Chronic Iron Overload Research Articles

Foodborne iron overload induces oxidative stress and causes mitochondrial damage in the liver of grass carp (Ctenopharyngodon idellus)

Iron is essential to biological processes such as energy metabolism and oxygen transport. However, excessive iron can cause iron overload and ultimately result in tissue damage. To date, the damage mechanism of foodborne iron overload in aquatic animals is still unclear. This study used grass carp (Ctenopharyngodon idellas) as the research subject to establish a chronic iron overload model by feeding diets with different iron levels, and combined in vitro experiments to investigate the mechanisms of iron overload-induced damage. The growth performance and liver HE staining indicated that a high‑iron diet led to decreased growth in grass carp, accompanied by hepatic iron deposition. ELISA and qRT-PCR analysis data revealed that a high‑iron diet disrupted the antioxidant balance and modulated the expression of genes associated with iron metabolism. CCK-8 determination results revealed that treatment of L8824 cells with ferri ammonii citras (FAC) resulted in iron overload, led to disruption of iron metabolism and enhanced the intracellular production of reactive oxygen species (ROS), and caused lipid peroxidation. Furthermore, qRT-PCR analysis results showed that the treatment of L8824 cells with FAC resulted in a significant up-regulation of genes associated with antioxidant, apoptosis, and necrosis pathways, and increased the rate of apoptosis. In addition, fluorescence microscopy observation and mitochondrial DNA detection data showed that excess iron could increase the iron accumulation in mitochondria and the production of mtROS, reduce the mitochondrial membrane potential, and finally cause mitochondria damage. In conclusion, our research offers invaluable insights that iron overload leads to disrupted intracellular iron pool stability, causing mitochondrial damage and oxidative stress, eventually causing cell death.

Liraglutide Impacts Iron Homeostasis in a Murine Model of Hereditary Hemochromatosis.

Classic hereditary hemochromatosis (HH) is an autosomal recessive iron-overload disorder resulting from loss-of-function mutations of the HFE gene. Patients with HH exhibit excessive hepatic iron accumulation that predisposes these patients to liver disease, including the risk for developing liver cancer. Chronic iron overload also poses a risk for the development of metabolic disorders such as obesity, type 2 diabetes, and insulin resistance. We hypothesized that liraglutide, GLP1 receptor agonist, alters iron metabolism while also reducing body weight and glucose tolerance in a mouse model of HH (global HFE knockout, HFE KO) and diet-induced obesity and glucose intolerance. The total body HFE KO and wild-type control mice were fed high-fat diet for 8 weeks. Mice were subdivided into liraglutide and vehicle-treated groups and received daily subcutaneous administration of the respective treatment once daily for 18 weeks. Liraglutide improved glucose tolerance and hepatic lipid markers and reduced body weight in a mouse model of HH, the HFE KO mouse, similar to wild-type controls. Importantly, our data show that liraglutide alters iron metabolism in HFE KO mice, leading to decreased circulating and stored iron levels in HFE KO mice. These observations highlight the potential that GLP1 receptor agonist could be used to reduce iron overload in addition to reducing body weight and improving glucose regulation in HH patients.

The Impact of the Combined Effect of Inhalation Anesthetics and Iron Dextran on Rats' Systemic Toxicity.

Disruption of any stage of iron homeostasis, including uptake, utilization, efflux, and storage, can cause progressive damage to peripheral organs. The health hazards associated with occupational exposure to inhalation anesthetics (IA) in combination with chronic iron overload are not well documented. This study aimed to investigate changes in the concentration of essential metals in the peripheral organs of rats after iron overload in combination with IA. The aim was also to determine how iron overload in combination with IA affects tissue metal homeostasis, hepcidin-ferritin levels, and MMP levels according to physiological, functional, and tissue features. According to the obtained results, iron accumulation was most pronounced in the liver (19×), spleen (6.7×), lungs (3.1×), and kidneys (2.5×) compared to control. Iron accumulation is associated with elevated heavy metal levels and impaired essential metal concentrations due to oxidative stress (OS). Notably, the use of IA increases the iron overload toxicity, especially after Isoflurane exposure. The results show that the regulation of iron homeostasis is based on the interaction of hepcidin, ferritin, and other proteins regulated by inflammation, OS, free iron levels, erythropoiesis, and hypoxia. Long-term exposure to IA and iron leads to the development of numerous adaptation mechanisms in response to toxicity, OS, and inflammation. These adaptive mechanisms of iron regulation lead to the inhibition of MMP activity and reduction of oxidative stress, protecting the organism from possible damage.

Exploring the Interplay between Asthma and Hemoglobinopathies: A Comprehensive Review.

Asthma, a prevalent chronic respiratory condition characterized by inflammation of the airways and bronchoconstriction, has demonstrated a potential association with hemoglobinopathies such as thalassemia and sickle cell disease (SCD). Numerous studies have highlighted a higher prevalence of asthma among thalassemia patients compared to the general population, with rates ranging around 30%. Similarly, asthma frequently coexists with SCD, affecting approximately 20-48% of patients. Children with SCD often experience heightened lower airway obstruction and airway hyper-reactivity. Notably, the presence of asthma in SCD exacerbates respiratory symptoms and increases the risk of severe complications like acute chest syndrome, stroke, vaso-occlusive episodes, and early mortality. Several studies have noted a decrease in various cytokines such as IFN-γ and IL-10, along with higher levels of both IL-6 and IL-8, suggesting an overactivation of pro-inflammatory mechanisms in patients with hemoglobinopathies, which could trigger inflammatory conditions such as asthma. The exact mechanisms driving this association are better elucidated but may involve factors such as chronic inflammation, oxidative stress, and immune dysregulation associated with thalassemia-related complications like chronic hemolytic anemia and iron overload. This review aims to comprehensively analyze the relationship between asthma and hemoglobinopathies, with a focus on thalassemia and SCD. It emphasizes the importance of interdisciplinary collaboration among pulmonologists, hematologists, and other healthcare professionals to effectively manage this complex interplay. Understanding this link is crucial for improving care and outcomes in affected individuals.

Frequency and potential risk factors of polyneuropathy in transfusion-dependent Β-thalassemia major patients: a cross-sectional study

BackgroundNeurological complications, including peripheral polyneuropathy, have been reported in β-thalassemia patients that negatively impact their quality of life. Chronic hypoxia, iron overload, average age, and iron chelators-induced neurotoxicity might contribute to the development of neuropathy. However, the leading offender of this complication remains not clear. We aimed to study the frequency and potential risk factors of polyneuropathy in β-thalassemia patients. We performed a cross-section study on 150 transfusion-dependent β-thalassemia major patients with a mean age of 16.44 ± 3.32 years. We performed electrophysiological studies for motor and sensory nerves.ResultsWe found that 31.3% of cases had neurological manifestations with significant relation to age, duration of the disease, and frequent transfusion. Out of 47 patients with neurological manifestations, 12 (25.5%) had abnormal nerve conduction velocity (NCV). Abnormal median, peroneal, and tibial nerve motor amplitudes were detected in 10.6%, 10.6%, and 14.9% of patients respectively. Abnormal median, peroneal, and sural nerve sensory amplitudes were detected in 4.3%, 2.2%, and 10.6% of patients respectively. Apart from a significant relation between abnormal NCV and older ages, no significant relation was detected with other studied clinical and laboratory parameters.ConclusionWe detected a high frequency of motor and sensory polyneuropathy in B-thalassemia patients. Polyneuropathy was predominately detected in older ages highlighting that neuropathy in thalassemia patients is probably age-dependent. Other factors including disease duration, transfusion frequency, and iron overload might have a contributing effect, however, that could not be confirmed in this study. Further studies are needed to verify the frequency and predictors of polyneuropathy in B-thalassemia patients.

Very low serum IGF-1 levels are associated with vertebral fractures in adult males with beta-thalassemia major.

Patients with beta-thalassemia major (BTM) often develop several endocrine disorders due to chronic iron overload. They are also prone to osteoporosis and vertebral fractures. Plasmatic insulin-like growth factor-1 (IGF-1) levels are often low in subjects with BTM, which origin is multifactorial. The aim of this study was to evaluate a possible relationship between serum IGF-1 levels and the presence of osteoporosis and/or vertebral fractures. We retrospectively evaluated the occurrence of vertebral fractures in 30 adult male patients affected by BTM (mean age 43.3 ± 7.9years) with low serum IGF-1 (median value 52.4ng/ml, 38.5-83.4). Only 6 of them (20.0%) were diagnosed with GH deficiency (GHD) after GHRH/arginine stimulation test, while 23 (76.7%) had osteoporosis and 12 (40.0%) had known vertebral fractures. All patients except one also showed at least one endocrine disorder. Serum IGF-1 was significantly lower in BTM patients with vertebral fractures compared to patients without vertebral fractures (U = 41.0, p = 0.005) while it was not significantly different between patients with low bone mass compared to patients without low bone mass. The diagnosis of GHD was significantly associated with lower serum IGF-1 (p = 0.001) and vertebral fractures (p = 0.002) but not with low bone mass. After ROC analysis, we found that very low IGF-1 (≤ 50.0ng/dl) was associated with vertebral fractures (sensitivity 83.3%, specificity 75.0%) and was also predictive of GHD (sensitivity 75.0%, specificity 100.0%). Our study shows that, in male patients with BTM, serum IGF-1 ≤ 50.0ng/dl is a marker of vertebral fractures and it is predictive of a diagnosis of GHD.

Chronic dietary iron overload affects hepatic iron metabolism and cognitive behavior in Wistar rats

BackgroundIron accumulation in organs affects iron metabolism, leading to deleterious effects on the body. Previously, it was studied that high dietary iron in various forms and concentrations influences iron metabolism, resulting in iron accumulation in the liver and spleen and cognitive impairment. However, the actual mechanism and impact of long-term exposure to high dietary iron remain unknown. As a result, we postulated that iron overload caused by chronic exposure to excessive dietary iron supplementation would play a role in iron dyshomeostasis and inflammation in the liver and brain of Wistar rats. MethodsAnimals were segregated into control, low iron (FAC-Ferric Ammonium Citrate 5000 ppm), and high iron dose group (FAC 20,000 ppm). The outcome of dietary iron overload on Wistar rats was evaluated in terms of body weight, biochemical markers, histological examination of liver and brain tissue, and cognitive-behavioral studies. Also, gene expression of rat brain tissue involving iron transporters Dmt1, TfR1, iron storage protein Fpn1, inflammatory markers Nf-kB, Tnf-α, Il-6, and hepcidin was performed. ResultsOur data indicate that excess iron supplementation for 30 weeks leads to decreased body weight, increased serum iron levels, and decreased RBC levels in iron fed Wistar rats. Morris water maze (MWM) studies after 30 weeks showed increased escape latency in the high iron dose group compared with the control group. Histological studies of the high iron dose group showed an iron accumulation in the liver and brain loss of cellular architecture, and cellular degeneration was observed. Excess iron treatment showed upregulation of the Dmt1 gene in iron metabolism and a remarkable increase in the Nf-kB gene in rat brain tissue. ConclusionThe results show chronic excess iron supplementation leads to iron accumulation in the liver, leading to inflammation in Wistar rats.

Correlation of anthropometric measurements with pretransfusion haemoglobin in transfusion dependent thalassemia major children

Background: The etio-pathogenesis of growth failure in transfusion dependent thalassemia major (TDTM) children is mainly because of chronic anemia, iron overload and endocrine complications. Aim was to determine the association between anthropometric measurements with pre-transfusion haemoglobin in TDTM children. Methods: Present cross-sectional study included total 55 children between 5-18 years of age who were diagnosed as TDTM. Mean pre transfusion hemoglobin of last 1 year was obtained from previous medical records. Anthropometric measurements like weight in kg and height in cm measured while body mass index (BMI) was calculated using standard formula in each patient. Weight for age, height for age, and BMI were plotted on WHO 2006 and Indian academy of paediatrics 2015 combined growth charts in terms of percentile. Data was analysed statistically. Results: Total 55 children of TDTM between 5-18 years of age were studied. The mean age was 10.42(4.07) years. The mean weight (kg), height (cm) and BMI was 23.76 (7.5), 123.94 (18.13) and 15.24 (1.76) respectively. Fifty-one (92.73%) children were having BMI less than 3rd centile (Underweight). Forty (93.02%) and 11 (91.66%) children between age group of 5-10 years and more than 10 years were underweight and was statistically significant (p<0.05). Total 50 (94.33%) children were having mean pre transfusion hemoglobin below 9 gm/dl who were underweight which was statistically significant. Conclusions: Low pre-transfusion hemoglobin is one of the risk factors for growth failure in children with TDTM and it should be maintained above 9 gm/dl may for normal growth in children with TDTM.

Dengue Fever with Hemolysis: Unmasking Beta-Thalassemia

Intravascular hemolysis is a rare but known complication of Dengue infection. Following is the description of a patient who presented with features of intravascular hemolysis with other sequelae of Dengue infection. Clinical stigmata of chronic iron overload led to a search for the aetiology of chronic hemolysis, which resulted in a diagnosis of non-transfusion-dependent beta-thalassemia.

Potential anticancer effect of free and nanoformulated Deferasirox for breast cancer treatment: in-vitro and in-vivo evaluation

Background Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects. Additionally, BC is recognized as one of the most resistant forms of malignancy to treatment. Consequently, there exists a critical need for innovative therapeutic agents that are both highly effective and exhibit reduced toxicity and side effects for patients. Deferasirox (DFX), an iron-chelating drug approved by the FDA for oral use, emerges as a promising contender in the fight against BC proliferation. DFX, primarily administered orally, is utilized to address chronic iron excess resulting from blood transfusions, and it is the inaugural treatment for chronic iron overload syndrome. However, DFX encounters limitations due to its poor water solubility. Aim This study aimed at incorporating DFX into lipid nanocapsules (DFX-LNCs) followed by investigating the anticancer effect of the DFX nanoform as compared to free DFX in-vitro and on an orthotopic BC mouse model in-vivo. Methods The DFX-LNCs was prepared and imaged using TEM and also characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI) using DLS. Moreover, drug release, cytotoxicity, and anticancer effect were assessed in-vitro, and in-vivo. Results The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC50 of 4.417 µg/ml and 16.114 µg/ml, respectively, while the plain LNCs didn’t show any cytotoxic effect on the 4T1 cell line (IC50 = 122.797 µg/ml). Besides, the apoptotic effect of DFX-LNCs was more pronounced than that of free DFX, as evidenced by Annexin V/PI staining, increased BAX expression, and decreased expression of BcL-2. Moreover, DFX-LNCs showed a superior antitumor effect in-vivo with potent antioxidant and anti-proliferative effects. Conclusion The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment.

Deferasirox: A comprehensive drug profile.

Deferasirox is an iron-chelating drug developed by Novartis company for treatment of diseases accompanied by chronic iron overload; such as β-thalassemia or sickle cell diseases. Owing to its advantages such as high affinity, specificity and wide therapeutic window, it is considered as first line treatment. The current chapter describes the physicochemical characteristics, mode of action, pharmacokinetics, therapeutic applications and synthetic methods for deferasirox. Moreover, it includes Fourier transform infrared spectrometry (FTIR) and nuclear magnetic resonance spectroscopy (NMR) analysis for its functional groups. In addition, the selected analytical methods are summarized to aid the analysts in their routine analysis of deferasirox.

Abstract B041: Understanding T-cell large granular lymphocytic leukemia: Diagnosis and treatment options

Abstract Introduction: T-cell large granular lymphocytic leukemia, or T-LGL leukemia, is rare cancer affecting T-cells and natural killer cells. It is characterized by the abnormal proliferation of mature T-cells expressing specific markers. Standard treatments involve immunosuppressive therapies. Understanding the diagnosis and treatment options is crucial for optimal care. Case Presentation: A 54-year-old male with chronic anemia and iron overload was initially diagnosed with myelodysplastic syndrome (MDS). Vidaza followed treatment with Danazol due to negative MDS and myeloproliferative neoplasm (MPN) results. Concerns of red cell aplasia led to corticosteroid and cyclosporin administration, discontinued during the COVID-19 outbreak. A subsequent biopsy revealed pure red cell aplasia, and the patient was prescribed Cyclosporin and later switched to Danazol. The patient underwent Anti-Thymocyte Globulin (ATG) treatment at a cancer center. A bone marrow biopsy confirmed T-LGL leukemia with abnormal CD8-positive T-cells. PCR analysis confirmed clonal T-cell proliferation. Cytogenetics and mutation analyses were negative. The patient is currently receiving Cyclosporin, prednisone, and Jadenu. Conclusion: This case highlights the challenges in diagnosing and managing T-LGL leukemia, a rare lymphoproliferative disorder. The patient's complex medical history and mimicking of other hematologic disorders underscore the need for a multidisciplinary approach. Individualized therapy based on clinical response is necessary due to limited treatment options. Further research and prospective trials are essential to establish a standard of care. Citation Format: Aliya M. Khan, Kierston R. Patterson, Raj Patel, Sophia Navajas Urisote. Understanding T-cell large granular lymphocytic leukemia: Diagnosis and treatment options [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B041.

Intracellular Iron Controls HSC Metabolism By Affecting Mitochondrial Fitness

Iron is an important source of reactive oxygen species (ROS) within the cell and recent evidence highlighted its role in regulating HSC self-renewal and differentiation. However, whether and how iron influences HSC metabolism is still undetermined. Cellular metabolism is a key regulator of HSC maintenance and HSCs adapt their metabolic state to their function. Quiescent HSCs have low energy requirements and depend on anaerobic glycolysis, whereas active HSCs require high energy for proliferation and differentiation thus enhancing oxidative phosphorylation (OXPHOS), glycolysis and fatty acid oxidation (FAO). To explore which metabolic pathways are triggered by intracellular iron levels, we took advantage of the thalassemic Hbb th3/+mice ( th3), characterized by chronic iron overload (IO). We previously demonstrated an impaired function of th3 HSCs due to persistence into altered BM niche ( Aprile et al., 2020). Th3 HSCs showed higher levels of intracellular free reactive iron (1.7±0.2 calcein MFI fold to wt, p<0.0001) and interestingly iron specifically accumulated in the mitochondria. As a result, mitochondria are impaired, with low mass and activity, as assessed by decreased mitochondrial membrane potential ( th3 1068±167 vs. wt 3215±686 MFI TMRE, p<0.05). These data, together with a reduced expression of mitochondrial biogenesis and mitophagy genes, indicate an accumulation of damaged mitochondria. To demonstrate a direct effect of iron on mitochondrial fitness in HSCs, we treated wt mice with iron dextran. Consistently, IO wt HSCs showed reduced mitochondrial activity following intracellular iron accumulation. Since mitochondria are the major site of cellular ATP production mostly through OXPHOS, we measured the metabolic state of HSCs in ß-thalassemia. ATP levels in sorted th3 HSCs was halved than the one in wt mice ( th3 3.7±0.3 vs. wt 9.8±2.6 ATP nM, p<0.01). Inhibition of OXPHOS by oligomycin lowered the ATP content in wt cells with a minor effect in th3 HSCs, thus indicating a reduced OXPHOS-dependent metabolism, despite their active cycling profile. Since mitochondria are damaged and OXPHOS and glycolysis are the two main metabolic pathways involved in cellular ATP generation, we hypothesized increased glycolytic dependency to compensate for reduced OXPHOS in th3 HSCs. Indeed, in these cells we observed a positive enrichment of glycolytic genes, such as Tpi1, Gapdh and Pklr, and a 1.4-fold higher glucose uptake ( th3 2401±85 vs. wt 1639±163 MFI 2NBDG, p<0.05). In vivo administration of the iron chelator DFO normalized intracellular iron content and rescued mitochondrial dysfunction in th3 mice, indicating the reversibility of mitochondrial defects. Moreover, HSCs from DFO-treated mice showed reduced glucose uptake, thus demonstrating that IO causes mitochondrial defects and metabolic adaptations of HSCs. Excess iron is expected to give rise to ROS and, consistently, th3 HSCs displayed high mitochondrial ROS (mtROS) levels ( th3 5205±459 vs. wt 2507±756 MFI MitoSOX, p<0.01). I n vivo reduction of mtROS by MitoQ administration restored mitochondrial activity and decreased glucose uptake. Remarkably, MitoQ rescued the quiescence and self-renewal ability of th3 HSCs, as shown by superior chimerism in secondary transplantation of HSCs from MitoQ-treated th3 donors in lethally irradiated recipients ( th3 HSC+MitoQ 81.7±1.6 vs. untreated th3 HSC 34.9±14.6 vs. % of chimerism, p<0.05), thus indicating that IO-derived ROS impair HSC function by affecting mitochondrial fitness and bioenergetics. Preliminary results confirmed intracellular IO and mitochondrial defects also in HSCs from Townes mice, a model of sickle cell anemia characterized by IO. Collectively, our study revealed that increased intracellular iron and ROS levels alter HSC metabolic programs by inducing mitochondrial dysfunction. Since mitochondria are defective, IO HSCs are unable to produce appropriate levels of ATP through OXPHOS and rely on glycolysis, despite their active cycling activity. Finally, the rescue of mitochondrial activity can restore the functional defects of th3 HSCs.

Adults with Transfusion-Dependent Thalassemia Have Variable Clinical Profiles Depending on Where They Receive Care: Thalassemia Treatment Center Vs Community

Introduction: Advances in the treatment of transfusion-dependent thalassemia (TDT) have decreased complications and improved survival. Established TDT guidelines have improved outcomes through regular red cell transfusions to maintain a pre-transfusion hemoglobin > 9-9.5 g/dL and chelation to maintain a serum ferritin < 1500 ng/mL, liver iron content < 5 mg/g dry weight and a cardiac T2*> 20 ms. Increased lifespan of individuals with TDT now necessitates adult hematology providers with capacity to manage uncomplicated thalassemia. While it is recommended that thalassemia care be provided through a multidisciplinary thalassemia treatment center (TTC), there are a limited number of TTCs in the United States. As a result many adults with TDT receive care in the community from hematologists with variable knowledge and experience with thalassemia. In this study, we thus sought to evaluate the prior care of patients referred to an adult TTC in order to determine if there was a significant difference in the care provided by a pediatric TTC compared to community hematologists. Methods: We evaluated adult patients (> 18 years old) with a diagnosis of TDT referred to the Penn Comprehensive Adult Thalassemia Program. Patients were either referred from the Children's Hospital of Philadelphia TTC via a dedicated transition program, or from community hematologists (Comm). Data collection was performed via manual chart review. Data collected included the mean of three consecutive pre-transfusion hemoglobin levels prior to the initial visit, serum ferritin, and most recent liver and cardiac iron quantitation by MRI. Results: Of the 94 patients with thalassemia referred to the adult program between 2013 and 2023, 54 had a diagnosis of TDT. Twenty-seven patients were referred each from the TTC and the community. At the initial adult thalassemia center visit, the median age was 38.5 years (TTC) and 28 years (Comm). More patients in the TTC group maintained a pre-transfusion Hgb > 9 g/dL (78% vs 52%). Serum ferritin trended lower in the TTC group (1725 vs 2629 ng/ml, p-value = 0.056). While 67% of the TTC group had a serum ferritin < 1500 ug/mL compared to 41% in the Comm group, there was no significant difference in the liver iron content between both groups (TTC 10.2 vs Comm 12.2 mg/g dry weight). However, 60% of the TTC group compared to 48% in the Comm group had a LIC < 5. Those followed at the TTC possibly have more cardiac iron with 4 vs 1 patient in the TTC vs Comm group having a T2* < 20 ms, likely reflective of more complicated patients being referred to the TTC. Conclusion : Patients managed by a TTC were more likely to be adequately transfused with serum ferritins < 1500 ng/mL. Maintaining a pre-transfusion hemoglobin > 9-9.5 g/dL and a serum ferritin < 1500 ng/mL are known to reduce long-term complications of chronic anemia, ineffective erythropoiesis and iron overload in thalassemia. Thus in order to improve long-term outcomes in patients with TDT, we propose that all adult hematology providers, regardless of care setting should aim to gain knowledge on the management of individuals with thalassemia and establish collaborative care relationships with experts in thalassemia care.

Glomerulotubular function in transfusion-dependent thalassemia children: a prospective cohort study

Introduction: Thalassemia is the most common hemoglobinopathy in Indonesia. Chronic anemia, iron overload, and treatment with iron chelating agents are factors that contribute to kidney dysfunction in children with transfusion-dependent thalassemia (TDT). Urine neutrophil gelatinase-associated lipocalin (uNGAL) and urine albumin-creatinine ratio (uACR) are markers of glomerular and tubular damage. Objectives: To analyze the glomerulotubular function in TDT children. Patients and Methods: This prospective cohort study recruited 40 TDT children aged ≤18 years old from thalassemia transfusion outpatient clinic, Dr. Cipto Mangunkusumo general hospital, Jakarta, Indonesia between February and June 2021. Disease history, treatment, and anthropometry were obtained during enrollment (T0). Blood and urine samples were taken at enrollment (T0) and at 1 (T1), 2 (T2), and 3 (T3) month follow-up appointments. Data analyzed were iron chelating agent, ferritin, hemoglobin, estimated glomerular filtration rate (eGFR ), uNGAL, uACR levels. Results: We observed kidney hyperfiltration in more than 30% of the participants. Transfusion volume was the most dominant factor for eGFR (β=-0.974, P=0.022) and uNGAL (β=0.872, P=0.015). A low-proportion of albuminuria was found with duration of disease as the predominant factor (β=-0.946, P=0.000). Deferiprone (DFP) and deferasirox (DFX) showed comparable association with all kidney biomarkers. Conclusion: The findings of this study indicate glomerular hyperfiltration in TDT children as the main early sign of glomerulotubular function impairment. In addition, a small proportion of proteinuria was also found in our study. Thus, both biomarkers should be part of long term kidney follow up in TDT children.

Haemochromatosis patients' research priorities: Towards an improved quality of life.

Chronic diseases are associated with a range of functional and psychosocial consequences that can adversely affect patients' quality of life (QoL). Haemochromatosis (HC) is a genetically heterogeneous disorder characterized by chronic iron overload that can ultimately lead to multiple organ dysfunction. Clinical diagnosis remains challenging due to the nonspecificity of symptoms and a lack of confirmatory genotyping in a substantial proportion of patients. Illness perception among HC patients has not been extensively investigated, lacking relevant information on how to improve their QoL. We present the results of the first worldwide survey conducted in nearly 1500 HC respondents, in which we collected essential demographic information and identified the aspects that concern HC patients the most. Out of all the participants, 45.3% (n = 676) voiced their concern about physical and psychological consequences such as HC-related arthropathies, which can ultimately affect their social functioning. A similar proportion of patients (n = 635, 42.5%) also consider that better-informed doctors are key for improved HC disease management. Taking a patient-centred approach, we expose differences in patients' disease perspective by social and economic influences. We identify potential targets to improve patients' health-related QoL and reflect on strategic measures to foster gender equity in access to health resources. Finally, we make a call for a highly coordinated effort across a range of public policy areas to empower participants in the HC research process and design. Nearly 1500 patients with hereditary HC responded to an anonymized online survey in which research and clinical priorities were addressed regarding this chronic and rare disease.

Growth profile of children with beta-thalassemia major

Background: Retarded growth in thalassemic patient is complex and multi-factorial, it includes chronic hypoxia secondary to anemia when pre-transfusion haemoglobin is below 9 g/dl. Development of secondary sexual characteristics in thalassemic children is markedly delayed as compared to their non-thalassemic siblings and to the expected development criteria due to chronic hypoxia and iron overload. The main objective of the present study is to monitor the growth of these patients longitudinally Methods: This was a observational, cross sectional field study in Pune, Maharashtra. Result: Patients with beta-thalassemia major on regular blood transfusions have growth failure, deranged liver function and hypocalcaemia in conjunction with high serum ferritin levels Conclusions: Beta thalassemia major, having the potential of leading to multisystemic complications, is a chronic disease that should be treated and followed-up by a multidisciplinary approach.

Erythroferrone exacerbates iron overload and ineffective extramedullary erythropoiesis in a mouse model of β-thalassemia.

β-thalassemia is characterized by chronic hepcidin suppression and iron overload, even in patients who have not undergone transfusion. The HbbTh3/+ (Th3/+) mouse model of nontransfusion-dependent β-thalassemia (NTDBT) partially recapitulates the human phenotype but lacks chronic hepcidin suppression, progressive iron accumulation into adulthood, or the interindividual variation of the rate of iron loading observed in patients. Erythroferrone (ERFE) is an erythroid regulator that suppresses hepcidin during increased erythropoiesis. ERFE concentrations in the sera of patients with NTDBT correlate negatively with hepcidin levels but vary over a broad range, possibly explaining the variability of iron overload in patients. To analyze the effect of high ERFE concentrations on hepcidin and iron overload in NTDBT, we crossed Th3/+ mice with erythroid ERFE-overexpressing transgenic mice. Th3/ERFE-transgenic mice suffered high perinatal mortality, but embryos at E18.5 showed similar viability, appearance, and anemia effects as Th3/+ mice. Compared with Th3/+ littermates, adult Th3/ERFE mice had similarly severe anemia but manifested greater suppression of serum hepcidin and increased iron accumulation in the liver, kidney, and spleen. The Th3/ERFE mice had much higher concentrations of serum ERFE than either parental strain, a finding attributable to both a higher number of erythroblasts and higher production of ERFE by each erythroblast.Th3/+ and Th3/ERFE mice had similar red blood cell count and shortened erythrocyte lifespan, but Th3/ERFE mice had an increased number of erythroid precursors in their larger spleens, indicative of aggravated ineffective extramedullary erythropoiesis. Thus, high ERFE concentrations increase the severity of nontransfusional iron overload and ineffective erythropoiesis in thalassemic mice but do not substantially affect anemia or hemolysis.

Clinical features and risk factors of renal dysfunctions in thalassemic patients.

Chronic anemia, iron overload, and iron chelation therapy are the main contributing factors for renal complications in thalassemia, e.g., nephrolithiasis, glomerular disease, and renal tubular dysfunction. The prevalence and associated factors for developing renal dysfunctions in Thai patients with thalassemia, however, remained limited. This study aimed to determine the prevalence and risk factors of renal dysfunctions in patients with thalassemia. A cross-sectional study was conducted on adult patients with thalassemia disease at Srinagarind Hospital, Khon Kaen University, Thailand. All patients were evaluated for complete blood count, blood chemistry, urinalysis, and urine biochemistry. Renal tubular dysfunction was defined as existing in at least one of the following parameters including; proteinuria, hypercalciuria, hypouricemia with uricosuria, or hypophosphatemia with phosphaturia. Logistic regression analysis was used to identify associated factors for renal dysfunctions. Of 105 patients, renal tubular dysfunction was found in 60 patients (57.1%). In multivariate analysis of the clinical risk factors for renal tubular dysfunction in thalassemia patients, age per 10year increase (adjusted odds ratio [AOR] = 1.4, 95% CI: 1.0-2.0, pvalue 0.01) and Hb E/beta-thalassemia (AOR = 3.6, 95% CI: 1.3-10.3, pvalue 0.01) were statistically proven to be associated with renal tubular dysfunction. Hyperuricosuria was a significantly associated factor for microhematuria. (AOR = 2.9, 95% CI: 1.1-8.0, pvalue 0.03). Renal dysfunctions are prevalent in thalassemia patients, with older age and Hb E/beta-thalassemia genotype as significant risk factors for renal tubular dysfunction. Hyperuricosuria is a risk factor for microhematuria. Renal dysfunctions should be recognized and monitored in aging patients with Hb E/beta-thalassemia.

Iron overload modulates follicular microenvironment via ROS/HIF-1α/FSHR signaling

Iron is essential for the health of reproductive system, and women with iron overload suffer from ovarian dysfunction and lack effective treatment in fertility preservation. However, the underlying mechanism of the detrimental effects of iron overload on ovarian function remains ambiguous. Here, we confirmed the excess iron in the circumjacent follicle near endometriomas, which negatively impacted the oocyte development in the affected ovaries. Further, by integrating cell line and chronic iron overload mice model, we demonstrated that iron overload can function as a ROS inducer to amplify mitochondria damage, which significantly elevated the release of cytochrome C and ultimately induced the apoptosis of granular cells. Besides, for the first time, our findings revealed that disruption of HIF-1α/FSHR/CYP19A1 signaling was critical for decreased estrogen synthesis of granular cells in response to iron overload, which can lead to apparent oocyte maldevelopment and subfertility. Overall. this study uncovered that iron overload modulated the follicular microenvironment and generated a deleterious effect on female infertility via ROS/HIF-1α/FSHR signaling. These results might provide potential implications for future clinical risk management of patients with endometrioma and hemopathy.