Inherited iron overload disorders

Piperno, Alberto; Pelucchi, Sara; Mariani, Raffaella

doi:10.21037/tgh.2019.11.15

Cited by 89 publications

(83 citation statements)

References 190 publications

(252 reference statements)

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“…Iron homeostasis is strictly controlled at the cellular and systemic levels to provide the right amounts of iron needed for the vital biological functions of cells and tissues, avoiding iron overload and iron-related toxicity [ 29 ]. Iron trafficking is an example of a circular economy [ 30 ]; the human body’s daily iron requirement is around 20–25 mg, which is mainly used in erythropoiesis.…”

Section: Mechanisms Of Ferroptosismentioning

confidence: 99%

“…Iron trafficking is an example of a circular economy [ 30 ]; the human body’s daily iron requirement is around 20–25 mg, which is mainly used in erythropoiesis. A balanced diet provides about 14 mg of iron as inorganic or organic iron [ 29 ]. In an adult at a steady-state, 1–2 mg iron is absorbed daily in the gut and compensates for an equal loss (bleeding and desquamation).…”

Section: Mechanisms Of Ferroptosismentioning

confidence: 99%

“…Cells treated before with nutlin-3 and then with erastin show a delay in the onset of ferroptosis. Moreover, nutlin-3 upregulates CDKN1A mRNA and p21 protein in p53 +/+ cells, but not in p53 −/− cells [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. The p53/p21 axis delays the execution of ferroptosis by reducing the consumption of GSH, but it is not clear how p21 promotes GSH biosynthesis.…”

Section: Mechanisms Of Ferroptosismentioning

confidence: 99%

“…Clinicians set 13–15 mg of iron/g of liver tissue as a critical threshold, which is associated with an increased risk of cirrhosis. [ 29 ]. The type of liver damage depends on the nature and the severity of the lesion.…”

Section: Ferroptosis In Liver Diseasesmentioning

confidence: 99%

“…Drug-induced liver injury (DILI) is the predominant cause of acute liver diseases (ALD) in Europe and the USA, with acetaminophen as the paradigmatic example [ 55 ]. The exposure of hepatic tissue to acetaminophen leads to the hepatocyte cell death [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. Its transformation by cytochrome p450 provokes liver-toxicity through its reactive metabolite NAPQI ( N -acetyl-p-benzoquinone imine) [ 56 ].…”

Section: Ferroptosis In Liver Diseasesmentioning

confidence: 99%

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Ferroptosis in Liver Diseases: An Overview

Capelletti

Manceau

Puy

et al. 2020

IJMS

248

169

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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.

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Section: Mechanisms Of Ferroptosismentioning

confidence: 99%

Section: Mechanisms Of Ferroptosismentioning

confidence: 99%

Section: Mechanisms Of Ferroptosismentioning

confidence: 99%

Section: Ferroptosis In Liver Diseasesmentioning

confidence: 99%

Section: Ferroptosis In Liver Diseasesmentioning

confidence: 99%

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Ferroptosis in Liver Diseases: An Overview

Capelletti

Manceau

Puy

et al. 2020

IJMS

248

169

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Adolescent-Onset and Adult-Onset Vitamin-Responsive Neurogenetic Diseases

et al. 2021

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dolescent-onset and adult-onset neurogenetic diseases are a heterogeneous group of disabling conditions, with extremely diverse phenotypes, numerous genes involved, and for the most part, no specific treatments. However, some of these diseases can respond to specific vitamin supplementation. 1 Vitamins are essential micronutrients produced in insufficient quantities or not produced by humans, who nonetheless have all the cellular machinery to transform them into active forms: the enzyme cofactors.Vitamin supplementation is easily available, usually without adverse effects, and dramatically efficient, especially if given early in the course of these diseases. Therefore, rapid identification of vitamin-responsive diseases is crucial for neurologists. This review aims at clarifying the adolescent-onset and adult-onset phenotypes of vitamin-responsive neurogenetic diseases, which are often different from early-onset forms. We also suggest clinical situations in which specific diagnostic tests should be performed and/or vitamins should be administered as a therapeutic trial. MethodsThrough a review process, we identified 24 neurogenetic diseases, characterized by possible neurological symptoms that started after the age of 10 years and a clear response to vitamin supplemen-tation for at least a subset of patients. These diseases, involving vitamins A, B 1 , B 2 , B 3 , B 6 , B 8 , B 9 , B 12 , E, and tetrahydrobiopterin (BH 4 ) coenzyme, are listed in the eAppendix and eTable 1 in the Supplement, among all other genetic vitamin-responsive diseases. We chose this age threshold (referred in the text as adult-onset) since, in our experience, inherited metabolic diseases starting after the age of 10 years show phenotypes usually similar to those of patients with later onset and are often different from earlier-onset forms. [2][3][4] Despite that BH 4 is not properly a vitamin, it is an organic compound that acts similarly to vitamin-derived cofactors, 5 which explains why we considered BH 4 -associated conditions to be part of vitaminresponsive diseases. 6 Review Following our analysis of the literature, we divided the pathophysiology of vitamin-responsive diseases in 4 major groups: those with (1) impaired cofactor synthesis from the vitamins; (2) impaired transport (intestinal absorption, blood transport, or cellular uptake);(3) a defect of an enzyme that requires a vitamin-derived cofactor; and (4) a secondary vitamin defect (attributable to abnormalities that are not associated with a gene defect directly involved in vitamin metabolism). Figure 1 illustrates this for cobalamin (Cbl) metabolism.IMPORTANCE Vitamin-responsive inherited diseases are among the rare genetic disorders with a specific pharmacological treatment. Many of these conditions have a prominent neurological phenotype that is mainly reported in children. Being rare and often strikingly different in adult-onset forms, they are still poorly known in the medical fields specific to adults.OBSERVATION This article reviews all articles reporting cases of pat...

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Hepcidin Signaling in Health and Disease: Ironing Out the Details

Kowdley

Gochanour

Sundaram

et al. 2021

Hepatology Communications

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Hepcidin, a peptide hormone produced by hepatocytes, is the central regulator of systemic iron homeostasis through its interaction with ferroportin, the major cellular iron export protein. Hepcidin binding to ferroportin results in reduced iron export from macrophages and intestinal absorptive cells, leading to decreased serum iron levels. Hepcidin expression is influenced by several factors that include serum and liver iron stores, erythropoiesis, hypoxia, inflammation, and infection. Erythropoietic drive and hypoxia suppress hepcidin expression and promote red cell production. In contrast, inflammation and infection are associated with increased hepcidin production to sequester iron intracellularly as a means of depriving microorganisms of iron. Chronic inflammation may up-regulate hepcidin expression through the interleukin-6 (IL-6)-Janus kinase 2 ( JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway. The bone morphogenetic protein (BMP)-mothers against decapentaplegic homolog (SMAD) pathway is a major positive driver of hepcidin expression in response to either increased circulating iron in the form of transferrin or iron loading in organs. Hereditary hemochromatosis (HH) consists of several inherited disorders that cause inappropriately reduced hepcidin expression in response to body iron stores, leading to increased iron absorption from a normal diet. The most common form of HH is due to a mutation in the HFE gene, which causes a failure in the hepatocyte iron-sensing mechanism, leading to reduced hepcidin expression; the clinical manifestations of HFE-HH include increased serum transferrin-iron saturation and progressive iron loading in the liver and other tissues over time among patients who express the disease phenotype. In this article, we review the physiologic mechanisms and cellular pathways by which hepcidin expression is regulated, and the different forms of HH resulting from various mutations that cause hepcidin deficiency. We also review other drivers of hepcidin expression and the associated pathophysiologic consequences. (Hepatology Communications 2021;0:1-13). Regulation of Systemic Iron StoresIron metabolism is tightly regulated to maintain a balance between availability of a sufficient quantity of this metal to maintain vital cellular processes and the risk of iron-related tissue toxicity. This balance is maintained through control of iron absorption in the intestine, storage and release from intracellular compartments in hepatocytes and reticuloendothelial system (RES) cells, as well as iron utilization by mitochondria. (1,2) Dietary iron is absorbed in the proximal duodenum (Fig.

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Inherited iron overload disorders

Cited by 89 publications

References 190 publications

Ferroptosis in Liver Diseases: An Overview

Ferroptosis in Liver Diseases: An Overview

Adolescent-Onset and Adult-Onset Vitamin-Responsive Neurogenetic Diseases

Hepcidin Signaling in Health and Disease: Ironing Out the Details

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