• Ferroportin disease
• Hepcidin
• MFS transporters
• Pathogenicity of missense variants
• SLC40A1-related hemochromatosis

• Female
• Humans
• Male
• Cation Transport Proteins/genetics
• Cation Transport Proteins/metabolism
• Cation Transport Proteins/chemistry
• Gain of Function Mutation
• Hemochromatosis/genetics
• Hemochromatosis/metabolism
• Hepcidins/genetics
• Hepcidins/metabolism
• Iron/metabolism
• Loss of Function Mutation
• Mutation, Missense
• Phenotype

• Humans
• Iron/metabolism

• Cartilage damage
• Hemochromatosis-associated arthropathy
• Iron overload
• Macrophages
• Mechanism

• Animals
• Rats
• Ferrocyanides
• Ferrozine
• Hemochromatosis/metabolism
• Hemochromatosis/pathology
• Interleukin-6
• Iron
• Iron Overload
• Mechanistic Target of Rapamycin Complex 1
• Osteoarthritis/metabolism
• Osteoarthritis/pathology
• Ribosomal Protein S6 Kinases, 70-kDa/metabolism
• Tumor Necrosis Factor-alpha

• nutrition
• mechanisms of disease

• Ferroportin
• Hepcidin
• Interleukin-6
• Non-transferrin bound iron
• Nutritional immunity

• Animals
• Hepcidins
• Inflammation
• Iron

• haemochromatosis
• hyperferritinaemia
• iron chelation
• juvenile haemochromatosis
• phlebotomy

• Adult
• Humans
• Child
• Hemochromatosis/diagnosis
• Hemochromatosis/genetics
• Hemochromatosis/therapy
• Retrospective Studies
• Hemochromatosis Protein/genetics
• Mutation
• Ferritins
• Histocompatibility Antigens Class I/genetics
• Iron Overload/genetics

• Humans
• Hep G2 Cells
• Reactive Oxygen Species/metabolism
• Iron Overload/metabolism
• Iron/metabolism

• Adult
• Male
• Humans
• Female
• Adolescent
• Hemochromatosis/complications
• Hemochromatosis/therapy
• Hepcidins/metabolism
• Adenocarcinoma/complications
• Ferritins
• Pancreatic Neoplasms/complications
• Iron Overload/drug therapy
• Iron Overload/etiology
• Iron/therapeutic use
• Iron/metabolism
• Transferrins
• Hemochromatosis Protein/metabolism

• COVID-19
• Deferoxamine
• Diabetes
• Ferritin
• Inflammatory response
• Iron overload

• Humans
• Hemochromatosis/diagnosis
• Hemochromatosis/genetics
• Hemochromatosis/therapy
• Iron Overload/diagnosis
• Iron Overload/etiology
• Iron Overload/therapy
• Liver Cirrhosis/complications
• Phlebotomy/adverse effects
• Genetic Testing

• COVID-19
• Fe-R-H regulators
• ferroptosis inhibitors
• host metabolic reprogramming (HMR)
• iron chelators
• iron-redox homeostasis (Fe-R-H)

• Humans
• Iron/metabolism
• Ferroptosis/physiology
• Anticoagulants/pharmacology
• Anticoagulants/therapeutic use
• COVID-19
• SARS-CoV-2/metabolism
• Oxidation-Reduction
• Iron Chelating Agents
• Iron Overload/drug therapy
• Homeostasis
• Cytokines/metabolism

Even in patients without a history of liver disease, liver injury caused by coronavirus disease 2019 (COVID-19) is gradually becoming more common. However, the precise pathophysiological mechanisms behind COVID-19's liver pathogenicity are still not fully understood. We hypothesize that inflammation may become worse by cytokine storms caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Elevated ferritin levels can initiate ferritinophagy mediated by nuclear receptor coactivator 4 (NCOA4), which leads to iron elevation, and ferroptosis. In COVID-19 patients, ferroptosis can be restricted to reduce disease severity and liver damage by targeting NCOA4-mediated ferritinophagy. To confirm the role of ferritinophagy-mediated ferroptosis in SARS-CoV-2 infection, further research is required.

• COVID-19
• Liver injury
• Ferritinophagy
• Ferroptosis
• Iron
• SARS-CoV-2

• Copper
• Ferroptosis
• Iron
• Mineral
• Non-alcoholic fatty liver disease
• Non-alcoholic steatohepatitis

• diagnosis
• hemochromatosis
• management
• testing
• transferrin
• venesection

• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/therapy
• Female
• Ferritins
• Fibrosis
• Hemochromatosis/diagnosis
• Hemochromatosis/genetics
• Hemochromatosis/therapy
• Hemochromatosis Protein/genetics
• Humans
• Iron
• Iron Overload/diagnosis
• Iron Overload/etiology
• Iron Overload/therapy
• Liver Cirrhosis/complications
• Liver Neoplasms/diagnosis
• Liver Neoplasms/etiology
• Liver Neoplasms/therapy
• Male
• Transferrin/analysis

• ferritin
• hereditary haemochromatosis
• non‐transferrin bound iron
• phlebotomy
• transferrin saturation

• Ferroptosis
• Non-alcoholic fatty liver disease
• Oxidative stress
• Therapy target

• Ferroptosis
• Humans
• Iron/metabolism
• Liver/metabolism
• Non-alcoholic Fatty Liver Disease/metabolism
• Oxidative Stress/physiology
• Reactive Oxygen Species/metabolism

Iron overload is a severe general complication of hereditary anemias. Treatment with iron chelators is hampered by important side‐effects, high costs, and the lack of availability in many countries with a high prevalence of hereditary anemias. In this phase III randomized placebo‐controlled trial, we assigned adults with non‐transfusion‐dependent hereditary anemias with mild‐to‐moderate iron overload to receive esomeprazole (at a dose of 40 mg twice daily) or placebo for 12 months in a cross‐over design. The primary end point was change of liver iron content measured by MRI. A total of 30 participants were enrolled in the trial. Treatment with esomeprazole resulted in a statistically significant reduction in liver iron content that was 0.55 mg Fe/g dw larger than after treatment with placebo (95%CI [0.05 to 1.06]; p = 0.03). Median baseline liver iron content at the start of esomeprazole was 4.99 versus 4.49 mg Fe/g dw at start of placebo. Mean delta liver iron content after esomeprazole treatment was −0.57 (SD 1.20) versus −0.11 mg Fe/g dw (SD 0.75) after placebo treatment. Esomeprazole was well tolerated, reported adverse events were mild and none of the patients withdrew from the study due to side effects. In summary, esomeprazole resulted in a significant reduction in liver iron content when compared to placebo in a heterogeneous group of patients with non‐transfusion‐dependent hereditary anemias. From an international perspective this result can have major implications given the fact that proton pump inhibitors may frequently be the only realistic therapy for many patients without access to or not tolerating iron chelators.

Coronavirus disease 2019 (COVID-19) is a global pandemic that has caused widespread loss of life. Notably, in this disease, severe inflammatory reactions characterized by cytokine storms are caused by severe acute respiratory syndrome coronavirus 2. The cytokine storms may promote hyper-ferritinemia which can further intensify the inflammation. Moreover, elevated ferritin levels trigger nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, in which ferritin is degraded and iron is released. Excess iron released from ferritinophagy can promote ferroptosis and cellular damage. Therefore, we propose that NCOA4-mediated ferritinophagy can be targeted to limit the ferroptosis and prevent the multi-organ damage and severity in COVID-19 patients.

• COVID-19
• NCOA4
• ferritinophagy
• hyperferritinemia
• iron

For the maintenance treatment of patients with hereditary hemochromatosis (HH), it is advised to keep the transferrin saturation (TSAT) <70% to prevent formation of non‐transferrin‐bound iron and labile plasma iron. The period of the initial iron depletion may last up to 1 year or longer and during this period, the patient is exposed to elevated TSAT levels. Therapeutic erythrocytapheresis (TE) is a modality which has proven to reduce treatment duration of patients with iron overload from HH. In this study, we investigated the time to reach TSAT <70% for both treatment modalities.

From a previous randomized controlled trial comparing erythrocytaphereses with phlebotomies (PBMs), we performed an analysis in a subgroup of patients who presented with TSAT >70%. Mann‐Whitney U tests were performed to compare the number of treatments and the number of weeks to reach the interim goal of a persistent level of <70% for TSAT between TE and PBM.

The period to reach TSAT levels of <70% was statistically significant shorter for the TE group compared to the PBM treatment group (median treatment procedures [IQR] 2.0 (5) vs 16.0 (23), P‐value: <.001, and median treatment duration [IQR]: 5.5 (11) vs 19.0 (29) weeks, P‐value: .007).

Patients with HH reach a safe TSAT <70% significantly sooner and with less treatment procedures with TE compared to PBM.

• hereditary hemochromatosis
• phlebotomy
• therapeutic erythrocytapheresis
• transferrin saturation

• glycerolipid
• glycerophospholipid
• iron overload
• lipidomics
• liver injury
• oxidative stress
• sphingolipid

Secondary iron overload is increasingly encountered in chronic kidney disease (CKD) patients because of the frequent use of parenteral iron products, especially in hemodialysis patients. Serum ferritin has been commonly used to monitor iron overload in these patients; however, other conditions can be associated with the high serum ferritin, like infections and inflammatory conditions. Currently, T2*MRI of the heart and liver is the preferred investigation for evaluating liver iron concentration (LIC) and cardiac iron concentration, which reflect the state of iron overload. Few studies observe a positive correlation between serum iron and LIC in CKD patients and postulate that serum ferritin exceeding 290 mcg/L should indicate significant iron overload and necessitates further MRI evaluation. However, here, we present a patient with a history of ESRD for which she underwent renal transplantation twice referred to our clinic due to persistent elevation in serum ferritin level (>1000 mcg/L) for several years. T2*MRI of the heart and liver revealed the absence of iron overload. Our objective of this case is to demonstrate the accuracy of T2*MRI over serum ferritin in evaluating iron overload and questioning the positive correlation between serum ferritin and LIC in CKD patients.

• T2*MRI
• chronic kidney disease
• liver iron concentration
• secondary iron overload
• serum ferritin

Iron overload disorders represent an important class of human diseases. Of the primary iron overload conditions, by far the most common and best studied is HFE-related hemochromatosis, which results from homozygosity for a mutation leading to the C282Y substitution in the HFE protein. This disease is characterized by reduced expression of the iron-regulatory hormone hepcidin, leading to increased dietary iron absorption and iron deposition in multiple tissues including the liver, pancreas, joints, heart and pituitary. The phenotype of HFE-related hemochromatosis is quite variable, with some individuals showing little or no evidence of increased body iron, yet others showing severe iron loading, tissue damage and clinical sequelae. The majority of genetically predisposed individuals show at least some evidence of iron loading (increased transferrin saturation and serum ferritin), but a minority show clinical symptoms and severe consequences are rare. Thus, the disorder has a high biochemical penetrance, but a low clinical prevalence. Nevertheless, it is such a common condition in Caucasian populations (1:100–200) that it remains an important clinical entity. The phenotypic variability can largely be explained by a range of environmental, genetic and physiological factors. Men are far more likely to manifest significant disease than women, with the latter losing iron through menstrual blood loss and childbirth. Other forms of blood loss, immune system influences, the amount of bioavailable iron in the diet and lifestyle factors such as high alcohol intake can also contribute to iron loading and disease expression. Polymorphisms in a range of genes have been linked to variations in body iron levels, both in the general population and in hemochromatosis. Some of the genes identified play well known roles in iron homeostasis, yet others are novel. Other factors, including both co-morbidities and genetic polymorphisms, do not affect iron levels per se, but determine the propensity for tissue pathology.

• HFE
• Hemochromatosis
• environmental modifiers
• genetic modifiers
• iron overload

• Animals
• Carbon Tetrachloride Poisoning/drug therapy
• Carbon Tetrachloride Poisoning/metabolism
• Carbon Tetrachloride Poisoning/pathology
• Cation Transport Proteins/deficiency
• Cation Transport Proteins/genetics
• Cyclohexylamines/pharmacology
• Cytokines/analysis
• Erythropoiesis/physiology
• Erythropoietin/analysis
• Female
• Ferroptosis/drug effects
• Ferroptosis/physiology
• Hepatocytes/metabolism
• Homeostasis
• Iron/metabolism
• Iron Overload/complications
• Iron, Dietary/toxicity
• Lipid Peroxidation
• Liver/metabolism
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle Proteins/analysis
• Phenylenediamines/pharmacology
• Transferrin/analysis
• Transferrin/physiology

Major advances in the understanding of genetic iron overload have led to a clarification of the nosology and terminology of the related diseases. The term hemochromatosis should be reserved to the entities where iron overload is related to hepcidin deficiency or hepcidin resistance. The diagnosis of hemochromatosis is non-invasive, based on clinical examination, blood investigations and, whenever possible, magnetic resonance imaging. Phlebotomies remain the mainstay of the treatment, but new therapeutic approaches should, in the future, constitute a valuable advance, hopefully both as an adjunct to bleeding in the induction phase and as its replacement in the maintenance phase. The goal of the present review is to update the terminology of hemochromatosis in light of major pathophysiological advances, and the main features of its diagnostic and therapeutic approaches.

• HFE
• ferroportin
• hemojuvelin
• hepcidin
• iron overload
• non-transferrin bound iron
• transferrin receptor 2

• Adult-onset Still’s disease
• Anti-viral
• COVID-19
• Catastrophic antiphospholipid syndrome
• Deferoxamine
• Hemophagocytic lymphohistiocytosis
• Hyperferritinemic
• Iron
• Iron depletion therapy
• Macrophage activation syndrome
• SARS-CoV-2

• Betacoronavirus/metabolism
• COVID-19
• Coronavirus Infections/blood
• Coronavirus Infections/drug therapy
• Coronavirus Infections/epidemiology
• Ferritins/blood
• Humans
• Iron/blood
• Iron Chelating Agents/therapeutic use
• Iron Overload/blood
• Iron Overload/drug therapy
• Iron Overload/epidemiology
• Pandemics
• Pneumonia, Viral/blood
• Pneumonia, Viral/drug therapy
• Pneumonia, Viral/epidemiology
• SARS-CoV-2

• Università degli Studi di Perugia

• Iron
• Metabolic syndrome
• Obesity
• Obesity surgery

• Cirrhosis
• Death
• Ferritin
• Infection
• Iron deficiency
• Overload
• Transferrin saturation

• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/surgery
• End Stage Liver Disease/blood
• End Stage Liver Disease/etiology
• End Stage Liver Disease/mortality
• End Stage Liver Disease/surgery
• Female
• Ferritins/blood
• Ferritins/metabolism
• Follow-Up Studies
• Humans
• Infections/etiology
• Infections/mortality
• Iron/blood
• Iron/metabolism
• Liver Neoplasms/blood
• Liver Neoplasms/complications
• Liver Neoplasms/epidemiology
• Liver Neoplasms/surgery
• Liver Transplantation/adverse effects
• Male
• Middle Aged
• Neoplasm Recurrence, Local/epidemiology
• Postoperative Complications/etiology
• Postoperative Complications/mortality
• Prospective Studies
• Retrospective Studies
• Risk Assessment/methods
• Risk Factors
• Survival Rate
• Transferrin/analysis
• Transferrin/metabolism

• Chronic kidney disease
• hemodialysis
• immunity
• infection
• intravenous iron
• iron deficiency
• safety

Patients with hereditary hemochromatosis and non-transfusion-dependent hereditary anemia develop predominantly liver iron-overload. We present a unique method allowing quantification of liver iron retention in humans during first-pass of ⁵⁹Fe-labeled iron through the portal system, using standard ferrokinetic techniques measuring red cell iron uptake after oral and intravenous ⁵⁹Fe administration. We present data from patients with iron deficiency (ID; N = 47), hereditary hemochromatosis (HH; N = 121) and non-transfusion-dependent hereditary anemia (HA; N = 40). Mean mucosal iron uptake and mucosal iron transfer (±SD) were elevated in patients with HH (59 ± 18%, 80 ± 15% respectively), HA (65 ± 17%, 74 ± 18%) and ID (84 ± 14%, 94 ± 6%) compared to healthy controls (43 ± 19%, 64 ± 18%) (p < 0.05) resulting in increased iron retention after 14 days compared to healthy controls in all groups (p < 0.01). The fraction of retained iron utilized for red cell production was 0.37 ± 0.17 in untreated HA, 0.55 ± 0.20 in untreated HH and 0.99 ± 0.22 in ID (p < 0.01). Interestingly, compared to red blood cell iron utilization after oral iron administration, red blood cell iron utilization was higher after injection of transferrin-bound iron in HA and HH. Liver iron retention was considerably higher in HH and HA compared to ID. We hypothesize that albumin serves as a scavenger of absorbed Fe(II) for delivering albumin-bound Fe(III) to hepatocytes.

• NTBI 3
• hemochromatosis 1
• hereditary anemia 4
• iron 2
• iron deficiency 5

• Administration, Intravenous
• Administration, Oral
• Adolescent
• Adult
• Aged
• Anemia, Hemolytic, Congenital/drug therapy
• Anemia, Hemolytic, Congenital/metabolism
• Anemia, Iron-Deficiency/drug therapy
• Anemia, Iron-Deficiency/metabolism
• Case-Control Studies
• Female
• Hemochromatosis/drug therapy
• Hemochromatosis/metabolism
• Humans
• Iron Radioisotopes/administration & dosage
• Iron Radioisotopes/pharmacokinetics
• Liver/chemistry
• Male
• Middle Aged
• Serum Albumin, Human/metabolism
• Transferrin/metabolism
• Young Adult

• Blood transfusion
• Cardiomyopathies
• Chelation therapy
• Ferritins
• Iron overload
• Magnetic resonance imaging
• Sickle cell anemia
• Thalassemia

• Alcohol
• BMI
• Evolution
• Genotype
• HFE hemochromatosis
• Phenotype
• Tobacco

Genetic hemochromatosis is an iron overload disease that is mainly related to the C282Y mutation in the HFE gene. This gene controls the expression of hepcidin, a peptide secreted in plasma by the liver and regulates systemic iron distribution. Homozygous C282Y mutation induces hepcidin deficiency, leading to increased circulating transferrin saturation, and ultimately, iron accumulation in organs such as the liver, pancreas, heart, and bone. Iron in excess may induce or favor the development of complications such as cirrhosis, liver cancer, diabetes, heart failure, hypogonadism, but also complaints such as asthenia and disabling arthritis. Iron depletive treatment mainly consists of venesections that permit the removal of iron contained in red blood cells and the subsequent mobilization of stored iron in order to synthesize hemoglobin for new erythrocytes. It is highly efficient in removing excess iron and preventing most of the complications associated with excess iron in the body. However, this treatment does not target the biological mechanisms involved in the iron metabolism disturbance. New treatments based on the increase of hepcidin levels, by using hepcidin mimetics or inducers, or inhibitors of the iron export activity of ferroportin protein that is the target of hepcidin, if devoid of significant secondary effects, should be useful to better control iron parameters and symptoms, such as arthritis.

• ferroportin
• genetic hemochromatosis
• hepcidin
• iron
• non transferrin bound iron
• venesections

• cardiac function
• echocardiography
• hepatitis C
• ledipasvir
• sofosbuvir
• thalassemia

• Clinical outcomes
• Iron chelation therapy
• Iron overload
• MDS
• Myelodysplastic syndromes

• Chronic kidney disease
• Hemodialysis
• Hepcidin
• Iron
• Iron overload
• Iron storage disorder
• Transferrin

• Administration, Intravenous
• Erythropoiesis/drug effects
• Homeostasis
• Humans
• Iron/administration & dosage
• Iron/adverse effects
• Iron/metabolism
• Renal Insufficiency, Chronic/metabolism
• Trace Elements/administration & dosage
• Trace Elements/adverse effects

NaCT is a Na⁺-coupled transporter for citrate expressed in hepatocytes and neurons. It is the mammalian ortholog of INDY (I’m Not Dead Yet), a transporter which modifies lifespan in Drosophila. Here we describe a hitherto unknown transport system for citrate in mammalian cells. When liver and mammary epithelial cells were pretreated with the iron supplement ferric ammonium citrate (FAC), uptake of citrate increased >10-fold. Iron chelators abrogated the stimulation of citrate uptake in FAC-treated cells. The iron exporter ferroportin had no role in this process. The stimulation of citrate uptake also occurred when Fe³⁺ was added during uptake without pretreatment. Similarly, uptake of Fe³⁺ was enhanced by citrate. The Fe³⁺-citrate uptake was coupled to Na⁺. This transport system was detectable in primary hepatocytes and neuronal cell lines. The functional features of this citrate transport system distinguish it from NaCT. Loss-of-function mutations in NaCT cause early-onset epilepsy and encephalopathy; the newly discovered Na⁺-coupled Fe³⁺-citrate transport system might offer a novel treatment strategy for these patients to deliver citrate into affected neurons independent of NaCT. It also has implications to iron-overload conditions where circulating free iron increases, which would stimulate cellular uptake of citrate and consequently affect multiple metabolic pathways.

• Ferroportin
• Hepcidin
• Iron chelation
• Iron overload
• Labile plasma iron
• Lipid peroxidation
• Liver fibrosis
• Non-transferrin bound iron
• Reactive oxygen species
• Tumorogenesis
• Venesection

• Hemochromatosis/chemically induced
• Hemochromatosis/metabolism
• Humans
• Iron/metabolism
• Iron/toxicity
• Iron Overload
• Liver/drug effects
• Liver/metabolism

• Hemochromatosis/diagnosis
• Hemochromatosis/genetics
• Hemochromatosis/physiopathology
• Hemochromatosis/therapy
• Hepcidins/physiology
• Humans
• Iron/metabolism

Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients. clinicaltrials.gov Identifier: 00600860.