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Concept: Iron overload

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Hereditary hemochromatosis (HH) is a genetic disorder of iron metabolism which may lead to iron overload. Clinical penetrance is low, however those afflicted may develop cirrhosis, hepatocellular carcinoma, diabetes mellitus and cardiomyopathy. Treatment involves regular phlebotomy to reduce the systemic iron burden. In many countries-including the United States-numerous blood centers do not accept donated blood obtained from HH patients during therapeutic phlebotomy and there are inconsistent positions regarding this globally. This refusal is borne out of a few concerns. First, there is a theoretical increase in the infectious risk of these blood products, particularly by siderophilic organisms such as Yersinia enterocolitica. Second, given the increased incidence of hepatitis C infection from non-voluntary donors in the 1970s, there is a concern that blood from HH donors may harbor additional risk given the non-voluntary nature of their presentation. In this review, we examine the existing biologic and clinical data concerning infectious risk and summarize clinical experience from centers allowing HH donors, and demonstrate that blood from HH patients is safe and should be allowed into the donor pool. We conclude that there is no convincing evidence to exclude this population from serving as blood donors. This article is protected by copyright. All rights reserved.

Concepts: Genetics, Diabetes mellitus, Cirrhosis, Hematology, Hepatitis C, Human iron metabolism, Blood donation, Iron overload

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Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers.

Concepts: Genetics, Natural selection, Evolution, Biology, Hematology, Human iron metabolism, Iron overload

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Iron overload is a systemic disorder and is either primary (genetic) or secondary (exogenous iron administration). Primary iron overload is most commonly associated with hereditary hemochromatosis and secondary iron overload with ineffective erythropoiesis (predominantly caused by β-thalassemia major and sickle cell disease) that requires long-term transfusion therapy, leading to transfusional hemosiderosis. Iron overload may lead to liver cirrhosis and hepatocellular carcinoma, in addition to cardiac and endocrine complications. The liver is one of the main iron storage organs and the first to show iron overload. Therefore, detection and quantification of liver iron overload are critical to initiate treatment and prevent complications. Liver biopsy was the historical reference standard for detection and quantification of liver iron content. Magnetic resonance (MR) imaging is now commonly used for liver iron quantification, including assessment of distribution, detection, grading, and monitoring of treatment response in iron overload. Several MR imaging techniques have been developed for iron quantification, each with advantages and limitations. The liver-to-muscle signal intensity ratio technique is simple and widely available; however, it assumes that the reference tissue is normal. Transverse magnetization (also known as R2) relaxometry is validated but is prone to respiratory motion artifacts due to a long acquisition time, is presently available only for 1.5-T imaging, and requires additional cost and delay for off-line analysis. The R2* technique has fast acquisition time, demonstrates a wide range of liver iron content, and is available for 1.5-T and 3.0-T imaging but requires additional postprocessing software. Quantitative susceptibility mapping has the highest sensitivity for detecting iron deposition; however, it is still investigational, and the correlation with liver iron content is not yet established.©RSNA, 2018.

Concepts: Cancer, Red blood cell, Cirrhosis, Liver, Hepatitis C, Sickle-cell disease, Blood transfusion, Iron overload

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Although autoimmune hepatitis (AIH) can be treated with corticosteroid-based first-line therapy, incomplete remission is associated with progressive liver fibrosis. So far accepted predictors of the subsequent treatment response of AIH patients are lacking. Therefore, we analysed baseline parameters, including iron homeostasis and cytokine levels, in 60 children with paediatric AIH (pAIH). In contrast to adults, elevated serum markers indicating iron overload were not commonly found in children. Therefore, ferritin was not predictive of the treatment response in pAIH. Although baseline immunoglobulins were lower in pAIH children with subsequent complete biochemical remission (BR) upon standard first-line therapy, only lower AIH scores (≤16 points) could predict BR upon standard therapy in our training and validation cohorts. Additionally, higher baseline IL-2 and MCP-1/CCL2 levels were associated with BR in a sub-cohort. A combined score of IL-2 level and a simplified AIH score predicted treatment response more precisely than both parameter alone in this sub-cohort. In conclusion, the baseline AIH score could be validated as a predictor of treatment response in pAIH. Additionally, low baseline IL-2 may help identify children who need salvage therapy. This could be important because the use of low-dose IL-2 therapies is being tested in various autoimmune diseases.

Concepts: Medicine, Prediction, Futurology, Prophecy, Cirrhosis, Gastroenterology, Primary biliary cirrhosis, Iron overload

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The iron overload disorder hereditary haemochromatosis is most commonly caused by HFE p.Cys282Tyr homozygosity. In the absence of results from any randomised trials, current evidence is insufficient to determine whether individuals with hereditary haemochromatosis and moderately elevated serum ferritin, should undergo iron reduction treatment. This trial aimed to establish whether serum ferritin normalisation in this population improved symptoms and surrogate biomarkers.

Concepts: Epidemiology, Randomized controlled trial, ClinicalTrials.gov, Iron deficiency anemia, Publication bias, Human iron metabolism, Iron overload, Iron metabolism

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Introduction Juvenile hemochromatosis is a rare but severe form of hereditary hemochromatosis that typically presents early in life and can be fatal if left untreated. Case presentation We present the case of a 30-year-old man with a clear symptomatology of juvenile hemochromatosis, but in whom the diagnosis was initially mistaken for alcoholic liver disease because of known excessive use of alcohol, with the consequence that an adequate treatment was postponed. Discussion In this report, we discuss the diagnosis and treatment of juvenile hemochromatosis, focusing on the interaction between hemochromatosis and alcohol induced liver disease and how to differentiate both. We conclude that every young patient with suspected alcoholic liver disease and signs of iron overload should have a testing to rule out other iron overloading pathology, since early recognition and treatment with phlebotomy may prevent organ damage and improve life expectancy.

Concepts: Cirrhosis, Liver, Alcoholism, Hematology, Hepatology, Alcohol abuse, Iron overload, Alcoholic liver disease

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Iron-overload cardiomyopathy is prevalent on a worldwide basis and is a major co-morbidity in patients with genetic hemochromatosis and secondary iron overload. Therapies are limited in part due to lack of a valid pre-clinical model, which recapitulates advanced iron-overload cardiomyopathy. Male hemojuvelin knockout (HJVKO) mice, which lack hemojuvelin (HJV), a bone morphogenetic co-receptor protein required for hepcidin expression and systemic iron homeostasis, were fed a high iron diet starting at 4 weeks of age for a duration of 1 year. Aged HJVKO mice in response to iron overload showed increased myocardial iron deposition and mortality coupled with oxidative stress and myocardial fibrosis culminating in advanced iron-overload cardiomyopathy. In a parallel group, iron-overloaded HJVKO mice received resveratrol (240 mg/day) at 9 months of age until 1 year of age. Echocardiography and invasive pressure-volume loop analyses revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. In addition, myocardial sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCA2a levels and suppressed upregulation of the sodium-calcium exchanger. Further, iron-mediated oxidative stress and myocardial fibrosis were suppressed by resveratrol treatment with concomitant activation of the phospho-Akt and phospho-AMP-activated protein kinase (AMPK) signaling pathways. A combination of aging and high-iron diet in male HJVKO mice results in a valid pre-clinical model that recapitulates iron-overload cardiomyopathy in humans. Resveratrol therapy resulted in normalization of cardiac function demonstrating that resveratrol represents a feasible therapeutic intervention to reduce the burden of iron-overload cardiomyopathy.

Concepts: Signal transduction, Adenosine triphosphate, Iron, Cardiology, Heart, Ageing, Human iron metabolism, Iron overload

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Non-classical Ferroportin Disease is a form of hereditary hemochromatosis caused by mutations in the iron transporter ferroportin (Fpn), resulting in parenchymal iron overload. Fpn is regulated by the hormone hepcidin, which induces Fpn endocytosis and cellular iron retention. We characterized 11 clinically-relevant and 5 nonclinical Fpn mutations using stably transfected, inducible, isogenic cell lines. All clinical mutants were functionally resistant to hepcidin as a consequence of either impaired hepcidin binding or impaired hepcidin-dependent ubiquitination despite intact hepcidin binding. Mapping the residues onto two computational models of the human Fpn structure indicated that i) mutations that caused ubiquitination-resistance were positioned at helix-helix interfaces, likely preventing the hepcidin-induced conformational change, ii) hepcidin binding occurred within the central cavity of Fpn, iii) hepcidin interacted with up to 4 helices, and iv) hepcidin binding should occlude Fpn and interfere with iron export independently of endocytosis. We experimentally confirmed hepcidin-mediated occlusion of Fpn in the absence of endocytosis in multiple cellular systems: HEK293 cells expressing an endocytosis-defective Fpn mutant (K8R), Xenopus oocytes expressing WT or K8R Fpn, and mature human RBCs. We conclude that non-classical Ferroportin Disease is caused by Fpn mutations that decrease hepcidin binding or hinder conformational changes required for ubiquitination and endocytosis of Fpn. The newly documented ability of hepcidin and its agonists to occlude iron transport may facilitate the development of broadly effective treatments for hereditary iron overload disorders.

Concepts: Cell culture, Hematology, Human iron metabolism, Iron overload, Iron metabolism

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Iron overload disorders are common and could lead to significant morbidity and mortality worldwide. Due to limited treatment options, there is a great need to develop novel strategies to remove the excess body iron. To discover potential epigenetic modulator in hepcidin upregulation and subsequently decreasing iron burden, we performed an epigenetic screen. The in vivo effects of the identified compounds were further tested in iron-overload mouse models, including Hfe-/-, Hjv-/- and hepatocyte-specific Smad4 knockout (Smad4fl/fl;Alb-Cre+) mice.

Concepts: Histone, Hematology, Murinae, Mouse, Mice, Human iron metabolism, Iron overload, Iron metabolism

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Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.

Concepts: DNA, Genetics, Mutation, Hematology, Human iron metabolism, Iron overload, Iron metabolism, Hepcidin