ascorbic-acid and beta-Thalassemia

Ascorbate is a cofactor in numerous metabolic reactions. Humans cannot synthesize ascorbate owing to inactivation of the gene encoding the enzyme l-gulono-γ-lactone oxidase, which is essential for ascorbate synthesis. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance nonheme iron absorption in the gut, ascorbate within mammalian systems can regulate cellular iron uptake and metabolism. Ascorbate modulates iron metabolism by stimulating ferritin synthesis, inhibiting lysosomal ferritin degradation, and decreasing cellular iron efflux. Furthermore, ascorbate cycling across the plasma membrane is responsible for ascorbate-stimulated iron uptake from low-molecular-weight iron-citrate complexes, which are prominent in the plasma of individuals with iron-overload disorders. Importantly, this iron-uptake pathway is of particular relevance to astrocyte brain iron metabolism and tissue iron loading in disorders such as hereditary hemochromatosis and β-thalassemia. Recent evidence also indicates that ascorbate is a novel modulator of the classical transferrin-iron uptake pathway, which provides almost all iron for cellular demands and erythropoiesis under physiological conditions. Ascorbate acts to stimulate transferrin-dependent iron uptake by an intracellular reductive mechanism, strongly suggesting that it may act to stimulate iron mobilization from the endosome. The ability of ascorbate to regulate transferrin iron uptake could help explain the metabolic defect that contributes to ascorbate-deficiency-induced anemia.

Topics: Anemia; Animals; Ascorbic Acid; Astrocytes; Basic Helix-Loop-Helix Transcription Factors; beta-Thalassemia; Biological Transport; Erythropoiesis; Ferritins; Hemochromatosis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Iron; Transferrin

Vitamin C, as antioxidant, increases the efficacy of deferoxamine (DFO).. To investigate the effects of vitamin C as an adjuvant therapy to the three used iron chelators in moderately iron-overloaded young vitamin C-deficient patients with β-thalassemia major (β-TM) in relation to tissue iron overload.. This randomized prospective trial that included 180 β-TM vitamin C-deficient patients were equally divided into three groups (n = 60) and received DFO, deferiprone (DFP), and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin C supplementation (100 mg daily) or not (n = 30). All patients received vitamin C (group A) or no vitamin C (group B) were followed up for 1 yr with assessment of transfusion index, hemoglobin, iron profile, liver iron concentration (LIC) and cardiac magnetic resonance imaging (MRI) T2*.. Baseline vitamin C was negatively correlated with transfusion index, serum ferritin (SF), and LIC. After vitamin C therapy, transfusion index, serum iron, SF, transferrin saturation (Tsat), and LIC were significantly decreased in group A patients, while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin C. The same improvement was found among DFO-treated patients post-vitamin C compared with baseline data. DFO-treated patients had the highest hemoglobin with the lowest iron, SF, and Tsat compared with DFP or DFX subgroups.. Vitamin C as an adjuvant therapy possibly potentiates the efficacy of DFO more than DFP and DFX in reducing iron burden in the moderately iron-overloaded vitamin C-deficient patients with β-TM, with no adverse events.

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; beta-Thalassemia; Biomarkers; Dietary Supplements; Drug Therapy, Combination; Female; Humans; Iron; Iron Chelating Agents; Iron Overload; Liver; Magnetic Resonance Imaging; Male; Treatment Outcome

To assess the effects of combined vitamin therapy on oxidant-antioxidant hepatic status and hemoglobin (Hb) derivatives on β-thalassemia major (β-TM), a prospective study of 60 β-TM patients aged 4 to 17 years, was conducted. Thirty-nine patients with initial low serum vitamins E, C and A, were treated with oral combined vitamins for 1 year compared to 21 patients with normal vitamin levels. Serum transaminases, serum ferritin, hepatic fibroscan elastography (TE) and magnetic resonance imaging R2* (MRI R2*) for liver iron concentration (LIC), were assessed before and after 6 and 12 months of therapy. Antioxidant capacity was assessed by levels of reduced glutathione (GSH), malondialdehyde (MDA), catalase, superoxide dismutase and GSH enzymes. The studied vitamins, reduced GSH and Hb levels were significantly elevated and paralleled by progressive decline in MDA and ferritin during therapy (p <0.001). Serum transaminase and superoxide dismutase were significantly decreased, while GSH reductase was significantly elevated during therapy (p <0.001). Improvement of hepatic fibrosis as 23.0% had TE (>12 kPa) at baseline compared to 20.5% after therapy (p >0.05), although LIC values were significantly decreased (p <0.001). Combined vitamin therapy improves the antioxidant/oxidant balance, LIC and hepatic fibrosis in young β-TM patients.

Topics: Adolescent; Antioxidants; Ascorbic Acid; beta-Thalassemia; Child; Child, Preschool; Female; Ferritins; Glutathione; Humans; Liver; Liver Cirrhosis; Male; Malondialdehyde; Prospective Studies; Superoxide Dismutase; Transaminases; Vitamin A; Vitamin E

We assessed whether oxidant-stress and inflammation in beta-thalassemia could be controlled by the novel oral iron chelator deferasirox as effectively as by deferoxamine.. Forty-nine subjects were enrolled from seven sites and studied at baseline, and after 1, 6, and 12 months of therapy. Malondialdehyde, protein carbonyls, vitamins E and C, total non-transferrin bound iron, transferrin saturation, C-reactive protein, cytokines, serum ferritin concentration and liver iron concentration were measured.. Liver iron concentration and ferritin declined significantly in both treatment groups during the study. This paralleled a significant decline in the oxidative-stress marker malondialdehyde (deferasirox -22%/year, deferoxamine -28%/year, average decline p=0.006). The rates of decline did not differ between treatment groups. Malondialdehyde was higher in both treatment groups than in a group of 30 non-thalassemic controls (p < 0.001). The inflammatory marker high-sensitivity C-reactive protein decreased significantly only in the group receiving deferasirox (deferasirox -51%/year, deferoxamine +8.5%/year, p = 0.02). This result was confounded by a chance difference in the level of high-sensitivity C-reactive protein between the two groups at baseline, but analyses controlling for this difference suggested an equally large treatment effect.. Iron chelation therapy with deferoxamine or with deferasirox was equally effective in decreasing iron burden and malondialdehyde. The possible differential effect of the two chelators on inflammation warrants further investigation.

Topics: Adolescent; Adult; Ascorbic Acid; Benzoates; beta-Thalassemia; C-Reactive Protein; Child; Deferasirox; Deferoxamine; Female; Humans; Iron Chelating Agents; Lipid Peroxidation; Male; Oxidants; Oxidative Stress; Triazoles; Vitamin E

The present study aimed to determine the benefits of vitamin C and vitamin E as antioxidant supplements in beta-Thalassemia children who are at risk of iron overload due to multiple blood transfusion and high oxidative stress. Antioxidant status, oxidative products, plasma free hemoglobin, total hemoglobin and bilirubin were discussed. Twenty children who had laboratory confirmation of major beta-Thalassemia at least 6 months with history of packed red cell transfusion without iron chelation were recruited. The informed consent for blood sample collection and antioxidant medication was performed. Most patients (85%) had hyperferritinemia and all of them had high oxidative stress. All of them had low vitamin C and vitamin E level at recruitment. Three months after vitamin C and vitamin E supplementation, plasma vitamin C, vitamin E and glutathione were significantly increased, while total bilirubin was slightly decreased without significance. Other parameters included total antioxidant status (TAS), plasma and erythrocyte malondialdehyde (MDA), hemoglobin and plasma free hemoglobin had no differences during the study period.. B-Thalassemia major children who had multiple blood transfusion are at risk in iron overload and high oxidative stress. From the present study, no significant improvement in raising hemoglobin and concerning low dose vitamin C is not contraindication in beta-Thalassemia patients. Therefore, vitamin C plus vitamin E supplementation have benefits more than vitamin E alone in promoting antioxidant status and may enhance liver function as total bilirubin tends to decrease.

Topics: Adolescent; Antioxidants; Ascorbic Acid; beta-Thalassemia; Bilirubin; Child; Child, Preschool; Female; Humans; Liver; Male; Oxidative Stress; Prospective Studies; Vitamin E

The oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1, deferiprone, CAS 30652-11-0) has been given daily for 3-11 months to 6 transfusion dependent iron loaded patients (myelodysplasia (MDS) 2, Diamond-Blackfan anaemia 1, thalassaemia intermedia 1, thalassaemia major 2). Daily doses of 3 g, 2 x 2 g and 3 x 2 g were administered for the first 2-7 months. Daily doses of 2 x 3 g were also used for periods up to 4 months. Urine iron excretion following 3 g of L1 was found to be related to the number of previous transfusions but not to serum ferritin or the amount of L1 excreted. In each case 24 h urinary iron excretion in response to 3 g L1 ranged from 5-21 mg in MDS, 13-25 mg in a thalassaemia intermedia and a Diamond-Blackfan patient and 16-110 mg in thalassaemia major patients. Further increases of urinary iron were observed in all the patients when the daily dose was increased. Serum ferritin levels have fluctuated but overall have remained unchanged. Biochemical assessment did not show any major abnormalities ascribed to L1 except from subnormal serum zinc levels in two patients and white blood cell absorbate in another. In a separate study we have compared urinary L1 and iron excretions in 7 transfusional iron loaded patients. In all the cases the concentration of L1 was in excess of iron and higher than the level required for 100% iron binding. There was no other apparent correlation between the concentrations of L1 and iron in the urines studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Ascorbic Acid; beta-Thalassemia; Deferiprone; Feces; Female; Ferritins; Humans; Iron; Iron Chelating Agents; Male; Middle Aged; Myelodysplastic Syndromes; Pyridones

Globally, β-thalassemia major (β-TM) is one of the most common hereditary disorders. Multiple blood transfusions, that are a life-saving therapy in patients with β-TM, is a major source of iron overload. Iron overload can lead to significant morbidity and mortality. Research evidence indicates that oxidative stress induced by iron overload, is one of the major precipitating causes of vitamin C deficiency in β-TM patients. It has previously been shown that patients with β-TM have significantly lower levels of vitamin C as compared to healthy individuals. It is believed that vitamin C can reduce both ferric (Fe(3+)) and ferrous (Fe(2+)) ions, and also facilitate the accessibility of iron to chelators through increase of iron release from the reticuloendothelial system. Despite the potential benefits of vitamin C in patients with β-TM, several areas of concern exist that should be addressed by high quality research designs. Some recommendations have been provided through this study.

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; beta-Thalassemia; Contraindications; Dietary Supplements; Humans; Iron Overload; Nutrition Policy; Oxidative Stress; Transfusion Reaction

During investigations of the phenotypic diversity of hemoglobin (Hb) E β thalassemia, a patient was encountered with persistently high levels of methemoglobin associated with a left-shift in the oxygen dissociation curve, profound ascorbate deficiency, and clinical features of scurvy; these abnormalities were corrected by treatment with vitamin C. Studies of erythropoietin production before and after treatment suggested that, as in an ascorbate-deficient murine model, the human hypoxia induction factor pathway is not totally dependent on ascorbate levels. A follow-up study of 45 patients with HbE β thalassemia showed that methemoglobin levels were significantly increased and that there was also a significant reduction in plasma ascorbate levels. Haptoglobin levels were significantly reduced, and the high frequency of the 2.2 haptoglobin genotype may place an additional pressure on ascorbate as a free-radical scavenger in this population. There was, in addition, a highly significant correlation between methemoglobin levels, splenectomy, and factors that modify the degree of globin-chain imbalance. Because methemoglobin levels are modified by several mechanisms and may play a role in both adaptation to anemia and vascular damage, there is a strong case for its further study in other forms of thalassemia and sickle-cell anemia, particularly when splenic function is defective.

Topics: Adult; Ascorbic Acid; Ascorbic Acid Deficiency; beta-Thalassemia; Family; Female; Hemoglobin E; Humans; Male; Methemoglobin; Methemoglobinemia; Young Adult

We report three cases of scurvy, with differing musculoskeletal presentations, from a tertiary teaching hospital in Sydney, Australia. Case 1 was a man with cerebral palsy who presented with knee swelling following a minor injury. In Case 2, a patient with thalassaemia major presented with purpuric rash, difficulty walking and distal thigh swelling and ecchymosis. Case 3 was a man with Down's syndrome who presented with acute ankle arthritis. Scurvy in Cases 1 and 3 were related to abnormal dietary preferences, whereas in Case 2, scurvy was thought to be related to thalassaemia. All three cases responded rapidly to vitamin C replacement. The subjects did not appear malnourished as they had adequate carbohydrate and protein intake.

Topics: Adult; Ascorbic Acid; Ascorbic Acid Deficiency; beta-Thalassemia; Cerebral Palsy; Down Syndrome; Feeding Behavior; Hospitals, Teaching; Humans; Male; Scurvy; Treatment Outcome

Data suggest a large variability in the effectiveness of the orally active iron chelator, deferiprone, in inducing a sustained decrease in body iron to concentrations compatible with the avoidance of complications from iron overload. We analyzed 19 patients with thalassemia major who were undergoing long-term therapy with deferiprone (75 mg/kg/day every 8 hours). In seven of the 19 patients, hepatic iron concentration had been reduced or maintained at less than 7 mg/g of dry weight liver tissue, associated with no evidence of iron-induced toxicity (group A). In the remaining 12, hepatic iron concentration had either stabilized at higher than 7 mg/g of dry weight liver tissue, or increased to such concentrations during therapy with deferiprone (group B). We studied in these patients determinants that may explain such variability, including initial hepatic iron concentrations, compliance, transfusion index, pharmacokinetic characteristics of deferiprone, and plasma vitamin C status. Patients in group B showed significantly decreased plasma vitamin C concentrations compared with those in group A, who demonstrated normal levels (0.04 mg/dl [0.04-0.19 mg/dl] and 0.62 mg/day [0.44-1.05 mg/day], respectively; p = 0.02). A significant difference in apparent volume of distribution (Vd/F) had developed between the groups over time, with a higher Vd/F in group B (1.66 [0.681, group A] and 3.16 [0.811, group B]; p = 0.006). Group B had started with hepatic iron concentrations that were significantly higher than those of group A, a difference that became more pronounced over time. In the initial analysis, serum ferritin concentrations were also higher in group B. The two groups did not differ in the remaining factors. The initial hepatic iron concentrations predicted the slope of change in this value. Regression analysis suggested that patients with initial hepatic iron concentration of less than or equal to 7.22 mg/g of dry weight liver tissue are unlikely to further decrease while taking deferiprone 75 mg/kg/day. Vitamin C deficiency developed in patients in group B over time. Vitamin C is an important biologic cofactor that plays a role in the distribution of iron. The trend of increase in Vd/F of deferiprone over time may imply a compartment shift of iron stores to one less accessed by deferiprone. This study confirmed the effectiveness of deferiprone in heavily iron-loaded patients and provided evidence that its effectiveness decreases in proportion to liver iron

Topics: Adult; Ascorbic Acid; beta-Thalassemia; Deferiprone; Ferritins; Humans; Iron; Iron Chelating Agents; Outcome Assessment, Health Care; Patient Compliance; Pyridones; Treatment Outcome

Topics: Ascorbic Acid; beta-Thalassemia; Child; Erythrocyte Transfusion; Humans; Male; Prognosis; Radiography; Risk Assessment; Scurvy; Treatment Outcome

Topics: Antioxidants; Ascorbic Acid; beta-Thalassemia; Deferoxamine; Humans; Iron; Iron Chelating Agents; Liver; Transferrin; Vitamin A; Vitamin E

Pathogenesis of diabetes-related microvascular complications involving oxidative damage by free radicals has been demonstrated. Free radical generation has been shown to derive largely from iron. Our objectives, therefore, were to determine if there is an increased incidence and/or an accelerated course of nephropathy in patients with diabetes, secondary to transfusional hemochromatosis, and to examine whether free radical activity contributes to the development of this complication.. We evaluated nine patients with homozygous beta-thalassemia, complicated by clinically overt diabetes, for diabetic nephropathy over a 7-year period. Lipid peroxidation was quantified by measuring the presence of 20 saturated and unsaturated aldehydes, and results were compared with five normotensive type 1 diabetic patients without iron overload.. Nephropathy developed in five of nine patients (55%) after a mean duration of overt diabetes of 3.6 +/- 2.0 years. Three patients showed evidence of progressive microalbuminuria over a 7-year period (24.7-46.2, 52.2-430.1, and 17.7-54.3 micrograms/min, respectively). Two patients with borderline microalbuminuria (19.9 and 14.5 micrograms/min, respectively) demonstrated stable albumin excretion rates over the follow-up period. Total aldehyde concentration was significantly higher in beta-thalassemia diabetic patients, compared with nonthalassemic diabetic control subjects (8,106 +/- 1,280 vs. 4,594 +/- 247 nmol/l; P < 0.0001). The three patients with progressive microalbuminuria demonstrated significantly higher total aldehyde concentration, compared with the other beta-thalassemia diabetic patients with stable albumin excretion (9,428 +/- 337 vs. 7,445 +/- 1,003 nmol/l; P < 0.01). Serum vitamin E concentrations were significantly lower in beta-thalassemia patients with diabetes, compared with diabetic patients without iron overload (12.1 +/- 6.0 vs. 25.9 +/- 11.4 mumol/l; P = 0.02). Serum vitamin C concentrations did not differ between the two groups. Multiple regression analysis demonstrated total aldehyde concentration to be the most significant predictor for the development of microalbuminuria (P = 0.01), followed by the duration of diabetes (P = 0.02) and glycemic control (P = 0.02).. Early development and an accelerated course of diabetic nephropathy in iron-loaded patients with beta-thalassemia are observed. These findings may be attributed to high oxidative stress in these patients, which is secondary to iron-derived free radicals and to the patients' diminished antioxidant reserves.

Topics: Adult; Albuminuria; Aldehydes; Antioxidants; Ascorbic Acid; beta-Thalassemia; Blood Glucose; Blood Pressure; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Fructosamine; Homozygote; Humans; Iron; Kidney Function Tests; Lipid Peroxidation; Oxidative Stress; Retrospective Studies; Transfusion Reaction; Vitamin E

It is well-documented that iron chelation by desferrioxamine protects/improves the cardiac function in blood transfusion-dependent children suffering from beta-thalassaemia. In patients who do not become dependent upon blood transfusion until adulthood (ANT-patients), iron chelation by desferrioxamine may affect the cardiac function in unknown ways, presumably because age-related changes in the heart may cause iron chelation to affect the cardiac function in different ways. We therefore followed the left ventricular ejection fraction (LVEF) by multigated radionuclide angiography in 16 iron-loaded ANT-patients during iron chelation alone and after increasing the efficacy of chelation by vitamin C supplementation. During 12 months of iron chelation the mean LVEF fell significantly from 63.3% to 58.0% (p=0.04). Individual changes in LVEF did not correlate significantly with age but with the pretreatment liver iron concentration. After initiation of vitamin C supplementation, the mean LVEF increased from 55.9% to 65.3% (p=0.01). Our data suggest that in ANT-patients prolonged desferrioxamine treatment without vitamin C supplementation may be associated with reduced LVEF, whereas vitamin C supplementation seems to benefit the cardiac function. Similar findings have not been described in beta-thalassaemia and may hence be specific for ANT-patients. However, our findings have to be confirmed by controlled studies.

Topics: Adolescent; Adult; Aged; Aging; Antidotes; Ascorbic Acid; beta-Thalassemia; Chelating Agents; Coronary Angiography; Deferoxamine; Female; Humans; Injections, Subcutaneous; Iron Overload; Male; Middle Aged; Transfusion Reaction; Ventricular Function, Left

Topics: Anemia; Ascorbic Acid; beta-Thalassemia; Child; Humans; Infant; Plasma; Thalassemia