Secondary Iron Overload in Pediatric Hematology: the Priority of Free-Breathing Liver Study at 3.0 T Magnetic Resonance Scanner in Children with Severe Iron Overload

The aim of the study was to compare the effectiveness and scanning features of iron detection in the liver based on 3T MR scanner data using a breath holding and free breathing sequences in children with iron overload. 108 patients aged of 3 to 17 years with secondary iron overload associated with the regular blood transfusions underwent an MRI study on a 3.0 T MR scanner using specialized sequences for obtaining relaxometric maps: 3T-mGRE and 3T-uTE. The quality of the images received by the 3T-mGRE and 3T-uTE sequences was assessed by determining the signal-to-noise ratio (SNR). The SNR of 3T-uTE was found to be 8 times higher than the SNR of 3T-mGRE. In addition, it was found that for patients with an iron overload less than 25 mg/g the 3T-mGRE and 3T-uTE sequences showed the same efficacy in iron detection in the liver (r = 0.99, p = 0.54). The concentration of iron in the liver in patients with extremely severe iron overload could be calculated only using 3T-uTE relaxometric maps due to the high approximation error of the results obtaining by 3T-mGRE maps. These data demonstrate the possibility of using the 3T-mGRE sequence to determine the concentration of iron in the liver below 25 mg/g. However, with extremely severe iron overload, it is better to use the 3T-uTE sequence.

Could the Crosstalk Between Mdscs and Tregs Have a Role in β-thalassemia?

Background: Secondary-iron overload, alloimmunization, and increased risk of infections are common complications in β-thalassemia major (BTM) patients. Tregs and myeloid-derived suppressor cells (MDSCs) play an essential role in preventing excessive immune responses. This research aimed to investigate the interaction between Tregs and MDSCs in BTM patients and their relation with disease severity.Methods: This case-control study included 26 patients with BTM and 23 healthy age- and sex-matched controls. All patients were investigated for complete blood picture, serum ferritin, and flow cytometric analysis of peripheral blood to detect Tregs, MDSCs, and MDSC subsets.Results: A significant increase was observed in the frequencies of Tregs and MDSCs, particularly MO-MDSCs, in the patients compared with the controls. These cells also showed direct relations with ferritin and TLC and an inverse association with hemoglobin. Furthermore, a positive correlation was seen between Tregs and each of the total MDSCs and MO-MDSCs. Conclusion: Our findings highlight the role Tregs and MDSCs cooperatively plays in the BTM and their importance in suppressing the high activity of the immune system found in those patients due to repeated blood transfusions and antigenic stimulation.

The Effects of Secondary Iron Overload and Iron Chelation on A Radiation-Induced Acute Myeloid Leukemia Mouse Model

Background: Patients with myelodysplastic syndrome (MDS) require chronic red blood cell (RBC) transfusion due to anemia. Multiple RBC transfusions cause secondary iron overload and subsequent excessive generation of reactive oxygen species (ROS), which leads to mutations, cell death, organ failure, and inferior disease outcomes. We hypothesize that iron loading promotes AML development by increasing oxidative stress and disrupting important signaling pathways in the bone marrow cells (BMCs). Conversely, iron chelation therapy (ICT) using deferasirox may reduce AML risk by lowering iron burden in the iron-loaded animals.Methods: We utilized a radiation-induced acute myeloid leukemia (RI-AML) animal model. Iron overload was introduced via intraperitoneal injection of iron dextran, and iron chelation via oral gavage of deferasirox. A total of 86 irradiated B6D2F1 mice with various levels of iron burden were monitored for leukemia development over a period of 70 weeks. The Kaplan-Meier estimator was utilized to assess leukemia free survival. In addition, a second cohort of 30 mice was assigned for early analysis at 5 and 7 months post-irradiation. The BMCs of the early cohort were assessed for alterations of signaling pathways, DNA damage response and gene expression. Statistical significance was established using Student’s t-test or ANOVA.Results: Iron loading in irradiated B6D2F1 mice accelerated AML development. However, there was a progressive decrease in AML risk for irradiated mice with increase in iron burden from 7.5 to 15 to 30 mg. In addition, ICT decreased AML incidence in the 7.5 mg iron-loaded irradiated mice, while AML onset was earlier for the 30 mg iron-loaded irradiated mice that received ICT. Furthermore, analysis of BMCs from irradiated mice at earlier intervals revealed accelerated dysregulation of signaling pathways upon iron loading, while ICT partially mitigated the effects.Conclusions: We concluded that iron is a promoter of leukemogenesis in vivo up to a peak iron dose, but further iron loading decreases AML risk by increasing cell death. ICT can partially mitigate the adverse effects of iron overload, and to maximize its benefit this intervention should be undertaken prior to the development of extreme iron overload.

Iron Overload in a Patient with Non-Transfusion-Dependent Hemoglobin H Disease and Borderline Serum Ferritin: Can We Rely on Serum Ferritin for Monitoring in This Group of Patients?

Secondary iron overload is a common complication in the context of hematological diseases, as iron accumulates due to different mechanisms including chronic transfusion, increased gastrointestinal absorption, chronic hemolysis and underlying genetic defects leading to an increase in gastrointestinal absorption of iron. Since the body does not have a mechanism to excrete excess iron, it gets deposited in the heart, endocrine organs, and the liver with the latest being affected less commonly than in primary iron overload disorders like hemochromatosis. Patients with hemoglobin H disease, which is a type of α-thalassemia, are usually transfusion independent, except in occasions where an external stressful factor leads to a drop in hemoglobin and necessitates blood transfusion. Despite this, secondary iron overload is commonly encountered in these patients due to increased gastrointestinal absorption of iron. To avoid the complications associated with iron overload, these patients are usually monitored with serum ferritin, which is an inexpensive widely available method to monitor iron overload. MRI of the liver (Ferriscan) is a more sensitive and specific method to monitor these patients and avoid the long-lasting and sometimes irreversible effect of secondary iron overload. Here we present an interesting case of a patient with hemoglobin H disease, who was monitored with serum ferritin. She had a serum ferritin level considered as a borderline risk for morbidities secondary to iron overload, and an MRI of her liver (Ferriscan) showed significant iron deposition in the liver associated with increased risk of complications secondary to iron overload.

Renal clearable nanochelators for iron overload therapy

Iron chelators have been widely used to remove excess toxic iron from patients with secondary iron overload. However, small molecule-based iron chelators can cause adverse side effects such as infection, gastrointestinal bleeding, kidney failure, and liver fibrosis. Here we report renal clearable nanochelators for iron overload disorders. First, after a singledose intravenous injection, the nanochelator shows favorable pharmacokinetic properties, such as kidney-specific biodistribution and rapid renal excretion (>80% injected dose in 4 h), compared to native deferoxamine (DFO). Second, subcutaneous (SC) administration of nanochelators improves pharmacodynamics, as evidenced by a 7-fold increase in efficiency of urinary iron excretion compared to intravenous injection. Third, daily SC injections of the nanochelator for 5 days to iron overload mice and rats decrease iron levels in serum and liver. Furthermore, the nanochelator significantly reduces kidney damage caused by iron overload without demonstrating DFO’s own nephrotoxicity. This renal clearable nanochelator provides enhanced efficacy and safety.