1,003 results on '"Hyperferritinemia"'
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1002. Differentiation of hyperferritinemia by non-invasive iron quantification and novel molecular mechanisms of iron storage in ferroportin disease
- Abstract
Hintergrund und Ziele: Die Hyperferritinämie ist ein unspezifischer Befund, der häufig im Zusammenhang mit Eisenüberladung, Entzündung und Zelltod auftritt. Eins der Ziele dieser Arbeit war es, einen diagnostischen Algorithmus zur Differentialdiagnose von Patienten mit hohem Serumferritin zu etablieren, der auf klinischen, biochemischen, genetischen und radiologischen Studien basiert. Über 80% der Patienten mit Hämochromatose zeigen eine Homozygotie für die C282Y-Variante in HFE. Rezente Studien haben gezeigt, dass pathogene Varianten in HAMP, HJV, HFE, TFR2 oder SLC40A1 nur bei einer Minderheit der Patienten mit klinisch vermuteter non-HFE-Hämochromatose vorhanden sind. Ein weiteres Ziel dieser Arbeit war es, die Landschaft und Häufigkeit von Mutationen in Hämochromatose-Genen zu beschreiben und festzustellen, ob die Patientenauswahl durch nicht-invasive Eisenquantifizierung mit R2* Magnetresonanztomographie (MRT) den positiven Vorhersagewert der Next-Generation-Sequenzierung (NGS) verbessert. Da das Zusammentreffen von Eisen und Fett in der Leber die R2* Werte beeinflussen kann, haben wir die Fettsättigungs- (FS) und nicht-FS-MRT-Methoden verglichen. Die Ferroportin-Erkrankung (FE) ist eine autosomal-dominante Störung, die mit Varianten des Funktionsverlusts im Ferroportin-kodierenden Gen SLC40A1 assoziiert ist. Die Pathogenese der systemischen Eisenüberladung im Rahmen eines verringerten zellulären Eisenexports bleibt jedoch unklar. Im zweiten Teil dieser Arbeit führten wir umfassende in vitro Experimente zu R178Q und Kontrollvarianten im Ferroportin durch und untersuchten ein neues Konzept, bei dem ein verringerter zellulärer Eisenexport auch mit einer Hepcidinresistenz zusammenhängen könnte. Methoden: Eine Kohorte von 410 Leberklinikpatienten mit hohem Serumferritin (definiert als ≥ 200 μg/L für Frauen und ≥ 300 μg/L für Männer) wurde mittels HFE-Genotypisierung und abdominaler R2* MRT zur Eisenquantifizierung untersucht. In einer Untergruppe ausgewählter Patie, Background and aims: Hyperferritinemia is a non-specific finding commonly present in association with iron overload, inflammation and cell death. Here, we set out to establish a diagnostic algorithm based on clinical, biochemical, genetic and radiological studies for evaluation of patients with high serum ferritin. Over 80% of patients with hemochromatosis are homozygous for the C282Y variant in HFE. Recent studies have shown that pathogenic variants in HAMP, HJV, HFE, TFR2 or SLC40A1 are present in only a minority of patients with clinically suspected non-HFE hemochromatosis. Another aim of this thesis was to describe the landscape and frequency of mutations in hemochromatosis genes and determine if patient selection by non-invasive iron quantification with R2* magnetic resonance imaging (MRI) improves the positive predictive value of next-generation sequencing (NGS). As coincidence of iron and fat in the liver can influence R2* values, we compared fat-saturation (FS) and non-FS MRI methods. Ferroportin disease (FD) is an autosomal dominant disorder associated with “loss of function” variants in the ferroportin encoding gene SLC40A1. The pathogenesis of systemic iron overload in a context of reduced cellular iron export remains unclear. In the second part of this thesis, we carried out in vitro studies on R178Q mutant ferroportin and explored a novel molecular disease mechanism of FD, where reduced cellular iron export might be also associated with hepcidin resistance. Methods: A cohort of 410 unselected liver clinic patients with high serum ferritin (defined as ≥200 μg/L for women and ≥300 μg/L for men) was investigated by HFE genotyping and abdominal R2* MRI for iron quantification. Evaluation for non-HFE hemochromatosis was carried out by NGS in a subgroup of selected patients. Furthermore, in order to compare two different R2* MRI methods with or without FS, 134 liver clinic patients with suspected iron overload were included in a prospective study where linear, Abweichender Titel laut Übersetzung der Verfasserin/des Verfassers, Kumulative Dissertation aus zwei Artikeln, Dissertation Medical University of Innsbruck 2020
1003. Inherited disorders of iron metabolism
- Author
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Manuela Födinger and Gere Sunder-Plassmann
- Subjects
Male ,Porphyria Cutanea Tarda ,heredity ,Iron ,African iron overload ,sideroblastic anemias ,Biology ,porphyria ,Cataract ,End stage renal disease ,Mice ,HLA Antigens ,Iron-Binding Proteins ,hyperferritinemia ,medicine ,Genetic predisposition ,microcytic anemia ,Animals ,Humans ,genetics ,idiopathic hemochromatosis ,Hemochromatosis Protein ,Cation Transport Proteins ,Hemochromatosis ,Metal Metabolism, Inborn Errors ,Genetics ,end-stage renal disease ,Metal metabolism ,Histocompatibility Antigens Class I ,Membrane Proteins ,Anemia ,Porphyria, Hepatoerythropoietic ,Iron-binding proteins ,Syndrome ,medicine.disease ,Founder Effect ,Porphyria ,Haplotypes ,Nephrology ,Hereditary hemochromatosis ,Ferritins ,Mutation ,Kidney Failure, Chronic ,Female ,Carrier Proteins ,Ferrochelatase - Abstract
Inherited disorders of iron metabolism. Recent molecular studies have resulted in the identification of genetic alterations underlying hereditary disorders of iron metabolism. One example is the discovery of the HFE gene that is mutated in patients suffering from hereditary hemochromatosis. This autosomal recessive disorder has an estimated carrier frequency that varies between 0.07 and 0.13, thus representing one of the most common genetically determined metabolic disorders. The identification of the hemochromatosis mutations has encouraged efforts to investigate other conditions with iron overload for a putative interaction with these genetic variants. Few data are already available suggesting, for example, that iron overload in patients with sporadic porphyria cutanea tarda is associated with mutations in the hereditary hemochromatosis gene. However, it is obvious that disorders of iron metabolism have a multifactorial pathogenesis, including environmental and genetic factors. Thus, many questions remain to be answered about whether a genetic predisposition exists for development of various iron-loading or iron-deficiency phenotypes. This review focuses on the most recent advances in the field of hereditary disorders of iron metabolism and discusses their potential implications for nephrologists.
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