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Depiction of the Haber-Weiss Cycle. Initially, ferric iron reacts with superoxide (·O 2 ) resulting in oxygen and ferric iron formation. Ferric iron can subsequently react with hydrogen peroxide forming hydroxyl radicals, hydrogen peroxide and ferric iron.
Source publication
Haemochromatosis remains the most prevalent genetic disorder of Caucasian populations in Australia and the United States, occurring in ∼1 of 200 individuals and having a carrier frequency of 10-14%. Hereditary haemochromatosis is an autosomal recessive condition, that is phenotypically characterised by a gradual accumulation of iron, above and beyo...
Contexts in source publication
Context 1
... mammalian body possesses a vast network of readily available antioxidant defence mechanisms including various enzymatic (e.g., superoxide dismutase) and non-enzymatic (e.g. Vitamin A, C, E) scavengers [56]. When production of oxidative species overcome the body's capacity to buffer these reactions, oxidative stress occurs. In untreated haemochromatosis patients, for example, when iron homeostasis cannot be maintained, the excess iron facilitates production of free radicals, thereby quenching available antioxidants [57]. Specifically, within a cell's mitochondrion, iron participates in a one-electron transfer reaction called the "Fenton Reaction" [58]. In the presence of hydrogen peroxide, ferrous iron catalyses the formation of highly reactive hydroxyl radicals, while increasing its own oxidation state (i.e., Fe 2+ → Fe 3+ ) [58]. The formation of both hydroxyl radicals and ferric iron is associated with widespread damage to biological structures, including nucleic acids, cell membranes, and proteins [59]. In tandem, the reaction of ferric iron and superoxide occurs, providing the ferrous iron needed to form hydroxyl radicals. The collective reaction is referred to as the Haber-Weiss Cycle (Fig. ...
Context 2
... both hydroxyl radicals and ferric iron is associated with widespread damage to biological structures, including nucleic acids, cell membranes, and proteins [59]. In tandem, the reaction of ferric iron and superoxide occurs, providing the ferrous iron needed to form hydroxyl radicals. The collective reaction is referred to as the Haber-Weiss Cycle (Fig. ...
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... Transfusion iron overload is a major concern in the management of patients with severe anemia, as iron can form free radicals, and accumulated iron in the body can cause tissue injuries [1]. Iron first accumulates in reticuloendothelial macrophages and later in the liver, pancreas, heart, and endocrine tissue, where it can lead to liver dysfunction, diabetes mellitus, cardiomyopathy, and endocrine disorders, including hypopituitarism and hypothyroidism [2][3][4]. ...
Background
Although roxadustat has been reported to cause central hypothyroidism, the details of the mechanisms and clinical characteristics of patients who are prone to developing hypothyroidism with roxadustat are uncertain.
Case presentation
A 53-year-old man with a 3-year history of hemodialysis due to diabetic kidney disease who had been treated with roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, for 2 years was admitted to the hospital because of worsening gait disturbance and impaired consciousness. He had also acquired pure red cell aplasia associated with T-cell large granular lymphocytic leukemia and received multiple blood transfusions. Because his serum concentration of thyroid hormones was low, we diagnosed him with hypothyroidism, and his consciousness level recovered to normal with thyroid hormone replacement therapy. Computed tomography revealed a high-intensity atrophic thyroid gland, and magnetic resonance imaging showed diffusely reduced T2 and T1 signals of the pituitary anterior gland. These findings confirmed the accumulation of iron in the pituitary and thyroid glands. Combined pituitary stimulation tests with thyrotropin-releasing hormone, luteinizing hormone-releasing hormone, and corticotropin-releasing hormone revealed that the patient had pan-hypopituitarism. After discontinuation of roxadustat, the patient was treated with another hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat. One month after switching medication, a stimulation test with thyrotropin-releasing hormone showed normal responses to thyroid-stimulating hormone. The patient was treated with levothyroxine 50 μg daily without any significant symptoms and is currently under follow-up observation as an outpatient.
Conclusions
We encountered a dialysis patient with roxadustat-induced hypothyroidism associated with transfusion iron overload. To our knowledge, this is the first case to clearly show that roxadustat can impair thyroid-stimulating hormone secretion in repeated thyrotropin-releasing hormone stimulation tests. Because the present patient had received roxadustat for more than 2 years before hypothyroidism became apparent, regular monitoring of the thyroid function may be needed in patients with renal anemia who have been treated with roxadustat, especially those at high risk of thyroid dysfunction.
... According to estimates, 10%-14% of US white patients have a genetic mutation, and one in every 200 of them has iron excess. Due to the absence of menstruation, men with primary hemochromatosis are more prone than women to have symptoms [48]. These reports suggest that iron could exacerbate the infectivity of SARS-CoV-2 in iron overloaded patients. ...
Coronavirus disease-19 (COVID-19) can induce severe inflammation of the lungs and respiratory system. Severe COVID-19 is frequently associated with hyper inflammation and hyper-ferritinemia. High iron levels are known to trigger pro-inflammatory effects. Cumulative iron loading negatively impacts on a patients innate immune effector functions and increases the risk for infection related complications. Prognosis of severe acute respiratory SARS-CoV-2 patients may be impacted by iron excess. Iron is an essential co-factor for numerous essential cellular enzymes and vital cellular operations. Viruses hijack cells in order to replicate, and efficient replication requires an iron-replete host. Utilizing iron loaded cells in culture we evaluated their susceptibility to infection by pseudovirus expressing the SARS-CoV-2 spike protein and resultant cellular inflammatory response. We observed that, high levels of iron enhanced host cell ACE2 receptor expression contributing to higher infectivity of pseudovirus. In vitro Cellular iron overload also synergistically enhanced the levels of; reactive oxygen species, reactive nitrogen species, pro-inflammatory cytokines (IL-1β, IL-6, IL-8 & TNF-α) and chemokine (CXCL-1&CCL-4) production in response to inflammatory stimulation of cells with spike protein. These results were confirmed using an in vivo mouse model. In future, limiting iron levels may be a promising adjuvant strategy in treating viral infection.
... 17 The mechanism for this impaired RBC deformability in HH is currently suggested to occur secondary to an increased blood iron concentration that precipitates free radical generation, leading to oxidative damage of the RBC membrane and increased rigidity of the cell. 18 Given that high-volume transfusion further exposes RBCs to high levels of shear stress, it is plausible that blood products derived from HH donors (with an already impaired cellular deformability) would exhibit a compounding effect of both oxidation and mechanical stress. Nevertheless, given that blood iron is well managed via venesection in HH, it is proposed that the level of impaired cell mechanics induced by iron-mediated oxidative stress may be ameliorated with successive therapies. ...
Background:
Individuals with hereditary hemochromatosis (HH) receive frequent blood withdrawals (ie, venesections) as part of their primary treatment to assist in normalizing blood iron levels. It remains unclear whether this source of blood is suitable for use in blood product development, as current data indicate that red blood cell (RBC) deformability, both before and after shear stress exposure, is impaired in individuals with HH, relative to healthy controls. Given that venesection therapy is known to significantly reduce circulating iron levels in individuals with HH, the current study examined whether venesection therapy is effective at improving RBC mechanical properties, both before and after shear stress exposure, in individuals with HH.
Study design and methods:
Blood samples were initially collected from untreated HH patients (age, 61 ± 9 years; 14% female) undergoing their first venesection, and then again during their second (approx. 9 weeks later) and third (approx. 16 weeks later) venesections. RBC deformability was measured at each time point with a commercial ektacytometer. Moreover, to determine cell responses to mechanical stimuli, the mechanical sensitivity of blood samples was determined at each time point.
Results:
The salient findings indicate that venesection therapy used for managing plasma ferritin concentration significantly improves the cellular deformability of RBC in individuals with HH. Further, the sensitivity of RBC to supraphysiological mechanical stress is decreased (ie, improved) in a dose-response fashion with routine venesection.
Conclusion:
While cellular mechanics of RBC from individuals with HH are impaired when untreated, venesection therapy significantly improves cellular properties of RBC, supporting the use of venesections in blood product development from individuals with well-managed HH.
... The HFE (hemochromatosis) gene, reported about two decades ago [13][14][15]-which was found in patients with hereditary hemochromatosis (HH)-is an autosomal recessive genetic disease producing an increase in the absorption of ingested iron. Affected subjects may develop iron overload, which leads to diabetes, heart disease, and liver disease, but afflicted individuals generally did not present symptoms until mid-to late-adulthood. ...
Research has shown that long-term exposure to lead harms the hematological system. The homeostatic iron regulator HFE (hemochromatosis) mutation, which has been shown to affect iron absorption and iron overload, is hypothesized to be related to lead intoxication in vulnerable individuals. The aim of our study was to investigate whether the HFE genotype modifies the blood lead levels that affect the distributions of serum iron and other red blood cell indices. Overall, 121 lead workers and 117 unexposed age-matched subjects were recruited for the study. The collected data included the blood lead levels, complete blood count, serum iron, total iron binding capacity, transferrin, and ferritin, which were measured during regular physical examinations. All subjects filled out questionnaires that included demographic information, medical history, and alcohol and tobacco consumption. HFE genotyping for C282Y and H63D was determined using polymerase chain reaction and restriction fragment length polymorphism (PCR/RFLP). The mean blood lead level in lead workers was 19.75 µg/dL and was 2.86 µg/dL in unexposed subjects. Of 238 subjects, 221 (92.9%) subjects were wild-type (CCHH) for HFE C282Y and H63D, and 17 (7.1%) subjects were heterozygous for a H63D mutation (CCHD). Multiple linear regression analysis showed that blood lead was significantly negatively associated with hemoglobin (Hb), mean corpuscular hemoglobin concentration (MCHC), and mean corpuscular volume (MCV), whereas the HFE variant was associated negatively with MCV and positively with ferritin. An interactive influence on MCV was identified between blood lead and HFE variants. Our research found a significant modifying effect of the HFE variant, which possibly affected MCV. The HFE H63D heterozygous (CCHD) variant seemed to provide a protective factor against lead toxicity. Future studies should focus on competing binding proteins between iron and lead influenced by gene variation.
... The HFE (hemochromatosis) gene, reported about two decades ago [13][14][15]-which was found in patients with hereditary hemochromatosis (HH)-is an autosomal recessive genetic disease producing an increase in the absorption of ingested iron. Affected subjects may develop iron overload, which leads to diabetes, heart disease, and liver disease, but afflicted individuals generally did not present symptoms until mid-to late-adulthood. ...
Research has shown that long-term exposure to lead harms the hematological system. The homeostatic iron regulator HFE (hemochromatosis) mutation, which has been shown to affect iron absorption and iron overload, is hypothesized to be related to lead intoxication in vulnerable individuals. The aim of our study was to investigate whether the HFE genotype modifies the blood lead levels that affect the distributions of serum iron and other red blood cell indices. Overall, 121 lead workers and 117 unexposed age-matched subjects were recruited for the study. The collected data included the blood lead levels, complete blood count, serum iron, total iron binding capacity, transferrin, and ferritin, which were measured during regular physical examinations. All subjects filled out questionnaires that included demographic information, medical history, and alcohol and tobacco consumption. HFE genotyping for C282Y and H63D was determined using polymerase chain reaction and restriction fragment length polymorphism (PCR/RFLP). The mean blood lead level in lead workers was 19.75 µg/dL and was 2.86 µg/dL in unexposed subjects. Of 238 subjects, 221 (92.9%) subjects were wild-type (CCHH) for HFE C282Y and H63D, and 17 (7.1%) subjects were heterozygous for a H63D mutation (CCHD). Multiple linear regression analysis showed that blood lead was significantly negatively associated with hemoglobin (Hb), mean corpuscular hemoglobin concentration (MCHC), and mean corpuscular volume (MCV), whereas the HFE variant was associated negatively with MCV and positively with ferritin. An interactive influence on MCV was identified between blood lead and HFE variants. Our research found a significant modifying effect of the HFE variant, which possibly affected MCV. The HFE H63D heterozygous (CCHD) variant seemed to provide a protective factor against lead toxicity. Future studies should focus on competing binding proteins between iron and lead influenced by gene variation.
Background
Patients with p.C282Y homozygous (p.C282Y) HFE mutations are more likely to develop hemochromatosis (HC) than p.C282Y/p.H63D compound heterozygotes (p.C282Y/H63D).
Research design and methods
We conducted a retrospective chart review of 90 p.C282Y and 31 p.C282Y/H63D patients at a referral practice to illustrate the differences in the natural history of the disease in these two HC cohorts.
Results
Over a median follow-up of 17 years, p.C282Y had higher mean serum ferritin (1105 mg/dL vs. 534 mg/dL, p = 0.001) and transferrin saturations (75.3% vs. 49.5%, p = 0.001) at diagnosis. p.C282Y underwent more therapeutic phlebotomies (TP) till de-ironing (mean 24 vs. 10), had higher mean mobilized iron stores (4759 mg vs. 1932 mg), and required more annual maintenance TP (1.9/year vs. 1.1/year, p = 0.039). p.C282Y/H63D were more likely to have obesity (45.2% vs. 20.2%, p = 0.007) at diagnosis, with a non-significant trend toward consuming more alcohol. There was no significant difference in the development of HC-related complications between the two cohorts.
Conclusions
p.C282Y have a higher mobilizable iron and require more TP. p.C282Y/H63D likely require additional insults such as obesity or alcohol use to develop elevated ferritin. De-ironing may mitigate the risk of developing HC-related complications.
The cardiovascular system requires iron to maintain its high energy demands and metabolic activity. Iron plays a critical role in oxygen transport and storage, mitochondrial function, and enzyme activity. However, excess iron is also cardiotoxic due to its ability to catalyze the formation of reactive oxygen species and promote oxidative damage. While mammalian cells have several redundant iron import mechanisms, they are equipped with a single iron-exporting protein, which makes the cardiovascular system particularly sensitive to iron overload. As a result, iron levels are tightly regulated at many levels to maintain homeostasis. Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich's ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives.
Liver Iron content is best correlated to total body iron stores and is thus the organ of choice for evaluation in iron overload diseases. Liver biopsy was the historic standard for iron evaluation, but the evaluation is localized, comes with increased risks due to its invasiveness, and is costly. MRI is now widely used for liver iron evaluation. The superparamagnetic properties of iron cause a disturbance in the magnetic resonance imaging process, which can be evaluated with various techniques. These include signal intensity ratio (SIR), T2 relaxometry, T2* relaxometry, and Dixon-based solutions. Each of the methods has its own advantages and disadvantages, and factors such as availability, ease of use, accuracy, reproducibility, and cost can all play a role in the ultimate technique used for liver iron quantification. Quantitative susceptibility mapping, and ultrashort TE sequences are promising supplemental methods, but are primarily used as research sequences, which may become more clinically accepted in the near future. Dual energy CT is also being explored as an alternative but is still in the nascent stages. Overall, accurate liver iron concentration is feasible with the current tools available at most MR imaging centers and is highly valuable for evaluation of iron overload diseases.
Background:
Hemochromatosis (HH) is characterized by chronic iron accumulation, leading to deleterious effects to various organ systems. A common approach to managing iron load involves large-volume venesection. Some countries authorize HH venesections to be used in the development of transfusable blood products, although concerns remain regarding suitability. Due to the high oxidative load associated with hyperferritinemia, it has been proposed that HH blood products may be susceptible to mechanical damage. This is particularly relevant given that typical blood product destinations (eg, transfusion, cardiopulmonary bypass) expose blood to supraphysiologic levels of mechanical stress. We sought to explore the mechanical tolerance of red blood cells (RBC) derived from HH venesections to varied magnitudes and durations of sublethal shear stress.
Study design and methods:
Initially, 110 individuals with HH were recruited; to eliminate the effects of comorbidities, only those who were untreated and uncomplicated were included for comparisons with age-matched healthy controls (Con). RBC were exposed to 25 discrete magnitudes (1-64 Pa) and durations (1-64 seconds) of shear stress. Cellular deformability was assessed before, and immediately after, each shear exposure.
Results:
In the absence of prior shear exposure, RBC deformability of HH was significantly decreased by 11.5%, compared with Con. For both HH and Con, supraphysiologic shear exposure significantly impaired RBC deformability, although the rate and magnitude of deterioration were elevated for HH.
Conclusion:
Given that blood products are commonly exposed to high-shear environments (eg, during high-volume transfusion), venesections from asymptomatic and untreated individuals with HH appear suboptimal for the development of therapeutic RBCs.
