Optimising the diagnosis and the treatment of iron overload diseases

International audienceA number of human disorders are related to chronic iron overload, either of genetic or acquired origin. The multi-organ damage produced by iron excess leads, in adults and in children, to severe clinical consequences, affecting both quality of life and life expectancy. The diagnosis is increasingly based on a non-invasive strategy, resorting to clinical, biological and imaging data. The treatment rests on either venesection or chelation therapy, depending on the etiology. Major advances in the fields of molecular biology, pharmacology, and biotechnology pave the road for key improvements in the diagnostic and therapeutic management of the patients

Surcharges en fer rares d'origine génétique (caractérisation clinique, fonctionnelle, et biologique)

L'hémochromatose génétique liée au gène HFE (HG) se caractérise par une augmentation de la saturation de la transferrine plasmatique, qui entraîne une surcharge en fer. Ces anomalies sont dues à une sécrétion basse d'hepcidine, le régulateur principal du métabolisme du fer, et définissent le phénotype d'hepcidino déficience. De nouvelles formes de surcharges en fer ayant un phénotype similaire ont été identifiées. Les mécanismes moléculaires en sont parfois mal compris. L'objectif général de ce travail a été de caractériser sur le plan clinique, fonctionnel, et biologique, des surcharges en fer rares d'origine génétique ayant pour point commun un phénotype d'hepcidino-déficience. Nous avons d'abord analysé une cohorte de patients porteurs d'une HG, forme type de l'hepcidino-déficience, et montré que la transplantation hépatique normalisait le métabolisme du fer, montrant ainsi le rôle majeur du foie dans le phénotype d'hepcidino-déficience de l'HG. Nous avons ensuite caractérisé des surcharges en fer à saturation de la transferrine élevée liées à des anomalies de transport du fer : i) nous avons rapporté un cinquième cas de mutations du gène DMT1 et montré le caractère pathogène de la mutation p.Asn491Ser ; ii) nous décrivons un groupe de 12 patients qui présentent une mutation hétérozygote du gène TF, l'augmentation de la saturation de la transferrine ne semblant pas être en rapport avec une hepcidino-déficience, et l'existence de cofacteurs pouvant faciliter la surcharge en fer. Nous avons ensuite décrit l'impact de mutations du gène TFR2, qui sont responsables d'une hepcidino déficience dont l'expression clinique est hétérogène mais qui peut être très précoce. Nous avons alors, pour préciser les mécanismes liant les mutations du gène TFR2 à une diminution anormale de l'hepcidine, montré in vitro que les mutations p.Asn12Ile et p.Gly430Arg altèrent l'adressage cellulaire de TFR2 tandis que la mutation p.Arg768Pro altère son interaction avec la transferrine. N'ayant pu parvenir à induire l'expression d'hepcidine sous l'effet de la transferrine, au contraire de certaines équipes mais en accord avec d'autres, nous n'avons pu analyser l'impact des mutations sur la transduction du signal liant TFR2 et hepcidine. Nos résultats contribuent à préciser les mécanismes impliqués dans l'apparition de surcharges en fer rares à saturation élevée de la transferrine.HFE related hemochromatosis (HH) is characterized by an increased plasma transferrin saturation level, which causes iron overload. These anomalies are due to low hepcidin secretion, the key regulator of iron metabolism, and define the hepcidin deficiency phenotype. New forms of iron overload with similar phenotype were identified, but their molecular mechanisms remain unclear. The main objective of this work was to characterize the clinical, functional, and biological aspects of rare genetic iron overload with an hepcidin deficiency phenotype. We firstly analyzed a cohort of HH patients, archetype of hepcidin-deficiency and showed that liver transplantation cured the disease, demonstrating the major role of the liver in the phenotype. We then characterized iron overloads with high transferrin saturation related to abnormalities of iron transport: i) we reported a fifth case of patient with DMT1 gene mutations and demonstrated the pathogenicity of the mutation p.Asn491Ser; ii) we described 12 patients with heterozygous mutation of the TF gene, leading to serum transferrin decrease. The increase of transferrin saturation associated to the disease does not seem to be related to a hepcidin-deficiency, and the presence of cofactors may facilitate iron overload. We then described the impact of mutations in the TFR2 gene, which induce hepcidin-deficiency whose expression is heterogeneous but that can occur in young peoples. Then we tried to clarify in vitro the mechanisms linking mutations in the TFR2 gene to an abnormal decrease of hepcidin and showed that the p.Asn12Ile and p.Gly430Arg mutations alter the TFR2 protein intracellular trafficking while the p.Arg768Pro mutation alters its interaction with transferrin. Being unable to induce expression of hepcidin in response to transferrin, unlike some authors, but in agreement with others, we were not able to analyze the impact of mutations on signal transduction toward hepcidin. Our results help to clarify the mechanisms involved in the development of iron overload in rare high saturation of transferrin.RENNES1-Bibl. électronique (352382106) / SudocSudocFranceF

The importance of the general practitioner as an information source for patients with hereditary haemochromatosis

Objective To explore hereditary haemochromatosis (HH) patients’ perspectives on genetic information, namely the types of sources used, preferred or trusted. Methods A survey online was conducted by the European Federation of Associations of Patients with Haemochromatosis (EFAPH) and applied to members of nine National Associations. Results From a total of 1019 validated questionnaires, 895 respondents had performed a genetic testing for HH. From these, 627 self-declared that they were sufficiently informed about the implications of the genetic test to their health. The majority (66%) obtained the information from a specialist doctor, but would like to obtain it from the family doctor. However, the specialist was still the one they trusted more (69%). Regarding the 298 respondents who did not feel sufficiently informed, the majority (78%) also would like to have information from the family doctor although they also trusted the specialist more (75%). A different perspective was reported when patients were asked about the implications of the genetic testing to their family members, where the majority of respondents preferred obtaining information from a specialist (69%). Conclusion This study elucidates the patients’ needs for information and identifies the general practitioner (GP) as the preferred source to obtain information about HH. Practice implications These results may have important implications in future strategies for HH awareness, giving a special emphasis on GPs as the main players

Transcripts of ceruloplasmin but not hepcidin, both major iron metabolism genes, exhibit a decreasing pattern along portocentral axis of mouse liver

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Mouse genetic background impacts both on iron and non-iron metals parameters and on their relationships

International audienceIron is reported to interact with other metals. In addition, it has been shown that genetic background may impact iron metabolism. Our objective was to characterize, in mice of three genetic backgrounds, the links between iron and several non-iron metals. Thirty normal mice (C57BL/6, Balb/c and DBA/2; n = 10 for each group), fed with the same diet, were studied. Quantification of iron, zinc, cobalt, copper, manganese, magnesium and rubidium was performed by ICP/MS in plasma, erythrocytes, liver and spleen. Transferrin saturation was determined. Hepatic hepcidin1 mRNA level was evaluated by quantitative RT-PCR. As previously reported, iron parameters were modulated by genetic background with significantly higher values for plasma iron parameters and liver iron concentration in DBA/2 and Balb/c strains. Hepatic hepcidin1 mRNA level was lower in DBA/2 mice. No iron parameter was correlated with hepcidin1 mRNA levels. Principal component analysis of the data obtained for non-iron metals indicated that metals parameters stratified the mice according to their genetic background. Plasma and tissue metals parameters that are dependent or independent of genetic background were identified. Moreover, relationships were found between plasma and tissue content of iron and some other metals parameters. Our data: (i) confirms the impact of the genetic background on iron parameters, (ii) shows that genetic background may also play a role in the metabolism of non-iron metals, (iii) identifies links between iron and other metals parameters which may have implications in the understanding and, potentially, the modulation of iron metabolis

Quality of life scores differs between genotypic groups of patients with suspected hereditary hemochromatosis

Background: Hereditary hemochromatosis (HH) encompasses a group of autosomal recessive disorders mainly characterized by enhanced intestinal absorption of iron and its accumulation in parenchymal organs. HH diagnosis is based on iron biochemical and magnetic resonance imaging (MRI) assessment, and genetic testing. Questionnaires, such as SF-36 (short form health survey), have been increasingly used to assess the impact of diseases on the patient's quality of life (QL). In addition, different genotypes are identified as results of genetic tests in patients with suspected primary iron overload. In the present study, our aim was to evaluate whether domains of QL are different according to genotypic groups in patients suspected of HH. Methods: Seventy-nine patients with primary iron overload were included and two genotypic groups were formed (group 1: homozygous genotype for the HFE p.Cys282Tyr mutationgroup 2: other genotypes). Results: Group 1 had higher means of plasma transferrin saturation (86 +/- 19%) and serum ferritin (1669 +/- 1209 ng/mL) compared to group 2 (71 +/- 12%, 1252 +/- 750 ng/mL, respectivelyp = 0.001). Four domains were significantly different among groups 1 and 2: physical functioning (p = 0.03), bodily pain (p = 0.03), vitality (p = 0.02) and social functioning (p = 0.01). Conclusions: Our main finding was that patients with p. Cys282Tyr homozygosity had a worse QL scenario assessed by SF-36, compared with patients with iron overload without the same genotype. Being aware of this relationship between genotypes and QL might be helpful in the overall management of patients suspected of hereditary hemochromatosis.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) [2013/09295-3]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Brazil [2013/20614-3]Univ Sao Paulo, Heart Inst InCor, Lab Genet & Mol Cardiol, Med Sch, Av Doutor Eneas de Carvalho Aguiar 44, BR-05403900 Sao Paulo, SP, BrazilSanta Casa Med Sch, Hematol & Hemotherapy Sect, Sao Paulo, BrazilAcad Ciencia & Tecnol, Sao Jose Do Rio Preto, BrazilFundacao Pro Sangue, Hemoctr Sao Paulo, Sao Paulo, SP, BrazilUniv Sao Paulo, Sao Paulo, SP, BrazilUniv Sao Paulo, Med Sch, Hosp Clin, Hematol Serv, Sao Paulo, BrazilUniv Sao Paulo, Med Sch, Hosp Clin, Hematol & Hemotherapy Discipline, Sao Paulo, BrazilUniv Rennes, Pontchaillou Univ Hosp, Liver Dis Unit, Rennes, FranceNatl Reference Ctr Rare Iron Overload Dis Genet O, Rennes, FranceUniv Fed Sao Paulo UNIFESP, Dept Pharmacol, Sao Paulo, BrazilUniv Fed Sao Paulo UNIFESP, Dept Pharmacol, Sao Paulo, BrazilCAPES: 2013/09295-3FAPESP: 2013/20614-3Web of Scienc

Importance of optimal dosing ≥30 mg/kg/d during deferasirox treatment: 2.7-yr follow-up from the ESCALATOR study in patients with β-thalassaemia

Following 1-yr deferasirox therapy in the ESCALATOR study, 57% of previously chelated patients with β-thalassaemia achieved treatment success (maintenance of or reduction in liver iron concentration (LIC) vs. baseline LIC). Seventy-eight per cent had dose increases at median of 26 wk, suggesting that 1-yr results may not have reflected full deferasirox efficacy. Extension data are presented here. Deferasirox starting dose was 20 mg/kg/d (increases to 30/40 mg/kg/d permitted in the core/extension, respectively). Efficacy was primarily assessed by absolute change in LIC and serum ferritin. Overall, 231 patients received deferasirox in the extension; 67.4% (P < 0.0001) achieved treatment success. By the end of the extension, 66.2% of patients were receiving doses ≥30 mg/kg/d. By the end of the 1-yr extension, mean LIC had decreased by 6.6 ± 9.4 mg Fe/g dw (baseline 19.6 ± 9.2; P < 0.001) and median serum ferritin by 929 ng/mL (baseline 3356; P < 0.0001). There was a concomitant improvement in liver function markers (P < 0.0001). Fewer drug-related adverse events were reported in extension than core study (23.8% vs. 44.3%). Doses ≥30 mg/kg/d were generally required because of high transfusional iron intake and high baseline serum ferritin levels, highlighting the importance of administering an adequate dose to achieve net negative iron balance

Iron overload across the spectrum of non-transfusion-dependent thalassaemias: role of erythropoiesis, splenectomy and transfusions

Non-transfusion-dependent thalassaemias (NTDT) encompass a spectrum of anaemias rarely requiring blood transfusions. Increased iron absorption, driven by hepcidin suppression secondary to erythron expansion, initially causes intrahepatic iron overload. We examined iron metabolism biomarkers in 166 NTDT patients with β thalassaemia intermedia (n = 95), haemoglobin (Hb) E/β thalassaemia (n = 49) and Hb H syndromes (n = 22). Liver iron concentration (LIC), serum ferritin (SF), transferrin saturation (TfSat) and non-transferrin-bound iron (NTBI) were elevated and correlated across diagnostic subgroups. NTBI correlated with soluble transferrin receptor (sTfR), labile plasma iron (LPI) and nucleated red blood cells (NRBCs), with elevations generally confined to previously transfused patients. Splenectomised patients had higher NTBI, TfSat, NRBCs and SF relative to LIC, than non-splenectomised patients. LPI elevations were confined to patients with saturated transferrin. Erythron expansion biomarkers (sTfR, growth differentiation factor-15, NRBCs) correlated with each other and with iron overload biomarkers, particularly in Hb H patients. Plasma hepcidin was similar across subgroups, increased with >20 prior transfusions, and correlated inversely with TfSat, NTBI, LPI and NRBCs. Hepcidin/SF ratios were low, consistent with hepcidin suppression relative to iron overload. Increased NTBI and, by implication, risk of extra-hepatic iron distribution are more likely in previously transfused, splenectomised and iron-overloaded NTDT patients with TfSat >70%

Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype

Although guidelines are available for hereditary hemochromatosis, a high percentage of the recommendations within them are not shared between the different guidelines. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training. This final version was approved at the Hemochromatosis International meeting on 12th May 2017 in Los Angeles