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Evaluation of the main regulators of systemic iron homeostasis in pyruvate kinase deficiency.

ABSTRACT: Iron homeostasis and dyserythropoiesis are poorly investigated in pyruvate kinase deficiency (PKD), the most common glycolytic defect of erythrocytes. Herein, we studied the main regulators of iron balance and erythropoiesis, as soluble transferrin receptor (sTfR), hepcidin, erythroferrone (ERFE), and erythropoietin (EPO), in a cohort of 41 PKD patients, compared with 42 affected by congenital dyserythropoietic anemia type II (CDAII) and 50 with hereditary spherocytosis (HS). PKD patients showed intermediate values of hepcidin and ERFE between CDAII and HS, and clear negative correlations between log-transformed hepcidin and log-EPO (Person's r correlation coefficient = - 0.34), log-hepcidin and log-ERFE (r = - 0.47), and log-hepcidin and sTfR (r = - 0.44). sTfR was significantly higher in PKD; EPO levels were similar in PKD and CDAII, both higher than in HS. Finally, genotype-phenotype correlation in PKD showed that more severe patients, carrying non-missense/non-missense genotypes, had lower hepcidin and increased ERFE, EPO, and sTFR compared with the others (missense/missense and missense/non-missense), suggesting a higher rate of ineffective erythropoiesis. We herein investigated the main regulators of systemic iron homeostasis in the largest cohort of PKD patients described so far, opening new perspectives on the molecular basis and therapeutic approaches of this disease.

SUBMITTER: Zaninoni A

PROVIDER: S-EPMC10020532 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Evaluation of the main regulators of systemic iron homeostasis in pyruvate kinase deficiency.

Zaninoni Anna A Marra Roberta R Fermo Elisa E Consonni Dario D Andolfo Immacolata I Marcello Anna Paola AP Rosato Barbara Eleni BE Vercellati Cristina C Barcellini Wilma W Iolascon Achille A Bianchi Paola P Russo Roberta R

Scientific reports 20230316 1

Iron homeostasis and dyserythropoiesis are poorly investigated in pyruvate kinase deficiency (PKD), the most common glycolytic defect of erythrocytes. Herein, we studied the main regulators of iron balance and erythropoiesis, as soluble transferrin receptor (sTfR), hepcidin, erythroferrone (ERFE), and erythropoietin (EPO), in a cohort of 41 PKD patients, compared with 42 affected by congenital dyserythropoietic anemia type II (CDAII) and 50 with hereditary spherocytosis (HS). PKD patients showed ...[more]

PMID: 36927785

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Project description:BackgroundIron is essential for all mammalian life, and either a deficiency or excess of iron can cause diseases. AMP-activated protein kinase (AMPK) is a critical regulator of metabolic homeostasis; however, it has not been established whether AMPK regulates iron metabolism.MethodsIron, hepcidin and ferroportin levels were examined in mice with global and hepatocyte-specific knockout of AMPKα1 and AMPKα2. Primary AMPKα1 or AMPKα2 deleted hepatocytes were isolated and cultured in hypoxia condition to explore PHD2, HIF and hydroxylated HIF1α levels. We performed immunoprecipitation, in vitro AMPK kinase assay and site-direct mutant assay to detect phosphorylation sites of PHD2. We also obtained liver tissues from patients with anaemia of chronic disease undergoing surgery, AMPKα1 and hydroxylated HIF1α levels were measured by immunohistochemical analysis.ResultsWe found that mice with global deficiency of AMPKα1, but not AMPKα2, exhibited hypoferraemia as well as iron sequestration in the spleen and liver. Hepatocyte-specific, but not myeloid-specific, ablation of AMPKα1 also reduced serum iron levels in association with increased hepcidin and decreased ferroportin protein levels. Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling. Inhibition of PHD2 hydroxylation ameliorated abnormal iron metabolism in hepatic AMPKα1-deficient mice. Furthermore, we found hepatic AMPKα/PHD2/HIFα/ hepcidin axes were highly clinically relevant to anaemia of chronic disease.ConclusionIn conclusion, these observations suggest that hepatic AMPKα1 has an essential role in maintaining iron homeostasis by PHD2-dependent regulation of hepcidin, thus providing a potentially promising approach for the treatment of iron disturbances in chronic diseases.

Project description:BackgroundPyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic hemolytic anemia and serious sequalae which negatively affect patient quality of life. This study aimed to psychometrically validate the first disease-specific patient-reported outcome (PRO) instruments: the 7-item PK Deficiency Diary (PKDD) and 12-item PK Deficiency Impact Assessment (PKDIA), designed to assess signs, symptoms, and impacts of PK deficiency in patients enrolled in the ACTIVATE global phase 3 study of mitapivat versus placebo (NCT03548220).MethodsAll validation analyses for the PKDD and PKDIA were performed on blinded data, with analyses on item integrity, scoring, reliability, and validity conducted on data from screening and baseline. Completion rates and baseline response distributions were characterized using descriptive statistics. Item response modelling was used to inform a weighted scoring system. Reliability was assessed by internal consistency and test-retest reliability; and validity by convergent and known-groups analyses.ResultsOf the 80 adults enrolled, baseline data were available for 77 (96.3%) and 78 (97.5%) patients for the PKDD and PKDIA, respectively. Item responses skewed right, indicating that mean values exceeded median values, especially for items utilizing a 0-10 numeric scale, which were subsequently recoded to a 0-4 scale; 4 items were removed from the PKDIA due to redundancy or low relevance to the trial population. Both the PKDD and PKDIA demonstrated high internal consistency (McDonald's coefficient ω = 0.86 and 0.90, respectively), test-retest reliability (intra-class coefficients of 0.94 and 0.87, respectively), and convergent validity with other PROs (linear correlation coefficients [|r|] between 0.30-0.73 and 0.50-0.82, respectively).ConclusionsThe findings provide evidence of validity and reliability for the PKDD and PKDIA, the first disease-specific PRO measures for PK deficiency, and can therefore increase understanding of, and more accurately capture, the wider impact of PK deficiency on health-related quality of life. Trial registration ClinicalTrials.gov, NCT03548220. Registered June 07, 2018; https://www.Clinicaltrialsgov/ct2/show/NCT03548220 .

Dataset Information

Evaluation of the main regulators of systemic iron homeostasis in pyruvate kinase deficiency.

Publications

Evaluation of the main regulators of systemic iron homeostasis in pyruvate kinase deficiency.

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