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
Patients with thalassemia major have inevitably suffered from complications of the disease, due to iron overload. Among such complications, cardiomyopathy is the leading cause of morbidity and mortality (63.6% to 71%). The major causes of death in this group of patients are congestive heart failure and fatal cardiac tachyarrhythmias leading to sudden cardiac death. The free radical-mediated pathway is the principal mechanism of iron toxicity. The consequent series of events caused by iron overload lead to catastrophic cardiac effects. The authors review the electrophysiological and molecular mechanisms, pathophysiology and correlated clinical insight of heart failure and arrhythmias in iron overload thalassemic cardiomyopathy.
Cardiomyopathy; Cardiovascular death; Iron overload; Thalassemia
Transfusional therapy for thalassemia major and sickle cell disease can lead to iron deposition and damage to the heart, liver, and endocrine organs. Iron causes the MRI parameters T1, T2, and T2* to shorten in these organs, which creates a potential mechanism for iron quantification. However, because of the danger and variability of cardiac biopsy, tissue validation of cardiac iron estimates by MRI has not been performed. In this study, we demonstrate that iron produces similar T1, T2, and T2* changes in the heart and liver using a gerbil iron-overload model.
Methods and Results
Twelve gerbils underwent iron dextran loading (200 mg · kg−1 · wk−1) from 2 to 14 weeks; 5 age-matched controls were studied as well. Animals had in vivo assessment of cardiac T2* and hepatic T2 and T2* and postmortem assessment of cardiac and hepatic T1 and T2. Relaxation measurements were performed in a clinical 1.5-T magnet and a 60-MHz nuclear magnetic resonance relaxometer. Cardiac and liver iron concentrations rose linearly with administered dose. Cardiac 1/T2*, 1/T2, and 1/T1 rose linearly with cardiac iron concentration. Liver 1/T2*, 1/T2, and 1/T1 also rose linearly, proportional to hepatic iron concentration. Liver and heart calibrations were similar on a dry-weight basis.
MRI measurements of cardiac T2 and T2* can be used to quantify cardiac iron. The similarity of liver and cardiac iron calibration curves in the gerbil suggests that extrapolation of human liver calibration curves to heart may be a rational approximation in humans.
magnetic resonance imaging; anemia; iron overload; thalassemia; cardiomyopathy
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.
Recent developments in the understanding of the molecular control of iron homeostasis provided novel
insights into the mechanisms responsible for normal iron balance. However in chronic anemias associated
with iron overload, such mechanisms are no longer sufficient to offer protection from iron toxicity, and iron
chelating therapy is the only method available for preventing early death caused mainly by myocardial and
hepatic damage. Today, long-term deferoxamine (DFO) therapy is an integral part of the management of
thalassemia and other transfusion-dependent anemias, with a major impact on well-being and survival.
However, the high cost and rigorous requirements of DFO therapy, and the significant toxicity of deferiprone
underline the need for the continued development of new and improved orally effective iron chelators.
Within recent years more than one thousand candidate compounds have been screened in animal models. The
most outstanding of these compounds include deferiprone (L1); pyridoxal isonicotinoyl hydrazone (PIH) and;
bishydroxy- phenyl thiazole. Deferiprone has been used extensively as a substitute for DFO in clinical trials
involving hundreds of patients. However, L1 treatment alone fails to achieve a negative iron balance in a
substantial proportion of subjects. Deferiprone is less effective than DFO and its potential hepatotoxicity is
an issue of current controversy. A new orally effective iron chelator should not necessarily be regarded as
one displacing the presently accepted and highly effective parenteral drug DFO. Rather, it could be employed
to extend the scope of iron chelating strategies in a manner analogous with the combined use of medications
in the management of other conditions such as hypertension or diabetes. Coadministration or alternating use
of DFO and a suitable oral chelator may allow a decrease in dosage of both drugs and improve compliance
by decreasing the demand on tedious parenteral drug administration. Combined use of DFO and L1 has
already been shown to result in successful depletion of iron stores in patients previously failing to respond to single drug therapy, and to lead to improved compliance with treatment. It may also result in a “shuttle effect” between weak intracellular chelators and powerful extracellular chelators or exploit the entero-hepatic cycle to promote fecal iron excretion. All of these innovative ways of chelator usage are now awaiting
evaluation in experimental models and in the clinical setting.
Iron cardiomyopathy remains the leading cause of death in patients with thalassemia major. Magnetic resonance imaging (MRI) is ideally suited for monitoring thalassemia patients because it can detect cardiac and liver iron burdens as well as accurately measure left ventricular dimensions and function. However, patients with thalassemia have unique physiology that alters their normative data. In this article, we review the physiology and pathophysiology of thalassemic heart disease as well as the use of MRI to monitor it. Despite regular transfusions, thalassemia major patients have larger ventricular volumes, higher cardiac outputs, and lower total vascular resistances than published data for healthy control subjects; these hemodynamic findings are consistent with chronic anemia. Cardiac iron overload increases the relative risk of further dilation, arrhythmias, and decreased systolic function. However, many patients are asymptomatic despite heavy cardiac burdens. We explore possible mechanisms behind cardiac iron-function relationships and relate these mechanisms to clinical observations.
iron; heart; MRI; ejection fraction; cardiac function; T2*
Dietary taurine-deficiency is a cause of dilated cardiomyopathy (DCM) in cats. While the incidence of clinical cases of feline DCM has markedly decreased since the association between DCM and taurine-deficiency was first recognized, not all cats maintained on taurine-deficient diets develop DCM. The objective was to temporally evaluate left ventricular (LV) function using M-mode echocardiography in 23 cats maintained on a taurine-deficient diet; 20 time-matched, taurine-supplemented cats served as controls. The duration of feeding trials ranged from 6-15 months. No diminution of myocardial function was recorded in a small number of taurine-deficient cats whereas cardiac performance in some taurine-deficient cats diminished to levels characteristic of DCM. Of the taurine-deficient cats, 17 (74%) experienced a greater than 25% reduction in fractional shortening and 21 (91%) had a greater than 25% increase in LV end-systolic short-axis diameter. On average, LV end-systolic short-axis diameter increased by 70% and fractional shortening decreased by 37% in taurine-deficient cats. Mean velocity of circumferential fiber shortening was similarly reduced in taurine-deficient cats. The greatest rate of change in M-mode echocardiographic variables occurred during the first four months on the taurine-deficient diet. Dietary taurine deficiency leads to a spectrum of changes in myocardial function in domestic cats. While DCM is observed in some cats, decreased systolic pump function and increased LV end-systolic short-axis diameter are more consistent findings.
Despite the availability of deferoxamine chelation therapy for more than 20 years, iron cardiomyopathy remains the leading cause of death in thalassemia major patients. Effective chelation of cardiac iron is difficult; cardiac iron stores respond more slowly to chelation therapy and require a constant gradient of labile iron species between serum and myocytes. We have previously demonstrated the efficacy of once-daily deferasirox in removing previously stored cardiac iron in the gerbil, but changes in cardiac iron were relatively modest compared with hepatic iron. We postulated that daily divided dosing, by sustaining a longer labile iron gradient from myocytes to serum, would produce better cardiac iron chelation than a comparable daily dose.
Twenty-four 8- to 10-week-old female gerbils underwent iron dextran—loading for 10 weeks, followed by a 1-week iron equilibration period. Animals were divided into three treatment groups of eight animals each and were treated with deferasirox 100 mg/kg/day as a single dose, deferasirox 100 mg/kg/day daily divided dose, or sham chelation for a total of 12 weeks. Following euthanasia, organs were harvested for quantitative iron and tissue histology.
Hepatic and cardiac iron contents were not statistically different between the daily single-dose and daily divided-dose groups. However, the ratio of cardiac to hepatic iron content was lower in the divided-dose group (0.78% vs 1.11%, p = 0.0007).
Daily divided dosing of deferasirox changes the relative cardiac and liver iron chelation profile compared with daily single dosing, trading improvements in cardiac iron elimination for less-effective hepatic chelation.
Iron overload occurs in patients who require regular blood transfusions to correct genetic and acquired anaemias, such as β-thalassaemia major, sickle cell disease, and myelodysplastic syndromes. Although iron overload causes damage in many organs, accumulation of cardiac iron is a leading cause of death in transfused patients with β-thalassaemia major. The symptoms of cardiac iron overload will occur long after the first cardiac iron accumulation, at a point when treatment is more complex than primary prevention would have been. Direct measurement of cardiac iron using T2* magnetic resonance imaging, rather than indirect methods such as measuring serum ferritin levels or liver iron concentration have contributed to earlier recognition of myocardial iron loading and prevention of cardiac toxicity. Cardiac siderosis occurs in all transfusional anaemias, but the relative risk depends upon the underlying disease state, transfusional load, and chelation history. All three available iron chelators can be used to remove cardiac iron, but each has unique physical properties that influence their cardiac efficacy. More prospective trials are needed to assess the effects of single-agent or combination iron chelation therapy on the levels of cardiac iron and cardiac function. Ultimately, iron chelation therapies should be tailored to meet individual patient needs and lifestyle demands.
Cardiac iron; Iron chelation therapy; Myelodysplastic syndrome; Sickle cell disease; β-Thalassaemia major
The relationship between iron deficiency and protein deficiency and infestation of the rat with the nematode Nippostrongylus brasiliensis was investigated. There was a significant delay in the expulsion of N. brasiliensis from the small intestine of both iron deficient and protein deficient animals and those with a combined deficiency of iron and protein. Iron repletion returned the time of worm expulsion to normal and this would appear to be related to iron deficiency per se rather than to anaemia. Antibody initiated damage to worms was normal in the control animals and in animals with nutritional deficiencies. This suggests that the defect in worm expulsion occurs either in the cell-mediated immune system or in one of the other mediators of expulsion. Extrapolation to the human situation has important therapeutic implications in that iron and protein deficiency may play an important role in the perpetuation of helminth infestations. Thus, to be successful antihelminth therapy should be accompanied by iron and protein supplementation.
Iron cardiomyopathy is a leading cause of death in transfusion dependent thalassemia major (TM) patients and MRI (T2*) can recognize preclinical cardiac iron overload, but, is unavailable to many centers.
Design and Methods
We evaluated the ability of 12-lead electrocardiography to predict cardiac iron loading in TM. 12-lead electrocardiogram and cardiac T2* measurements were performed prospectively, with a detectable cardiac iron cutoff of T2*less than 20 ms. Patients with and without cardiac iron were compared using two-sample statistics and against population norms using age and gender-matched Z-scores.
45/78 patients had detectable cardiac iron. Patients having cardiac iron were older and more likely female but had comparable liver iron burdens and serum ferritin. Increased heart rate (HR) and prolonged corrected QT interval (QTc) were present, regardless of cardiac iron status. Repolarization abnormalities were the strongest predictors of cardiac iron, including QT/QTc prolongation, left shift of T-wave axis, and interpretation of ST/T-wave morphology. Recursive partitioning of the data for females using T-axis and HR and for males using QT, HR and T-axis produced algorithms with AUROC’s of 88.3 and 87.1 respectively.
Bradycardia and repolarization abnormalities on 12-lead electrocardiography were the most specific markers for cardiac iron in thalassemia major. Changes in these variables may be helpful to stratify cardiac risk when cardiac MRI is unavailable. However, diagnostic algorithms need to be vetted on larger and more diverse patient populations and longitudinal studies are necessary to determine reversibility of the observed abnormalities.
Electrocardiogram; Thalassemia Major; Cardiac Iron; MRI
Most of the techniques for measuring iron stores such as serum iron concentration, iron binding capacity, serum ferritin level, liver biopsy can be troublesome or invasive for patients with thalassemia. The salivary iron measurement could be of potential advantage being an easy and non invasive approach for diagnosis of iron deficiency and iron overload . The aim of this study was to compare the levels of iron and ferritin in saliva and serum of patients affected by thalassemia or iron deficiency anemia. For this purpose, 96 patients with iron overload (71 with thalassemia major, 10 with thalassemia intermedia and 15 with thalassemia trait), 30 patients with iron deficiency anemia, and 35 healthy children as control group were involved in this study. Their saliva and serum iron and ferritin levels were measured. Iron and ferritin levels were higher in iron overload groups than in control group and lower in iron deficiency group (p<0.05). Furthermore serum and saliva iron and ferritin levels paralleled in all groups. In conclusion, iron and ferritin saliva can be routinely used for diagnosis of both iron overload and deficiency; furthermore this procedure may be an important advantage for blood donors being easily available and not invasive.
Iron plays a central role in host-parasite interactions, since both intervenients need iron for survival and growth, but are sensitive to iron-mediated toxicity. The host's iron overload is often associated with susceptibility to infection. However, it has been previously reported that iron overload prevented the growth of Leishmania major, an agent of cutaneous leishmaniasis, in BALB/c mice. In order to further clarify the impact of iron modulation on the growth of Leishmania in vivo, we studied the effects of iron supplementation or deprivation on the growth of L. infantum, the causative agent of Mediterranean visceral leishmaniasis, in the mouse model. We found that dietary iron deficiency did not affect the protozoan growth, whereas iron overload decreased its replication in the liver and spleen of a susceptible mouse strain. The fact that the iron-induced inhibitory effect could not be seen in mice deficient in NADPH dependent oxidase or nitric oxide synthase 2 suggests that iron eliminates L. infantum in vivo through the interaction with reactive oxygen and nitrogen species. Iron overload did not significantly alter the mouse adaptive immune response against L. infantum. Furthermore, the inhibitory action of iron towards L. infantum was also observed, in a dose dependent manner, in axenic cultures of promastigotes and amastigotes. Importantly, high iron concentrations were needed to achieve such effects. In conclusion, externally added iron synergizes with the host's oxidative mechanisms of defense in eliminating L. infantum from mouse tissues. Additionally, the direct toxicity of iron against Leishmania suggests a potential use of this metal as a therapeutic tool or the further exploration of iron anti-parasitic mechanisms for the design of new drugs.
Leishmania are important vector-borne protozoan pathogens that cause different forms of disease, ranging from cutaneous self-healing lesions to life-threatening visceral infection. L. infantum is the most common species causing visceral leishmaniasis in Europe and the Mediterranean basin. Iron plays a critical role in host-pathogen interactions. Both the microorganism and its host need iron for growth. However, iron may promote the formation of toxic reactive oxygen species, which contribute to pathogen elimination, but also to host tissue pathology. We investigated the effect of manipulating host iron status on the outcome of L. infantum infection, using the mouse as an experimental model. We found that dietary iron deprivation had no effect on L. infantum growth, and iron-dextran injection decreased the multiplication of L. infantum in mouse organs. The fact that this anti-parasitic effect of iron was not observed in mice genetically deficient in superoxide and nitric oxide synthesis pathways indicates that iron is likely to act in synergy with reactive oxygen and nitrogen species produced by the host's macrophages. This work clearly shows that iron supplementation improves the host's capacity to eliminate L. infantum parasites and suggests that iron may be further explored as a therapeutic tool to fight this type of infection.
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.
Regular blood transfusions as supportive care for patients with chronic anemia inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload cause significant morbidity and mortality if not effectively treated with chelation therapy. Based on a comprehensive clinical development program, the once-daily, oral iron chelator deferasirox (Exjade®) is approved for the treatment of transfusional iron overload in adult and pediatric patients with various transfusion-dependent anemias, including β-thalassemia and the myelodysplastic syndromes. Deferasirox dose should be titrated for each individual patient based on transfusional iron intake, current iron burden and whether the goal is to decrease or maintain body iron levels. Doses of >30 mg/kg/day have been shown to be effective with a safety profile consistent with that observed at doses <30 mg/kg/day. Recent data have highlighted the ability of deferasirox to decrease cardiac iron levels and to prevent the accumulation of iron in the heart. The long-term efficacy and safety of deferasirox for up to 5 years of treatment have now been established. The availability of this effective and generally well tolerated oral therapy represents a significant advance in the management of transfusional iron overload.
deferasirox; Exjade; oral; iron chelation; iron overload; cardiac iron
Iron overload is the principal cause of morbidity and mortality in β-thalassemia with or without transfusion dependence. Iron homeostasis is regulated by the hepatic peptide hormone hepcidin. Hepcidin controls dietary iron absorption, plasma iron concentrations, and tissue iron distribution. Hepcidin deficiency is the main or contributing factor of iron overload in iron-loading anemias such as β-thalassemia. Hepcidin deficiency results from a strong suppressive effect of the high erythropoietic activity on hepcidin expression. Although in thalassemia major patients iron absorption contributes less to the total iron load than transfusions, in non-transfused thalassemia, low hepcidin and the consequent hyperabsorption of dietary iron is the major cause of systemic iron overload. Hepcidin diagnostics and future therapeutic agonists may help in management of patients with β-thalassemia.
hepcidin; β-thalassemia; iron overload
Iron overload is an important issue in the state of thalassemic patients due to the harmful effect of high concentration of iron deposited in different tissues in human body including endocrine glands. In the present work, an attempt is carried out to estimate the effect of iron overload in thalassemic patients on the function of endocrine glands through the estimation of their ability to secrete adequate amounts of certain hormones.
Materials and Methods:
Seventy eight male children with beta-thalassemia, in the age-group of 4–11 years, were enrolled for this research. These children were being treated with frequent transfusions and long-term iron chelation therapy. Thirty age and sex matched children without thalassemia constituted the control group. Ferritin and different hormones were estimated by ELISA technique.
The results showed a mild reduction in the function of endocrine glands through the decrease in the level of some hormones. These changes due mainly to the hypoxia and precipitation of iron in certain glands and overlapping with the synthesis or secretion of the hormones.
There is a different hormonal disturbances in beta thalassemia patients. Reduction of total body iron store is an important goal of the treatment of thalassemia and measuring the hormones concentration is necessary for the follow up of the thalassemic patients especially during puberty.
Glands; hormones; iron overload; thalassemia
Iron cardiomyopathy in β-thalassemia major patients is associated with vitamin D deficiency. Stores of 25-OH-D3 are markedly reduced, while the active metabolite, 1-25-(OH)-D3, is normal or increased. Interestingly, the ratio of 25-OH-D3 to 1-25-(OH)-D3 (a surrogate for parathyroid hormone (PTH)) is the strongest predictor of cardiac iron. Increased PTH and 1-25-OH-D3 levels have been shown to up-regulate L-type voltage-gated calcium channels (LVGCC), the putative channel for cardiac iron uptake. Therefore, we postulate that vitamin D deficiency increases cardiac iron by altering LVGCC regulation. Hemojuvelin knockout mice were calcitriol treated, PTH treated, vitamin D-depleted, or untreated. Half of the animals in each group received the Ca2+-channel blocker verapamil. Mn2+ was infused to determine LVGCC activity. Hearts and livers were harvested for iron, calcium, and manganese measurements as well as histology. Cardiac iron did not differ amongst the treatment groups; however, liver iron was increased in vitamin D-depleted animals (p<0.0003). Cardiac iron levels did not correlate with manganese uptake, but were proportional to cardiac calcium levels (r2 = 0.6, p < 0.0001). Verapamil treatment reduced both cardiac (p <0.02) and hepatic (p < 0.003) iron levels significantly by 34% and 28%. The association between cardiac iron and calcium levels was maintained after verapamil treatment (r2 = 0.3, p < 0.008). Vitamin D-depletion is associated with an increase in liver, but not cardiac, iron accumulation. Cardiac iron uptake was strongly correlated with cardiac calcium stores and was significantly attenuated by verapamil, suggesting that cardiac calcium and iron are related.
b-thalassemia; vitamin D; iron overload; hemojuvelin
Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl’s Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination.
This study aimed to determine whether taurine supplementation improves metabolic disturbances and diabetic complications in an animal model for type 2 diabetes. We investigated whether taurine has therapeutic effects on glucose metabolism, lipid metabolism, and diabetic complications in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term duration of diabetes. Fourteen 50-week-old OLETF rats with chronic diabetes were fed a diet supplemented with taurine (2%) or a non-supplemented control diet for 12 weeks. Taurine reduced blood glucose levels over 12 weeks, and improved OGTT outcomes at 6 weeks after taurine supplementation, in OLETF rats. Taurine significantly reduced insulin resistance but did not improve β-cell function or islet mass. After 12 weeks, taurine significantly decreased serum levels of lipids such as triglyceride, cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol. Taurine significantly reduced serum leptin, but not adiponectin levels. However, taurine had no therapeutic effect on damaged tissues. Taurine ameliorated hyperglycemia and dyslipidemia, at least in part, by improving insulin sensitivity and leptin modulation in OLETF rats with long-term diabetes. Additional study is needed to investigate whether taurine has the same beneficial effects in human diabetic patients.
diabetes mellitus, type 2; dyslipidemias; hyperglycemia; rats, Long-Evans; taurine
The present study was carried out to evaluate the ameliorating effect of Caesalpinia crista Linn. (CCME) extract on iron-overload-induced liver injury. Iron overload was induced by intraperitoneal administration of iron dextran into mice. CCME attenuated the percentage increase in liver iron and serum ferritin levels when compared to control group. CCME also showed a dose-dependent inhibition of lipid peroxidation, protein oxidation, and liver fibrosis. The serum enzyme markers were found to be less, whereas enhanced levels of liver antioxidant enzymes were detected in CCME-treated group. In presence of CCME, the reductive release of ferritin iron was increased significantly. Furthermore, CCME exhibited DPPH radical scavenging and protection against Fe2+-mediated oxidative DNA damage. The current study confirmed the hepatoprotective effect of CCME against the model hepatotoxicant iron overload and the activity is likely related to its potent antioxidant and iron-chelating property.
Myocardial siderosis is known as the major cause of death in thalassemia major (TM) patients since it can lead to iron overload cardiomyopathy. Although this condition can be prevented if timely effective intensive chelation is given to patients, the mortality rate of iron overload cardiomyopathy still remains high due to late detection of this condition. Various direct and indirect methods of iron assessment, including serum ferritin level, echocardiogram, non-transferrin-bound iron, cardiac magnetic resonance T2*, heart rate variability, and liver biopsy and myocardial biopsy, have been proposed for early detection of cardiac iron overload in TM patients. However, controversial evidence and limitations of their use in clinical practice exist. In this review article, all of these iron assessment methods that have been proposed or used to directly or indirectly determine the cardiac iron status in TM reported from both basic and clinical studies are comprehensively summarized and presented. Since there has been growing evidence in the past decades that cardiac magnetic resonance imaging as well as cardiac autonomic status known as the heart rate variability can provide early detection of cardiac involvement in TM patients, these two methods are also presented and discussed. The existing controversy regarding the assessment of cardiac involvement in thalassemia is also discussed.
Thalassemia; Iron overload; Cardiomyopathy; Serum ferritin; Heart rate variability; Magnetic resonance; Non-transferrin-bound iron
In general, in women with transfusion-dependent thalassemia, during pregnancy, iron chelation therapy is ceased. We report a splenectomized patient, who was an excellent complier with chelation therapy, who before embarking on a pregnancy showed no evidence of iron overload, with normal cardiac, thyroid function and glucose metabolism. Laboratory findings showed ferritin 67 μg/L, myocardial T2* of 34 ms and liver magnetic resonance imaging (MRI) liver iron concentration of 1 mg/g dry weight. She became pregnant by in vitro fertilization in October 2006, delivery occurred in June 2007. She breast fed for 2 months. After 12 months without iron chelation, ferritin was 1583 μg/L. Quantitative MRI showed myocardial T2* of 27 ms, that the liver iron concentration had increased to 11.3 mg/g dry weight, indicative of moderate to heavy iron load. This case demonstrates that iron overload can develop rapidly and that physicians caring for patients with transfusion-dependent thalassemia should be particularly alert to any discontinuation of chelation therapy over time.
thalassemia major; pregnancy; transfusion iron load; chelation therapy
Recipients of hematopoietic stem cell transplantation (HSCT) frequently have iron overload resulting from chronic transfusion therapy for anemia. In some cases, for example, in patients with myelodysplastic syndromes and thalassemia, this can be further exacerbated by increased absorption of iron from the gut as a result of ineffective erythropoiesis. Accumulating evidence has established the negative impact of elevated pretransplantation serum ferritin, a surrogate marker of iron overload, on overall survival and nonrelapse mortality after HSCT. Complications of HSCT associated with iron overload include increased bacterial and fungal infections as well as sinusoidal obstruction syndrome and possibly other regimen-related toxicities. Based on current evidence, particular attention should be paid to prevention and management of iron overload in allogeneic HSCT candidates, especially in patients with thalassemia and myelodysplastic syndromes. The pathophysiology of iron overload in the HSCT patient and optimum strategies to deal with iron overload during and after HSCT require further study.
Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although transgenic hepcidin replacement in mouse models of these diseases prevents iron overload or decreases its potential toxicity, natural hepcidin is prohibitively expensive for human application and has unfavorable pharmacologic properties. Here, we report the rational design of hepcidin agonists based on the mutagenesis of hepcidin and the hepcidin-binding region of ferroportin and computer modeling of their docking. We identified specific hydrophobic/aromatic residues required for hepcidin-ferroportin binding and obtained evidence in vitro that a thiol-disulfide interaction between ferroportin C326 and the hepcidin disulfide cage may stabilize binding. Guided by this model, we showed that 7–9 N-terminal amino acids of hepcidin, including a single thiol cysteine, comprised the minimal structure that retained hepcidin activity, as shown by the induction of ferroportin degradation in reporter cells. Further modifications to increase resistance to proteolysis and oral bioavailability yielded minihepcidins that, after parenteral or oral administration to mice, lowered serum iron levels comparably to those after parenteral native hepcidin. Moreover, liver iron concentrations were lower in mice chronically treated with minihepcidins than those in mice treated with solvent alone. Minihepcidins may be useful for the treatment of iron overload disorders.