Endocrine complications due to haemosiderosis are present in a significant number of patients with beta-thalassemia major (BTM) worldwide and often become barriers in their desire for parenthood. Thus, although spontaneous fertility can occur, the majority of females with BTM is infertile due to hypogonadotropic hypogonadism (HH) and need assisted reproductive techniques. Infertility in these women seems to be attributed to iron deposition and iron-induced oxidative stress (OS) in various endocrine organs, such as hypothalamus, pituitary, and female reproductive system, but also through the iron effect on other organs, such as liver and pancreas, contributing to the impaired metabolism of hormones and serum antioxidants. Nevertheless, the gonadal function of these patients is usually intact and fertility is usually retrievable. Meanwhile, a significant prooxidants/antioxidants imbalance with subsequent increased (OS) exists in patients with BTM, which is mainly caused by tissue injury due to overproduction of free radicals by secondary iron overload, but also due to alteration in serum trace elements and antioxidant enzymes. Not only using the appropriate antioxidants, essential trace elements, and minerals, but also regulating the advanced glycation end products, could probably reduce the extent of oxidative damage and related complications and retrieve BTM women's infertility.
β-thalassemia/Hb E is known to cause oxidative stress induced by iron overload. The glutathione system is the major endogenous antioxidant that protects animal cells from oxidative damage. This study aimed to determine the effect of disease state and splenectomy on redox status expressed by whole blood glutathione (GSH)/glutathione disulfide (GSSG) and also to evaluate glutathione-related responses to oxidation in β-thalassemia/Hb E patients. Twenty-seven normal subjects and 25 β-thalassemia/Hb E patients were recruited and blood was collected. The GSH/GSSG ratio, activities of glutathione-related enzymes, hematological parameters, and serum ferritin levels were determined in individuals. Patients had high iron-induced oxidative stress, shown as significantly increased serum ferritin, a decreased GSH/GSSG ratio, and increased activities of glutathione-related enzymes. Splenectomy increased serum ferritin levels and decreased GSH levels concomitant with unchanged glutathione-related enzyme activities. The redox ratio had a positive correlation with hemoglobin levels and negative correlation with levels of serum ferritin. The glutathione system may be the body's first-line defense used against oxidative stress and to maintain redox homeostasis in thalassemic patients based on the significant correlations between the GSH/GSSH ratio and degree of anemia or body iron stores.
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
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
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.
Oxidative stress; Beta-thalassemia; Lipid peroxidation; Beta-globins; Thiobarbituric acid reactive substances; Mutation
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.
β-Thalassemia Major; Oxidative Stress; Antioxidants; Ferritin; Uric Acid
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.
Repeated blood transfusion in beta thalassemia major patients may lead to peroxidative tissue injury by secondary iron overload. In the present study, 72 children with beta thalassemia major were included. Serum levels of total lipid peroxides, Iron, Total Iron Binding Capacity, Copper, Zinc, Vitamin E, plasma Total Antioxidant Capacity, activity of Erythrocyte Superoxide Dismutase, were measured. The findings were compared with 72 age matched healthy controls irrespective of sex. A significant increase in the levels of lipid peroxide and Iron (p<0.001), whereas, significant decrease in the levels of vitamin-E, Total Antioxidant Capacity and Total Iron Binding Capacity (p<0.001) was observed. Serum Zinc was significantly increased (p<0.001) with significant decrease in the levels of copper (p<0.001). Non Significant increase in the activity of Erythrocyte Superoxide Dismutase (p>0.05) was found in the patients when compared with controls. This suggest that oxidative stress and reduced antioxidant defense mechanism play an important role in pathogenesis of beta thalassemia major.
Beta thalassemia major; Oxidative stress; Antioxidants
Accelerated oxidative damage is one of the hallmarks in both sickle cell disease (SCD) and thalassemia major (TM). A decreased antioxidant level is found in both diseases. Our study was carried out to evaluate the variation in serum levels of Selenium and Vitamin E among a group of transfusion dependant Egyptian SCD and TM patients, further more to correlate these levels with iron overload status or transfusion requirements. A case-control study was conducted at the Cairo University Pediatric Hospital to assess the serum levels of Selenium using Atomic Absorption Spectrometer and Vitamin E using commercially available ELISA Kit in transfusion dependent children, 30 with beta thalassemia and 30 with SCD in a steady state aged from 6 to 18 years, these findings were compared to 30 age/sex matched healthy controls. Our results revealed a depleted antioxidants level in the studied group of Egyptian children with TM and SCD relative to healthy controls (P < 0.05). A significant positive correlation was found between Vitamin E levels and ferritin (r = 0.26, p = 0.047) in SCD and TM patients. Nonsignificant correlation was detected between serum Selenium and Vitamin E. Moreover, values of these antioxidants did not correlate with indices of hemolysis nor with those of inflammation in chronically transfused TM and SCD patients.
Antioxidants; Vitamin E; Selenium; Sickle cell anemia; β-thalassemia; Egyptian children
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.
β-thalassemic major; diabetes mellitus; insulin resistance; oxidative stress
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.
Antioxidants; Children; Free radicals; Respiratory burst enzymes; Sickle cell disease
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.
β-Thalassemia major; β-Thalassemia/HbE; Iron overload; Oxidative stress; Hepatic damage; Dyslipidemia
Treatment of thalassemia depends on the clinical diagnosis. Almost all severe alpha thalassemia, Hb Bart’s hydrops fetalis, die intra utero or a few minute after birth. However, pregnant woman with Hb Bart’s hydrops fetus may develop toxemia of pregnancy and antepartum and postpartum hemorrhage. Those homozygous beta thalassemias (transfusion dependent thalassemia, TDT) are severely anemic after 6 months. At birth the baby is asymptomatic because Hb F level is high. As Hb F production waning off, replaced by inefficient beta globin chain production, at the age of 6 to 12 months, the baby begins to be anemic with hepatosplenomegaly. A group of non transfusion dependent thalassemia (NTDT) includes the majority of beta thalassemia/Hb E, Hb H disease and a few cases of homozygous beta thalassemias. The thalassemia minor including both alpha and beta thalassemia carriers and some homozygous state like homozygous alpha+ thalassemia, homozygous Hb E are asymptomatic and does not need any regular treatment. All thalassemia major, TDT, patients need regular blood transfusion, every 3-4 weeks, to maintain the hemoglobin around 10-12 g/dL. For those NTDT blood is given only when necessary. Usually patients with hemoglobin level higher than 6 g/dL require no blood transfusion. In infants and children if the hemoglobin levels can be maintained at 7 g/dL or above, defective physical development and bone changes can be prevented until they reached third or fourth decades of life that osteoporosis is almost always presented in those with low hemoglobin level. Iron overload occurs in moderate and severe case without exception. This will lead to dark skin, liver cirrhosis, cardiac arrhythmia and congestive heart failure. Diabetes mellitus secondary to iron deposition in the pancreas and other endocrine dysfunction does develop if the patients live long enough. Iron chelation with 1-2 gm/day of desferrioxamine intravenously or intramuscularly every day, at least 5 days a week, is recommended for those patients who have hemochromatosis. Oral iron chelator such as deferiprone and deferasirox is recently available. This helps patients to have better compliance with the iron chelator. Stem cell transplantation has been tried with a very good result in class I cases. Because some difficulty in finding appropriated HLA matched donor lately people try to perform haploidentical stem cell transplantation with some good results. Lupstaercept (ACE-536) and Sotatarcept (ACE-011), a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemia due to ineffective erythropoiesis. Preliminary data showed that the compound could increase hemoglobin levels 1.5 g/dL after two weeks of treatment in NTDT case and decrease blood transfusion in 60% of cases with TDT. Research is in progress to find better agents to enhance Hb F production.
Thalassemia; stem cell transplantation; Hb F production
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.
Iron overload; Taurine; Heart; Liver; Antioxidants
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.
β−Thalassemic children have oxidative stress and antioxidant deficiency even without iron overload status. In these patients, tissue damage due to oxidative stress may be occurred. Also, it seems that thalassemic patients have higher levels of ALT, AST therefore, the main aim of the present study was to determine the benefits of vitamin E as an antioxidant supplements in β-Thalassemia children.
Materials and Methods
This clinical trial was carried out on 45 beta-thalassemic patients undergoing occasional transfusions (24 males, 21 females), mean age 16± 8 years, admitted to Yazd and Shahid Sadoughi hospital in 2011. Fallowing three months treatment of vitaminE (vitamin E 400-600 unit/day),liver function test and hemopoitic system parameters were measured.
Fourty five patients with laboratory confirmation of β-Thalassemia were recruited following three months vitamin E supplementation, liver function test had higher improvement compared to hemopoitic system parameters , and also serum SGOT was significantly reduced (P-value<0.004 ).
It seems clear that treatments of β-thalassemic patients with vitamins E have benefits in promoting antioxidant status and may improve liver function test, as AST and ALT to decrease but this supplement is not effective for hemopoietic system variables.
Vitamin E; Hemopoietic System; Liver Function Tests
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.
Oxidant-antioxidant; superoxide dismutase; thalassaemia
Beta-thalassemia is a severe genetic blood disorder caused by a mutation in the gene encoding for the beta chains of hemoglobin. Individuals with beta-thalassemia major require regular lifelong Red Blood Cell transfusions to survive. Ocular involvement is quite common and may have serious implications.
Extensive review of observational studies on beta-thalassemia, to determine the prevalence and spectrum of ocular abnormalities, by clinical examination and multimodal imaging, and to investigate risk factors for their development.
Frequency of ocular involvement differs among various studies (41.3–85 %, three studies). Ocular findings in beta-thalassemia may correlate to the disease itself, iron overload or the chelating agents used. Beta-thalassemia ocular manifestations include ocular surface disease, as demonstrated by tear function parameters (two studies). Lens opacities are present in 9.3–44 % (five studies). Lenticular opacities and RPE degeneration correlated positively with use of desferrioxamine and deferriprone respectively (two studies). Ocular fundus abnormalities characteristic of pseudoxanthoma elasticum (PXE), including peau d’orange, angioid streaks, pattern dystrophy-like changes, and optic disc drusen are a consistent finding in seven studies. Patients with PXE-like fundus changes were older than patients without these fundus changes (two studies). Age (two studies) and splenectomy (one study) had the strongest association with presence of PXE-like fundus changes. Increased retinal vascular tortuosity independently of the PXE-like fundus changes was found in 11–17.9 % (three studies), which was associated with aspartate amino transferase, hemoglobin and ferritin levels (two studies). Fundus autofluorescence and electrophysiological testing (ERG and EOG) may indicate initial stages or more widespread injury than is suggested by fundus examination (two studies).
Beta-thalassemia may present with various signs, both structural and functional. Pseudoxanthoma elasticum like fundus changes are a frequent finding in patients with b-thalassemia. These changes increase with duration or severity of the disease. Retinal vascular tortuosity may be an additional disease manifestation related to the severity and duration of anemia and independent of the PXE-like syndrome. Patients with long-standing disease need regular ophthalmic checkups because they are at risk of developing PXE-like fundus changes and potentially of subsequent choroidal neovascularization.
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.
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.
Background and Aim. Trace elements and vitamins play a vital role in human body to perform its function properly. Thalassemic patients are at risk of micronutrient deficiency. This study estimated levels of vitamins A, C, E, B12, folic acid, total homocysteine (tHcy), and methylmalonic acid (MMA) along with trace elements, zinc, copper, and selenium in Beta-thalassemia-major patients. Methods. This study included 108 patients with Beta-thalassemia-major and 60 age and sex matched healthy children. Serum levels of vitamin A, E, C, tHcy, and MMA were estimated by high pressure liquid chromatography while serum levels of folic acid and B12 were estimated by thin layer chromatography. Serum zinc, copper, and selenium were determined by atomic absorption spectrometry. Results. There was a significant decrease of vitamins A, C, E, and B12 and trace elements zinc, copper, and selenium in thalassemic patients as compared to controls. tHcy and MMA were significantly elevated in patients. No significant correlations were found between the serum levels of the studied vitamins and trace elements as regards age, frequency of transfusion, duration of transfusion, and serum ferritin. Conclusion. The level of various nutritional biomarkers (vitamins A, C, E, and B12 and trace elements zinc, copper, selenium) was reduced in chronically transfused Egyptian thalassemic patient. These patients should have periodic nutritional evaluation and supplementation. Multicenter studies are highly recommended.
The aim of this study was to determine the frequency of beta S-globin gene (βS globin) haplotypes and alpha thalassemia with 3.7 kb deletion (−α3.7kb thalassemia) in the northwest region of Paraná state, and to investigate the oxidative and clinical-hematological profile of βS globin carriers in this population. Of the 77 samples analyzed, 17 were Hb SS, 30 were Hb AS and 30 were Hb AA. The βSglobin haplotypes and −α3.7kb thalassemia were identified using polymerase chain reaction.Trolox equivalent antioxidant capacity (TEAC) and lipid peroxidation (LPO) were assessed spectophotometrically. Serum melatonin levels were determined using high-performance liquid chromatography coupled to coulometric electrochemical detection. The haplotype frequencies in the SS individuals were as follows: Bantu- 21 (62%), Benin - 11 (32%) and Atypical- 2 (6%). Bantu/Benin was the most frequent genotype. Of the 47 SS and AS individuals assessed, 17% (n = 8) had the −α3.7kb mutation. Clinical manifestations, as well as serum melatonin, TEAC and LPO levels did not differ between Bantu/Bantu and Bantu/Benin individuals (p > 0.05). Both genotypes were associated with high LPO and TEAC levels and decreased melatonin concentration. These data suggest that the level of oxidative stress in patients with Bantu/Bantu and Bantu/Benin genotypes may overload the antioxidant capacity.
antioxidants; hemoglobinopathies; melatonin; sickle cell disease; 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.
Thalassemia; non-labile iron; malondialdehyde; total carbonyl
The thalassemic syndromes originate from mutations of the globin genes that cause, besides the characteristic clinical picture, also an increased Hb F amount. It is not yet clear if there are more factors, besides the beta globin genotype, determining the Hb F production. We have tried to find out if there are relations between total Hb and Hb F, between erythropoietin (Epo) and Hb F, between Hb F and point mutations of the gamma gene promoters.
Materials and Methods
Hematologic parameters, iron status, alpha/non-alpha globin ratio, Epo level, and thalassemic defects of the alpha-, beta-, and gamma-globin genes were explored using standard methods in patients affected by thalassemic diseases. Ninety-five non thalassemic individuals have been examined as controls.
Two clinical variants of beta-thalassemia intermedia referred to as beta-thal int sub-silent and evident are associated with distinct sets of mutations of the beta-globin gene. Silent beta thal mutations are invariably associated with sub-silent beta thal int; beta° or severe beta+ thal mutations are associated with evident beta thal int (88%) and almost invariably (98%) with thalassemia major. A positive correlation was observed between the severity of the disease and the Hb F level, but no correlation was found between the Hb F and erythropoietin (Epo) level. The mutation Ggamma -158 C→T was detected in 26.9% of patients affected by beta-thal int sub-silent and evident, respectively, but only in 2% of patients with thalassemia major.
The severity of beta-thal int and the increased Hb F level are strictly dependent from the type of beta-globin gene mutations. No relation is found between Hb F synthesis and Epo secretion. The mutation Ggamma -158 C→T, common among patients affected by beta-thal int and very rare in thal major patients, does not seem, in this study, to influence the Hb F content in beta thal int patients.
Iron-overload cardiomyopathy is a major cause of death in thalassemia patients due to the lack of an early detection strategy. Although cardiac magnetic resonance (CMR) T2* is used for early detection of cardiac iron accumulation, its availability is limited. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and found to be depressed in thalassemia. However, its direct correlation with cardiac iron accumulation has never been investigated. We investigated whether HRV can be used as an alternative indicator for early identification of cardiac iron deposition in thalassemia patients.
Ninety-nine non-transfusion dependent thalassemia patients (23.00 (17.00, 32.75) years, 35 male) were enrolled. The correlation between HRV recorded using 24-hour Holter monitoring and non-transferrin bound iron (NTBI), hemoglobin (Hb), serum ferritin, LV ejection fraction (LVEF), and CMR-T2* were determined.
The median NTBI value was 3.15 (1.11, 6.59) μM. Both time and frequency domains of HRV showed a significant correlation with the NTBI level, supporting HRV as a marker of iron overload. Moreover, the LF/HF ratio showed a significant correlation with CMR-T2* with the receiver operating characteristic (ROC) curve of 0.684±0.063, suggesting that it could represent the cardiac iron deposit in thalassemia patients. HRV was also significantly correlated with serum ferritin and Hb.
This novel finding regarding the correlation between HRV and CMR-T2* indicates that HRV could be a potential marker in identifying early cardiac iron deposition prior to the development of LV dysfunction, and may be used as an alternative to CMR-T2* for screening cardiac iron status in thalassemia patients.
Patients with beta thalassemia major are at increased risk for bacterial infections specially splenectomized patients. The aim of this study was to determine the anti-tetanus antibody concentration among patients with beta thalassemia major.
Materials and Methods
The anti-tetanus antibody concentration was investigated in 224 patients with thalassemia major and 224 healthy subjects matched for age and gender. Tetanus antibody and ferritin serum level were determined by enzyme-linked immunosorbent assay method using commercial kits. Subjects who had antibody level ≥ 0.1 IU/mL was defined as complete protection, 0.01 to < 0.1 IU/mL as partial protection and < 0.01 IU/mL as no protection. For the analysis, we used SPSS version 11.5 software. A two-sided p-value less 0.05 was considered statistically significant.
In patients with beta thalassemia major, antibody level against tetanus was inversely dependent about 29.3% to serum ferritin level. Thus, when serum ferritin increased 1 ng/mL, serum antibody against tetanus decreased 0.002 IU/mL. Mean anti-tetanus (IgG) antibody titers was lower in thalassemia patients compared to healthy subjects (1.53 ± 1.71 vs. 2.02 ± 2.05, p = 0.007) that was no significantly associated to age and gender in both study groups. All of participants had serum antibody level 0.01 IU/mL or greater. The complete protective level of anti-tetanus antibody was lower in thalassemia subjects in compare to healthy persons (71% vs. 87.9%, p < 0.001).
Patients with thalassemia had lower anti-tetanus antibody level than healthy subjects. Thus the vaccine recommendation seems essential for patients with beta thalassemia major.
Tetanus; Thalassemia; Immunity; Antibodies
Thalassemia is a common inherited hemoglobin disorder in Vietnam. The alpha thalassemia, beta thalassemia, and HbE are popular in Vietnam but its variance depends on ethnics. The research for frequency of some ethnics almost in electrophoresis includes: Kinh (beta thalassemia carrier 1.49%, HbE 1.24%), Muong (beta thalassemia carrier 10.7%, HbE 11.7%), Tay (beta thalassemia carrier 11%, HbE 1%). In the recent years, we have conducted researches on thalassemia gene in the Northern and Southern areas of Vietnam. The two researches on beta thalassemia conducted at National Hospital of Pediatrics were Cd17 (33.8%), Cd41/42 (29.4%) following are HbE (19.1%), Cd 71/72 (7.3%), -28 (5.9%), IVS 2-625 (1.5%), IVS 1-5 (1.5%), IVS 1-1 (1.5%). In Vietnam, we have a thalassemia centre at the National Institute of Hematology and Blood Transfusion and several outpatient clinics at National Hospital of Pediatrics, Children No. 1 Hospital, Blood Transfusion and Hematology Hospital Ho Chi Minh city, Central Hue Hospital. In provincial hospitals, we have transfusion service but very variance. That the number of patients with thalassemia requires regular blood transfusion has been increasing results in big shortage of blood supply. At Department of Clinical Hematology-NHP, we provide patients with screening for HIV, HCV and HBV in every 6 months. Patients were done antibody screening test. Deferoxamine, deferiprone and deferasirox are currently used but in short supply. We are facing the difficulty that almost hospitals in Vietnam lack the drug which is unique for each type of chelation. We have to apply ferritin level to follow the chelation effective and MRI to measure iron overload in patients’ liver and heart. We are only able to provide SCT for the modest number of patients with thalassemia. In almost cases, we used sibling donor in SCT for patients with thalassemia. Regarding prevention service, we offer genetic counseling and prenatal diagnosis at three hospitals. We organized prevention program in Hoa Binh province on national budget. The most important future planning is expanding prevention program in provinces with high prevalence and after that in the all country. Our future plan is to set up more thalassemia centres in provincial and central hospitals where overload with patient’s demand. We also launch for appeal for blood and iron chelation to patients with thalassemia. In near future, use of haplo SCT to treatment thalassemia patients will be more.
Thalassemia; gene; treatment; planning; prevalence