-
Deutsches Arzteblatt International Dec 2021In the western world, 10-15% of women of child-bearing age suffer from iron-deficiency anemia. Iron overload due to chronic treatment with blood transfusions or... (Review)
Review
BACKGROUND
In the western world, 10-15% of women of child-bearing age suffer from iron-deficiency anemia. Iron overload due to chronic treatment with blood transfusions or hereditary hemochromatosis is much rarer.
METHODS
This review is based on pertinent publications retrieved by a selective search on the pathophysiology, clinical features, and diagnostic evaluation of iron deficiency and iron overload.
RESULTS
The main causes of iron deficiency are malnutrition and blood loss. Its differential diagnosis includes iron-refractory iron deficiency anemia (IRIDA), a rare congenital disease in which the hepcidin level is pathologically elevated, as well as the more common anemia of chronic disease (anemia of chronic inflammation), in which increased amounts of hepcidin are formed under the influence of interleukin-6 and enteric iron uptake is blocked as a result. Iron overload comes about through long-term transfusion treatment or a congenital disturbance of iron metabolism (hemochromatosis). Its diagnostic evaluation is based on clinical and laboratory findings, imaging studies, and specific mutation analyses.
CONCLUSION
Our improving understanding of the molecular pathophysiology of iron metabolism aids in the evaluation of iron deficiency and iron overload and may in future enable treatment not just with iron supplementation or iron chelation, but also with targeted pharmacological modulation of the hepcidin regulatory system.
Topics: Anemia; Anemia, Iron-Deficiency; Female; Humans; Iron; Iron Deficiencies; Iron Overload
PubMed: 34755596
DOI: 10.3238/arztebl.m2021.0290 -
Biomedicine & Pharmacotherapy =... Jan 2023Iron homeostasis plays a positive role in articular cartilage health. Excessive iron or iron overload can induce oxidative stress damage in chondrocytes and ferroptosis...
BACKGROUND
Iron homeostasis plays a positive role in articular cartilage health. Excessive iron or iron overload can induce oxidative stress damage in chondrocytes and ferroptosis cell death, advancing knee osteoarthritis (KOA). However, up to date, few effective agents treat iron overload-induced KOA (IOKOA). Chinese herbal medicine (CHM) provides abundant resources for drug selection to manage bone metabolic conditions, including osteoporosis. Biochanin A (BCA) is a novel bioactive multifunctional natural compound isolated from Huangqi, which has protective effects on bone loss. Nevertheless, the function and mechanism of BCA in treating IOKOA are still elusive.
PURPOSE
This study seeks to uncover the potential therapeutic targets and mechanisms of BCA in the management of KOA with iron accumulation.
METHODS
Iron dextrin (500 mg/kg) was intraperitoneally injected into mice to establish the iron overloaded mice model. OA was induced through surgery, and the progression was evaluated eight weeks following surgery. OA severity was evaluated with micro-CT and Safranin-O/Fast green staining in vivo. Iron deposition in the knee joint and synovium was assessed using Perl's Prussian blue staining. Ferric ammonium citrate (FAC) was then administered to primary chondrocytes to evaluate iron regulators mediated iron homeostasis. Toluidine blue staining was utilized to identify chondrocytes in vitro. The vitality of the cells was assessed using the CCK-8 test. The apoptosis rate of cells was measured using Annexin V-FITC/PI assay. The intracellular iron level was detected utilizing the calcein-AM test. Reactive oxygen species (ROS), lipid-ROS, and mitochondrial membrane potentiality were reflected via fluorescence density. Utilizing RT-qPCR and western blotting, the expression level was determined.
RESULTS
Micro-CT and histological staining of knee joints showed greater cartilage degradation and higher iron buildup detected in iron-overloaded mice. BCA can reduce iron deposition and the severity of KOA. Toluidine blue staining and the CCK-8 assay indicated that BCA could rescue chondrocytes killed by iron. Cell apoptosis rates were increased due to iron overload but improved by BCA. Further, the intracellular content of iron, ROS, and lipid-ROS was increased with ferric ammonium citrate (FAC) treatment but restored after treatment with different concentrations of BCA. JC-1 staining revealed that BCA could reduce mitochondrial damage induced by iron overload.
CONCLUSION
Iron overload was shown to promote chondrocyte ferroptosis in vivo and in vitro. Moreover, iron overload suppressed the expression of collagen II and induced MMP expression by catalyzing ROS generation with mitochondrial dysfunction. Our results showed that BCA could directly reduce intracellular iron concentration by inhibiting TfR1 and promoting FPN but also target the Nrf2/system xc-/GPX4 signaling pathway to scavenge free radicals and prevent lipid peroxidation. The results of this research indicate that BCA regulates iron homeostasis during the progression of osteoarthritis, which can open a new field of treatment for KOA.
Topics: Animals; Mice; Chondrocytes; Iron; Iron Overload; Lipids; Osteoarthritis, Knee; Reactive Oxygen Species; Tolonium Chloride
PubMed: 36379122
DOI: 10.1016/j.biopha.2022.113915 -
Annual Review of Physiology Feb 2023High iron is a risk factor for type 2 diabetes mellitus (T2DM) and affects most of its cardinal features: decreased insulin secretion, insulin resistance, and increased... (Review)
Review
High iron is a risk factor for type 2 diabetes mellitus (T2DM) and affects most of its cardinal features: decreased insulin secretion, insulin resistance, and increased hepatic gluconeogenesis. This is true across the normal range of tissue iron levels and in pathologic iron overload. Because of iron's central role in metabolic processes (e.g., fuel oxidation) and metabolic regulation (e.g., hypoxia sensing), iron levels participate in determining metabolic rates, gluconeogenesis, fuel choice, insulin action, and adipocyte phenotype. The risk of diabetes related to iron is evident in most or all tissues that determine diabetes phenotypes, with the adipocyte, beta cell, and liver playing central roles. Molecular mechanisms for these effects are diverse, although there may be integrative pathways at play. Elucidating these pathways has implications not only for diabetes prevention and treatment, but also for the pathogenesis of other diseases that are, like T2DM, associated with aging, nutrition, and iron.
Topics: Humans; Iron; Diabetes Mellitus, Type 2; Iron Overload; Liver; Insulin Resistance
PubMed: 36137277
DOI: 10.1146/annurev-physiol-022522-102832 -
Trends in Pharmacological Sciences Aug 2021Iron is essential in many physiological processes, including DNA metabolism, oxygen transport, and cellular energy generation. Deregulated iron metabolism, which results... (Review)
Review
Iron is essential in many physiological processes, including DNA metabolism, oxygen transport, and cellular energy generation. Deregulated iron metabolism, which results in iron overload or iron deficiency, is observed in many different diseases. We here summarize recent progress in the pathophysiology and pharmacology of iron-overload diseases, such as hereditary hemochromatosis, as well as iron-deficiency disorders, which are typically associated with anemia. The role of iron in immunity and the connection between iron and cancer are also addressed. We finally summarize and discuss the current (pre-) clinical landscape of pharmacotherapies targeting key players involved in iron metabolism.
Topics: Hemochromatosis; Humans; Iron; Iron Overload; Neoplasms
PubMed: 34090703
DOI: 10.1016/j.tips.2021.05.001 -
Minerva Endocrinologica Jun 2017Approximately one third of patients with non-alcoholic fatty liver disease (NAFLD) show signs of disturbed iron homeostasis as indicated by elevated serum ferritin with... (Review)
Review
Approximately one third of patients with non-alcoholic fatty liver disease (NAFLD) show signs of disturbed iron homeostasis as indicated by elevated serum ferritin with normal or mildly elevated transferrin saturation. Mild hepatic iron deposition is the typical histological finding in these subjects and the term "dysmetabolic iron overload syndrome (DIOS)" is now used to describe this syndrome. From a clinical point of view, excess iron likely aggravates the natural course of NAFLD with regard to liver-related endpoints and extrahepatic disease complications although sound evidence is still lacking. The detrimental effect of iron is attributed to its capability to catalyse the formation of toxic hydroxyl radicals resulting in cellular damage. Conversely, reduction of body iron restores insulin sensitivity, and epidemiological evidence suggests that it delays the onset of complications such as T2DM, cardiovascular disease and also advanced liver disease. Iron accumulation in NAFLD is mainly due to inhibition of iron mobilisation from hepatocytes and Kupffer cells. Impaired iron export is related to inflammation and metabolic derangements that appear to impact on iron regulators, such as hepcidin, ferroportin and to a lesser degree on transferrin receptor, ferritin or copper. This review summarizes the current understanding of the role of iron in NAFLD.
Topics: Humans; Iron; Iron Overload; Non-alcoholic Fatty Liver Disease
PubMed: 27834478
DOI: 10.23736/S0391-1977.16.02565-7 -
Cell Metabolism Aug 2022Hepatocytes have important roles in liver iron homeostasis, abnormalities in which are tightly associated with liver steatosis and fibrosis. Here, we show that...
Hepatocytes have important roles in liver iron homeostasis, abnormalities in which are tightly associated with liver steatosis and fibrosis. Here, we show that non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are characterized by iron-deficient hepatocytes and iron overload in hepatic stellate cells (HSCs). Iron deficiency enhances hepatocyte lipogenesis and insulin resistance through HIF2α-ATF4 signaling. Elevated secretion of iron-containing hepatocyte extracellular vesicles (EVs), which are normally cleared by Kupffer cells, accounts for hepatocyte iron deficiency and HSC iron overload in NAFLD/NASH livers. Iron accumulation results in overproduction of reactive oxygen species that promote HSC fibrogenic activation. Conversely, blocking hepatocyte EV secretion or depleting EV iron cargo restores liver iron homeostasis, concomitant with mitigation of NAFLD/NASH-associated liver steatosis and fibrosis. Taken together, these studies show that iron distribution disorders contribute to the development of liver metabolic diseases.
Topics: Animals; Disease Models, Animal; Fibrosis; Hepatic Stellate Cells; Hepatocytes; Iron; Iron Overload; Kupffer Cells; Lipogenesis; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease
PubMed: 35921818
DOI: 10.1016/j.cmet.2022.07.006 -
EMBO Reports Aug 2022Ferroptosis is an iron-dependent form of non-apoptotic cell death implicated in liver, brain, kidney, and heart pathology. How ferroptosis is regulated remains poorly...
Ferroptosis is an iron-dependent form of non-apoptotic cell death implicated in liver, brain, kidney, and heart pathology. How ferroptosis is regulated remains poorly understood. Here, we show that PPARα suppresses ferroptosis by promoting the expression of glutathione peroxidase 4 (Gpx4) and by inhibiting the expression of the plasma iron carrier TRF. PPARα directly induces Gpx4 expression by binding to a PPRE element within intron 3. PPARα knockout mice develop more severe iron accumulation and ferroptosis in the liver when fed a high-iron diet than wild-type mice. Ferrous iron (Fe ) triggers ferroptosis via Fenton reactions and ROS accumulation. We further find that a rhodamine-based "turn-on" fluorescent probe(probe1) is suitable for the in vivo detection of Fe . Probe1 displays high selectivity towards Fe , and exhibits a stable response for Fe with a concentration of 20 μM in tissue. Our data thus show that PPARα activation alleviates iron overload-induced ferroptosis in mouse livers through Gpx4 and TRF, suggesting that PPARα may be a promising therapeutic target for drug discovery in ferroptosis-related tissue injuries. Moreover, we identified a fluorescent probe that specifically labels ferrous ions and can be used to monitor Fe in vivo.
Topics: Animals; Ferroptosis; Fluorescent Dyes; Iron; Iron Overload; Liver; Mice; Mice, Knockout; PPAR alpha; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 35703725
DOI: 10.15252/embr.202052280 -
Signal Transduction and Targeted Therapy Jul 2020Iron homeostasis is essential for health; moreover, hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia. Here, we...
Iron homeostasis is essential for health; moreover, hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia. Here, we identified iron modulators by functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells. We validated the results in C57BL/6J mice and a mouse model of hemochromatosis (Hfe mice). Our screen revealed that the anti-rheumatoid arthritis drug auranofin (AUR) potently upregulates hepcidin expression. Interestingly, we found that canonical signaling pathways that regulate iron, including the Bmp/Smad and IL-6/Jak2/Stat3 pathways, play indispensable roles in mediating AUR's effects. In addition, AUR induces IL-6 via the NF-κB pathway. In C57BL/6J mice, acute treatment with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation. Whereas chronically treating male Hfe mice with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling, decreasing systemic iron overload, but less effective in females. Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells, providing a mechanistic explanation for ineffectiveness of AUR in female Hfe mice. Notably, high-dose AUR (25 mg/kg) induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase (TXNRD) activity. We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by high-dose AUR without comprising its beneficial effect on iron metabolism. In conclusion, our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis, and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms, suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.
Topics: Animals; Auranofin; Cell Line, Tumor; Female; Ferroptosis; HEK293 Cells; Hemochromatosis; Humans; Iron Overload; Male; Mice; Mice, Knockout; Signal Transduction
PubMed: 32732975
DOI: 10.1038/s41392-020-00253-0 -
Blood Sep 2023The intricate interplay of anemia and iron overload under the pathophysiological umbrella of ineffective erythropoiesis in non-transfusion-dependent β-thalassemia...
The intricate interplay of anemia and iron overload under the pathophysiological umbrella of ineffective erythropoiesis in non-transfusion-dependent β-thalassemia (NTDT) results in a complex variety of clinical phenotypes that are challenging to diagnose and manage. In this article, we use a clinical framework rooted in pathophysiology to present 4 common scenarios of patients with NTDT. Starting from practical considerations in the diagnosis of NTDT, we delineate our strategy for the longitudinal care of patients who exhibit different constellations of symptoms and complications. We highlight the use of transfusion therapy and novel agents, such as luspatercept, in the patient with anemia-related complications. We also describe our approach to chelation therapy in the patient with iron overload. Although tackling every specific complication of NTDT is beyond the scope of this article, we touch on the management of the various morbidities and multisystem manifestations of the disease.
Topics: Humans; beta-Thalassemia; Iron Chelating Agents; Thalassemia; Iron Overload; Chelation Therapy
PubMed: 37478396
DOI: 10.1182/blood.2023020683 -
Radiology Apr 2023Accumulation of excess iron in the body, or systemic iron overload, results from a variety of causes. The concentration of iron in the liver is linearly related to the... (Review)
Review
Accumulation of excess iron in the body, or systemic iron overload, results from a variety of causes. The concentration of iron in the liver is linearly related to the total body iron stores and, for this reason, quantification of liver iron concentration (LIC) is widely regarded as the best surrogate to assess total body iron. Historically assessed using biopsy, there is a clear need for noninvasive quantitative imaging biomarkers of LIC. MRI is highly sensitive to the presence of tissue iron and has been increasingly adopted as a noninvasive alternative to biopsy for detection, severity grading, and treatment monitoring in patients with known or suspected iron overload. Multiple MRI strategies have been developed in the past 2 decades, based on both gradient-echo and spin-echo imaging, including signal intensity ratio and relaxometry strategies. However, there is a general lack of consensus regarding the appropriate use of these methods. The overall goal of this article is to summarize the current state of the art in the clinical use of MRI to quantify liver iron content and to assess the overall level of evidence of these various methods. Based on this summary, expert consensus panel recommendations on best practices for MRI-based quantification of liver iron are provided.
Topics: Humans; Liver; Iron Overload; Magnetic Resonance Imaging; Iron; Biopsy
PubMed: 36809220
DOI: 10.1148/radiol.221856