Search

Background: In patients with thalassemia major, examination routinely used for the evaluation of iron load in Indonesia is serum ferritin, but it is strongly influenced by other factors such as infections, inflammation and vitamin C levels. Evaluation of urinary iron excretion is an important and easy method to indicate iron chelation efficacy., Objective: To determine the efficacy of iron chelation therapy by urinary iron examination and to evaluate its correlation with the time of transfusion, serum ferritin level, transferrin saturation and T2* MRI., Methods: Prospective cohort study was conducted in children with thalassemia major aged 7-<18 years old who received DFP therapy. Twenty-four-hour urine collections were examined through inductively coupled plasma - mass spectrometry (ICP-MS). Patient's serum ferritin, transferrin saturation, peripheral blood, differential count and T2* MRI was documented during the study. Data analysis is based on urine iron level, body iron balance and the correlation between urine iron level, serum ferritin, transferrin saturation and T2* MRI and dosage of DFP., Results: Thirty (55%) subjects showed a higher urine iron level on the day prior to transfusion (mean: 12,828 SD ±12,801 μg/24 h) in comparison to post transfusion (mean: 10,985 SD ±10,023 μg/24 h). All subjects had positive iron balance (mean 524 SD ±230 mg). There were positive correlation between urine iron level and transferrin saturation (r = 0.559, p = 0.01) and serum ferritin (r = 0.291, p = 0.03), no correlation found with T2* MRI results., Conclusions: There is a relationship to urinary iron excretion in response to chelation therapy and the degree of iron load., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Recent advancements have promoted the use of T2* magnetic resonance imaging (MRI) in the non-invasive detection of iron overload in various organs for thalassemia major patients. This study aims to determine the iron load in the heart and liver of patients with thalassemia major using T2* MRI and to evaluate its correlation with serum ferritin level and iron chelation therapy., Methods: This cross-sectional study included 162 subjects diagnosed with thalassemia major, who were classified into acceptable, mild, moderate, or severe cardiac and hepatic iron overload following their T2* MRI results, respectively, and these were correlated to their serum ferritin levels and iron chelation therapy., Results: The study found that 85.2% of the subjects had normal cardiac iron stores. In contrast, 70.4% of the subjects had severe liver iron overload. A significant but weak correlation (r = -0.28) was found between cardiac T2* MRI and serum ferritin, and a slightly more significant correlation (r = 0.37) was found between liver iron concentration (LIC) and serum ferritin., Discussion: The findings of this study are consistent with several other studies, which show that patients generally manifest with liver iron overload prior to cardiac iron overload. Moreover, iron accumulation demonstrated by T2* MRI results also show a significant correlation to serum ferritin levels., Conclusion: This is the first study of its kind conducted in Indonesia, which supports the fact that T2* MRI is undoubtedly valuable in the early detection of cardiac and hepatic iron overload in thalassemia major patients.

Patients with thalassemia become iron overloaded from increased absorption of iron, ineffective erythropoiesis, and chronic transfusion. Before effective iron chelation became available, thalassemia major patients died of iron-related cardiac failure in the second decade of life. Initial treatment goals for chelation therapy were aimed at levels of ferritin and liver iron concentrations associated with prevention of adverse cardiac outcomes and avoidance of chelator toxicity. Cardiac deaths were greatly reduced and survival was much longer. Epidemiological data from the general population draw clear associations between increased transferrin saturation (and, by inference, labile iron) and early death, diabetes, and malignant transformation. The rate of cancers now seems to be significantly higher in thalassemia than in the general population. Reduction in iron can reverse many of these complications and reduce the risk of malignancy. As toxicity can result from prolonged exposure to even low levels of excess iron, and survival in thalassemia patients is now many decades, it would seem prudent to refocus attention on prevention of long-term complications of iron overload and to maintain labile iron and total body iron levels within a normal range, if expertise and resources are available to avoid complications of overtreatment., (© 2016 New York Academy of Sciences.)

With repeated blood transfusions, patients with thalassemia major rapidly become loaded with iron, often surpassing hepatic metal accumulation capacity within ferritin shells and infiltrating heart and endocrine organs. That pathological scenario contrasts with the physiological one, which is characterized by an efficient maintenance of all plasma iron bound to circulating transferrin, due to a tight control of iron ingress into plasma by the hormone hepcidin. Within cells, most of the acquired iron becomes protein-associated, as once released from endocytosed transferrin, it is used within mitochondria for the synthesis of protein prosthetic groups or it is incorporated into enzyme active centers or alternatively sequestered within ferritin shells. A few cell types also express the iron extrusion transporter ferroportin, which is under the negative control of circulating hepcidin. However, that system only backs up the major cell regulated iron uptake/storage machinery that is poised to maintain a basal level of labile cellular iron for metabolic purposes without incurring potentially toxic scenarios. In thalassemia and other transfusion iron-loading conditions, once transferrin saturation exceeds about 70%, labile forms of iron enter the circulation and can gain access to various types of cells via resident transporters or channels. Within cells, they can attain levels that exceed their ability to chemically cope with labile iron, which has a propensity for generating reactive oxygen species (ROS), thereby inducing oxidative damage. This scenario occurs in the heart of hypertransfused thalassemia major patients who do not receive adequate iron-chelation therapy. Iron that accumulates in cardiomyocytes forms agglomerates that are detected by T2* MRI. The labile forms of iron infiltrate the mitochondria and damage cells by inducing noxious ROS formation, resulting in heart failure. The very rapid relief of cardiac dysfunction seen after intensive iron-chelation therapy in some patients with thalassemia major is thought to be due to the relief of the cardiac mitochondrial dysfunction caused by oxidative stress or to the removal of labile iron interference with calcium fluxes through cardiac calcium channels. In fact, improvement occurs well before there is any significant improvement in the total level of cardiac iron loading. The oral iron chelator deferiprone, because of its small size and neutral charge, demonstrably enters cells and chelates labile iron, thereby rapidly reducing ROS formation, allowing better mitochondrial activity and improved cardiac function. Deferiprone may also rapidly improve arrhythmias in patients who do not have excessive cardiac iron. It maintains the flux of iron in the direction hemosiderin to ferritin to free iron, and it allows clearance of cardiac iron in the presence of other iron chelators or when used alone. To date, the most commonly used chelator combination therapy is deferoxamine plus deferiprone, whereas other combinations are in the process of assessment. In summary, it is imperative that patients with thalassemia major have iron chelators continuously present in their circulation to prevent exposure of the heart to labile iron, reduce cardiac toxicity, and improve cardiac function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Chronically transfused sickle cell disease (SCD) patients have lower risk of myocardial iron overload (MIO) than comparably transfused thalassemia major (TM) patients. However, cardioprotection is incomplete. We present the clinical characteristics of six patients who have prospectively developed MIO, to identify potential risk factors for cardiac iron accumulation. From 2002 to 2011, cardiac, hepatic, and pancreatic iron overload were assessed by R2 and R2 * magnetic resonance imaging techniques in 201 chronic transfused SCD patients as part of their clinical care. At the time, they developed MIO, five of six patients had been on chronic transfusion for more than 11 years; only one was on exchange transfusion. The time to MIO was correlated with reticulocyte and hemoglobin S percentages. All patients had qualitatively poor chelation compliance (<50%). All patients had serum ferritin levels >4600 ng/ml and liver iron concentration >22 mg/g. Pancreatic R2 * was >100 Hz in every patient studied (5/6). Cardiac iron rose proportionally to pancreas R2 *, with all patients having pancreas R2 *>100 Hz when cardiac iron was present. MIO had a threshold relationship with liver iron that was higher than observed in TM patients. In conclusion, MIO occurs in a small percentage of chronically transfused SCD patients and is only associated with exceptionally poor control of total body iron stores. Duration of chronic transfusion is clearly important but other factors, such as levels of effective erythropoiesis, appear to contribute to cardiac risk. Pancreas R2 * can serve as a valuable screening tool for cardiac iron in SCD patients., (© 2014 Wiley Periodicals, Inc.)

Chronic blood transfusions start at a very young age in subjects with transfusion-dependent anemias, the majority of whom have hereditary anemias. To understand how rapidly iron overload develops, we retrospectively reviewed 308 MRIs for evaluation of liver, pancreatic, or cardiac iron in 125 subjects less than 10 years old. Median age at first MRI evaluation was 6.0 years. Median liver iron concentrations in patients less than 3.5 years old were 14 and 13 mg/g dry weight in thalassemia major (TM) and Diamond-Blackfan anemia (DBA) patients, respectively. At time of first MRI, pancreatic iron was markedly elevated (> 100 Hz) in DBA patients, and cardiac iron ( R₂* >50 Hz) was present in 5/112 subjects (4.5%), including a 2.5 years old subject with DBA. Five of 14 patients (38%) with congenital dyserythropoietic anemia (CDA) developed excess cardiac iron before their 10th birthday. Thus, clinically significant hepatic and cardiac iron accumulation occurs at an early age in patients on chronic transfusions, particularly in those with ineffective or absent erythropoiesis, such as DBA, CDA, and TM, who are at higher risk for iron cardiomyopathy. Performing MRI for iron evaluation in the liver, heart, and pancreas as early as feasible, particularly in those conditions in which there is suppressed bone marrow activity is very important in the management of iron loaded children in order to prescribe appropriate chelation to prevent long-term sequelae. ., (Copyright © 2013 Wiley Periodicals, Inc.)

Patients with chronic anemia develop compensatory ventricular dilation, even when maintained on chronic transfusion regimens. It is important to characterize these effects to interpret pathological changes in cardiac dimensions and function introduced by iron overload and sickle cell vasculopathy. Our primary goal was to compare biventricular dimensions and function assessed by cardiovascular magnetic resonance (CMR) in pediatric, chronically-transfused sickle-cell disease (SCD) and thalassemia major (TM) patients who had normal cardiac iron levels. Moreover, we explored systematic sex differences in ventricular dimensions in both populations. We identified 261 studies suitable for analysis from 64 patients with SCD (34 females) and 49 patients with TM (20 females). All demographic and CMR parameters were inversely weighted by the number of exams. In both populations, males had larger left and right ventricular dimensions than females, with a more marked effect observed in patients with SCD. Compared to patients with TM, patients with SCD showed significantly greater biventricular dilation and left ventricular hypertrophy. This difference could not be explained by different hemoglobin levels, cardiac iron overload, and systolic blood pressure. The left ventricular (LV) ejection fraction (EF) for the males and the right ventricular (RV) EF for both the sexes were comparable between SCD and TM groups, while females with SCD had significantly lower LV EF than females with TM. Our results represent important baseline findings that place changes introduced by iron overload as well as systemic and pulmonary vasculopathy in proper context., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Thalassaemia major (TM) patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular (LV) function but little is known of their relative effects on the right ventricle (RV), which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT) comparing these chelators was retrospectively analysed to assess the RV responses to these drugs., Methods: In the RCT, 61 TM patients were randomised to receive either deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment., Results: From baseline to 12 months, deferiprone reduced RV end systolic volume (ESV) from 37.7 to 34.2 mL (p=0.008), whilst RV ejection fraction (EF) increased from 69.6 to 72.2% (p=0.001). This was associated with a 27% increase in T2* (p<0.001) and 3.1% increase in LVEF (p<0.001). By contrast, deferoxamine showed no change in RVESV (38.1 to 39.1 mL, p=0.38), or RVEF (70.0 to 69.9%, p=0.93) whereas the T2* increased by 13% (p<0.001), but with no change in LVEF (0.32%; p=0.66). Analysis of between drugs treatment effects, showed significant improvements favouring deferiprone with a mean effect on RVESV of -1.82 mL (p=0.014) and 1.16% for RVEF (p=0.009). Using regression analysis the improvement in RVEF at 12 months was shown to be greater in patients with lower baseline EF values (p<0.001), with a significant difference in RVEF of 3.5% favouring deferiprone over deferoxamine (p=0.012)., Conclusion: In this retrospective analysis of a prospective RCT, deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with deferiprone.

Cardiac Magnetic Resonance (CMR) has replaced all other surrogate measurements in the determination of transfusional cardiac iron overload in patients with thalassaemia major. We aimed to determine the diagnostic value of CMR T2* with respect to cardiac dysfunction (CD) as determined by CMR-derived left ventricular ejection fraction (LVEF). Cardiac T2* values and LVEF measured by CMR were recorded in 303 patients with thalassaemia major, at the time of their first CMR. T2* was correlated with LVEF (regression coefficient: 0·57, P<0·001). The prevalence of CD was 32·9% in patients with T2*≤8 ms, 12·5% in patients with T2*>8 ms and ≤14 ms and reduced to 9·1% in patients with T2* between 14-20 ms. As the probability of CD is progressively, and not suddenly, reduced with increasing values of T2*, CMR has a limited diagnostic value for CD (Receiver operating characteristic analysis, area under the curve = 0·68). Patients with cardiac T2*≤8 ms require careful and intensive management. This risk decreases with increasing values of T2* but even in mildly loaded patients the probability of impaired LVEF is not negligible., (© 2010 Blackwell Publishing Ltd.)

Cardiac and endocrine disorders are common sequelae of iron overload in transfused thalassaemia patients. Combined chelation with desferrioxamine (DFO) and deferiprone (DFP) is well tolerated and produces an additive/synergistic effect superior to either drug alone. 52 thalassaemia major patients were transitioned from DFO to combined chelation with DFO and DFP. Serum ferritin, cardiac and hepatic iron levels were monitored regularly for up to 7 years, as were cardiac and endocrine function. Patients' iron load normalized, as judged by ferritin and cardiac and hepatic magnetic resonance imaging findings. In all 12 patients receiving treatment for cardiac dysfunction, symptoms reversed following combined chelation, enabling nine patients to discontinue heart medications. In the 39 patients with abnormal glucose metabolism, 44% normalized. In 18 requiring thyroxine supplementation for hypothyroidism, 10 were able to discontinue, and four reduced their thyroxine dose. In 14 hypogonadal males on testosterone therapy, seven stopped treatment. Of the 19 females, who were hypogonadal on DFO monotherapy, six were able to conceive. Moreover, no patients developed de novo cardiac or endocrine complications. These results suggest that intensive combined chelation normalized patients' iron load and thereby prevented and reversed cardiac and multiple endocrine complications associated with transfusion iron overload.

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 microg/L, myocardial T(2)* 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 microg/L. Quantitative MRI showed myocardial T(2)* 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.