Impact Of Iron Overload Research Articles

Impact of iron overload on incidence of diabetes mellitus, cardiac disease, and death in congenital hemolytic anemias

AbstractIron overload and its complications are recognized to be morbid and fatal in patients with congenital hemolytic anemias. In patients with iron overload caused by congenital hemolytic anemias, there has been no study evaluating the dose-response relationship between serum markers of iron overload and long-term health complications. Filling this critical gap was the aim of this study. We evaluated outcomes in a 5-hospital observational cohort study of adults with congenital hemolytic anemias diagnosed with iron overload over a 40-year period and assessed associations between depth and duration of iron overload, as well as clinical complications including diabetes, heart disease, malignancy, bone density disorders, and death. One hundred seventy patients with congenital hemolytic anemias developing iron overload were included. More years experienced of ferritin >500 ng/mL and >1000 ng/mL were associated with the development of diabetes mellitus, with adjusted odds ratios (ORs) of 2.61 per 10-year increment (P = .034) and 3.24 per 10-year increment (P = .035), respectively. More years experienced of ferritin >1000 ng/mL were associated with the development of heart disease (adjusted OR, 5.30 per 10-year increment; P = .002). Peak lifetime ferritin of >10 000 ng/mL was associated with sixfold odds of developing diabetes (P = .04) and 10-fold odds of developing heart disease (P = .007). A peak ferritin >10 000 ng/mL was associated with an increase in mortality (adjusted OR, 6.77; P = .033). In conclusion, iron overload in patients with congenital hemolytic anemias is associated with diabetes mellitus, cardiac disease, and death. Prolonged exposure to relatively modest iron overload was associated with nearly threefold increased odds of diabetes.

Dietary Iron Overload Triggers Hepatic Metabolic Disorders and Inflammation in Laying Hen.

Iron, an essential trace element, is involved in various physiological processes; however, consumption of excessive iron possesses detrimental effects. In practical feed production, the iron content added to feeds often far exceeds the actual demand, resulting in an excess of iron in the body. The liver as a central regulator of iron homeostasis is susceptible to damage caused by disorders in iron metabolism. A model of hepatic iron overload in laying hens was developed in this study by incorporating iron into their diet, and the specific mechanisms underlying iron overload-induced hepatic injury were investigated. Firstly, this study revealed that a high-iron diet resulted in hepatic iron overload, accompanied by impaired liver function. Next, assessment of oxidative stress markers indicated a decrease in activities of T-SOD and CAT, coupled with an increase in MDA content, pointing to the iron-overloaded liver oxidative stress. Thirdly, the impact of iron overload on hepatic glycolipid and bile acid metabolism-related gene expressions were explored, including PPAR-α, GLUT2, and CYP7A1, highlighting disruptions in hepatic metabolism. Subsequently, analyses of inflammation-related genes such as iNOS and IL-1β at both protein and mRNA levels demonstrated the presence of inflammation in the liver under conditions of dietary iron overload. Overall, this study provided comprehensive evidence that dietary iron overload contributed to disorders in glycolipid and bile acid metabolism, accompanied by inflammatory responses in laying hens. Further detailing the specific pathways involved and the implications of these findings could offer valuable insights for future research and practical applications in poultry nutrition.

Renal-specific loss of ferroportin disrupts iron homeostasis and attenuates recovery from acute kidney injury.

Chronic kidney disease is increasing at an alarming rate and correlates with the increase in diabetes, obesity, and hypertension that disproportionately impact socioeconomically disadvantaged communities. Iron plays essential roles in many biological processes including oxygen transport, mitochondrial function, cell proliferation, and regeneration. However, excess iron induces the generation and propagation of reactive oxygen species, which lead to oxidative stress, cellular damage, and ferroptosis. Iron homeostasis is regulated in part by the kidney through iron resorption from the glomerular filtrate and exports into the plasma by ferroportin (FPN). Yet, the impact of iron overload in the kidney has not been addressed. To test more directly whether excess iron accumulation is toxic to kidneys, we generated a kidney proximal tubule-specific knockout of FPN. Despite significant intracellular iron accumulation in FPN mutant tubules, basal kidney function was not measurably different from wild type kidneys. However, upon induction of acute kidney injury (AKI), FPN mutant kidneys exhibited significantly more damage and failed recovery, evidence for ferroptosis, and increased fibrosis. Thus, disruption of iron export in proximal tubules, leading to iron overload, can significantly impair recovery from AKI and can contribute to progressive renal damage indicative of chronic kidney disease. Understanding the mechanisms that regulate iron homeostasis in the kidney may provide new therapeutic strategies for progressive kidney disease and other ferroptosis-associated disorders.NEW & NOTEWORTHY Physiological iron homeostasis depends in part on renal resorption and export into the plasma. We show that specific deletion of iron exporters in the proximal tubules sensitizes cells to injury and inhibits recovery. This can promote a chronic kidney disease phenotype. Our paper demonstrates the need for iron balance in the proximal tubules to maintain and promote healthy recovery after acute kidney injury.

Diabetes mellitus progression in β-thalassaemia major patients: The impact of iron overload

ABSTRACT Regular blood transfusion therapy and enhanced iron absorption in patients with β-thalassemia major lead to progressive accumulation of iron in the patient’s tissues. Iron overload disrupts the function of pancreatic β-cell, deteriorates insulin resistance, increases blood glucose levels, and precipitates diabetes mellitus (DM). A family history of DM, obesity, sedentary lifestyle, and age increase the risk of DM in β-thalassemia patients. The prevalence of DM among individuals with β-thalassemia major is on the rise despite considerable screening and management efforts. Therefore, more research is still warranted to fully understand the molecular underpinnings linking β-thalassemia major and the onset and progression of DM to develop more robust screening and management approaches. In this context, no reliable biomarkers are currently available to predict or detect DM in such patients. In this review, we elaborate on key tentative links between thalassemia and DM and expand on established metabolic alterations that associate with DM in patients with β-thalassemia major. The review also addresses the prevalence rates and patient management strategies and underscores the need for identifying DM-related predictive and diagnostic biomarkers in β-thalassemia major patients.

Impact of Iron Overload and Iron Chelation with Deferasirox on Outcomes of Patients with Severe Aplastic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation

Patients suffering from severe aplastic anemia (SAA) need frequent blood transfusions during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these transfusions can result in an excess of iron in the body tissues, which can negatively impact the success of transplantation. This study aimed to examine the impact of pretransplantation iron overload (IO) on the outcomes of allo-HSCT in patients with SAA. It also investigated whether iron chelation (IC) therapy is necessary to enhance transplantation outcomes in SAA patients by providing guidelines for determining when excess iron should be chelated. The study consisted of 2 parts. In cohort 1, which was retrospective and conducted from April 2012 to December 2018, SAA patients receiving their first allo-HSCT were divided into 2 groups based on their pretransplantation serum ferritin (SF) level: the IO group (SF >1000 ng/mL; n=17) and the non-IO group (SF ≤1000 ng/mL; n=48). Cohort 2, a prospective clinical trial conducted from January 2019 to July 2020, included SAA patients diagnosed with IO who were treated with IC therapy using deferasirox at a dose of 10 to 30 mg/kg. Patients were separated into 2 groups based on their pretransplantation SF level: the IC success (ICsuccess) group (SF ≤1000 ng/mL; n=18) and the IC failure (ICfailure) group (SF >1000 ng/mL; n=28). All participants were evaluated for the correlation between pretransplantation SF level and transplantation outcomes. A P value <.05 was considered statistically significant. There was no significant difference in the speed of engraftment among the 3 cell lineages or in the incidence of 100-day grade II-IV acute graft-versus-host disease (aGVHD), grade III-IV aGVHD, or 3-year chronic GVHD between the 2 groups in both cohorts. Of note, however, in cohort 1, both 1-year overall survival (OS) (41.2% versus 83.3%; P < .001) and 3-year OS (35.3% versus 83.3%; P < .001) were significantly worse in the IO group. Furthermore, 180-day transplantation related mortality (TRM) (47.1% versus 14.6%; P=.005) and 1-year TRM (52.9% versus 16.7%; P=.002) were significantly higher in the IO group. The IO group was significantly associated with inferior 3-year OS in both univariate and multivariate analyses. In cohort 2, 1-year OS (88.9% versus 42.9%; P=.003) and 3-year OS (83.3% versus 42.9%; P=.007) were significantly better in the ICsuccess group, whereas 180-day TRM (11.1% versus 39.3%; P=.040) and 1-year TRM (11.1% versus 57.1%; P=.003) were significantly lower in the ICsuccess group. These differences were confirmed in both univariate and multivariate analyses. This study involving 2 cohorts shows that pre-HSCT IO has a negative impact on transplantation outcomes in SAA patients. Chelating excess iron with an SF level <1000 ng/mL was found to be necessary and could potentially improve the outcomes.

The Evolution of Iron-Related Comorbidities and Hospitalization in Patients with Hemochromatosis: An Analysis of the Nationwide Inpatient Sample.

Hemochromatosis, either hereditary hemochromatosis (HH) or secondary hemochromatosis, consists of the accumulation of iron in the liver, heart, and other organs. It leads to end-organ damage in a proportion of affected subjects. Although liver-related morbidity (cirrhosis and hepatocellular carcinoma [HCC]) and mortality are well established, the frequency of these complications remains controversial. The aim of this study is to examine the rate of hospitalization and the incidence of iron overload-related comorbidities in patients with hemochromatosis between the years of 2002 and 2010. We queried the Nationwide Inpatient Sample (NIS) database from the year 2002 to 2010. We included adults (age ≥18 years) and used the ICD-CM 9 code 275.0x to identify hospitalized patients with a diagnosis of hemochromatosis. Data analysis for this study was generated using SAS software version 9.4. A total of 168,614 hospitalized patients between 2002 and 2010 had a diagnosis of hemochromatosis. The majority were males (57%) with a median age of 54 years (37-68), with a predominance of white patients (63.3%) followed by black (26.8%). The rate of hospitalization among patients with hemochromatosis increased by 79% between the years 2002 and 2010 (34.5/100,000 in 2002 vs 61.4/100,000 in 2010). The main associated diagnoses were diabetes mellitus (20.2%), cardiac disease, including arrhythmias (14%) and cardiomyopathy (dilated 3.8%; peri-, endo-, myocarditis 1.3%), liver cirrhosis (8.6%), HCC (1.6%), and acute liver failure (0.81%). Of note, HCC was associated with cirrhosis in 1188 patients (43% of HCC patients) and male sex (87%). Diagnostic biopsies were performed in 6023 (3.6%) of those patients and liver transplant was performed in 881 (0.5%). In-hospital mortality occurred in 3638 (2.16%) patients. In this large database study, we found a rising trend in hospitalization for hemochromatosis, possibly due to the increased recognition of this entity and billing for the condition. The incidence of cirrhosis in hemochromatosis was found to be similar to other studies (8.6% vs 9%). However, the rate of HCC was lower than previous reports (1.6% vs 2.2%-14.9%), and only 43% of HCC was associated with cirrhosis. This raises important pathophysiologic questions regarding the impact of iron overload in HCC. There has been an increase in the rate of hospitalization for patients with a diagnosis of hemochromatosis. This may be related to an increased recognition of hemochromatosis as the underlying etiology for conditions such as diabetes, cardiomyopathy, cirrhosis, and HCC. Further prospective studies are needed to clarify the burden of liver disease in HH and secondary iron overload.

Impact of iron overload on poor graft function after allo-HSCT in a patient with transfusion-dependent low-risk MDS: A case report and literature review.

Poor graft function (PGF) occurs in 5% to 27% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high life-threatening complications. The etiology of PGF is complex and multifactorial, and iron overload (IOL) is considered as a predictive factor. A 45-years-old woman who was diagnosed as low-risk myelodysplastic syndrome in 2012 has been transfusion dependent and developed severe IOL. Due to transfusion dependency and also ineffective erythropoiesis, this patient was diagnosed as IOL and developed PGF after allo-HSCT. Deferasirox (20mg/kg/d) was administered regularly after allo-HSCT for 2 years. Hematopoiesis was gradually recovered during iron chelation therapy treatment after allo-HSCT and PGF was reverted. IOL, as a prognostic factor for PGF, is a common problem in Transfusion dependent myelodysplastic syndrome patients undergoing HSCT. IOL issues should be considered at the time of diagnosis and throughout the treatment course for patients who are potential candidates for HSCT.

Iron overload reduces adiponectin receptor expression via a ROS/FOXO1‐dependent mechanism leading to adiponectin resistance in skeletal muscle cells

Iron overload (IO) is a common yet underappreciated finding in metabolic syndrome (MetS) patients. With the prevalence of MetS continuing to rise, it is imperative to further elucidate cellular mechanisms leading to metabolic dysfunction. Adiponectin has many beneficial effects and is a therapeutic target for the treatment of MetS and cardiovascular diseases. IO positively correlates with reduced circulating adiponectin levels yet the impact of IO on adiponectin action is unknown. Here, we established a model of IO in L6 skeletal muscle cells and found that IO-induced adiponectin resistance. This was shown via reduced p38 mitogen-activated protein kinase phosphorylation in response to the small molecule adiponectin receptor (AdipoR) agonist, AdipoRon, in presence of IO. This correlated with reduced messenger RNA and protein levels of AdipoR1 and its facilitative signaling binding partner, APPL1. IO caused phosphorylation, nuclear extrusion, and thus inhibition of FOXO1, a known transcription factor regulating AdipoR1 expression. The antioxidant N-acetyl cystine attenuated the production of reactive oxygen species (ROS) by IO, and blunted its effect on FOXO1 phosphorylation and removal from the nucleus, as well as subsequent adiponectin resistance. In conclusion, our study identifies a ROS/FOXO1/AdipoR1 axis as a cause of skeletal muscle adiponectin resistance in response to IO. This new knowledge provides insight into a cellular mechanism with potential relevance to disease pathophysiology in MetS patients with IO.

Impact of iron overload by transfusion on survival and leukemia transformation of myelodysplastic syndromes in a single center of China

ABSTRACT Introduction Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases which are prone to progress into acute myeloid leukemia (AML). Iron overload (IOL) caused by transfusion occurred in most MDS patients. But how IOL influences MDS progression has not been clarified yet. Methods Herein, we collected clinical data from 143 MDS patients to investigate the impacts of IOL on patients survival and AML transformation. Results We found that median survival time, 3-year survival rate, leukemia-free survival (LFS) time were significantly shorter in patients with IOL than those with non-iron overload (NIOL) (P = 0.040; P = 0.044; P = 0.037). Besides, IOL was more likely to be found in higher-risk subgroups (assessed by IPSS and WPSS) of MDS patients which also promoted 2-year AML transformation. Furthermore, the serum ferritin (SF) was significantly correlated with the overall survival (OS) of MDS patients (r = −0.311, P < 0.05). The concentrations of both intracellular iron and reactive oxygen species (ROS) in CD34+ cells of bone marrow were higher in the IOL group than the NIOL group, respectively (P = 0.0426; P = 0.0185). Moreover, ROS level was closely correlated with the percentage of bone marrow blasts (r = 0.7200, P = 0.0370). Collectively, IOL threatened the survival of MDS patients and promoted AML transformation. Conclusion Elevated intracellular iron and ROS in CD34+ cells of bone marrow could accelerate the abnormal proliferation of blasts.

Prognostic Impact of Iron Overload and Iron Chelation in Myelodysplastic Syndromes

Prognostic Impact of Iron Overload and Iron Chelation in Myelodysplastic Syndromes

Impact of iron overload on bone remodeling in thalassemia.

Iron overload, a state with excessive iron storage in the body, is a common complication in thalassemia patients which leads to multiple organ dysfunctions including the bone. Iron overload-induced bone disease is one of the most common and severe complications of thalassemia including osteoporosis. Currently, osteoporosis is still frequently found in thalassemia even with widely available iron chelation therapy. Relevant publications published before December 2019 in PubMed database were reviewed. Both pre-clinical studies and clinical trials were obtained using iron overload, thalassemia, osteoporosis, osteoblast, and osteoclast as keywords. Increased ROS production is a hallmark of iron overload-induced impaired bone remodeling. At the cellular level, oxidative stress affects bone remodeling by both osteoblast inhibition and osteoclast activation via many signaling pathways. In thalassemia patients, it has been shown that bone resorption was increased while bone formation was concurrently reduced. In this review, reports on the cellular mechanisms of iron overload-associated bone remodeling are comprehensively summarized and presented to provide current understanding this pathological condition. Moreover, current treatments and potential interventions for attenuating bone remodeling in iron overload are also summarized to pave ways for the future discoveries of novel agents that alleviate this condition.

The Impact of Iron Overload and Ferroptosis on Reproductive Disorders in Humans: Implications for Preeclampsia.

Iron is an essential element for the survival of most organisms, including humans. Demand for iron increases significantly during pregnancy to support growth and development of the fetus. Paradoxically, epidemiologic studies have shown that excessive iron intake and/or high iron status can be detrimental to pregnancy and is associated with reproductive disorders ranging from endometriosis to preeclampsia. Reproductive complications resulting from iron deficiency have been reviewed elsewhere. Here, we focus on reproductive disorders associated with iron overload and the contribution of ferroptosis—programmed cell death mediated by iron-dependent lipid peroxidation within cell membranes—using preeclampsia as a model system. We propose that the clinical expressions of many reproductive disorders and pregnancy complications may be due to an underlying ferroptopathy (elemental iron-associated disease), characterized by a dysregulation in iron homeostasis leading to excessive ferroptosis.

The Impact of Iron Overload in Patients with Acute Leukemia and Myelodysplastic Syndrome on Hepatic and Endocrine functions.

Patients with hematologic malignancies undergoing chemotherapy and requiring blood transfusion usually have an elevated serum ferritin. These findings have led to the suggestion that iron overload is common and may have deleterious effects in these patients. However, the relationship between serum ferritin and parenchymal iron overload in such patients is unknown. Therefore, we measured the liver iron content (LIC) by the FerriScan® method and investigated the liver function and some endocrine tests in 27 patients with acute leukemia (AL) or myelodysplastic syndromes (MDS). Using FerriScan® method, the normal mean LIC levels are: 4.3±2.9 mg Fe/g dry weight (d.w.). In our patients, the mean serum ferritin level was 1965±2428 ng/mL. In our patients, the mean total iron in the blood received by them was 7177±5009 mg. In 6 out of 27 patients LIC was >7 mg Fe/g d.w. and in 11/27 serum ferritin was >1000 ng/ml. Measuring fasting blood glucose revealed 3/27 with diabetes mellitus and 4/27 with impaired fasting glucose (IFG). All patients had normal serum concentrations of calcium, parathormone (PTH), free thyroxine (FT4) and thyrotropin (TSH). Four patients had elevated serum alanine transferase (ALT). LIC was correlated significantly with ferritin level (r=0.5666; P<0.001) and the cumulative amount of iron in the transfused blood (r=0.523; P<0.001). LIC was correlated significantly with ALT (r=0.277; P = 0.04) and fasting blood glucose (FBG) was correlated significantly with the amount of iron transfused (r=0.52, p<0.01) and ALT level (r=0.44; P<0.01). The age of patients did not correlate with LIC, FBG or ALT. In conclusions, these results contribute to our understanding of the prevalence of dysglycemia and hepatic dysfunction in relation to parenchymal iron overload in patients with hematologic malignancies undergoing chemotherapy and requiring blood transfusions. (www.actabiomedica.it)

The Impact of Iron Overload in Acute Leukemia: Chronic Inflammation, But Not the Presence of Nontransferrin Bound Iron is a Determinant of Oxidative Stress.

In the literature, studies on the oxidant effects of nontransferrin bound iron [NTBI (eLPI assay)] during chemotherapy of acute lymphoblastic leukemia and acute myeloblastic leukemia are lacking. We established NTBI and oxidative stress determinants (OSD), iron parameters, high-sensitive C-reactive protein (hs-CRP) levels, liver tests, cumulative chemotherapeutic doses, and transfused blood in 36 children with acute leukemia throughout chemotherapy. These parameters were determined at the beginning and end of chemotherapy blocks (11 time points) and in 20 healthy children using enzyme-linked immunosorbent assay, and colorimetric and fluorometric enzymatic methods. In acute lymphoblastic leukemia, NTBI, OSD, and hs-CRP were higher than controls at 4/11, 7/11, and 9/11 time points (P<0.05). At 3 time points, NTBI and OSD concurrently increased. Ferritin, soluble transferrin receptor, serum iron, and transferrin saturation were higher than in controls at 5 to 11/11 time points (P<0.05). Those with NTBI had higher iron parameters than those without NTBI (P<0.05), but showed similar OSD, hs-CRP, liver enzymes, cumulative chemotherapeutics, and transfused blood (P>0.05). OSD did not correlate with NTBI, but correlated with hs-CRP. In conclusion, NTBI is a poor predictor of OSD in acute leukemia possibly because of the heterogeneity of NTBI and chronic inflammation. Further studies are needed to delineate the pathophysiology of these diseases.

Hypogonadotropic hypogonadism in men with hereditary hemochromatosis

Hereditary hemochromatosis is a genetic disease that progresses silently. This disease is often diagnosed late when complications appear. Hypogonadotropic hypogonadism (HH) is one of the classical complications of hemochromatosis. Its frequency is declining probably because of earlier diagnosis and better informed physicians. Certain symptoms linked to HH can have an impact on a patient’s sexuality, such as decreased libido, erectile dysfunction, and impairment of ejaculation, as well as on his reproductive capacities.This review is based on an online search in English, French and German language publications found in PubMed/Medline, up to 23 September 2016 using the following key word: Male infertility, Hypogonadotropic Hypogonadism, Hereditary Hemochromatosis.Thirty-four papers met these inclusion criteria. This review describes the impact of iron overload on male fertility, resulting in hypogonadotropic hypogonadism and proposes treatment modalities.

258 - Risks for Infection in Patients with Myelodysplastic and Myelodysplastic/Myeloproliferative Syndromes: Impact of Iron Overload

258 - Risks for Infection in Patients with Myelodysplastic and Myelodysplastic/Myeloproliferative Syndromes: Impact of Iron Overload

Toxicity of iron overload and iron overload reduction in the setting of hematopoietic stem cell transplantation for hematologic malignancies

Iron is an essential element for key cellular metabolic processes. However, transfusional iron overload (IOL) may result in significant cellular toxicity. IOL occurs in transfusion dependent hematologic malignancies (HM), may lead to pathological clinical outcomes, and IOL reduction may improve outcomes. In hematopoietic stem cell transplantation (SCT) for HM, IOL may have clinical importance; endpoints examined regarding an impact of IOL and IOL reduction include transplant-related mortality, organ function, infection, relapse risk, and survival. Here we review the clinical consequences of IOL and effects of IOL reduction before, during and following SCT for HM. IOL pathophysiology is discussed as well as available tests for IOL quantification including transfusion history, serum ferritin level, transferrin saturation, hepcidin, labile plasma iron and other parameters of iron-catalyzed oxygen free radicals, and organ IOL by imaging. Data-based recommendations for IOL measurement, monitoring and reduction before, during and following SCT for HM are made.

Iron Metabolism before Allo-HSCT in Patients with Acute Leukemia and Impact of Iron Overload on Transplantation

▪Objective: Iron overload is common in patients with acute leukemia who undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT). We performed a comprehensive analysis of iron parameters to assess these patients' iron metabolism, and studied the prognostic impact of pretransplant iron overload on the outcome of transplantation.Methods: In this retrospective study, we studied 124 patients undergoing myeloablative allo-HSCT between 2012 and 2014. Serum iron (SI), serum ferritin (SF), hepcidin (Hepc) and soluble transferrin receptor (sTfR) were measured before transplant. We analyzed the effect of elevated pretransplant ferritin on acute graft versus host disease (aGVHD), infectious complications, overall survival (OS) and non-relapse mortality (NRM).Results: Date of 124 patients (including 56 cases of acute lymphocytic leukemia and 68 cases of acute myeloid leukemia) were analyzed. Median SI, SF, Hepc and sTfR values were 12.15 umol/L, 667.05 ng/ml, 369.50 ng/L and 7.69 ng/ml, respectively. Iron overload (defined as SF>1000 ng/ml) were observed in 27.42% of patients. Pretransplant iron overload was significantly associated with increased risk of bacterial infections during the early post-transplant period, and with reduced risk of aGVHD. Pretransplant iron overload increased NRM and reduced OS, but there were no significant differences.Conclusion: Patients with acute leukemia regularly develop iron overload before they undergoing allo-HSCT. Pretransplant iron overload was correlated with transplantation outcome. DisclosuresNo relevant conflicts of interest to declare.

Iron overload by Superparamagnetic Iron Oxide Nanoparticles is a High Risk Factor in Cirrhosis by a Systems Toxicology Assessment

Superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent have been widely used in magnetic resonance imaging for tumor diagnosis and theranostics. However, there has been safety concern of SPIONs with cirrhosis related to excess iron-induced oxidative stress. In this study, the impact of iron overload by SPIONs was assessed on a mouse cirrhosis model. A single dose of SPION injection at 0.5 or 5 mg Fe/kg in the cirrhosis group induced a septic shock response at 24 h with elevated serum levels of liver and kidney function markers and extended impacts over 14 days including high levels of serum cholesterols and persistent low serum iron level. In contrast, full restoration of liver functions was found in the normal group with the same dosages over time. Analysis with PCR array of the toxicity pathways revealed the high dose of SPIONs induced significant expression changes of a distinct subset of genes in the cirrhosis liver. All these results suggested that excess iron of the high dose of SPIONs might be a risk factor for cirrhosis because of the marked impacts of elevated lipid metabolism, disruption of iron homeostasis and possibly, aggravated loss of liver functions.

The Impact of Iron Overload on Transplant-Related Complications and Prognosis of Acute Leukemias.

The impacts of serum iron parameters and/or radiological evidence of systemic iron overload on the prognosis of hematopoietic stem cell transplantation (HSCT) in acute leukemia are controversial. Unfortunately, some of the studies evaluating iron overload in transplant setting did not precisely show the patients with iron overload, mainly due to ignoring consideration of transferrin saturation along with hyperferritinemia for elimination of non-iron overload etiologies of hyperferritinemia. The aim of this study is to assess the effect of iron overload on transplantation related complications and prognosis in acute leukemia. Patients who undergone allogeneic HSCT for acute leukemia in Hacettepe University Medical School Department of Hematology were screened retrospectively in order to find cases with serum iron tests within 9 months before transplant. The endpoints investigated were overall and disease-free survivals, acute and chronic graft-versus-host disease and veno-oclussive disease (VOD). There were 84 patients suitable for inclusion. When various ferritin plus transferrin saturation (TS) cut-off values were investigated for a possible relationship with major transplant-related complications/results only ferritin> 2000 plus TS> 45% was found to have an association with VOD at borderline significance (p= 0.067). In conclusion, we observed a non-significant borderline relationship between iron overload and post-transplant VOD. We did not confirm other post-transplant complications reported in the literature. It must be noticed that although many studies intended to investigate the relationship between iron status and transplant outcomes, only a few of them have really looked for the effect of iron overload.