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Background: In patients with thalassemia, different organs are affected differently by iron overload. Nevertheless, the reasons for this could be the same key transporters. This study investigated the iron deposition in different organs of transfusion-dependent thalassemia (TDT) patients and its correlation., Research Design and Methods: This cross-sectional study involved 54 TDT patients who underwent MRI T2* examinations of the heart, liver, pancreas, spleen, kidneys, and pituitary. The study analyzed the iron deposition in each organ and evaluated the correlation of iron deposition using Spearman's test., Results: Among the 54 patients with TDT, liver iron overload was found in 49/54 (90.7%) cases, pancreas iron overload in 43/54 (79.6%) cases, spleen iron overload in 18/26 (69.2%) patients, heart iron overload in 20/54 (37.0%) cases, and kidney iron overload in 8/54 (14.8%) patients. Most patients (66.7%) with iron overload in the liver but not in the heart exhibited spleen iron abnormalities. Pituitary T2* and pancreas T2* (r = 0.790), pituitary T2* and kidney T2* (r = 0.692), kidney T2* and pancreas T2* (r = 0.672) showed positive correlation (all p < 0.05)., Conclusions: Patients with TDT exhibited significant organ-specific iron overload. These findings highlight the importance of routine MRI screening for monitoring and managing iron overload in patients with TDT. Pituitary, pancreas, and kidney may have similar iron-loading mechanisms.

Luspatercept, a ligand-trapping fusion protein, binds select TGF-β superfamily ligands implicated in thalassemic erythropoiesis, promoting late-stage erythroid maturation. Luspatercept reduced transfusion burden in the BELIEVE trial (NCT02604433) of 336 adults with transfusion-dependent thalassemia (TDT). Analysis of biomarkers in BELIEVE offers novel physiological and clinical insights into benefits offered by luspatercept. Transfusion iron loading rates decreased 20% by 1.4 g (~7 blood units; median iron loading rate difference: -0.05 ± 0.07 mg Fe/kg/day, p< .0001) and serum ferritin (s-ferritin) decreased 19.2% by 269.3 ± 963.7 μg/L (p < .0001), indicating reduced macrophage iron. However, liver iron content (LIC) did not decrease but showed statistically nonsignificant increases from 5.3 to 6.7 mg/g dw. Erythropoietin, growth differentiation factor 15, soluble transferrin receptor 1 (sTfR1), and reticulocytes rose by 93%, 59%, 66%, and 112%, respectively; accordingly, erythroferrone increased by 51% and hepcidin decreased by 53% (all p < .0001). Decreased transfusion with luspatercept in patients with TDT was associated with increased erythropoietic markers and decreasing hepcidin. Furthermore, s-ferritin reduction associated with increased erythroid iron incorporation (marked by sTfR1) allowed increased erythrocyte marrow output, consequently reducing transfusion needs and enhancing rerouting of hemolysis (heme) iron and non-transferrin-bound iron to the liver. LIC increased in patients with intact spleens, consistent with iron redistribution given the hepcidin reduction. Thus, erythropoietic and hepcidin changes with luspatercept in TDT lower transfusion dependency and may redistribute iron from macrophages to hepatocytes, necessitating the use of concomitant chelator cover for effective iron management., (© 2023 Bristol Myers Squibb and The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Iron is an essential micronutrient for oxygen transport, cellular energy metabolism, and many enzymatic reactions. Complex physiological processes have evolved for iron acquisition to meet metabolic needs while avoiding toxicity from iron-generated free radicals. Systemic iron homeostasis is centered around the regulation of iron absorption from duodenum and iron release from stores by hepcidin. Intracellular iron is maintained under tight control by iron regulatory proteins acting at post-transcriptional level. Despite these elaborate mechanisms, iron status is frequently altered by environmental or genetic influences. Iron deficiency anemia is the most common nutritional disorder affecting a quarter of the world population. Iron deficiency is associated with impaired cognitive development and reduced capacity for physical work, making it a high priority for public health initiatives. Chronic inflammation from infections or other causes limits iron availability and contributes to anemia of chronic disease. At the opposite end are conditions where iron overload leads to serious complications from organ damage. Mutations in HFE gene are the most frequent cause of hereditary hemochromatosis in European population, but rare elsewhere in the world. Iron overload develops in dyserythropoietic anemias from increased intestinal absorption. Transfusional iron overload, most often observed in thalassemia, is increasing among cancer survivors due to the use of protocols requiring intensive transfusion support. Tissue-specific brain iron overload is observed in some degenerative neurological diseases without an increase in systemic iron. New insights into iron metabolism are guiding the development of novel therapies for iron deficiency and iron overload.

Background and Objective: Cardiac involvement due to iron overload is the most common cause of morbidity and mortality in patients with thalassemia, and many patients remain asymptomatic until the late stages. Therefore, early detection of heart problems in such patients at subclinical stages can improve the prognosis of these patients. We investigated the role of speckled tracking (SI) and tissue Doppler echocardiography (TDI) in early detection of iron overload in these patients., Methods: 52 thalassemic patients who were receiving regular blood transfusion with normal global LV function were examined by two- and three-dimensional echocardiography. Cardiac MRI was done and T2* images were considered as the non-invasive gold standard for evaluating cardiac iron deposition. Serum ferritin level was assessed and the relationships between serum ferritin levels and echo finding with cardiac MRI T 2 * was investigated., Results: No significant relationship was seen between serum ferritin levels and cardiac MRI T 2 * . Among the echocardiographic findings, septal systolic myocardial velocity (P = 0.002 and r = 0.43) and global strain (GLS) (P = 0.000 and r = 0.60) were significantly associated with T 2 * . A GLS < 19.5 could predict a T 2 * level below 20 by 82.14% sensitivity and 86.36% specificity (area under the curve = 0.87; p < 0.0001)., Conclusion: While serum ferritin level and ejection fraction are not useful candidates, GLS may be used as a valuable marker to screen thalassemia patients for myocardial iron deposition, using a cut off value below - 19.5. This approach may facilitate the cardiac follow up, reduce the costs, and contribute to preventing deterioration of cardiac function in countries with limited availability of cardiac MRI.

Although both iron chelators and T-type calcium channel (TTCC) blockers have been shown to exert cardioprotection by decreasing cardiac iron deposition and reducing left ventricular (LV) dysfunction via different channels in iron-overloaded rodent models, the cardioprotective effects of combined iron chelator and TTCC blocker treatment in thalassemic mice has not been investigated. We hypothesized that a combined iron chelator and TTCC blocker exerts better cardioprotection than monotherapy by decreasing cardiac iron accumulation, apoptosis and oxidative stress. An iron-overload condition was induced in heterozygous β KO thalassemic (HT) mice and wild-type (WT) mice by high iron diet consumption (FE) for 3 months. Then, the iron chelator deferiprone (DFP), the TTCC blocker efonidipine (Efo), and combined DFP plus Efo were fed via oral gavage for 1 month whilst the high iron diet was continued. LV function, heart rate variability (HRV), apoptosis and cardiac iron accumulation were determined. Chronic iron-overload in mice led to increased cardiac iron deposition, oxidative stress, apoptosis, and impaired LV function and HRV. Although DFP and Efo showed similar cardioprotective efficacy, the combined DFP plus Efo therapy exerted greater efficacy in reducing cardiac iron deposition and cellular apoptosis than either of the monotherapies in iron-overload thalassemic mice., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cardiosiderosis is a leading cause of mortality in transfusion-dependent thalassemias. Plasma non-transferrin-bound iron and its redox-active component, labile plasma iron, are key sources of iron loading in cardiosiderosis. Risk factors were identified in 73 patients with or without cardiosiderosis. Soluble transferrin receptor-1 levels were significantly lower in patients with cardiosiderosis (odds ratio 21). This risk increased when transfusion-iron loading rates exceeded the erythroid transferrin uptake rate (derived from soluble transferrin receptor-1) by >0.21 mg/kg/day (odds ratio 48). Labile plasma iron was >3-fold higher when this uptake rate threshold was exceeded, but non-transferrin-bound iron and transferrin saturation were comparable. The risk of cardiosiderosis was decreased in patients with low liver iron, ferritin and labile plasma iron, or high bilirubin, reticulocyte counts or hepcidin. We hypothesized that high erythroid transferrin uptake rate decreases cardiosiderosis through increased erythroid re-generation of apotransferrin. To test this, iron uptake and intracellular reactive oxygen species were examined in HL-1 cardiomyocytes under conditions modeling transferrin effects on non-transferrin-bound iron speciation with ferric citrate. Intracellular iron and reactive oxygen species increased with ferric citrate concentrations especially when iron-to-citrate ratios exceeded 1:100, i.e. conditions favoring kinetically labile monoferric rather than oligomer species. Excess iron-binding equivalents of apotransferrin inhibited iron uptake and decreased both intracellular reactive oxygen species and labile plasma iron under conditions favoring monoferric species. In conclusion, high transferrin iron utilization, relative to the transfusion-iron load rate, decreases the risk of cardiosiderosis. A putative mechanism is the transient re-generation of apotransferrin by an active erythron, rapidly binding labile plasma iron-detectable ferric monocitrate species., (Copyright© 2017 Ferrata Storti Foundation.)

Background: In transfusion-dependent anaemias, while absolute serum ferritin levels broadly correlate with liver iron concentration (LIC), relationships between trends in these variables are unclear. These relationships are important because serum ferritin changes are often used to adjust or switch chelation regimens when liver magnetic resonance imaging (MRI) is unavailable., Objectives and Methods: This post hoc analysis of the EPIC study compared serum ferritin and LIC in 317 patients with transfusion-dependent thalassaemia before and after 1 yr of deferasirox., Results: Serum ferritin responses (decreases) occurred in 73% of patients, 80% of whom also have decreased LIC. However, 52% of patients without a serum ferritin response did decrease LIC and by >1 mg Fe/g dw (median 3.9) in 77% of cases. Absolute serum ferritin and LIC values correlated significantly only when serum ferritin was <4000 ng/mL (r = 0.59; P < 0.0001) and not at higher levels (≥4000 ng/mL; r = 0.19). Serum ferritin response was accompanied by decreased LIC in 89% and 70% of cases when serum ferritin was <4000 or ≥4000 ng/mL, respectively., Conclusions: As serum ferritin non-response was associated with LIC decrease in over half of patients, use of liver MRI may be particularly useful for differentiating true from apparent non-responders to deferasirox based on serum ferritin trends alone., (© 2016 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

Anemia is a prevalent disease with multiple possible etiologies and resultant complications. Iron deficiency anemia is a common cause of anemia and is typically due to insufficient intake, poor absorption, or overt or occult blood loss. Distinguishing iron deficiency from other causes of anemia is integral to initiating the appropriate treatment. In addition, identifying the underlying cause of iron deficiency is also necessary to help guide management of these patients. We review the key components to an evidence-based, cost-conscious evaluation of suspected iron deficiency anemia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

It has been clearly shown that iron overload adds progressively significant morbidity and mortality in patients with non-transfusion-dependent thalassemia (NTDT). The lack of physiological mechanisms to eliminate the excess of iron requires effective iron chelation therapy. The reduced compliance to deferoxamine and the risk of severe hematological adverse events during deferiprone treatment have limited the use of both these drugs to correct iron imbalance in NTDT. According to the principles of evidence-based medicine, following the demonstration of the effectiveness and the safety of deferasirox (Exjade(®)) in a prospective, randomized, controlled trial, deferasirox was approved by the US Food and Drug Administration in May 2013 for the treatment of iron overload associated with NTDT. This review, assessing the available scientific literature, will focus on the profile of DFX in the treatment of non-transfusional hemosiderosis in patients with NTDT.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Iron overload cardiomyopathy is one of the most common causes of death in thalassemia patients. Although new iron chelating agents have been developed, the mortality rate from heart failure remains elevated as a result of iron overload. This could be due to the fact that our understanding of the underlying mechanism of iron uptake into cardiomyocytes is still unclear, thus impeding the discovery and refinement of more effective therapy for thalassemia therapeutic strategies in thalassemic iron overload cardiomyopathy. Growing evidence indicates that multiple routes of iron entry into cardiomyocytes exist under iron overload conditions. These include both L-type (LTCC) and T-type (TTCC) calcium channels, divalent metal transporter 1 (DMT1) and transferrin receptors (TfRs). In this review, the routes of iron uptake into cardiomyocytes under iron overload conditions are presented. Evidence from pharmacological interventions in support or against the possible route of iron entry of each portal in cardiomyocytes are also comprehensively summarized and discussed.

Introduction: Sideroblastic cardiomyopathy secondary to repeated blood transfusions is a feared complication in thalassaemia. Control of myocardial iron is thus becoming the cornerstone of thalassaemia management. Recent evidence suggests a role for L-type Ca(2+) channels in mediating iron uptake by the heart. Blocking the cellular iron uptake through these channels may add to the benefit of therapy to standard chelation in reducing myocardial iron. We aim to determine the efficacy of amlodipine (a calcium channel blocker) as an adjunct to standard aggressive chelation in retarding myocardial iron deposition in thalassaemics with or without cardiomyopathy., Outcomes: The primary outcome is to compare the efficacy of amlodipine+chelation (intervention) versus standard chelation (control) in retarding myocardial iron deposition. Secondary outcomes include the effect of amlodipine therapy on systolic and diastolic function, strain and strain rate and liver iron content., Methods and Analysis: This is a single-centre, parallel-group, prospective randomised control trial. Twenty patients will be randomised in a 1:1 allocation ratio into the intervention and control arms. In addition to conventional echocardiography, MRI T2* values for assessment of cardiac and liver iron load will be obtained at baseline and at 6 and 12 months. Cardiac T2* will be reported as the geometric mean and per cent coefficient of variation, and an increase in cardiac T2* values from baseline will be used as an end point to compare the efficacy of therapy. A p Value of <0.05 will be considered significant., Study Setting: Department of Pediatric and Child Health, Aga Khan University Hospital, Karachi, Pakistan., Ethics and Dissemination: This study has been approved by the Ethics Review Committee and Clinical Trials Unit at The Aga Khan University with respect to scientific content and compliance with applicable research and human subjects regulations. Findings will be reported through scientific publications and research conferences and project summary papers for participants., Trial Registration Number: ClinicalTrials.Gov. Registration no: NCT02065492., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload and related complications, and may require iron chelation. However, the risk of over-chelation emerges as patients reach low, near-normal body iron levels and dose adjustments may be needed. In the THALASSA study, the threshold for chelation interruption was LIC <3 mg Fe/g dw (LIC<3); 24 patients receiving deferasirox for up to 2 yr reached this target. A post hoc analysis was performed to characterize the safety profile of deferasirox as these patients approached LIC<3., Methods: THALASSA was a randomized, double-blind, placebo-controlled study of two deferasirox regimens (5 and 10 mg/kg/d) versus placebo in patients with NTDT. Patients randomized to deferasirox or placebo in the core could enter a 1-yr extension, with all patients receiving deferasirox (extension starting doses based on LIC at end-of-core and prior chelation response). The deferasirox safety profile was assessed between baseline and 6 months before reaching LIC<3 (Period 1), and the 6 months immediately before achieving LIC<3 (Period 2)., Results: Mean ± SD deferasirox treatment duration up to reaching LIC<3 was 476 ± 207 d, and deferasirox dose was 9.7 ± 3.0 mg/kg/d. The exposure-adjusted AE incidence regardless of causality was similar in periods 1 (1.026) and 2 (1.012). There were no clinically relevant differences in renal and hepatic laboratory parameters measured close to the time of LIC<3 compared with measurements near the previous LIC assessment., Conclusions: The deferasirox safety profile remained consistent as patients approached the chelation interruption target, indicating that, with appropriate monitoring and dose adjustments in relation to iron load, low iron burdens may be reached with deferasirox with minimal risk of over-chelation., (© 2014 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

Background: Iron may damage sarcomeric proteins through oxidative stress. We explored the left ventricular (LV) torsional mechanics in patients with beta-thalassaemia major and its relationship to myocardial iron load. Using HL-1 cell and B6D2F1 mouse models, we further determined the impact of iron load on proteolysis of the giant sarcomeric protein titin., Methods and Results: In 44 thalassaemia patients aged 25 ± 7 years and 38 healthy subjects, LV torsion and twisting velocities were determined at rest using speckle tracking echocardiography. Changes in LV torsional parameters during submaximal exercise testing were further assessed in 32 patients and 17 controls. Compared with controls, patients had significantly reduced LV apical rotation, torsion, systolic twisting velocity, and diastolic untwisting velocity. T2* cardiac magnetic resonance findings correlated with resting diastolic untwisting velocity. The increments from baseline and resultant LV torsion and systolic and diastolic untwisting velocities during exercise were significantly lower in patients than controls. Significant correlations existed between LV systolic torsion and diastolic untwisting velocities in patients and controls, both at rest and during exercise. In HL-1 cells and ventricular myocardium of B6D2F1 mice overloaded with iron, the titin-stained pattern of sarcomeric structure became disrupted. Gel electrophoresis of iron-overloaded mouse myocardial tissue further showed significant decrease in the amount of titin isoforms and increase in titin degradation products., Conclusions: Resting and dynamic LV torsional mechanics is impaired in patients with beta-thalassaemia major. Cell and animal models suggest a potential role of titin degradation in iron overload-induced alteration of LV torsional mechanics.

Iron is an essential component in the structure of certain molecules such as hemoglobin (Hb), myoglobin, cytochrome C and some enzymes. The iron gateway to cells is transferrin receptor (TfR). Soluble transferrin receptor (sTfR) is a product of the TfR that circulates in plasma, its concentration therefore, is proportional to the total concentration of cellular TfR. Expression of TfR is elevated in anemia. The aim of this study was to evaluate the efficacy of sTfR determination in the diagnosis of iron deficiency in thalassemia carriers. In this cross-sectional study, 168 cases were examined. The subdivision of cases included: iron deficiency, concurrent thalassemia and iron deficiency, severe α-thalassemia (α-thal) (α-thal-1), mild α-thal (α-thal-2) and β-thal minor. Hematological and biochemical variables were analyzed by the Statistical Package for Social Sciences (SPSS) version 16 statistical software. Analysis of variance was carried out using the non parametric Kruskal-Wallis test. Significant differences were observed in median values in sTfR concentration and sTfR/log ferritin (sTfR-F index) iron deficient groups, compared to thalassemia groups (p value <0.001), with both variables having higher values in iron deficient groups. In this study it was demonstrated that in iron deficient thalassemic patients, high sTfR can be a good indicator of iron deficiency anemia. The result of the sTfR test can be used for calculation of the sTfR-log ferritin index (sTfR-F index) (obtained by division of sTfR into log ferritin). This is a more sensitive parameter for iron deficiency diagnosis because in its calculation, two valuable amounts of sTfR and ferritin were taken into consideration.

The effect of deferasirox dosing tailored for iron burden and iron loading based on liver iron concentration (LIC) was assessed over 1 year in less versus more heavily iron-overloaded patients in a substudy of the Evaluation of Patients' Iron Chelation with Exjade®. Deferasirox starting dose was 10-30 mg/kg/day, depending on blood transfusion frequency, with recommended dose adjustments every 3 months. Therapeutic goals were LIC maintenance or reduction in patients with baseline LIC <7 or ≥7 mg Fe/g dry weight (dw), respectively. Changes in LIC (R2-magnetic resonance imaging) and serum ferritin after 1 year were assessed. Adverse events (AEs) and laboratory parameters were monitored throughout. Of 374 patients, 71 and 303 had baseline LIC <7 and ≥7 mg Fe/g dw, respectively; mean deferasirox doses were 20.7 and 27.1 mg/kg/day (overall average time to dose increase, 24 weeks). At 1 year, mean LIC and median serum ferritin levels were maintained in the low-iron cohort (-0.02 ± 2.4 mg Fe/g dw, -57 ng/mL; P = not significant) and significantly decreased in the high-iron cohort (-6.1 ± 9.1 mg Fe/g dw, -830 ng/mL; P < 0.0001). Drug-related gastrointestinal AEs, mostly mild to moderate, were more frequently reported in the <7 versus ≥7 mg Fe/g dw cohort (39.4 versus 20.8 %; P = 0.001) and were not confounded by diagnosis, dosing, ethnicity, or hepatitis B and/or C history. Reported serum creatinine increases did not increase in low- versus high-iron cohort patients. Deferasirox doses of 20 mg/kg/day maintained LIC <7 mg Fe/g dw and doses of 30 mg/kg/day were required for net iron reduction in the high-iron cohort, with clinically manageable safety profiles. The higher incidence of gastrointestinal AEs at lower iron burdens requires further investigation.

Most of the endocrine complications in thalassaemia are attributable to iron overload which may be the result of economic circumstances (expense of the chelation therapy), late onset of chelation therapy or poor compliance with the iron chelation therapy. The major difficulties reported by hematologists or pediatric endocrinologists experienced in thalassaemias or thalassaemia syndromes in following growth disorders and endocrine complications were: lack of familiarity with medical treatment of endocrine complications (40%), interpretation of endocrine tests (30%), costs (65%), absence of paediatric endocrinologist for consultation on growth disorders and endocrine complications (27%), facilities (27%), other (e.g. lack of collaboration and on-time consultation between thalassaemic Centers supervised by hematologists and endocrinologists) (17%). Because any progress we make in research into growth disorders and endocrine complications in thalassaemia should be passed on to all those suffering from it, guaranteeing them the same therapeutic benefits and the same quality of life, on the 8th of May, 2009 in Ferrara (Italy), the International Network on Endocrine Complications in Thalassemia (I-CET) was founded. The I-CET group is planning to conduct, in Ferrara in May 2012, a workshop, "MRI and Endocrine Complications in Thalassaemia", and in Doha (Qatar) in September 2012, a 3-day intensive course entitled, "Growth disorders and Endocrine Complications in Thalassaemia", to provide interested pediatricians, physicians and hematologists from all over the world with an in-depth approach to the diagnosis and management of growth and endocrine disorders in thalassaemic patients.

Iron deficiency was absent in a recent population assessment of rural Bangladeshi women exhibiting anemia (57%), suggesting other causes of low hemoglobin. We assessed the relative influence on anemia of thalassemia, groundwater arsenic and iron, and diet among women of reproductive age living in rural Bangladesh. Women (n=207) sampled from a previous antenatal nutrient intervention trial in rural Bangladesh were visited during two seasons in 2008. Collected data included 7-day dietary and 24-hour drinking water intake recalls, 7-day morbidity recall, anthropometry, and drinking water arsenic and iron concentrations. Capillary blood was analyzed for iron (plasma ferritin, soluble transferrin receptor), inflammation (C-reactive protein) and thalassemia (β thalassemia and Hb E) status. In stratified, adjusted analyses, only parity was associated with anemia (odds ratio, OR (95% CI): 11.34 (1.94, 66.15)) for those with thalassemia (28% prevalent). In contrast, groundwater iron intake (>30 mg/d, 0.48 (0.24, 0.96)) and wasting (2.32 (1.17, 4.62)) were associated with anemia among those without thalassemia. Elevated groundwater arsenic (>50 μg/L, 12% of tubewells) and a diverse diet were unrelated to anemia regardless of thalassemia diagnosis (p>0.70 and >0.47, respectively). Among women in this typical rural Bangladeshi area, the prevalence of thalassemia was high and, unlike iron deficiency which was absent most likely due to high iron intake from groundwater, contributed to the risk of anemia. In such settings, the influence of environmental sources of iron and the role of thalassemias in contributing to anemia at the population level may be underappreciated.

Background: Cardiac complications secondary to iron overload remain a significant matter in patients with transfusion dependent anemias., Patients and Methods: To evaluate cardiac siderosis, Magnetic resonance imaging T2* (MRI T2*) was performed in 3 cohorts of transfusion dependent patients: 99 with thalassemia major (TM), 20 with thalassemia intermedia (TI), and 10 with acquired anemias (AA). Serum ferritin was measured and all patients underwent echocardiographic evaluation., Results: In TM patients cardiac T2* pathologic values (below 20 ms) were found in 37 patients. Serum ferritin was negatively associated with age (r=-0.32, p=0.001) and weakly with T2* values (r=-0.19, p=0.057). A positive correlation was found between T2* and LVEF (r=0.27, p=0.006). Out of 37 patients with T2*<20 ms, 18 (48%) had serum ferritin values<1000 ng/ml. In TI cohort, 3 patients had cardiac T2* pathologic values. In AA cohort, pathologic T2* values were found in 2 patients, who received 234 and 199 PRBC units, respectively, and were both on chelation therapy (in one patient ferritin value was 399 ng/ml). T2* values were negatively associated, but not significantly, with the number of PRBC transfused (r=-0.53, p=0.07)., Conclusion: In our experience, 37% of TM patients had a myocardial iron overload assessed by MRI T2*; this value is higher than in TI patients. Serum ferritin measurement was a poor predictor of myocardial siderosis. In patients with AA, more than 200 PRBC units transfused were required to induce cardiac hemosiderosis, in spite of chelation therapy and, in one patient, of normal ferritin values., (Copyright © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Iron overload is a major cause of morbidity and mortality in transfusion-dependent anemias. Greater understanding of the mechanisms of iron regulation and the role of toxic iron moieties and their predilection for certain organs has enhanced our ability to better target therapies in recent years, as illustrated by the Thalassemia syndromes.

The present study investigated myocardial T2* heterogeneity in thalassaemia major (TM) patients by cardiac magnetic resonance (CMR), to determine whether is related to inhomogeneous iron overload distribution. A total of 230 TM patients consecutively referred to our laboratory were studied retrospectively. Three short-axis views (basal, medium and apical) of the left ventricle (LV) were obtained by multislice multiecho T2* CMR. T2* segmental distribution was mapped on a 16-segment LV model. The level of heterogeneity of the T2* segmental distribution, evaluated by the coefficient of variation (CoV), was compared with that of a surrogate data set, to determine whether the inhomogeneous segmental distribution of T2* could be generated by susceptibility artefacts. Susceptibility artefacts offer an explanation for the T2* heterogeneity observed in patients without iron overload. In subjects with global T2* below the lower limit of the normal, T2* heterogeneity increased abruptly which could not be explained by artefactual effects. Some segmental T2* values were below and others above the limit of normal threshold (20 ms) in 104 (45%) TM patients. Among these patients, 74% showed a normal T2* global value. In conclusion, a true heterogeneity in the iron overload distribution may be present in TM patients. Heterogeneity seemingly appears in the borderline myocardial iron and stabilizes at moderate to severe iron burden., (2009 John Wiley & Sons, Ltd.)

Purpose: The aim of our study was to compare the value of cardiac DECT (cDECT) for detection of myocardial iron deposition to T2*w cardiac MRI (cMRI)., Material and Methods: Nineteen patients with clinical history of Thalassaemia underwent T2*-weighted cardiac MRI (cMRI) with a 1.5 T MR scanner (MAGNETOM Symphony, Siemens Medical Solutions, Erlangen, Germany) and cardiac dual energy CT (cDECT) with a DSCT scanner (SOMATOM Definition, Siemens Medical Solutions, Erlangen, Germany) on the same day. HU values obtained from cDECT scans and T2*-values from cMRI were statistically correlated to calculate significance levels. Table times were measured for both cDECT and cMRI and compared. Patients were asked to grade their subjective comfort during the examination., Results: In all patients cDECT scans were successfully acquired. HU values of septal muscle correlated strongly with T2*-values, whereas no correlation was found for paraspinal muscle. Table time was significantly shorter for cDECT compared to cMRI (mean: 3.7 min vs. 11.2 min) and subjective patient comfort was rated comfortable for cDECT and average to poor for cMRI. Mean radiation dose was 0.71 mSv., Conclusion: cDECT scans seem to be possible for evaluation of myocardial iron load in pediatric Thalassaemia patients.

Background: Despite large populations carrying traits for thalassemia in countries implementing universal iron fortification, there are few data on the absorption and utilization of iron in these persons., Objective: We aimed to determine whether iron absorption or utilization (or both) in women heterozygous for beta-thalassemia, alpha-thalassemia 1, or hemoglobin E (HbE) differed from that in control subjects and compound HbE/beta-thalassemia heterozygotes., Design: In Thai women (n = 103), red blood cell indexes, iron status, non-transferrin-bound iron, and growth differentiation factor 15 were measured, and body iron was calculated. Fractional iron absorption was measured from meals fortified with isotopically labeled ((57)Fe) Fe sulfate, and iron utilization was measured by the infusion of ((58)Fe) Fe citrate., Results: Iron utilization was approximately 15% lower in alpha-thalassemia 1 or beta-thalassemia heterozygotes than in controls. When corrected for differences in serum ferritin, absorption was significantly higher in the alpha- and beta-thalassemia groups, but not the HbE heterozygotes, than in controls. HbE/beta-thalassemia compound heterozygotes had lower iron utilization and higher iron absorption and body iron than did controls. Nontransferrin-bound iron and growth differentiation factor 15 were higher in the compound heterozygotes, but not in the other groups, than in the controls., Conclusions: In alpha-thalassemia 1 and beta-thalassemia heterozygotes with ineffective erythropoesis, dietary iron absorption is not adequately down-regulated, despite a modest increase in body iron stores. In populations with a high prevalence of these traits, a program of iron fortification could include monitoring for possible iron excess and for iron deficiency.

Myocardial T*2 measurement has been increasingly used for iron quantification to assess the risk of cardiac complications in thalassemia patients. In this study the noise effects were evaluated along with different curve-fitting models on an iron overloaded ex vivo heart in order to determine the optimal method of T*2 measurement and to help understand issues affecting reproducibility and accuracy. Gradient multiecho short axis images were acquired with differing numbers of excitations to generate varying signal-to-noise ratio (SNR) images. A noise correction method was implemented; linear and nonlinear curve-fitting algorithms were compared and different curve-fitting models (monoexponential, truncation, baseline subtraction, and offset) were evaluated. This study suggests that the T*2 decay curve in an ex vivo heart can be fitted by a monoexponential model and accurate T*2 measurements can be obtained with proper noise correction. With MRI noise, T*2 is generally overestimated by including late low SNR data points, but underestimated by the offset or baseline subtraction models, which are in fact equivalent. In this situation the truncation model proves to be reproducible and more accurate than the other models. The study also shows that the nonlinear algorithm is preferred in T*2 curve fitting., ((c) 2008 Wiley-Liss, Inc.)

Transfusional iron overload leads to gonadal failure and low bone mass in patients with thalassemia (Thal). However, gonadal failure is rarely reported in transfused patients with sickle cell disease (SCD) and the literature regarding fracture prevalence in SCD is limited. The objective of this study was to assess self-reported fracture prevalence and its relationship to endocrinopathy in transfused Thal or SCD subjects and compare to non-transfused subjects with SCD (NonTxSCD). Eligibility was based on age> or =12 years and liver iron concentration> or =10 mg/g dry wt or serum ferritin> or =2000 ng/mL (Thal or TxSCD) or for NonTxSCD, ferritin<500 ng/mL. Data were collected by patient interview and chart review at 31 clinical centers in the U.S., Canada and the U.K. 152 subjects with Thal (52% Male; 25.6+/-0.7 years), 203 subjects with TxSCD (44% Male, 24.7+/-0.9 years: Mean+/-SE), and 65 NonTxSCD (50% Male, 22.2+/-1.3 years) were enrolled. Overall, male subjects with Thal were more likely to have sustained a fracture in their lifetime (51%) compared to TxSCD (28%) or NonTxSCD (32%) (p=0.005). There was no difference in fracture prevalence among women (Thal: 26%, TxSCD 17%, NonTxSCD: 16%). Fracture was most frequently reported in the upper extremities (53.3% of all fractures) while spine and pelvic fractures were relatively common for such a young cohort: 10.6%. Though overall fracture prevalence was not distinctly different from published healthy cohorts, fewer fractures occurred during the adolescent years. In multivariate analysis, the significant predictors of fracture prevalence were Thal diagnosis (Odds Ratio: 2.3; 1.2-4.6; 95%CI), male gender (OR: 2.6; 1.5-4.5), hypothyroidism (OR: 3.3; 1.1-9.8) and age (OR: 1.1; 1.03-1.08). These data suggest that despite similar iron burden, transfused patients with Thal are at greater risk for fracture than subjects with SCD. Male subjects with Thal and hypothyroidism are at particular risk for fracture, in contrast, transfused subjects with SCD had no greater risk of fracture compared to non-transfused SCD. Though ethnic differences in fracture risk cannot be ignored, endocrinopathy is rare in TxSCD which may also provide some protection from fracture.

Thalassemia is anemia of variable severity, arising from mutations of genes encoding the hemoglobin alpha and beta chains. Severe thalassemia is associated with iron overload, tissue lesions, and high risk for cardiovascular complications, and iron-mediated cardiomyopathy is the main cause of death in this condition. Thalassemia major (TM) patients exhibit cardiovascular abnormalities consistent with chronic anemia; these include enlargement of the ventricular chambers, increased cardiac output, and reduced total vascular resistance. Cardiac iron overload in TM patients due to long-term transfusion can cause further chamber dilation, decreased contractility, and arrhythmia. Paradoxically, many such patients remain asymptomatic until decompensation occurs. For decades, magnetic resonance imaging and echocardiography have been performed to detect advanced cardiac dysfunction; however, reliable evaluation tools for the early detection of cardiac abnormalities are currently in demand. This article reviews the mechanisms underlying the development of heart disease in thalassemia and strategies for therapeutic intervention in TM patients with congestive heart failure.

Deferoxamine mesylate (DFO) reduces morbidity and mortality associated with transfusional iron overload. Data on the utilization and costs of care among U.S. patients receiving DFO in typical clinical practice are limited however. This was a retrospective study using a large U.S. health insurance claims database spanning 1/97-12/04 and representing 40 million members in >70 health plans. Study subjects (n = 145 total, 106 sickle cell disease [SCD], 39 thalassemia) included members with a diagnosis of thalassemia or SCD, one or more transfusions (whole blood or red blood cells), and one or more claims for DFO. Mean transfusion episodes were 12 per year. Estimated mean DFO use was 307 g/year. Central venous access devices were required by 20% of patients. Cardiac disease was observed in 16% of patients. Mean total medical costs were $59,233 per year including $10,899 for DFO and $8,722 for administration of chelation therapy. In multivariate analyses, potential complications of iron overload were associated with significantly higher medical care costs. In typical clinical practice, use of DFO in patients with thalassemia and SCD receiving transfusions is low. Administration costs represent a large proportion of the cost of chelation therapy. Potential complications of iron overload are associated with increased costs., ((c) 2007 Wiley-Liss, Inc.)

Cardiac damage caused by iron overload toxicity is the main cause of death in thalassemia patients. Biopsy samples of poorly chelated thalassemia patients who suffered congestive cardiac failure (CCF) show extensive iron deposition in the myocardium. In one patient who survived CCF, a cardiac biopsy was performed during the removal of a thrombus caused by a port-a-cath, which was used for the administration of intravenous (iv) deferoxamine (DFO). Ultrastructural pathology studies of the cardiac biopsy indicated extensive iron deposition in myocytes with accumulation of iron mainly in lysosomes, leading in some cases to their disruption. Damage to other intracellular components of the myocytes and loss of myofibers was also observed. The patient became intolerant to iv and subcutaneous (sc) DFO 2 years after the CCF, and was then treated with deferiprone (L1) for 7 years. Within 1 year of L1 treatment at 75-80 mg/kg/day, serum ferritin levels were reduced to <0.45 mg/L and she became asymptomatic, needing no further drugs for her cardiomyopathy. Lowering the L1 dose to 50-70 mg/kg/day caused an increase in serum ferritin levels. Maintenance of normal iron stores during the last 3 years as detected by cardiac and liver magnetic resonance imaging (MRI) T2 and T2* and normalization of serum ferritin levels (<0.15 mg/L) was observed following L1 therapy at 80-85 mg/kg/day. Deferiprone (>80 mg/kg/day) appears to be effective in the rapid clearance of cardiac iron, in the reversal of iron overload related cardiomyopathy, in the maintenance of normal iron stores and the overall long-term survival of thalassemia patients.

Iron overload is a well-documented complication in thalassemia intermedia. Moreover, it is seen that the number of blood transfusions received does not correlate with the degree of overload. Since, HFE gene is associated with iron overload; the present study was conducted in an attempt to evaluate its role in thalassemia intermedia. The subjects were consecutive thalassemia intermedia cases attending the Hematology outpatient clinic. Controls were healthy hospital staff with negative family history of hemolytic anemia or liver disease. The molecular analysis for HFE mutations H63D and C282Y were done with primers described earlier. ELISA was used to measure serum ferritin. Sixty-three patients of thalassemia intermedia including 48 beta-homozygous/heterozygous thalassemia intermedia and 15 HbE-beta-thalassemia were studied. Six (12.5%) of the former and two (13.3%) of the latter were heterozygous for H63D; one of which, a 51-year old male also had clinical features of hemochromatosis. In healthy controls, prevalence of H63D heterozygosity was 7.5% (6/80). An interesting feature observed was that though the age and transfusions taken were similar in both groups, the serum ferritin greater than 500 ng/dl were observed in all patients (100%) with HFE mutation whereas it was seen in 12/42 (28.6 %) of patients without the mutation (p = 0.002). Thus, it is concluded that thalassemia intermedia patients with co-existent HFE mutation have a higher likelihood of developing iron overload and may require early iron chelation.

Magnetic resonance T2* values of the myocardium are directly related to tissue iron levels. Minor effects from myocardial oxygenation and fibrosis are overwhelmed by the highly dominant iron effect in clinically relevant levels of myocardial iron overload. Myocardial T2* values less than 20 ms indicate iron overload, and this is considered severe when T2* is less than 10 ms. Decreasing myocardial T2* levels are associated with systolic and diastolic ventricular dysfunction. Most recorded cases of heart failure in thalassemia to date have occurred in patients with very low T2* values (in the severe range). Exceptions to this have occurred in patients with other causes of heart failure such as concomitant congenital heart disease. In patients presenting with heart failure who undergo aggressive chelation with continuous intravenous deferoxamine, longitudinal studies show that myocardial T2* increases, and this is accompanied by increases in ejection fraction and relief of heart failure. In cross-sectional studies, the myocardial T2* and ejection fraction of patients on deferiprone was superior to that of patients on deferoxamine. Randomized controlled prospective trials comparing these two drugs for their action in clearing myocardial iron, as measured by myocardial T2*, are under way and should report in 2005/2006. These trials will clarify the role of different chelators in the management of myocardial iron overload and may be valuable in reducing the toll of death in thalassemia from heart failure.

Measurement of liver iron concentration (LIC) is an important clinical procedure in the management of transfusional iron overload with iron chelation. LIC gives an indication of over- or underchelation. Although chemical assay of needle biopsy samples from the liver has been considered the "gold standard" of LIC measurement, needle biopsy sampling errors can be surprisingly large owing to the natural spatial variation of LIC throughout the liver and the small size of biopsy specimens. A magnetic resonance imaging technique has now been developed that enables safe noninvasive measurement and imaging of LIC with a known accuracy and precision. Measurements of LIC can be made over the range of LIC encountered in clinical practice. The technique is based on the measurement and imaging of proton transverse relaxation rates (R2) within the liver. The R2 imaging technique can be implemented on most clinical 1.5-T MRI instruments, making it readily available to the clinical community.

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.

Heart failure from iron overload causes 71% of deaths in thalassaemia major, yet reversal of siderotic cardiomyopathy has been reported. In order to determine the changes in myocardial iron during treatment, we prospectively followed thalassaemia patients commencing intravenous desferrioxamine for iron-induced cardiomyopathy during a 12-month period. Cardiovascular magnetic resonance assessments were performed at baseline, 3, 6 and 12 months of treatment, and included left ventricular (LV) function and myocardial and liver T2*, which is inversely related to iron concentration. One patient died. The six survivors showed progressive improvements in myocardial T2* (5.1 +/- 1.9 to 8.1 +/- 2.8 ms, P = 0.003), liver iron (9.6 +/- 4.3 to 2.1 +/- 1.5 mg/g, P = 0.001), LV ejection fraction (52 +/- 7.1% to 63 +/- 6.4%, P = 0.03), LV volumes (end diastolic volume index 115 +/- 17 to 96 +/- 3 ml, P = 0.03; end systolic volume index 55 +/- 16 to 36 +/- 6 ml, P = 0.01) and LV mass index (106 +/- 14 to 95 +/- 13, P = 0.01). Iron cleared more slowly from myocardium than liver (5.0 +/- 3.3% vs. 39 +/- 23% per month, P = 0.02). These prospective data confirm that siderotic heart failure is often reversible with intravenous iron chelation with desferrioxamine. Myocardial T2* improves in concert with LV volumes and function during recovery, but iron clearance from the heart is considerably slower than from the liver.

In thalassemia, iron overload is the joint outcome of excessive iron absorption and transfusional siderosis. While iron absorption is limited by a physiologic ceiling of about 3 mg/d, plasma iron turnover in thalassemia may be 10 to 15 times normal, caused by the wasteful, ineffective erythropoiesis of an enormously expanded erythroid marrow. This outpouring of catabolic iron exceeds the iron-binding capacity of transferrin and appears in plasma as non-transferrin-plasma iron (NTPI). The toxicity of NTPI is much higher than of transferrin-iron as judged by its ability to promote hydroxyl radical formation resulting in peroxidative damage to membrane lipids and proteins. In the heart, this results in impaired function of the mitochrondrial respiratory chain and abnormal energy metabolism manifested clinically in fatal hemosiderotic cardiomyopathy. Ascorbate increases the efficacy of iron chelators by expanding the intracellular chelatable iron pool, but, at suboptimal concentrations is a pro-oxidant, enhancing the catalytic effect of iron in free radical formation. NTPI is removed by i.v. DFO in a biphasic manner and reappears rapidly upon cessation of DFO, lending support to the continuous, rather than intermittent, use of chelators. Unlike DFO and other hexadentate chelators, bidentate chelators such as L1 may produce incomplete intermediate iron complexes at suboptimal drug concentrations.

In summary, long-term studies of DFO therapy in multiply-transfused patients with beta-thalassemia major have clearly shown it to be generally safe and effective. Appropriate use of DFO can remove excess iron, prevent iron-induced organ damage, and improve survival in thalassemia patients. Patients who begin treatment at a young age can be protected from the lethal complications of iron overload for at least two decades, but chelation therapy may not always prevent or ameliorate late growth failure and/or delayed or absent puberty. Those with iron damage to the heart and possibly other organs may experience stability or improvement in function with intense chelation. High-dose intravenous DFO produces a rapid decrease in hepatic iron content and improved cardiac function but can also cause severe toxicity, as can normal doses in patients with a low iron burden. Continuing studies of DFO are necessary to help further define its long-term efficacy and toxicity. In particular, significant attention should be paid to new strategies aimed at fostering improved compliance with its use.

Background: Iron overload in patients with thalassemia is a common feature which requires continuous chelation therapy and monitoring. Serum ferritin determination is widely accepted as a simple method for following iron load in patients with primary hemochromatosis; however, several reports on thalassemic patients emphasize that ferritinemia is not accurate and that other methods such as direct measurement of iron in the liver (HIC) and magnetic resonance imaging (MRI) are more precise., Materials and Methods: In order to contribute to the general understanding of iron load in thalassemia we used liver MRI to study 33 thalassemic patients, most of whom were also evaluated for iron content by liver biopsy. The data were then compared with serum ferritin levels., Results: Ferritin levels ranged between 276 and 8031 ng/mL, and liver iron content ranged from 1.6 to 31.0 mg/g dry weight; grade III or IV liver siderosis was recorded in 23/33 patients, just as 23/33 patients were found to have severe or very severe siderosis at MRI. Significant correlations with ferritin levels were recorded between grade IV and grades III, II and I (p < 0.01, p = 0.02, and p = 0.03, respectively). Ferritinemia also showed significant linearity with liver iron content (r = 0.603, p = 0.001). No significant differences of levels were recorded, however, between patients found to have severe and those with mild iron load at MRI (p = 0.073)., Conclusions: Our study shows that serum ferritin levels exhibit a tendency to be significantly correlated with the true status of hemochromatosis in thalassemic patients; however, the discrepancies recorded in several patients and the scarce or total lack of correlation with MRI suggest exploring other approaches to this problem in order to make proper decisions about therapy.

Patients with homozygous beta-thalassemia are at increased risk of serious infections. Yersinia enterocolitica is an organism with a predilection for these and other iron-overloaded patients. Three young adult patients with beta-thalassemia who were chronically transfused and developed yersiniosis are reported. Iron overload and desferrioxamine use are predisposing factors, as supported by clinical, animal, and in vitro data. Iron excess both immunologically compromises the host and greatly enhances yersinial growth. Desferrioxamine may make host iron even more bioavailable to Yersinia. Recognition of this association and unusual manifestations in these patients such as an appendicitis-like syndrome may direct clinicians to earlier antiyersinial therapy and temporary cessation of chelation.

Iron overload is frequently present in patients with thalassemia intermedia, and it becomes evident mainly after the second and third decades of life. The degree of the iron load is heterogeneous ranging from mild to severe. In this study we evaluated the iron status of 38 adult patients with thalassemia intermedia and we looked for factors possibly related to the observed heterogeneity of the iron status. The levels of transferrin saturation (TS), serum ferritin (SF) and desferrioxamine-induced urinary iron excretion (DFU) were spread in a wide range from normal to markedly increased. These indices did not correlate with other parameters such as age, hemoglobin levels and entity of the erythropoietic status. A significant difference in the degree of iron overload was observed between patients who underwent splenectomy and non-splenectomized patients. TS, SF and DFU were significantly higher in splenectomized than in non- splenectomized patients, indicating that the spleen could have a role in the regulation of iron metabolism in these patients.

This paper describes the status of iron stores, the incidence and the hematological characteristics of iron deficiency anemia in children heterozygous for beta-thalassemia. In beta-thalassemia heterozygotes, iron stores were similar to the controls in infancy and tended to increase with age, reaching levels of moderate iron overload solely in adult males. Iron deficiency anemia occurred less frequently in children heterozygous for beta-thalassemia as compared to normal controls, while no difference between the two groups was observed in the incidence of iron deficiency. Ineffective erythropoiesis, typical of heterozygous beta-thalassemia, by causing an increase of iron absorption may limit the effect of iron shortage. At similar levels of iron depletion, however, children heterozygous for beta-thalassemia develop a more severe anemia as compared to non beta-thalassemic children. With the exception of two children, HbA2 levels in the presence of iron deficiency anemia remain in the range of heterozygous beta-thalassemia. In conclusion, our results indicate that children heterozygous for beta-thalassemia have normal iron stores but are relatively protected against the development of iron deficiency. When iron deficiency anemia develops, its clinical expression is usually more severe than in non beta-thalassemic children.

The occurrence of a hepatocellular adenoma is described in a young woman with beta-thalassemia and secondary iron overload. This patient had no history of oral contraceptive use, and in fact was hypogonadal as a result of iron deposition in pituitary and gonadal tissue. Although hepatocellular carcinoma frequently occurs in diseases associated with iron overload, this is the first report of a benign liver tumor associated with secondary iron overload.

Thirty-seven patients with SCD were studied: 24 were diagnosed as homozygous Hb S on the basis of their haematological findings, and alpha:non-alpha globin chain ratios were found to be balanced in all. Thirteen patients were thought to have alpha or beta thalassaemia interaction with Hb S on the basis of low MCV and MCH, family history and/or presence of Hb A on electrophoresis. Six of them had abnormal alpha:non-alpha ratio (one had a ratio of 0.72 suggestive of alpha thalassaemia, and five had ratios between 1.4 and 1.9, compatible with beta thalassaemia interaction). The remaining seven patients with microcytosis had balanced globin chain synthesis and five were found to be iron deficient. Five additional patients (3 with Hb SS and 2 with Hb S/beta thalassaemia) had lower than normal serum ferritin concentration. The analysis of case histories disclosed that peptic ulceration, recurrent epistaxis and multiple pregnancies could account for iron loss in seven patients. These findings indicate that iron deficiency may be common in SCD and should be excluded as a cause of microcytosis. Microcytosis, in the absence of conclusive family studies and/or presence of Hb A on electrophoresis, is an unreliable indicator of alpha or beta thalassaemia interaction with Hb S.