Ferroportin Disease (FD) is an autosomal dominant hereditary iron loading disorder associated with heterozygote mutations of the ferroportin-1 (
) gene. It represents one of the commonest causes of ...genetic hyperferritinemia, regardless of ethnicity. FPN1 transfers iron from the intestine, macrophages and placenta into the bloodstream. In FD, loss-of-function mutations of FPN1 limit but do not impair iron export in enterocytes, but they do severely affect iron transfer in macrophages. This leads to progressive and preferential iron trapping in tissue macrophages, reduced iron release to serum transferrin (i.e. inappropriately low transferrin saturation) and a tendency towards anemia at menarche or after intense bloodletting. The hallmark of FD is marked iron accumulation in hepatic Kupffer cells. Numerous FD-associated mutations have been reported worldwide, with a few occurring in different populations and some more commonly reported (e.g. Val192del, A77D, and G80S). FPN1 polymorphisms also represent the gene variants most commonly responsible for hyperferritinemia in Africans. Differential diagnosis includes mainly hereditary hemochromatosis, the syndrome commonly due to either
or
,
,
, and, in rare instances,
itself. Here, unlike FD, hyperferritinemia associates with high transferrin saturation, iron-spared macrophages, and progressive parenchymal cell iron load. Abdominal magnetic resonance imaging (MRI), the key non-invasive diagnostic tool for the diagnosis of FD, shows the characteristic iron loading SSL triad (spleen, spine and liver). A non-aggressive phlebotomy regimen is recommended, with careful monitoring of transferrin saturation and hemoglobin due to the risk of anemia. Family screening is mandatory since siblings and offspring have a 50% chance of carrying the pathogenic mutation.
In the late 1800s, hemochromatosis was considered an odd autoptic finding. More than a century later, it was finally recognized as a hereditary, multi-organ disorder associated with a polymorphism ...that is common among white people: a 845G→A change in HFE that results in C282Y in the gene product. Hemochromatosis is now a well-defined syndrome characterized by normal iron-driven erythropoiesis and the toxic accumulation of iron in parenchymal cells of liver, heart, and endocrine glands. It can be caused by mutations that affect any of the proteins that limit the entry of iron into the blood. In mice, deletion of the iron hormone hepcidin and any of 8 genes that regulate its biology, including Hfe, transferrin receptor 2 ( Tfr2 ), and hemojuvelin ( Hjv ) (which all sense the accumulation of iron that hepcidin corrects) or ferroportin ( Fpn ) (the cellular iron exporter down-regulated by hepcidin), cause iron overload but not organ disease. In humans, loss of TfR2, HJV, and hepcidin itself or FPN mutations result in full-blown hemochromatosis. Unlike these rare instances, in white people, homozygotes for C282Y polymorphism in HFE are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, when these individuals abuse alcohol or from other unidentified modifying factors. HFE gene testing can be used to diagnose hemochromatosis, but analyses of liver histology and clinical features are still required to identify patients with rare, non-HFE forms of the disease. The role of hepcidin in the pathogenesis of hemochromatosis reveals its similarities to endocrine diseases such as diabetes and indicates new approaches to diagnosis and management of this common disorder in iron metabolism.
The discovery of hepcidin in 2000 and the subsequent unprecedented explosion of research and discoveries in the iron field have dramatically changed our understanding of human disorders of iron ...metabolism. Today, hereditary hemochromatosis, the paradigmatic iron-loading disorder, is recognized as an endocrine disease due to the genetic loss of hepcidin, the iron hormone produced by the liver. This syndrome is due to unchecked transfer of iron into the bloodstream in the absence of increased erythropoietic needs and its toxic effects in parenchymatous organs. It is caused by mutations that affect any of the proteins that help hepcidin to monitor serum iron, including HFE and, in rarer instances, transferrin-receptor 2 and hemojuvelin, or make its receptor ferroportin, resistant to the hormone. In Caucasians, C282Y HFE homozygotes are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, due to alcohol abuse or concurrent genetic modifiers that are now being identified. HFE gene testing can be used to diagnose hemochromatosis in symptomatic patients, but analyses of liver histology and full gene sequencing are required to identify patients with rare, non-HFE forms of the disease. Due to the central pathogenic role of hepcidin, it is anticipated that nongenetic causes of hepcidin loss (eg, end-stage liver disease) can cause acquired forms of hemochromatosis. The mainstay of hemochromatosis management is still removal of iron by phlebotomy, first introduced in 1950s, but identification of hepcidin has not only shed new light on the pathogenesis of the disease and the approach to diagnosis, but etiologic therapeutic applications from these advances are now foreseen.
Iron and the liver Pietrangelo, Antonello
Liver international,
01/2016, Letnik:
36, Številka:
S1
Journal Article
Recenzirano
Odprti dostop
Humans have evolved to retain iron in the body and are exposed to a high risk of iron overload and iron‐related toxicity. Excess iron in the blood, in the absence of increased erythropoietic needs, ...can saturate the buffering capacity of serum transferrin and result in non‐transferrin‐bound highly reactive forms of iron that can cause damage, as well as promote fibrogenesis and carcinogenesis in the parenchymatous organs. A number of hereditary or acquired diseases are associated with systemic or local iron deposition or iron misdistribution in organs or cells. Two of these, the HFE‐ and non‐HFE hemochromatosis syndromes represent the paradigms of genetic iron overload. They share common clinical features and the same pathogenic basis, in particular, a lack of synthesis or activity of hepcidin, the iron hormone. Before hepcidin was discovered, the liver was simply regarded as the main site of iron storage and, as such, the main target of iron toxicity. Now, as the main source of hepcidin, it appears that the loss of the hepcidin‐producing liver mass or genetic and acquired factors that repress hepcidin synthesis in the liver may also lead to iron overload. Usually, there is low‐grade excess iron which, through oxidative stress, is sufficient to worsen the course of the underlying liver disease or other chronic diseases that are apparently unrelated to iron, such as chronic metabolic and cardiovascular diseases. In the future, modulation of hepcidin synthesis and activity or hepcidin hormone‐replacing strategies may become therapeutic options to cure iron‐related disorders.
The discovery of hepcidin has triggered a virtual explosion of studies on iron metabolism and related disorders, the results of which have profoundly changed our view of human diseases associated ...with excess of iron, iron deficiency or iron misdistribution. Not only has new light been shed on the pathogenesis of these disorders, but therapeutic applications from these advances are now foreseen. The notion that hepcidin excess or deficiency may contribute to the dysregulation of iron homeostasis in hereditary and acquired iron disorders raises the possibility that hepcidin-lowering or enhancing agents may be an effective strategy for curing the main consequences of hepcidinopathies, anemia or iron overload, respectively. Experimental pre-clinical and clinical studies have shown that hepcidin antibodies, agonists or antagonists, cytokine receptor antibodies and small-molecules that modify hepcidin expression also reverse iron abnormalities in vivo , in a number of disease models. While future studies addressing safety and long-term efficacy of hepcidin-targeted treatments will clarify risks and benefits, a new era has begun based on the treatment of disorders of iron homeostasis through the modulation of its regulatory hormone, hepcidin.
The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. ...Here we show that, compared with healthy controls, COVID-19 patients' T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1
CD57
exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4
T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.
Iron and steatohepatitis Corradini, Elena; Pietrangelo, Antonello
Journal of gastroenterology and hepatology,
March 2012, Letnik:
27, Številka:
s2
Journal Article
Recenzirano
Odprti dostop
As the main iron storage site in the body and the main source of the iron‐regulatory hormone, hepcidin, the liver plays a pivotal role in iron homeostasis. A variable degree of hepatic iron ...accumulation has long been recognized in a number of chronic liver diseases. Both alcoholic and non‐alcoholic steatohepatitis display increased iron deposits in the liver, with an hepatocellular, mesenchymal, or mixed pattern, and recent reports have documented a concomitant aberrant hepcidin expression that could be linked to different coincidental pathogenic events (e.g. the etiological agent itself, necroinflammation, metabolic derangements, genetic predisposition). The present study reviews the pathogenic mechanisms of iron accumulation in steatohepatitis during alcoholic and non‐alcoholic liver disease and the role of excess iron in chronic disease progression.
Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. ...Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element-binding protein H), an ER stress-activated transcription factor, binds to and transactivates the hepcidin promoter. Hepcidin induction in response to exogenously administered toxins or accumulation of unfolded protein in the ER is defective in CREBH knockout mice, indicating a role for CREBH in ER stress-regulated hepcidin expression. The regulation of hepcidin by ER stress links the intracellular response involved in protein quality control to innate immunity and iron homeostasis.
PDF
