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      Oxidative Stress (Malondialdehyde) in Adults Beta-Thalassemia Major and Intermedia: Comparison Between Before and After Blood Transfusion and Its Correlation with Iron Overload

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          Abstract

          Background

          Iron overload is a major problem in both transfusion-dependent (TDT) and non-transfusion-dependent thalassemia (NTDT). It has been known to increase oxidative stress. Meanwhile, blood transfusion as main therapy for thalassemia increases iron overload. One of the markers of oxidative stress is malondialdehyde (MDA). This study aims to provide data on MDA levels in adult thalassemia patients, and to compare the levels before and after transfusion in patients with TDT and NTDT.

          Methods

          This is a cross-sectional, pre-post study in adult patients with thalassemia major and intermedia that received blood transfusion with or without iron-chelating agents in Cipto Mangunkusumo Hospital. Blood samples were taken immediately before the transfusion and one day after. Serum ferritin (SF) assays were conducted by electrochemiluminescence immunoassay method, while transferrin saturation (TS) was calculated by dividing serum iron by the binding capacity. Subsequently, plasma MDA levels assays were performed using the Wills method, and data analysis was conducted using the t-test/Mann–Whitney and Pearson/Spearman correlation test, depending on the data distribution.

          Results

          The 63 respondents recruited consist of 51 TDT and 12 NTDT patients, and their median plasma MDA level before and after transfusion was 0.49 µmol/L and 0.45 µmol/L, respectively. Before transfusion, there was no correlation between SF and MDA, and TS and MDA levels. After the transfusion, there was no correlation between, SF and MDA, or TS and MDA levels.

          Conclusion

          There is no significant difference in MDA levels before and after transfusion. Although blood transfusion increases the iron load in thalassemia patients, there was no increase in median MDA level after transfusion. Meanwhile, there was no correlation between markers of iron overload and MDA level in thalassemia patients both before and after transfusion.

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          Most cited references27

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          Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors.

          Malondialdehyde (MDA) is one of the most frequently used indicators of lipid peroxidation. To generate reliable reference intervals for plasma malondialdehyde (P-MDA), a reference sample group was established in Funen, Denmark. The group consisted of 213 individuals (107 men, 106 women), ages 20-79 years. P-MDA was measured in EDTA-treated plasma after derivatization by thiobarbituric acid (TBA) and separation on HPLC. UV detection was performed at 532 nm. A reference interval was calculated as recommended by IFCC with REFVAL 3.42. The estimated reference limits (0.025 and 0.975 fractals) for the group were 0.36 and 1.24 mumol/L. The data were analyzed for gender- and age-related differences. Analysis of variance showed no interaction between gender and age, but separate analyses showed an independent effect of gender (P = 0.03), but not of age (P = 0.11). Daily smokers had a slightly higher average concentration of P-MDA than nonsmokers (P = 0.05), and P-MDA correlated with daily exposure to cigarette smoke (r = 0.162; P = 0.03). A positive correlation was also demonstrated between P-MDA and weekly alcohol consumption (r = 0.153; P = 0.03). Within-subject and day-to-day variations of P-MDA indicated that the potential of P-MDA as a biomarker for individuals is questionable. However, on a group basis, the present data support that P-MDA may be a potential biomarker for oxidative stress.
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            Body iron metabolism and pathophysiology of iron overload

            Iron is an essential metal for the body, while excess iron accumulation causes organ dysfunction through the production of reactive oxygen species. There is a sophisticated balance of body iron metabolism of storage and transport, which is regulated by several factors including the newly identified peptide hepcidin. As there is no passive excretory mechanism of iron, iron is easily accumulated when exogenous iron is loaded by hereditary factors, repeated transfusions, and other diseased conditions. The free irons, non-transferrin-bound iron, and labile plasma iron in the circulation, and the labile iron pool within the cells, are responsible for iron toxicity. The characteristic features of advanced iron overload are failure of vital organs such as liver and heart in addition to endocrine dysfunctions. For the estimation of body iron, there are direct and indirect methods available. Serum ferritin is the most convenient and widely available modality, even though its specificity is sometimes problematic. Recently, new physical detection methods using magnetic resonance imaging and superconducting quantum interference devices have become available to estimate iron concentration in liver and myocardium. The widely used application of iron chelators with high compliance will resolve the problems of organ dysfunction by excess iron and improve patient outcomes.
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              Hypogonadism, diabetes mellitus, hypothyroidism, hypoparathyroidism: incidence and prevalence related to iron overload and chelation therapy in patients with thalassaemia major followed from 1980 to 2007 in the Ferrara Centre.

              273 patients with thalassaemia major followed from diagnosis in the Ferrara Centre were divided into 3 cohorts (C) according to the year of birth (C1=1954-1964, 85 patients; C2=1965-1974, 129 patients; C3=1975-2001, 59 patients) in order to study the trends of endocrine complications. Menarche occurred in 52 out of 112 patients (46%), without significant differences among the 3 groups, at the mean age of 13.9+/-1.4 years. Sixty-five percent of these patients had secondary amenorrhoea at the mean age of 18.8+/-3.7 years. In males complete pubertal development occurred in 48% of patients (C1:31%, C2: 44%, C3: 63%, p<0.05) followed by secondary hypogonadism in 24% of patients above 21 years of age. Primary (80%) and central 20%) hypothyroidism were diagnosed in 31% of patients (C1: 55%, C2: 31.5%, C3: 13.4%, p<0.05), diabetes mellitus (DM) in 17% of patients (C1: 28.6%, C2: 17.2%, C3: 3.4%, p<0.05), and hypoparathyroidism in 10.6% of cases (C1: 18.7%, C2: 10.1%, C3: 3.4%, p<0.05). No difference was found in patient mean age of diagnosis of hypothyroidism, DM or hypoparathyroidism (20.4+/-8.2 years, 19+/-5 yrs and 18.5+/-5.8 yrs respectively) but in all three groups age at diagnosis significantly increased over time (hypothyroidism and DM: p<0.001; hypoparathyroidism: p<0.01). Over time the prevalence of hypothyroidism, diabetes mellitus and hypoparathyroidism increased to 24.4%, 14.7%, and 6.7%, respectively, at the time of the study. Incidences peaked in the early 1980's, and declined in the following years (primary hypothyroidism from 6.5% in 1981 to 0.9% in 2007, p<0.01; DM from 3.9% in 1986 to 0.8% in 2007, p<0.05; hypoparathyroidism 2.4% in 1984 to 0% in 2007, p<0.01) and correlated with the decrease in annual mean serum ferritin levels in all patients (p<0.001). The main risk factors associated with endocrine complications were high serum ferritin levels, poor compliance with desferioxamine (DFO) therapy, early onset of transfusion therapy (only for hypogonadism) and splenectomy (only for hypothyroidism). Serum ferritin levels of approximately 2000 ng/ml were found to correlate with hypogonadism, and 3000 ng/ml for hypothyroidism, hypoparathyroidism and DM. The incidences of hypothyroidism, DM and hypoparathyroidism were not significantly different in 18 patients on long term treatment with deferiprone (DPO) compared with 64 patients continuously treated with DFO, from 1995 to 2007. In conclusion, our longitudinal study shows that in the last 30 years in the Ferrara Centre the incidences of hypothyroidism, diabetes mellitus, and hypoparathyroidism declined, and pubertal development in males with thalassemia major improved in patients, on DFO treatment, born after 1976. The efficacy of alternative chelation regimes with deferiprone or deferasirox to monotherapy with desferioxamine remains to be established.
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                Author and article information

                Journal
                Int J Gen Med
                Int J Gen Med
                ijgm
                International Journal of General Medicine
                Dove
                1178-7074
                07 October 2021
                2021
                : 14
                : 6455-6462
                Affiliations
                [1 ]Division of Hematology-Medical Oncology, Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital/Faculty of Medicine Universitas Indonesia , Jakarta, Indonesia
                [2 ]Division of Hematology-Medical Oncology, Department of Internal Medicine, Gatot Soebroto Army Hospital Jakarta/Faculty of Medicine Universitas Indonesia , Jakarta, Indonesia
                [3 ]Division of Hematology-Medical Oncology, Department of Internal Medicine, Dharmais National Cancer Hospital Jakarta/Faculty of Medicine Universitas Indonesia , Jakarta, Indonesia
                Author notes
                Correspondence: Tubagus Djumhana Atmakusuma Division of Hematology-Medical Oncology, Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital/Faculty of Medicine Universitas Indonesia , Jalan Diponegoro No. 71, Jakarta Pusat, DKI, Jakarta, Indonesia Email hom_fkui@yahoo.com
                Author information
                http://orcid.org/0000-0003-0029-5446
                Article
                336805
                10.2147/IJGM.S336805
                8504476
                34675613
                b9755503-1921-4de2-8873-b203f8a0bfa3
                © 2021 Atmakusuma et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 01 September 2021
                : 27 September 2021
                Page count
                Figures: 1, Tables: 8, References: 27, Pages: 8
                Categories
                Original Research

                Medicine
                iron overload,malondialdehyde,oxidative stress,non-transfusion dependent thalassemia,transfusion-dependent thalassemia

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