Impact of natural neuromedin‐B receptor variants on iron metabolism

Rametta, Raffaela; Dongiovanni, Paola; Baselli, Guido; Pelusi, Serena; Meroni, Marica; Busti, Fabiana; Castagna, Annalisa; Scarlini, Stefania; Corradini, Elena; Pietrangelo, Antonello; Girelli, Domenico; Valenti, Luca

doi:10.1002/ajh.25679

Cited by 9 publications

(4 citation statements)

References 48 publications

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“…Essentially there are 2 reasons: Some show a “digenic” inheritance, deriving from the combination of pathogenic variants in 2 different genes involved in iron metabolism (eg, single p.Cys282Tyr + heterozygous variants in HJV , HAMP , or TFR2 ). 90 , 92 , 93 , 94 , 95 Although there are still only few cases reported, digenic inheritance must also be considered in cases whose HFE genotype per se does not fully explain the clinical picture, for example, in patients with p.Cys282Tyr homozygosity and very early/severe IO. Others do not display variants in any of the 5 classical hemochromatosis genes (ie, HFE, HAMP , HJV , TFR2 , and SLC40A1 ).…”

Section: The Former Classifications: Strengths and Shortcomingsmentioning

confidence: 99%

Hemochromatosis classification: update and recommendations by the BIOIRON Society

Girelli

Busti

Brissot

et al. 2022

Blood

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Hemochromatosis (HC) is a genetically heterogeneous disorder in which uncontrolled intestinal iron absorption may lead to progressive iron overload responsible for disabling and life-threatening complications such as arthritis, diabetes, heart failure, hepatic cirrhosis, and hepatocellular carcinoma. The recent advances in the knowledge of pathophysiology and molecular basis of iron metabolism have highlighted that HC is caused by mutations in at least five genes, resulting in insufficient hepcidin production or, rarely, resistance to hepcidin action. This has led to an HC classification based on different molecular subtypes, mainly reflecting successive gene discovery. This scheme was difficult to adopt in clinical practice and therefore needs revision. Here we present recommendations for unambiguous HC classification developed by a working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) including both clinicians and basic scientists during a meeting in Heidelberg, Germany. We propose to deemphasize the use of the molecular subtype criteria in favor of a classification addressing both clinical issues and molecular complexity. Ferroportin Disease (former type 4a) has been excluded because of its distinct phenotype. The novel classification aims to be of practical help whenever a detailed molecular characterization of HC is not readily available.

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Section: The Former Classifications: Strengths and Shortcomingsmentioning

confidence: 99%

Hemochromatosis classification: update and recommendations by the BIOIRON Society

Girelli

Busti

Brissot

et al. 2022

Blood

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“…• Male sex 4,7,30 • Heterozygous presence of the HFE p.C282Y pathogenic variant or homozygous presence of the p.H63D variant or, in particular, compound heterozygosity for p.C282Y/p.H63D variants 7,30,101 • PCSK7 variants 102 • Absence of TMPRSS6 p.A736V variant 37,103 • Heterozygous presence of SERPINA1 PiZ and PiS pathogenic variants 104 • Heterozygous pathogenic variants of β-globin gene (HBB), that is, β-thalassaemia trait 18 • Rare NMBR variants 105 • Heterozygous pathogenic variants of the gene that encodes ceruloplasmin 31…”

Section: Geneticmentioning

confidence: 99%

Consensus Statement on the definition and classification of metabolic hyperferritinaemia

et al. 2023

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Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes. Sections MethodologyGiven the high prevalence of hyperferritinaemia in clinical practice, combined with a growing understanding of the underlying pathophysiology and clinical implications, an updated definition and grading system is warranted. The overall goal of this Consensus Statement was therefore to provide a proposal for a more accurate diagnosis and classification of MHF, to be validated by prospective studies, to provide suggestions on the design of these studies and to highlight some of the main unmet research needs in the field. Owing to the current absence of robust evidence to support the recommendation to screen for and diagnose MHF and then to treat this condition with a specific approach (such as iron depletion), the current Consensus Statement is mainly directed at clinicians who work in tertiary referral centres and clinical and basic researchers. The updated MHF definition will enable larger collaborative studies on the clinical implications, pathophysiology and therapy of this condition, although it will still require prospective validation and further refinement. The long-term goal is the improvement of clinical management of patients with MHF. On the basis of current evidence, we also provide expert recommendations for clinicians on the diagnosis, management, follow-up and treatment of this condition (presented in the Supplementary material).Consensus was reached by a multidisciplinary global panel of expert researchers with an interest in MHF from five continents and 14 countries working in the fields of iron metabolism, clinical endocrinology, ...

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“…In the hypoxic intestinal environment, HIF-2alpha plays a crucial role in regulating iron absorption by affecting the DMT1 gene ( 123 ). Abnormal iron-induced hepcidin release, influenced by natural genetic variants may enhance iron absorption ( 124 ). Additionally, excess free fatty acids (FFAs) disrupt hepatic iron metabolism, encouraging iron uptake via IRP1 and TfR-1 ( 125 ).…”

Section: Minerals and Mafldmentioning

confidence: 99%

Exploring the interactions between metabolic dysfunction-associated fatty liver disease and micronutrients: from molecular mechanisms to clinical applications

Liu,

Qin,

Chen

et al. 2024

Front. Nutr.

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Metabolic (dysfunction)-associated fatty liver disease (MAFLD) has emerged as a significant global health concern, representing a major cause of liver disease worldwide. This condition spans a spectrum of histopathologic stages, beginning with simple fatty liver (MAFL), characterized by over 5% fat accumulation, and advancing to metabolic (dysfunction)-associated steatohepatitis, potentially leading to hepatocellular carcinoma. Despite extensive research, there remains a substantial gap in effective therapeutic interventions. This condition’s progression is closely tied to micronutrient levels, crucial for biological functions like antioxidant activities and immune efficiency. The levels of these micronutrients exhibit considerable variability among individuals with MAFLD. Moreover, the extent of deficiency in these nutrients can vary significantly throughout the different stages of MAFLD, with disease progression potentially exacerbating these deficiencies. This review focuses on the role of micronutrients, particularly vitamins A, D, E, and minerals like iron, copper, selenium, and zinc, in MAFLD’s pathophysiology. It highlights how alterations in the homeostasis of these micronutrients are intricately linked to the pathophysiological processes of MAFLD. Concurrently, this review endeavors to harness the existing evidence to propose novel therapeutic strategies targeting these vitamins and minerals in MAFLD management and offers new insights into disease mechanisms and treatment opportunities in MAFLD.

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Impact of natural neuromedin‐B receptor variants on iron metabolism

Cited by 9 publications

References 48 publications

Hemochromatosis classification: update and recommendations by the BIOIRON Society

Hemochromatosis classification: update and recommendations by the BIOIRON Society

Consensus Statement on the definition and classification of metabolic hyperferritinaemia

Exploring the interactions between metabolic dysfunction-associated fatty liver disease and micronutrients: from molecular mechanisms to clinical applications

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