Replacing the suppressed hormone: toward a better treatment for iron overload in β-thalassemia major?
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ABSTRACT:
SUBMITTER: Girelli D
PROVIDER: S-EPMC7327657 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:β Thalassemia is one of the most common groups of hereditary haemoglobinopathies. Affected people with thalassemia major are dependent on regular blood transfusion which on the long term leads to iron overload. Hepcidin is a peptide hormone and an important regulator of iron homeostasis, especially in thalassemia. Expression of this hormone is influenced by polymorphisms within the hepcidin gene, HAMP. Several studies emphasized the role of single nucleotide polymorphisms (SNPs) located in the promoter region of the gene. This study aimed to analyze the association between three SNPs in promoter of HAMP, c.-582A > G, c.-443C > T, and c.-153C > T, with iron overload in β-thalassemia major patients. METHODS:A total of 102 samples from β thalassemia major patients were collected. Genomic DNA was extracted and segments of DNA encompassing rs10421768 and rs142126068 were sequenced. Statistical analysis was performed by SPSS Statistics 23 using independent t test and Fisher's exact test. RESULTS:A total of 102 adult β-thalassemia major patients were genotyped for three SNPs in the promoter region of HAMP gene by PCR and direct sequencing. Most of the patients (71.3%) were iron overloaded (based on plasma ferritin > 1000 ng/ml) in spite of receiving regular iron-chelating therapy. Our analysis revealed a statistically significant difference between the level of cardiac iron accumulation and c.-582A > G variant (p = 0.02). For c.-443C > T statistical analysis was on the edge of the significant relationship between the minor allele and serum ferritin (p = 0.058). All samples were homozygous for allele C of c.-153C > T. CONCLUSIONS:Despite chelating therapy, iron overload is still one of the main complications of thalassemia. Our findings and others emphasize the role of hepcidin -582A > G polymorphism as a key component of iron homeostasis in these patients.
| S-EPMC7140315 | biostudies-literature
Project description:ObjectiveMultisystem iron poisoning is a major concern for long-term beta-thalassemia management. Quantitative MRI-based techniques routinely show iron overload in heart, liver, endocrine glands and kidneys. However, data on the brain are conflicting and monitoring of brain iron content is still matter of debate.MethodsThis 3T-MRI study applied a well validated high-resolution whole-brain quantitative MRI assessment of iron content on 47 transfusion-dependent (mean-age: 36.9?±?10.3 years, 63% females), 23 non-transfusion dependent (mean-age: 29.2?±?11.7 years, 56% females) and 57 healthy controls (mean-age: 33.9?±?10.8 years, 65% females). Clinical data, Wechsler Adult Intelligence Scale scores and treatment regimens were recorded. Beside whole-brain R2* analyses, regional R2*-values were extracted in putamen, globus pallidum, caudate nucleus, thalamus and red nucleus; hippocampal volumes were also determined.ResultsRegional analyses yielded no significant differences between patients and controls, except in those treated with deferiprone that showed lower R2*-values (p<0.05). Whole-brain analyses of R2*-maps revealed strong age-R2* correlations (r2=0.51) in both groups and clusters of significantly increased R2*-values in beta-thalassemia patients in the hippocampal formations and around the Luschka foramina; transfusion treatment was associated with additional R2* increase in dorsal thalami. Hippocampal formation R2*-values did not correlate with hippocampal volume; hippocampal volume did not differ between patients and controls. All regions with increased R2*-values shared a strict anatomical contiguity with choroid plexuses suggesting a blooming effect as the likely cause of R2* increase, in agreement with the available histopathologic literature evidence.ConclusionAccording to our MRI findings and the available histopathologic literature evidence, concerns about neural tissue iron overload in beta-thalassemia appear to be unjustified.
| S-EPMC6849415 | biostudies-literature
Project description:Thalassemia is an inherited blood disorder in which the body produces defective hemoglobin. One of the important processes to reduce the complication of major β-thalassemia is blood transfusion that leads to elevated ferritin levels in the blood. Many patients who have major β-thalassemia may have hemochromatosis conditions resulting from iron metabolism disorders. In patients who have β-thalassemia, the mutation Y250X in the TFR2 gene may play a role in the incidence of hemochromatosis. This study aimed to determine the relationship between ferritin levels and Y250X mutation in major β-thalassemia patients. In the present study, 12 blood samples were divided into nine major β-thalassemia patients and three healthy controls. The DNA was isolated from blood samples and the amplification of the target region was performed based on the specific primers. Sanger sequencing was used to find genetic single nucleotide polymorphisms associated with iron overload. Blood parameters, such as hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, and serum ferritin levels were analyzed and the recorded data showed the following results: 8.1±0.8 g/dL, 84.6±5.5 fL, 27±0.7 pg, respectively. The recorded data showed that the mean serum ferritin level in major β-thalassemia patients was 1921.7±848 ng/mL. The Y250X mutation was not found in major β-thalassemia patients and healthy controls.
| S-EPMC8934061 | biostudies-literature
Project description:ObjectivePatients with thalassemia major (TM) have the highest mortality rate due to heart failure induced by myocardial iron overload. However, T2* weighted MR imaging is currently a gold standard approach for measuring iron overload. Examining ventricular volumes with magnetic resonance imaging (MR imaging) and measuring myocardial iron overload in TM patients allows for an early prediction of heart failure. This dataset includes cardiac MR images of TM patients and the control group with clinical and echocardiographic data. This dataset may be useful to researchers investigating myocardial iron overload. This dataset can also be used for medical image processing applications, such as ventricle segmentation.Data descriptionThis study provides open-source cardiac MR images of 50 subjects and clinical and echocardiographic data. From February 2016 to January 2019, all images and clinical data were obtained from the MRI department of a general hospital in Mashhad, Iran. All the images are 16-bit gray-scale and stored in DICOM format. All patient-specific information is removed from image headers to preserve patient privacy. In addition, all images associated with each subject are compressed and saved in the RAR format.
| S-EPMC8375112 | biostudies-literature
Project description:Mutations in HFE lead to hereditary hemochromatosis (HH) because of inappropriately high iron uptake from the diet resulting from decreased hepatic expression of the iron-regulatory hormone hepcidin. -thalassemia is a congenital anemia caused by partial or complete loss of -globin synthesis causing ineffective erythropoiesis, anemia, decreased hepcidin production, and secondary iron overload. Tmprss6 is postulated to regulate hepcidin production by cleaving Hemojuvelin (Hjv), a key modulator of hepcidin expression, from the hepatocyte surface. On this basis, we hypothesized that treatment of mouse models of HH (Hfe(-/-)) and -thalassemia intermedia (Hbb(th3/+)) with Tmprss6 siRNA formulated in lipid nanoparticles (LNPs) that are preferentially taken up by the liver would increase hepcidin expression and lessen the iron loading in both models. In the present study, we demonstrate that LNP-Tmprss6 siRNA treatment of Hfe(-/-) and Hbb(th3/+) mice induces hepcidin and diminishes tissue and serum iron levels. Furthermore, LNP-Tmprss6 siRNA treatment of Hbb(th3/+) mice substantially improved the anemia by altering RBC survival and ineffective erythropoiesis. Our results indicate that pharmacologic manipulation of Tmprss6 with RNAi therapeutics isa practical approach to treating iron overload diseases associated with diminished hepcidin expression and may have efficacy in modifying disease-associated morbidities of -thalassemia intermedia.
| S-EPMC3655736 | biostudies-literature
Project description:Hepcidin is a 25-amino acid peptide, derived from cleavage of an 84 amino acid pro-peptide produced predominantly by hepatocytes. This molecule, encoded by the hepcidin antimicrobial peptide (HAMP) gene shows structural and functional properties consistent with a role in innate immunity. Moreover, as demonstrated in mice and humans, hepcidin is a major regulator of iron metabolism, and acts by binding to ferroportin and controlling its concentration and trafficking. In this study we investigated the influence that mutations in HAMP and/or hemocromatosis (HFE) genes might exert on iron metabolism in a group of poly-transfused thalassemic patients in preparation for bone marrow transplantation. Our results showed that the presence of the c.-582 A>G polymorphism (rs10421768) placed in HAMP promoter (HAMP-P) might play a role in iron metabolism, perhaps varying the transcriptional activation that occurs through E-boxes located within the promoter.
| S-EPMC2738723 | biostudies-literature
Project description:Enterocyte damage and gut dysbiosis are caused by iron-overload in thalassemia (Thl), possibly making the gut vulnerable to additional injury. Hence, iron-overload in the heterozygous β-globin deficient (Hbbth3/+) mice were tested with 3% dextran sulfate solution (DSS). With 4 months of iron-gavage, iron accumulation, gut-leakage (fluorescein isothiocyanate dextran (FITC-dextran), endotoxemia, and tight junction injury) in Thl mice were more prominent than WT mice. Additionally, DSS-induced mucositis in iron-overloaded mice from Thl group was also more severe than the WT group as indicated by mortality, liver enzyme, colon injury (histology and tissue cytokines), serum cytokines, and gut-leakage (FITC-dextran, endotoxemia, bacteremia, and the detection of Green-Fluorescent Producing Escherichia coli in the internal organs after an oral administration). However, Lactobacillus rhamnosus GG attenuated the disease severity of DSS in iron-overloaded Thl mice as indicated by mortality, cytokines (colon tissue and serum), gut-leakage (FITC-dextran, endotoxemia, and bacteremia) and fecal dysbiosis (microbiome analysis). Likewise, Lactobacillus conditioned media (LCM) decreased inflammation (supernatant IL-8 and cell expression of TLR-4, nuclear factor κB (NFκB), and cyclooxygenase-2 (COX-2)) and increased transepithelial electrical resistance (TEER) in enterocytes (Caco-2 cells) stimulated by lipopolysaccharide (LPS) and LPS plus ferric ion. In conclusion, in the case of iron-overloaded Thl, there was a pre-existing intestinal injury that wask more vulnerable to DSS-induced bacteremia (gut translocation). Hence, the prevention of gut-derived bacteremia and the monitoring on gut-leakage might be beneficial in patients with thalassemia.
| S-EPMC8209035 | biostudies-literature
Project description:Thalassemic disorders lie on a phenotypic spectrum of clinical severity that depends on the severity of the globin gene mutation and coinheritance of other genetic determinants. Iron overload is associated with increased morbidity in both patients with transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The predominant mechanisms driving the process of iron loading include increased iron burden secondary to transfusion therapy in TDT and enhanced intestinal absorption secondary to ineffective erythropoiesis and hepcidin suppression in NTDT. Different organs are affected differently by iron overload in TDT and NTDT owing to the underlying iron loading mechanism and rate of iron accumulation. Serum ferritin measurement and noninvasive imaging techniques are available to diagnose iron overload, quantify its extent in different organs, and monitor clinical response to therapy. This chapter discusses the general approach to iron chelation therapy based on organ involvement using the available iron chelators: deferoxamine, deferiprone, and deferasirox. Other novel experimental options for treatment and prevention of complications associated with iron overload in thalassemia are briefly discussed.
| S-EPMC6142532 | biostudies-literature
Project description:Iron overload causes iron deposition and accumulation in the liver, heart, skin, and other tissues resulting in serious tissue damages. Significant blood clearance from iron and ferritin using wet cupping therapy (WCT) has been reported. WCT is an excretory form of treatment that needs more research efforts. WCT is an available, safe, simple, economic, and time-saving outpatient modality of treatment that has no serious side effects. There are no serious limitations or precautions to discontinue WCT. Interestingly, WCT has solid scientific and medical bases (Taibah mechanism) that explain its effectiveness in treating many disease conditions differing in etiology and pathogenesis. WCT utilizes an excretory physiological principle (pressure-dependent excretion) that resembles excretion through renal glomerular filtration and abscess evacuation. WCT exhibits a percutaneous excretory function that clears blood (through fenestrated skin capillaries) and interstitial fluids from pathological substances without adding a metabolic or detoxification burden on the liver and the kidneys. Interestingly, WCT was reported to decrease serum ferritin (circulating iron stores) significantly by about 22.25% in healthy subjects (in one session) and to decrease serum iron significantly to the level of causing iron deficiency (in multiple sessions). WCT was reported to clear blood significantly of triglycerides, low-density lipoprotein (LDL) cholesterol, total cholesterol, uric acid, inflammatory mediators, and immunoglobulin antibodies (rheumatoid factor). Moreover, WCT was reported to enhance the natural immunity, potentiate pharmacological treatments, and to treat many different disease conditions. There are two distinct methods of WCT: traditional WCT and Al-hijamah (WCT of prophetic medicine). Both start and end with skin sterilization. In traditional WCT, there are two steps, skin scarification followed by suction using plastic cups (double S technique); Al-hijamah is a three-step procedure that includes skin suction using cups, scarification (shartat mihjam in Arabic), and second skin suction (triple S technique). Al-hijamah is a more comprehensive technique and does better than traditional WCT, as Al-hijamah includes two pressure-dependent filtration steps versus one step in traditional WCT. Whenever blood plasma is to be cleared of an excess pathological substance, Al-hijamah is indicated. We will discuss here some reported hematological and therapeutic benefits of Al-hijamah, its medical bases, methodologies, precautions, side effects, contraindications, quantitative evaluation, malpractice, combination with oral honey treatment, and to what extent it may be helpful when treating thalassemia and other conditions of iron overload and hyperferremia.
| S-EPMC4222535 | biostudies-literature
Project description:Iron homeostasis is regulated by hepcidin (HEPC) that controls the dietary iron absorption and iron recycling. HEPC deficiency contributes to iron overload in β-thalassemia patients. The present study aimed to investigate the correlation between HEPC concentration and serum iron status among hemoglobin E (HbE)/β-thalassemia patients and their parents (HbE trait and β-thalassemia trait) compared with healthy controls. This study is a comparative cross-sectional study in which iron profile and HEPC level were examined in 65 HbE/β-thalassemia patients (pretransfusion) and 65 parents at the Hospital Sultanah Nur Zahirah and in 130 students as healthy controls from Univesiti Sultan Zainal Abidin, Terengganu, Malaysia. Furthermore, six samples from each group (HbE/β-thalassemia patients, parents and healthy controls) were randomly selected for gene expression analysis of HEPC and ferroportin1 (FPN1) using reverse transcription quantitative PCR. The results demonstrated that serum HEPC level were significantly decreased in HbE/β-thalassemia patients and their parents (P<0.001) compared with healthy controls. In addition, the gene expression analysis showed a dramatically downregulated HEPC in HbE/β-thalassemia patients and their parents (P=0.001) compared with healthy controls. However, there was a marked upregulation of FPN1 in HbE/β-thalassemia patients and their parents (P=0.001) compared with healthy controls. Iron profiling results revealed a significantly increased serum ferritin in HbE/β-thalassemia patients and their parents compared with healthy controls (P<0.001). In summary, the present study demonstrated that HEPC expression level and serum level were significantly decreased in HbE/β-thalassemia patients and their parents, which was combined with a marked increased FPN1 expression level and serum ferritin level compared with healthy volunteers. These findings supported the hypothesis that downregulated HEPC could lose its function as a negative regulator of FPN1, resulting in iron overload in HbE/β-thalassemia patients. Subsequently, assessing HEPC and FPN1 gene expression may be a useful tool to determine the risk of iron toxicity in patients with HbE/β-thalassemia and their parents, and could therefore be considered as a therapeutic target in the management of iron burden in these patients.
| S-EPMC8524734 | biostudies-literature