinoma, the most common form of primary liver cancer

Impact of iron deficiency diagnosis using hepcidin mass spectrometry dosage methods on hospital stay and costs after a prolonged ICU stay: Study protocol for a multicentre, randomised, single-blinded medico-economic trial

International audienceIron deficiency (ID) is frequent but difficult to diagnose in critically ill patients. ID may be responsible for prolonged post-ICU hospital stays, since it results in fatigue, muscle weakness and anaemia. Hepcidin, the key iron metabolism hormone, may be a good marker of ID in these patients. The aim of this study is to determine whether using mass spectrometry hepcidin determination to diagnose (and treat) ID after prolonged ICU stays may reduce patients' subsequent hospital stays and costs in comparison with conventional (ferritin) methods