-
La Revue de Medecine Interne Dec 2023Etiological investigation of hyperferritinemia includes a full clinical examination, with the measurement of waist circumference, and simple biological tests including... (Review)
Review
Etiological investigation of hyperferritinemia includes a full clinical examination, with the measurement of waist circumference, and simple biological tests including transferrin saturation. The classification between hyperferritinemia without iron overload (inflammation, excessive alcohol intake, cytolysis, L-ferritin mutation) or with iron overload is then relatively easy. Dysmetabolic iron overload syndrome is the most common iron overload disease and is defined by an unexplained serum ferritin level elevation associated with various metabolic syndrome criteria and mild hepatic iron content increase assessed by magnetic resonance imaging. Bloodlettings are often poorly tolerated without clear benefit. Type 1 genetic hemochromatosis (homozygous C282Y mutation on the HFE gene) leads to iron accumulation through an increase of dietary iron absorption due to hypohepcidinemia. More than 95% of hemochromatosis are type 1 hemochromatosis but the phenotypic expression is highly variable. Elastography is recommended to identify advanced hepatic fibrosis when serum ferritin exceeds 1000μg/L. Life expectancy is normal when bloodlettings are started early. Ferroportin gene mutation is an autosomal dominant disease with generally moderate iron overload. Chelators are used in iron overload associated with anaemia (myelodysplastic syndromes or transfusion-dependent thalassemia). Chelation is initiated when hepatic iron content exceeds 120μmol/g. Deferasirox is often used as first-line therapy, but deferiprone may be of interest despite haematological toxicity (neutropenia). Deferoxamine (parenteral route) is the treatment of choice for severe iron overload or emergency conditions.
Topics: Humans; Hemochromatosis; Hyperferritinemia; Iron Overload; Iron; Ferritins
PubMed: 37507250
DOI: 10.1016/j.revmed.2023.07.002 -
Gastroenterologia Y Hepatologia Apr 2024
Topics: Humans; Crohn Disease; Deferasirox; Colitis; Ileitis
PubMed: 37468041
DOI: 10.1016/j.gastrohep.2023.07.002 -
Chemical Research in Toxicology Aug 2023Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver...
Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver injury due to exposure to DFS has been documented, and the toxic mechanisms of DFS are unknown. The present study aimed to investigate the reactive metabolites of DFS and to help us understand the mechanisms of DFS hepatotoxicity. Two hydroxylated metabolites (5-OH and 5'-OH) were identified during incubation of DFS-supplemented rat liver microsomes. Such microsomal incubations fortified with glutathione (GSH) or -acetylcysteine (NAC) as capture agents offered two GSH conjugates and two NAC conjugates. These GSH conjugates and NAC conjugates were also detected in bile and urine of rats given DFS. CYP1A2 and CYP3A4 were found to dominate the metabolic activation of DFS. Administration of DFS induced decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole and 1-aminobenzotrizole made hepatocytes less susceptible to the cytotoxicity of DFS.
Topics: Rats; Animals; Activation, Metabolic; Deferasirox; Liver; Hepatocytes; Microsomes, Liver; Acetylcysteine; Glutathione
PubMed: 37435843
DOI: 10.1021/acs.chemrestox.2c00416 -
Medical Molecular Morphology Sep 2023Hereditary hemochromatosis type 4 is an autosomal-dominant inherited disease characterized by a mutation in the SLC40A1 gene encoding ferroportin. This condition can be...
Hereditary hemochromatosis type 4 is an autosomal-dominant inherited disease characterized by a mutation in the SLC40A1 gene encoding ferroportin. This condition can be further subdivided into types 4A (loss-of-function mutations) and 4B (gain-of-function mutations). To date, only a few cases of type 4B cases have been reported, and the treatment has not been clearly mentioned. Here, we report a genotype of hereditary hemochromatosis type 4B involving the heterozygous mutation c.997 T > C (p. Tyr333His) in SLC40A1. The patient was treated with red blood cell apheresis every month for 1 year, followed by oral deferasirox, and the combined therapy was found to be effective.
Topics: Humans; Genotype; Hemochromatosis; Iron Overload; Mutation
PubMed: 37382698
DOI: 10.1007/s00795-023-00359-8 -
Journal of Biochemical and Molecular... Sep 2023During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and... (Review)
Review
During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B (1) and isavuconazole (2) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole (3) and deferasirox (4) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 (5) and APX001A (6), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.
Topics: Humans; Antifungal Agents; Mucormycosis; COVID-19; Amphotericin B; Mucorales
PubMed: 37345721
DOI: 10.1002/jbt.23417 -
Annals of Hematology Aug 2023Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient...
Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient preference between film-coated tablet (FCT) and dispersible tablet (DT) in transfusion-dependent thalassemia (TDT) or non-TDT (NTDT) patients treated with both formulations in a sequential manner. The primary endpoint was patient-reported preference for FCT over DT, while secondary outcomes included patient reported outcomes (PROs) evaluated by overall preference, and by age, thalassemia transfusion status, and previous ICT status. Out of 183 patients screened, 140 and 136 patients completed the treatment periods 1 and 2 of the core study, respectively. At week 48, the majority of patients preferred FCT over DT (90.3 vs. 7.5%; difference of percentage: 0.83 [95% confidence interval (CI), 0.75-0.89; P < 0.0001]). FCT scored better on secondary PROs and showed less severe gastrointestinal symptoms than DT, except in the change of modified Satisfaction with Iron Chelation Therapy (mSICT) preference scores, which were similar for both the formulations. Patients with TDT had stable ferritin levels, while it showed a downward trend up to week 48 in patients with NTDT on deferasirox treatment. Overall, 89.9% of patients reported ≥ 1 adverse event (AE), of which 20.3% experienced ≥ 1 serious AE. The most common treatment-emergent AEs were proteinuria, pyrexia, urine protein/creatinine ratio increase, diarrhea, upper respiratory tract infections, transaminase increase, and pharyngitis. Overall, this study reinforced the observations from the previous study by showing a distinct patient preference for FCT over DT formulation and further supported the potential benefits of life-long compliance with ICT.
Topics: Humans; Deferasirox; Iron Overload; Patient Preference; Thalassemia; Tablets; Iron; Iron Chelating Agents; Benzoates
PubMed: 37227493
DOI: 10.1007/s00277-023-05240-3 -
Blood Transfusion = Trasfusione Del... Jan 2024In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on...
Longitudinal prospective comparison of pancreatic iron by magnetic resonance in thalassemia patients transfusion-dependent since early childhood treated with combination deferiprone-desferrioxamine vs deferiprone or deferasirox monotherapy.
BACKGROUND
In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on pancreatic iron of a combined deferiprone (DFP) + desferrioxamine (DFO) regimen versus either oral iron chelator as monotherapy over a follow-up of 18 months.
MATERIALS AND METHODS
We selected patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network who received a combined regimen of DFO+DFP (No.=28) or DFP (No.=61) or deferasirox (DFX) (No.=159) monotherapy between the two magnetic resonance imaging scans. Pancreatic iron overload was quantified by the T2* technique.
RESULTS
At baseline no patient in the combined treatment group had a normal global pancreas T2* (≥26 ms). At follow-up the percentage of patients who maintained a normal pancreas T2* was comparable between the DFP and DFX groups (57.1 vs 70%; p=0.517).Among the patients with pancreatic iron overload at baseline, global pancreatic T2* values were significantly lower in the combined DFO+DFP group than in the DFP or DFX groups. Since changes in global pancreas T2* values were negatively correlated with baseline pancreas T2* values, the percent changes in global pancreas T2* values, normalized for the baseline values, were considered. The percent changes in global pancreas T2* values were significantly higher in the combined DFO+DFP group than in either the DFP (p=0.036) or DFX (p=0.030) groups.
DISCUSSION
In transfusion-dependent patients who started regular transfusions in early childhood, combined DFP+DFO was significantly more effective in reducing pancreatic iron than was either DFP or DFX.
Topics: Humans; Child, Preschool; Iron; Deferasirox; Deferiprone; Deferoxamine; Iron Chelating Agents; Pyridones; beta-Thalassemia; Benzoates; Triazoles; Drug Therapy, Combination; Thalassemia; Iron Overload; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Pancreas
PubMed: 37146300
DOI: 10.2450/BloodTransfus.485 -
Transplantation and Cellular Therapy Aug 2023Patients suffering from severe aplastic anemia (SAA) need frequent blood transfusions during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However,...
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 (IC) group (SF ≤1000 ng/mL; n = 18) and the IC failure (IC) 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 IC 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 IC 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.
Topics: Humans; Anemia, Aplastic; Deferasirox; Retrospective Studies; Prospective Studies; Treatment Outcome; Iron Overload; Iron; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Iron Chelating Agents
PubMed: 37116582
DOI: 10.1016/j.jtct.2023.04.016 -
Journal of Biochemistry Jul 2023Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation. The heme-responsive transcription factor BTB and CNC homology 1 (BACH1) promotes...
Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation. The heme-responsive transcription factor BTB and CNC homology 1 (BACH1) promotes ferroptosis by repressing the transcription of genes involved in glutathione (GSH) synthesis and intracellular labile iron metabolism, which are key regulatory pathways in ferroptosis. We found that BACH1 re-expression in Bach1-/- immortalized mouse embryonic fibroblasts (iMEFs) can induce ferroptosis upon 2-mercaptoethanol removal, without any ferroptosis inducers. In these iMEFs, GSH synthesis was reduced, and intracellular labile iron levels were increased upon BACH1 re-expression. We used this system to investigate whether the major ferroptosis regulators glutathione peroxidase 4 (Gpx4) and apoptosis-inducing factor mitochondria-associated 2 (Aifm2), the gene for ferroptosis suppressor protein 1, are target genes of BACH1. Neither Gpx4 nor Aifm2 was regulated by BACH1 in the iMEFs. However, we found that BACH1 represses AIFM2 transcription in human pancreatic cancer cells. These results suggest that the ferroptosis regulators targeted by BACH1 may vary across different cell types and animal species. Furthermore, we confirmed that the ferroptosis induced by BACH1 re-expression exhibited a propagating effect. BACH1 re-expression represents a new strategy for inducing ferroptosis after GPX4 or system Xc- suppression and is expected to contribute to future ferroptosis research.
Topics: Animals; Humans; Mice; Fibroblasts; Ferroptosis; Phospholipid Hydroperoxide Glutathione Peroxidase; Iron; Glutathione; Basic-Leucine Zipper Transcription Factors
PubMed: 37094356
DOI: 10.1093/jb/mvad036 -
Spectrochimica Acta. Part A, Molecular... Sep 2023A novel triphenylamine (TPA) based sensor TTU was rationally designed and synthesized that exhibited reversible mechanochromic and aggregation induced emission...
A novel triphenylamine (TPA) based sensor TTU was rationally designed and synthesized that exhibited reversible mechanochromic and aggregation induced emission enhancement (AIEE) properties. The AIEE active sensor was employed for fluorometric detection of Fe in aqueous medium, with distinguished selectivity. The sensor showed a highly selective quenching response towards Fe that is ascribed to complex formation with paramagnetic Fe. Subsequently, TTU-Fe complex acted as a fluorescence sensor for the detection of deferasirox (DFX). The subsequent addition of DFX to TTU-Fe complex led to the recovery of fluorescence emission intensity of sensor TTU that was attributed to the displacement of Fe by DFX and release of sensor TTU. The proposed sensing mechanisms for Fe and DFX was confirmed through H NMR titration experiment and DFT calculations. Frontier molecular orbitals (FMO), density of states (DOS), natural bond orbital (NBO), non-covalent interaction (NCI) and electron density difference (EDD) analysis were performed using DFT calculations to support the experimental results. Moreover, sensor TTU displayed colorimetric detection of Fe. Further, the sensor was employed for the detection of Fe and DFX in real water samples. Finally, logic gate was fabricated by using sequential detection strategy.
PubMed: 37084683
DOI: 10.1016/j.saa.2023.122745