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1.  Correlation of Oxidative Stress with Serum Trace Element Levels and Antioxidant Enzyme Status in Beta Thalassemia Major Patients: A Review of the Literature 
Anemia  2012;2012:270923.
Beta thalassemia major is an inherited disease resulting from reduction or total lack of beta globin chains. Patients with this disease need repeated blood transfusion for survival. This may cause oxidative stress and tissue injury due to iron overload, altered antioxidant enzymes, and other essential trace element levels. The aim of this review is to scrutinize the relationship between oxidative stress and serum trace elements, degree of damage caused by oxidative stress, and the role of antioxidant enzymes in beta thalassemia major patients. The findings indicate that oxidative stress in patients with beta thalassemia major is mainly caused by tissue injury due to over production of free radical by secondary iron overload, alteration in serum trace elements and antioxidant enzymes level. The role of trace elements like selenium, copper, iron, and zinc in beta thalassemia major patients reveals a significant change of these trace elements. Studies published on the status of antioxidant enzymes like catalase, superoxide dismutase, glutathione, and glutathione S-transferase in beta thalassemia patients also showed variable results. The administration of selective antioxidants along with essential trace elements and minerals to reduce the extent of oxidative damage and related complications in beta thalassemia major still need further evaluation.
PMCID: PMC3357501  PMID: 22645668
2.  Association of Iron Overload with Oxidative Stress, Hepatic Damage and Dyslipidemia in Transfusion-Dependent β-Thalassemia/HbE Patients 
Blood transfusion can be a life-saving therapy for β-thalassemia major and β-thalassemia/HbE (β-TM) patients with chronic anemia, major caused severe iron overload particularly in β-TM patients received only blood transfusion therapy. We aim to evaluate the association of iron overload with oxidative stress, liver damage, and elevated very low density lipoprotein cholesterol (VLDL-C) in transfusion-dependent β-TM patients. Serum ferritin, malondialdehyde (MDA), liver profiles, triglycerides levels, and VLDL-C were significantly higher while total cholesterol, low-density lipoprotein cholesterol, high density lipoprotein cholesterol and total antioxidant capacity were lower in β-TM than controls. Serum ferritin was significantly correlated with MDA, liver enzymes and lipid profiles (p < 0.05). Multiple forward stepwise linear regression analyses of the significant variables showed that in these β-TM patients, independent predictors of iron overload were MDA (β = 0.410, r2 = 0.671, p < 0.001), ALT (β = 0.493, r2 = 0.578, p < 0.001), and VLDL-C (β = 0.253, r2 = 0.711, p < 0.001). In conclusion, iron overload associated with increased oxidative stress, lipid peroxidation, liver damage, decreased TC, LDL-C, HDL-C and over production of VLDL-C, is significantly problem in transfusion-dependent β-TM patients. These appeared the major cause of future morbidity and mortality in β-TM patients.
PMCID: PMC4062663  PMID: 24966477
β-Thalassemia major; β-Thalassemia/HbE; Iron overload; Oxidative stress; Hepatic damage; Dyslipidemia
3.  Oxidative stress and antioxidant status in beta-thalassemia heterozygotes 
Several studies have evaluated the oxidant and antioxidant status of thalassemia patients but most focused mainly on the severe and intermediate states of the disease. Moreover, the oxidative status has not been evaluated for the different beta-thalassemia mutations.
To evaluate lipid peroxidation and Trolox equivalent antioxidant capacity in relation to serum iron and ferritin in beta thalassemia resulting from two different mutations (CD39 and IVS-I-110) compared to individuals without beta-thalassemia.
One hundred and thirty subjects were studied, including 49 who were heterozygous for beta-thalassemia and 81 controls. Blood samples were subjected to screening tests for hemoglobin. Allele-specific polymerase chain reaction was used to confirm mutations for beta-thalassemia, an analysis of thiobarbituric acid reactive species was used to determine lipid peroxidation, and Trolox equivalent antioxidant capacity evaluations were performed. The heterozygous beta-thalassemia group was also evaluated for serum iron and ferritin status.
Thiobarbituric acid reactive species (486.24 ± 119.64 ng/mL) and Trolox equivalent antioxidant capacity values (2.23 ± 0.11 mM/L) were higher in beta-thalassemia heterozygotes compared to controls (260.86 ± 92.40 ng/mL and 2.12 ± 0.10 mM/L, respectively; p-value < 0.01). Increased thiobarbituric acid reactive species values were observed in subjects with the CD39 mutation compared with those with the IVS-I-110 mutation (529.94 ± 115.60 ng/mL and 453.39 ± 121.10 ng/mL, respectively; p-value = 0.04). However, average Trolox equivalent antioxidant capacity values were similar for both mutations (2.20 ± 0.08 mM/L and 2.23 ± 0.12 mM/L, respectively; p-value = 0.39). There was no influence of serum iron and ferritin levels on thiobarbituric acid reactive species and Trolox equivalent antioxidant capacity values.
This study shows an increase of oxidative stress and antioxidant capacity in beta-thalassemia heterozygotes, mainly in carriers of the CD39 mutation.
PMCID: PMC3905823  PMID: 24478607
Oxidative stress; Beta-thalassemia; Lipid peroxidation; Beta-globins; Thiobarbituric acid reactive substances; Mutation
4.  Total Antioxidant Status in Patients with Major β-Thalassemia 
Iranian Journal of Pediatrics  2011;21(2):159-165.
Beta-thalassemia major is an autosomal recessive disease causing severe and hemolytic anemia, which begins about 2-6 months after birth. Iron overload, which arises from recurrent transfusion and ineffective erythropoiesis, can enhance oxidative stress in thalassemic patients. The aim of this study was to evaluate the serum total antioxidant capacity of patients with ß-Thalassemia major.
Sixty six Iranian patients with β-thalassemia major and 66 age-gender matched controls were evaluated for serum total antioxidant status (TAS), uric acid (UA), bilirubin and albumin. In addition, serum ferritin and transaminases were recorded in these subjects.
Significant increases of TAS, UA, and bilirubin were observed in the patient group, compared with the control group (P<0.01). Mean TAS and bilirubin in male patients was higher than in females (P=0.005 and P=0.008, respectively). There was also direct correlation between TAS and albumin (P<0.001), bilirubin (P<0.001) and UA (P=0.002).
Endogenous antioxidants such as ferritin, UA and bilirubin can result in increased level of TAS in the patients with Beta-thalassemia major. Compensatory excess of TAS to oxidative stress could also be the reason for difference between our findings and previous studies.
PMCID: PMC3446157  PMID: 23056782
β-Thalassemia Major; Oxidative Stress; Antioxidants; Ferritin; Uric Acid
5.  A Study of Oxidative Stress Biomarkers and Effect of Oral Antioxidant Supplementation in Severe Acute Malnutrition 
Background: Malnutrition represents one of the most severe health problems in India. Free radicals play an important role in immunological response, which induces the oxidative surplus in severe acute malnutrition. Severe dietary deficiency of nutrients leads to increased oxidative stress in cellular compartments.
Aim: The goal of this study was to inspect impact of oxidative stress in the form of serum malondialdehyde as product of lipid peroxidation, vitamin E, zinc and erythrocyte superoxide dismutase in patients with severe acute malnutrition.
Material and Methods: Sixty severe acute malnutrition patients were studied before and after supplementation of antioxidants for one month, and their status were compared with those of 60 age and sex matched healthy controls.
The level of serum MDA was analyzed by the Kei Satoh method, serum vitamin E concentration was measured by Baker and Frank Method, serum zinc was measured by using Atomic Absorption Spectrophotometer (AAS) and erythrocyte superoxide dismutase was measured by Kajari Das Method.
Results: Significantly increased levels of serum malondialdehyde (p<0.001) were found in the patients as compared to those in controls, and significant depletions were found in the levels of serum vitamin E, zinc and erythrocyte superoxide dismutase in patients with severe acute malnutrition as compared to those in controls.
After supplementation of antioxidants for one month, the levels of malondialdehyde were found to be decreased significantly (p<0.001) and zinc and erythrocyte superoxide dismutase capacity levels were increased significantly (p<0.05). Also, there was a non–significant (p>0.05) increase in vitamin E levels as compared to those before supplementation results.
Conclusion: Harsh deficiency of various nutrients in severe acute malnutrition leads to generation of heavy oxidative stress. These effects may be minimized with supplementation of antioxidants.
PMCID: PMC3842512  PMID: 24298460
Severe acute malnutrition; Oxidative stress; Zinc
6.  Effects of Vitamin E and Zinc Supplementation on Antioxidants in Beta thalassemia major Patients 
Iranian Journal of Pediatrics  2011;21(1):8-14.
In beta thalassemic patients, tissue damage occurs due to oxidative stress and it happens because of the accumulation of iron in the body. This study was conducted to determine the effect of zinc and vitamin E supplementation on antioxidant status in beta-thalassemic major patients.
This double blind randomized clinical trial was carried out on 120 beta thalassemic patients older than 18 years. Patients were randomly categorized in four groups. Zinc (50mg/day) and vitamin E (400mg/day) supplements were administered for former and latter group, respectively. In the third group both supplements were administered in similar doses. The fourth (control) group received no supplement. The effect of supplementations on serum zinc and vitamin E, superoxide dismutase (SOD), glutathione peroxidase (GPX), total antioxidant capacity (TAC) and body mass index (BMI) were measured at the beginning and the end of the study.
Serum zinc levels in group 1 and 3 were significantly increased (P<0.007 and P<0.005, respectively). Serum vitamin E levels in group 2 and 3 were also increased significantly (P<0.001). Mean GPX activity in group1, 2 and 3 decreased significantly (P<0.015, P<0.032 and P<0.029, respectively). Mean SOD activity and TAC did not show significant change after supplementation. BMI had significant increase in all treated groups (P<0.001).
Our results suggest that beta thalassemic patients have enhanced oxidative stress and administration of selective antioxidants may preclude oxidative damage.
PMCID: PMC3446117  PMID: 23056757
Vitamin E; Zinc; Glutathione Peroxidase; Superoxide Dismutase; Body Mass Index; Antioxidants
7.  Glucose homeostasis in Egyptian children and adolescents with β-Thalassemia major: Relationship to oxidative stress 
Oxidative stress in children with β-thalassemia may contribute to shortened life span of erythrocytes and endocrinal abnormalities.
This study was aimed to evaluate glucose homeostasis in Egyptian children and adolescents with β-thalassemia major and its relation to oxidative stress.
Materials and Methods:
Sixty children and adolescents with β-thalassemia major were studied in comparison to 30 healthy age and sex-matched subjects. Detailed medical history, thorough clinical examination, and laboratory assessment of oral glucose tolerance test (OGTT), serum ferritin, alanine transferase (ALT), fasting insulin levels, plasma malondialdehyde (MDA) as oxidant marker and serum total antioxidants capacity (TAC) were performed. Patients were divided into two groups according to the presence of abnormal OGTT.
The prevalence of diabetes was 5% (3 of 60) and impaired glucose tolerance test (IGT) was 8% (5 of 60). Fasting blood glucose, 2-hour post-load plasma glucose, serum ferritin, ALT, fasting insulin level, homeostatic model assessment for insulin resistance index (HOMA-IR) and MDA levels were significantly elevated while TAC level was significantly decreased in thalassemic patients compared with healthy controls (P < 0.001 for each). The difference was more evident in patients with abnormal OGTT than those with normal oral glucose tolerance (P < 0.001 for each). We also observed that thalassemic patients not receiving or on irregular chelation therapy had significantly higher fasting, 2-h post-load plasma glucose, serum ferritin, ALT, fasting insulin, HOMA-IR, oxidative stress markers OSI and MDA levels and significantly lower TAC compared with either those on regular chelation or controls. HOMA-IR was positively correlated with age, serum ferritin, ALT, MDA, and negatively correlated with TAC.
The development of abnormal glucose tolerance in Egyptian children and adolescents with β--thalassemia is associated with alteration in oxidant-antioxidant status and increase in insulin resistance.
1- Glucose tolerance tests, HOMA-IR, and MDA should be an integral part of the long-term follow-up of children and adolescents with β-thalassemia major. 2- Regular iron chelation and antioxidant therapy should be advised for thalassemic patients to improve glucose hemostasis.
PMCID: PMC4056131  PMID: 24944927
β-thalassemic major; diabetes mellitus; insulin resistance; oxidative stress
8.  Antioxidant-Mediated Effects in a Gerbil Model of Iron Overload 
Acta haematologica  2007;118(4):193-199.
Iron cardiomyopathy is a lethal complication of transfusion therapy in thalassemia major. Nutritional supplements decreasing cardiac iron uptake or toxicity would have clinical significance. Murine studies suggest taurine may prevent oxidative damage and inhibit Ca2+-channel-mediated iron transport. We hypothesized that taurine supplementation would decrease cardiac iron-overloaded toxicity by decreasing cardiac iron. Vitamin E and selenium served as antioxidant control.
Animals were divided into control, iron, taurine, and vitamin E/selenium groups. Following sacrifice, iron and selenium measurements, histology, and biochemical analyses were performed.
No significant differences were found in heart and liver iron content between treatment groups, except for higher hepatic dry-weight iron concentrations in taurine-treated animals (p < 0.03). Serum iron increased with iron loading (751 ± 66 vs. 251 ± 54 μg/dl, p < 0.001) and with taurine (903 ± 136 μg/dl, p = 0.03).
Consistent with oxidative stress, iron overload increased cardiac malondialdehyde levels, decreased heart glutathione peroxidase (GPx) activity, and increased serum aspartate aminotransferase. Taurine ameliorated these changes, but only significantly for liver GPx activity. Selenium and vitamin E supplementation did not improve oxidative markers and worsened cardiac GPx activity. These results suggest that taurine acts primarily as an antioxidant rather than inhibiting iron uptake. Future studies should illuminate the complexity of these results.
PMCID: PMC2892915  PMID: 17940334
Iron overload; Taurine; Heart; Liver; Antioxidants
9.  Studies on biochemical changes with special reference to oxidant and antioxidants in malaria patients 
Oxidative stress plays an important role in the development of malarial anemia. The present study was undertaken to study the role of oxidant and antioxidants in the patients ofPlasmodium falciparum malaria (n=25),Plasmodium vivax malaria (n=25) as against the normal control subjects (n=25). The parameters included are the hematological [hemoglobin, erythrocyte adenosine deaminase (ADA) activity, ADP-induced platelet aggregation] and serum total lipid peroxide as an index of oxidative stress and antioxidants [erythrocytic superoxide dismutase (SOD) activity, serum vitamin E] & serum iron.
Significant alterations in all above parameters were noted in both groups of malaria patients as compared to control subjects. Maximum significant alterations in hematological parameters were noticed inP. falciparum infection as compared toP. vivax malaria (p<0.001). Substantial rise in serum total lipid peroxides and a significant reduction in antioxidants such as serum vitamin E and serum iron were noted inP. falciparum malaria as compared toP. vivax malaria (p<0.001), whereas maximum decline in erythrocytic SOD activity was observed inP. vivax infection as compared toP. falciparum malaria (p<0.05). Follow-up examination revealed the restoration of the levels of all biochemical parameters to the normal level after 20 days of antimalarial therapy.
The study specified severity ofP. falciparum malaria and also functional duality of oxidant.
PMCID: PMC3453864  PMID: 23105405
Hematological Parameters; Lipid Peroxidation; Antioxidants; Malaria
10.  Respiratory Burst Enzymes, Pro-Oxidants and Antioxidants Status in Bangladeshi Population with β-Thalassemia Major 
Oxidative stress is intimately associated with many diseases, including β-thalassemia.
The study was to estimate the status of respiratory burst enzymes, pro-oxidants, and antioxidants in β-thalassemia major patients in Bangladesh and to compare with apparently healthy individuals.
Materials and Methods:
A total of 49 subjects were recruited which included 25 patients (age range 5 to 40 years) with β-thalassemia major and 24 controls (age and sex matched). Superoxide dismutase (SOD) and catalase (CAT) represented respiratory burst enzymes; malondialdehyde (MDA), lipid hydroperoxide (LHP), and xanthine oxidase (XO) were measured as pro-oxidants; and glutathione S transferase (GST), vitamin C (Vit.C), and glutathione (GSH) were the measured antioxidants.
The activity of SOD was significantly (P < 0.001) increased by about 79% and the activity of CAT was significantly (P < 0.001) decreased by more than 34% in the blood of β-thalassemia major patients compared to the control group. The content of pro-oxidants such as MDA, LHP, and XO was significantly (P < 0.001) higher in patients by about 228%, 241.3% and 148.1% respectively compared to control group. The level of GSH and Vit.C were significantly (P = 0.000) decreased in patients by about 59% and 81% versus the healthy group, respectively; and GST activity was significantly (P < 0.001) declined by 44.25% in patients group.
β-thalassemia major patients demonstrate raised oxidative stress compared to healthy subjects.
PMCID: PMC4488991  PMID: 26199921
Antioxidants; Children; Free radicals; Respiratory burst enzymes; Sickle cell disease
11.  Antioxidant Enzymes and Oxidative Stress in the Erythrocytes of Iron Deficiency Anemic Patients Supplemented with Vitamins 
Iranian Biomedical Journal  2014;18(2):82-87.
Background: Iron deficiency anemia is one of the major causes of morbidity and mortality worldwide. Evidences from epidemiological and clinical studies suggest a possible correlation between antioxidant levels and the anemic disease risk. The present work is to investigate antioxidant levels and lipid peroxidation in anemic patients. Methods: A number of 30 patients (15 males and 15 females) were selected for the study. Likewise, 30 age- and gender-matched healthy volunteers (15 males and 15 females) were selected with their informed consent. Patients and healthy subjects were supplemented with vitamins C and E for 15 days. The lipid peroxidation both in plasma and erythrocyte lysates was determined by thiobarbituric acid reactive substances and lipid peroxides. The antioxidant vitamins A, C, and E and total antioxidant activity were also analyzed. The antioxidant enzyme superoxide dismutase, catalase, and glutathione peroxidase were also determined. Results: Based on analysis, we found that the increase in lipid peroxidation was higher in the anemic subjects before vitamin supplementation, which was statistically significant at P<0.05. The antioxidant enzymes were higher in the patients before antioxidant supplementation when compared with patients after vitamin supplementation. Conclusion: Our data revealed higher oxidative stress before vitamin supplementation in iron deficiency anemic patients and after supplementation, lower lipid peroxidation and increased antioxidant vitamins were achieved.
PMCID: PMC3933916  PMID: 24518548
Iron deficiency anemia; Lipid hydroperoxides (LOOH); Vitamin C; Vitamin E; Thiobarbituric acid reactive substances (TBARS)
12.  Lack of correlation between non-labile iron parameters, total carbonyl and malondialdehyde in major thalassemia 
Thalassemia patients are at high risk of iron-induced toxicity and oxidative stress consequences. The present cross-sectional study is conducted to determine whether or not lipid peroxidation or protein oxidation is correlated with iron parameters in patients with thalassemia major. To prove this hypothesis, malondialdehyde and total carbonyl were correlated with the degree of excess iron concentration in the patients. A total of 118 Arabic Iraqi patients and 30 healthy children were participated in the present study. Results showed a significant increase (p<0.05) in serum total carbonyls, malondialdehyde and the iron indices of patients as compared with the control group. Total iron binding capacity and transferrin concentrations decreased significantly (p<0.05) in patients with thalassemia compared with the control group. The results also showed a lack of a significant correlation between each serum malondialdehyde and total carbonyl with each component of iron status. In conclusion, total carbonyls and malondialdehyde were increased in thalassemia patients indicating the vulnerability of these patients to tissue injury caused by oxidative stress. The formation of total carbonyl and malondialdehyde are independent of excess non-labile iron concentration, indicating that different mechanisms are involved in injury caused by the labile iron and in the formation of oxidation end products.
PMCID: PMC4227823  PMID: 25411527
Thalassemia; non-labile iron; malondialdehyde; total carbonyl
13.  Effect of excess alpha-hemoglobin chains on cellular and membrane oxidation in model beta-thalassemic erythrocytes. 
Journal of Clinical Investigation  1993;91(4):1706-1712.
While red cells from individuals with beta thalassemias are characterized by evidence of elevated in vivo oxidation, it has not been possible to directly examine the relationship between excess alpha-hemoglobin chains and the observed oxidant damage. To investigate the oxidative effects of unpaired alpha-hemoglobin chains, purified alpha-hemoglobin chains were entrapped within normal erythrocytes. These "model" beta-thalassemic cells generated significantly (P < 0.001) greater amounts of methemoglobin and intracellular hydrogen peroxide than did control cells. This resulted in significant time-dependent decreases in the protein concentrations and reduced thiol content of spectrin and ankyrin. These abnormalities correlated with the rate of alpha-hemoglobin chain autoxidation and appearance of membrane-bound globin. In addition, alpha-hemoglobin chain loading resulted in a direct decrease (38.5%) in catalase activity. In the absence of exogenous oxidants, membrane peroxidation and vitamin E levels were unaltered. However, when challenged with an external oxidant, lipid peroxidation and vitamin E oxidation were significantly (P < 0.001) enhanced in the alpha-hemoglobin chain-loaded cells. Membrane bound heme and iron were also significantly elevated (P < 0.001) in the alpha-hemoglobin chain-loaded cells and lipid peroxidation could be partially inhibited by entrapment of an iron chelator. In contrast, chemical inhibition of cellular catalase activity enhanced the detrimental effects of entrapped alpha-hemoglobin chains. In summary, entrapment of purified alpha-hemoglobin chains within normal erythrocytes significantly enhanced cellular oxidant stress and resulted in pathological changes characteristic of thalassemic cells in vivo. This model provides a means by which the pathophysiological effects of excess alpha-hemoglobin chains can be examined.
PMCID: PMC288150  PMID: 7682576
14.  Serum lipid profiles in patients with beta-thalassemia major and intermedia in southern Iran 
Beta-thalassemia is considered to be the most frequent hereditary blood disorder worldwide. Lipid abnormalities have been detected in different types of beta-thalassemia. The aim of this study is to assess the lipid profiles in beta-thalassemia major (BTM) and beta-thalassemia intermedia (BTI) patients in southern Iran.
The study group consisted of 55 BTM patients and 50 BTI patients. The control group included 130 sex-and age-matched healthy participants. Serum lipids profiles (total cholesterol, triglycerides, LDL-cholesterol, and HDL-cholesterol) as well as hemoglobin (Hb) and ferritin, were compared between the three groups. P value < 0.05 was considered statistically significant.
There were no significant differences between BTM and BTI patients regarding age or sex. Mean triglyceride concentration was not significantly different between patients and controls. Total cholesterol and LDL-cholesterol were significantly lower in patients with BTM and BTI in comparison with controls (p < 0.001). HDL-cholesterol was significantly lower in patients with BTI than in controls (p < 0.03).
In patients with BTM and BTI, total cholesterol and LDL-cholesterol were lower than in control participants. The mechanisms that may account for these findings are increased erythropoiesis and cholesterol consumption in BTI, and iron overload and oxidative stress in BTM.
PMCID: PMC3082801  PMID: 21526074
Beta-Thalassemia Major; Beta-Thalassemia Intermedia; Total Cholesterol; LDL-Cholesterol; HDL-Cholesterol; Triglycerides
15.  Status of Superoxide Dismutase in Transfusion Dependent Thalassaemia 
Thalassemia is a collection of genetic impairments in beta and alpha genes causing various states of anemia. Severe types of the disease need lifelong transfusions, leading to oxidant-antioxidant disturbance due to massive iron deposits.
The aim of this study was to assess the antioxidant enzyme Superoxide Dismutase (SOD) and ferritin levels of thalassemia major patients in a peripheral health facility.
Materials and Methods:
Two hundred and nine probands were recruited and performed laboratory experiments for SOD and Ferritin levels. Chelation administration and clinical score were taken from interviewing the family and from medical report data.
The study showed that SOD intensity was lower (162.41 u/ml) compared to the normal cutoff point (P = 0.001), while the mean of Ferritin levels was ten times over the normal value (4226,67 ng/dl). Observations also reported that chelation medicine was not administrated properly.
The data indicates that thalassemic patients have oxidant-antioxidant uproar due to oxidative stress. Monitored chelating administration, selective antioxidant, and a well-balanced diet may prevent oxidative injury.
PMCID: PMC4462814  PMID: 26110130
Oxidant-antioxidant; superoxide dismutase; thalassaemia
16.  Therapeutic Value of Combined Therapy with Deferasirox and Silymarin on Iron Overload in Children with Beta Thalassemia 
Beta thalassemia is an inherited hemoglobin disorder resulting in a severe, chronic anemia requiring life-long blood transfusion that induces iron overload. Silymarin is a flavonoid complex isolated from Silybin marianum with a strong antioxidant activity, inducing an hepatoprotective action, and probably, a protective effect on iron overload. The aim of this work was to determine the silymarin value in improving iron chelation in thalassemic patients with iron overload treated with Deferasirox.
Patients and Methods
This study was conducted on 40 children with beta thalassemia major under follow-up at Hematology Unit, Pediatric Department, Tanta University Hospital with serum ferritin level more than 1000 ng/ml and was divided into two groups. Group IA: Received oral Deferasirox (Exjade) and silymarin for 6 months. Group IB: Received oral Deferasirox (Exjade) and placebo for 6 months and 20 healthy children serving as a control group in the period between April 2011 and August 2012 and was performed after approval from research ethical committee center in Tanta University Hospital and obtaining an informed written parental consent from all participants in this study.
Serum ferritin levels were markedly decreased in group IA cases compared with group IB (P= 0.001).
From this study we concluded that, silymarin in combination with Exjade can be safely used in the treatment of iron-loaded thalassemic patients as it showed good iron chelation with no sign of toxicity.
We recommend extensive multicenter studies in a large number of patients with longer duration of follow-up and more advanced techniques of assessment of iron status in order to clarify the exact role of silymarin in reducing iron overload in children with beta thalassemia.
PMCID: PMC3867224  PMID: 24363880
17.  Beta-thalassemia 
Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with thalassemia major usually present within the first two years of life with severe anemia, requiring regular red blood cell (RBC) transfusions. Findings in untreated or poorly transfused individuals with thalassemia major, as seen in some developing countries, are growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. Regular transfusion therapy leads to iron overload-related complications including endocrine complication (growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands), dilated myocardiopathy, liver fibrosis and cirrhosis). Patients with thalassemia intermedia present later in life with moderate anemia and do not require regular transfusions. Main clinical features in these patients are hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis and its complications (osteoporosis, masses of erythropoietic tissue that primarily affect the spleen, liver, lymph nodes, chest and spine, and bone deformities and typical facial changes), gallstones, painful leg ulcers and increased predisposition to thrombosis. Thalassemia minor is clinically asymptomatic but some subjects may have moderate anemia. Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0) synthesis of the beta chains of hemoglobin (Hb). Transmission is autosomal recessive; however, dominant mutations have also been reported. Diagnosis of thalassemia is based on hematologic and molecular genetic testing. Differential diagnosis is usually straightforward but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as juvenile myelomonocytic leukemia and aplastic anemia). Genetic counseling is recommended and prenatal diagnosis may be offered. Treatment of thalassemia major includes regular RBC transfusions, iron chelation and management of secondary complications of iron overload. In some circumstances, spleen removal may be required. Bone marrow transplantation remains the only definitive cure currently available. Individuals with thalassemia intermedia may require splenectomy, folic acid supplementation, treatment of extramedullary erythropoietic masses and leg ulcers, prevention and therapy of thromboembolic events. Prognosis for individuals with beta-thalassemia has improved substantially in the last 20 years following recent medical advances in transfusion, iron chelation and bone marrow transplantation therapy. However, cardiac disease remains the main cause of death in patients with iron overload.
PMCID: PMC2893117  PMID: 20492708
18.  Renal functions in pediatric patients with beta-thalassemia major: relation to chelation therapy: original prospective study 
In β-thalassemia, profound anemia and severe hemosiderosis cause functional and physiological abnormalities in various organ systems. In recent years, there have been few published studies mainly in adult demonstrating renal involvement in β-thalassemia. This prospective study was aimed to investigate renal involvement in pediatric patients with transfusion dependant beta-thalassemia major (TD-βTM), using both conventional and early markers of glomerular and tubular dysfunctions, and to correlate findings to oxidative stress and iron chelation therapy.
Sixty-nine TD-βTM patients (aged 1-16 years) and 15 healthy controls (aged 3-14 years) were enrolled in this study. Based on receiving chelation therapy (deferoxamine, DFO), patients were divided into two groups: group [I] with chelation (n = 34) and group [II] without chelation (n = 35). Levels of creatinine (Cr), calcium (Ca), inorganic phosphorus (PO4), uric acid (UA) and albumin were measured by spectrophotometer. Serum (S) levels of cystatin-C (SCysC) and total antioxidant capacity (STAC) and urinary (U) levels of β2-microglobulin (Uβ2MG) were measured by immunosorbent assay (ELISA). Urinary N-acetyl-beta-D-glucosaminidase (UNAG) activity and malondialdehyde (UMDA) were measured by chemical methods. Estimated glomerular filtration rate (eGFR) was determined from serum creatinine.
In patient with and without chelation, glomerular [elevated SCysC, SCr, Ualbumin/Cr and diminished eGFR]; and tubular dysfunctions [elevated SUA, SPO4, UNAG/Cr, Uβ2MG/Cr] and oxidative stress marker disturbances [diminished STAC and elevated UMDA/Cr] were reported than controls. In patients with chelation, SCysC was significantly higher while, STAC was significantly lower than those without chelation. In all patients, SCysC showed significant positive correlation with SCr and negative correlation with eGFR; STAC showed significant positive correlation with eGFR and negative correlation with SCysC, SCr, UNAG/Cr; UMDA/Cr showed significant positive correlation with Ualbumin/Cr, Uβ2MG/Cr, UNAG/Cr.
Our data confirm high frequency of glomerular and tubular dysfunctions in TD-βTM pediatric patients which could be attributed to oxidative stress and DFO therapy.
PMCID: PMC2894023  PMID: 20500848
19.  Coexisting Iron Deficiency Anemia and Beta Thalassemia Trait: Effect of Iron Therapy on Red Cell Parameters and Hemoglobin Subtypes 
ISRN Hematology  2014;2014:293216.
Background. Coexistence of iron deficiency anemia (IDA) and beta thalassemia trait (BTT) has been the topic of few studies. However, no study from our country was found evaluating the effect of iron therapy in patients with concomitant IDA and BTT. Methods. Over a period of two years, 30 patients with concomitant IDA and BTT were included. All the patients had a complete blood count, serum iron studies, and thalassemia screening using BIORADTM hemoglobin testing system. The patients received oral iron therapy in appropriate dosages for a period of twenty weeks, after which all the investigations were repeated. Appropriate statistical methods were applied for comparison of pre- and posttherapy data. Results. All except two patients were adults with a marked female preponderance. Oral iron therapy led to statistically significant improvement in hemoglobin, red cell indices (P < 0.05), and marked change in serum iron, ferritin, and HbA2 levels (P < 0.001). There was a significant reduction in the total iron binding capacity levels. Conclusion. The present study shows the frequent occurrence of iron deficiency anemia in patients with beta thalassemia trait, which can potentially confound the diagnosis of the latter. Hence, iron deficiency should be identified and rectified in patients with suspicion of beta thalassemia trait.
PMCID: PMC3972954  PMID: 25006473
20.  Effect of Vitamin E Supplementation on Biochemical Parameters in Pesticides Sprayers of Grape Gardens of Western Maharashtra (India) 
The aim of this study was to see the biochemical effects of pesticides on sprayers of grape gardens before and after 15 days of vitamin E supplementations in Western Maharashtra (India), who were occupationally exposed to various pesticides over a long period of time (about 5 to 15 years). Blood samples were collected from all study group subjects for biochemical parameters assays before and after 15 days of vitamin E supplementation. Sprayers of grape gardens were given 400 mg of vitamin E tablet/day for 15 days. After 15 days of vitamin E supplementation to sprayers of grape gardens, we observed significantly decreased aspartate transaminase (10.88 %, P < 0.05, r = 0.88), alanine transaminase (25.92 %, P < 0.01, r = 0.46) and total proteins (3.32 %, P < 0.01, r = 0.33), whereas, no statistically significant change was found in serum acetyl cholinesterase, C-reactive proteins, albumin (ALB), globulins and ALB/globulin ratio as compared to before vitamin E supplementation. Sprayers of grape gardens, who received vitamin E supplementation, showed significantly decreased serum lipid peroxide (LP) (18.75 %, P < 0.001, r = 0.63) and significantly increased RBC-superoxide dismutase (SOD) (12.88 %, P < 0.001, r = 0.85), RBC-Catalase (CAT) (24.49 %, P < 0.001, r = 0.70), plasma ceruloplasmin (CP) (4.6 %, P < 0.01, r = 0.80), serum zinc (4.57 %, P < 0.01, r = 0.83) and serum copper (4.37 %, P < 0.01, r = 0.79) as compared to values before vitamin E supplementation. These results showed that vitamin E supplementation has ameliorating effects on these transaminase enzymes, suggesting that it may have a protective effect on liver, from pesticides induced damage. In this study vitamin E supplementation might have decreased LP levels by breaking chain reaction of lipid peroxidation. Present results indicate that vitamin E plays a crucial role in restoring the antioxidant enzymes such as SOD, CAT and CP, in population exposed to pesticides. This helps to enhance its antioxidant ability. Therefore, it is suggested that farmers, pesticide applicators, workers in the pesticide industry and other pesticide users, who come in regular contact with pesticides, may be benefited by supplementation with vitamin E.
PMCID: PMC3358367  PMID: 23543683
Acetylcholinesterase; C-reactive proteins; Aspartate transaminase; Alanine transaminase; Lipid peroxidation; Superoxide dismutase; Catalase; Ceruloplasmin; Glutathione-S-transferase
21.  Venous versus arterial iron administration in haemodialysis. Influence on erythrocytes antioxidant parameters  
Journal of Medicine and Life  2015;8(Spec Issue):69-73.
Introduction Intravenous iron administration in patients treated by haemodialysis for end stage renal disease can exacerbate oxidative stress by increasing the level of free redox active iron. A way to reduce the impact of iron on oxidative stress in haemodialysis patients may be the administration of iron through arterial extracorporeal circuit.
Objective The aim of our study was to compare the influence of iron route of administration (venous versus arterial extracorporeal circuit infusion) on antioxidant parameters in red blood cells of haemodialysis patients in order to clarify if arterial iron administration can have positive impacts related to iron induced oxidative stress.
Method Twenty stable patients on regular haemodialysis treatment were selected for the study. They were investigated in a cross-over design at 3 mid-week HD sessions, one week apart, without iron [HD basal] and with either IV infusion of 100mg iron sucrose over the first 20 minutes of HD session, via venous line [HDvenous], or the same solution infused on the arterial extracorporeal circulation [HDarterial].
Blood samples were drawn at 0 min, 40 min and 270 min. Erythrocytes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activity, non-protein thiol levels and total antioxidant capacity (TEAC) were analysed.
Conclusion Haemodialysis significantly decreases the total antioxidant activity in erythrocytes. Iron supplementation, through venous or arterial extracorporeal route has no impact on the total antioxidant activity in red blood cells. Venous iron administration increases GPx activity in erythrocytes suggesting increased lipid peroxidation compared with arterial extracorporeal administration.
PMCID: PMC4564030  PMID: 26361515
haemodialysis; erythrocytes; antioxidant parameters
22.  Effect of pretreatment with coenzyme Q10 on isoproterenol-induced cardiotoxicity and cardiac hypertrophy in rats 
Background: Coenzyme Q10 (CoQ10) is a lipid-soluble, vitamin-like substance found in the hydrophobic interior of the phospholipid bilayer of most cellular membranes. It appears to be involved in the coordinated regulation between oxidative stress and antioxidant capacity of heart tissue when the heart is subjected to oxidative stress in various pathogenic conditions.
Objective: The objective of the present study was to investigate the effect of pretreatment with CoQ10 (100 mg/kg) on isoproterenol (ISO)-induced cardiotoxicity and cardiac hypertrophy in rats.
Methods: Albino male Wistar rats (250–300 g) were evenly divided by lottery method into 1 of the following 3 groups: the ISO group (olive oil 2 mL/kg orally for 18 days and ISO 1 mg/kg IP from days 9–18); the CoQ10 + ISO group (CoQ10 100 mg/kg orally for 18 days and ISO 1 mg/kg IP from days 9–18); and the control group (olive oil 2 mL/kg orally for 18 days and water IP from days 9–18). Twenty-four hours after the last dose of water or ISO, the rats were anesthetized and an ECG was recorded. Blood was withdrawn by retro-orbital puncture for estimation of serum creatine kinase-MB (CK-MB) isoenzyme levels, lactate dehydrogenase (LDH) levels, and aspartate aminotransferase activities. The animals were euthanized using an overdose of ether. The hearts of 6 animals from each group were used for estimation of superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, lipid peroxidation (LPO), malondialdehyde (MDA), and total protein concentration. Histopathology of the 2 remaining hearts in each group was carried out by a blinded technician.
Results: A total of 24 rats (8 in each group) were used in this study; all rats survived to study end. Compared with the control group, the ISO-treated rats had a significant change in heart to body weight ratio (P < 0.001); significant changes in the endogenous antioxidants (ie, significantly higher myocardial MDA concentration [P < 0.001]; significantly lower myocardial GSH concentration [P < 0.001] and SOD activity [P < 0.01]); and significantly higher serum activities of marker enzymes (eg, CK-MB [P < 0.001] and LDH [P < 0.001]). Compared with the ISO group, the CoQ10 + ISO group had a significant change in heart to body weight ratio (P < 0.001); significant changes in the endogenous antioxidants (ie, significantly lower MDA concentration [P < 0.05]; significantly higher myocardial GSH concentration [P < 0.001] and SOD activity [P < 0.05]); and significantly lower serum activities of marker enzymes (eg, CK-MB [P < 0.05] and LDH [P < 0.01]).
Conclusion: Pretreatment with CoQ10 (100 mg/kg) for 18 days was associated with moderate protection against ISO-induced cardiotoxicity and cardiac hypertrophy, and with lower myocardial injury by preserving endogenous antioxidants and reducing LPO in rat heart.
PMCID: PMC3969979  PMID: 24692838
antioxidants; cardiac hypertrophy; coenzyme Q10; isoproterenol
23.  Oxidative stress and antioxidant status in cervical cancer patients 
Cervical cancer (CaCx) is a global public health problem as it is the second most common cancer leading to the death of women worldwide. Many references revealed that the low levels of antioxidants induce the generation of free radicals leading to DNA damage and further mutations. In the present study attempt have been made to evaluate the levels of serum Lipid peroxide, Nitric Oxide (NO.) Erythrocytic—Superoxide Dismutase (RBC-SOD), Vitamin-C, serum Copper (Cu) and serum Zinc (Zn). 120 patients were divided in 4 groups according to the increasing CaCx stages i.e. stage I, II, III & IV respectively. All the patients were around the age group of 25–65 years. 30 healthy women between the same age group were treated as controls. Highly significant increased values of MDA, NO. and Cu were observed (p<0.001) whereas the activity of RBC-SOD, levels of Vitamin-C and Zn were significantly decreased in CaCx patients as compared with healthy controls (p<0.001). Cu/Zn ratio was found to be altered in CaCx patients. From our findings it can be concluded that the oxidative stress is induced among CaCx patients, which inturn increases the risk of CaCx.
PMCID: PMC3453822  PMID: 23105702
Lipid peroxide; Cervical cancer; RBC-SOD; Nitric Oxide; Vitamin-C; Copper; Zinc
24.  Role of reactive oxygen species in pathogenesis of nephrotic syndrome 
Nephrotic syndrome is the common chronic disorder characterized by alteration of permeability of the glomerular capillary wall, resulting in its inability to restrict the urinary loss of proteins. Nephrotic syndrome is characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia associated with peripheral edema. The molecular basis of glomerular permselectivity remains largely unknown. In recent years it has been proposed that Nephrotic syndrome is a consequence of an imbalance between oxidant and antioxidant activity. The present study was aimed to test that the reactive oxygen species are the mediators of excessive protein permeability and other complications of Nephrotic syndrome. For this 30 adults with Nephrotic syndrome were studied. The control group comprised 30 healthy adults matched for age. Serum levels of lipid peroxides, nitric oxide (NO⊙), α- tocopherol, ascorbic acid, erythrocyte superoxide dismutase activity, serum albumin, uric acid, cholesterol and plasma total antioxidant capacity were measured. Student’s ‘t’ test was applied for statistical analysis. There was a significant increase in lipid peroxide (1.58 ± 0.42 in controls, 3.64 ±1.3 in patients) (P<0.001) levels in study group as compared with controls. α-tocopherol (12.95 ± 1.04 in controls, 9.93 ± 1.43 in patients) (P<0.001), erythrocyte SOD activity(1.88 ± 0.9 in controls 1.07 ± 0.5 in patients) (P=0.01), serum albumin(4.06 ± 0.50 in controls, 3.04 ± 0.11 in patients) (P<0.001), and plasma total antioxidant capacity (847.33 ± 126.83 in controls, 684.00±102.94 in patients) (P<0.001) were significantly decreased. There was non-significant increase in uric acid (P>0.05), a non-significant decrease in NO⊙ (38.48 ± 15.47 in controls 37.47 ± 14.27 in patients) (P>0.05) and ascorbic acid levels ascorbic acid,( 0.95 ± 0.31in controls 0.79 ± 0.30 in patients) (P>0.05) in study group as compared with controls. Imbalance between oxidants and antioxidants may contribute to pathogenesis of proteinuria and related complications in nephrotic syndrome.
PMCID: PMC3453014  PMID: 23105890
Nephrotic syndrome; Lipid peroxide; Antioxidants; Erythrocyte Superoxide dismutase
25.  Nutritional deficiencies in iron overloaded patients with hemoglobinopathies 
American journal of hematology  2009;84(6):344-348.
One of the hallmarks of both sickle cell disease (SCD) and thalassemia major (TM) is accelerated oxidative damage. Decreased antioxidant levels and increased oxidant stress biomarkers are found in both diseases. Although isolated vitamin deficiencies have been reported in TM and nontransfused SCD patients, a comprehensive evaluation of vitamin and trace mineral levels has never been performed in chronically transfused SCD or TM patients. As vitamins and trace minerals may be consumed as a result of chronic oxidative stress; we hypothesized that levels of these compounds would correlate with surrogates of iron overload, hemolysis, and inflammation in chronically transfused patients. Using a convenience sample of our group of chronically transfused patients we studied 43 patients with SCD (17 male, 26 female) and 24 patients with TM (13 male and 11 female). The age range for our patients varied from 1.5 to 31.4 years. Levels of vitamins A, thiamin, B6, B12, C, D, E as well as selenium, zinc, copper, and ceruloplasmin were measured. We found that 40–75% of the patients were deficient in A, C, D and selenium and 28–38% of the patients had low levels of B vitamins and folate. There was little association with iron overload, hemolysis, or inflammation. Although the precise mechanism of these deficiencies is unclear, they may contribute to the morbidity of chronically transfused hemoglobinopathy patients.
PMCID: PMC2887656  PMID: 19415722

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