Myocardial iron deposition can be reproducibly quantified using myocardial T2* and this is the most significant variable for predicting the need for ventricular dysfunction treatment. Myocardial iron content cannot be predicted from serum ferritin or liver iron, and conventional assessments of cardiac function can only detect those with advanced disease. Early intensification of iron chelation therapy, guided by this technique, should reduce mortality from this reversible cardiomyopathy.

Most deaths in beta-thalassemia major result from cardiac complications due to iron overload. Differential effects on myocardial siderosis may exist between different chelators. A randomized controlled trial was performed in 61 patients previously maintained on subcutaneous deferoxamine. The primary end point was the change in myocardial siderosis (myocardial T2*) over 1 year in patients maintained on subcutaneous deferoxamine or those switched to oral deferiprone monotherapy. The dose of deferiprone was 92 mg/kg/d and deferoxamine was 43 mg/kg for 5.7 d/wk. Compliance was 94% ؎ 5.3% and 93% ؎ 9.7% (P ‫؍‬ .81), respectively. The improvement in myocardial T2* was significantly greater for deferiprone than deferoxamine (27% vs 13%; P ‫؍‬ .023). Left ventricular ejection fraction increased significantly more in the deferipronetreated group (3.1% vs 0.3% absolute units; P ‫؍‬ .003). The changes in liver iron level (؊0.93 mg/g dry weight vs ؊1.54 mg/g dry weight; P ‫؍‬ .40) and serum ferritin level (؊181 g/L vs ؊466 g/L; P ‫؍‬ .16), respectively, were not significantly different between groups. The most frequent adverse events were transient gastrointestinal symptoms for deferipronetreated patients and local reactions at the infusion site for deferoxamine. There were no episodes of agranulocytosis. Deferiprone monotherapy was significantly more effective than deferoxamine over 1 year in improving asymptomatic myocardial siderosis in beta-thalassemia major. (Blood. 2006;107: 3738-3744)

SummaryHeart 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* (5AE1 ± 1AE9 to 8AE1 ± 2AE8 ms, P ¼ 0AE003), liver iron (9AE6 ± 4AE3 to 2AE1 ± 1AE5 mg/g, P ¼ 0AE001), LV ejection fraction (52 ± 7AE1% to 63 ± 6AE4%, P ¼ 0AE03), LV volumes (end diastolic volume index 115 ± 17 to 96 ± 3 ml, P ¼ 0AE03; end systolic volume index 55 ± 16 to 36 ± 6 ml, P ¼ 0AE01) and LV mass index (106 ± 14 to 95 ± 13, P ¼ 0AE01). Iron cleared more slowly from myocardium than liver (5AE0 ± 3AE3% vs. 39 ± 23% per month, P ¼ 0AE02). 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.

Purpose:To assess tissue iron concentrations by the use of a gradient echo T2* multiecho technique. Materials and Methods:We compared the results of measurements of heart T2* from 32 patients using the established multiple breath-hold variable TR technique with a new multiecho sequence that acquires all images within a single breath-hold with constant TR. Results:There was good agreement of myocardial T2* values between both methods in the abnormal range of T2* Ͻ 20 msec (mean difference 0.2msec, 95% CI -1.3 to 0.9 msec, r ϭ 0.97, P Ͻ 0.0001). The coefficient of variability between the methods was 3.5%. The interstudy reproducibility using the multiecho sequence had a variability coefficient of 2.3% in the abnormal T2* range and 5.8% over all T2* values. There was good agreement between the techniques for the liver T2* values. Conclusions:The use of the single breath-hold, multiecho acquisition allowed reliable quantification of myocardial T2*. The good reproducibility, speed, and T1 independence of this technique allows greater accuracy, faster patient throughput, and, therefore, reduced costs (which is important in developing countries where thalassemia is most prevalent).

No abstract

Cooley's original description of beta-thalassaemia major included marked bone deformities as a characteristic feature. These were thought to be due to expansion of haemopoiesis attempting to compensate for the congenital anaemia. Regular blood transfusions from infancy prevents these skeletal problems. Nevertheless, symptoms due to bone disease frequently occur in adult patients. Osteoporosis has not previously been reported as a cause of severe morbidity in thalassaemia major. The present study shows a high prevalence of low bone mass among thalassaemia major patients and analyses the predisposing causes. Bone density scans were performed in 82 patients with transfusion-dependent beta thalassaemia. Factors known to be associated with low bone mass such as gender, endocrine disorders and lifestyle activities, together with factors specific to the thalassaemia and its management, were included in a series of univariate analyses to ascertain any significant associations. 42 (51%) of the patients had severely low bone mass and a further 37 (45%) had low bone mass. The three factors showing a statistically significant association with severely low bone mass were male sex, 24/38 (63%) males had severely low bone mass, compared with 18/44 (41%) females, the lack of spontaneous puberty, 22/32 (69%) who required therapeutic induction of pubertal development had severely low bone mass, compared with 19/47 (40%) with spontaneous puberty and diabetes, 8/10 (80%) diabetic patients had severely low bone mass, compared with 23/56 (41%) with normal glucose tolerance. There was no association between the bone mineral density measurements and the haematological characteristics or treatment details of these patients. Severely low and low bone mass are common findings in patients with beta-thalassaemia major despite optimal transfusion and iron chelation. The associated features suggest that the severely low bone mass is due to endocrine abnormalities, in contrast to the haematological causes of bone disease characteristically seen in untreated thalassaemics.

Clinical complications of transfusional iron overload are still common in patients with thalassaemia major (TM) and it is not clear how best to monitor body iron stores during long‐term follow‐up to anticipate tissue damage. In this study, we have reviewed a group of 32 patients who underwent liver biopsy between 1984 and 1986. We developed a method of assessing the trend in serum ferritin (TSF) during long‐term monitoring and compared this with mean serum ferritin (MSF) and initial liver iron (LI) concentration to determine whether, individually or in combination, they were accurate in predicting clinical outcome. LI levels were low (< 7 mg/g), medium (7–15 mg/g) and high (> 15 mg/g dry weight) in 15, 7 and 10 patients respectively. MSF was low (< 1500 μg/l), medium (1500–2500 μg/l) and high (> 2500 μg/l) in 10, 14 and 8 patients. TSF was low, medium and high risk in 9, 9 and 11 out of 29 evaluable patients. During a median follow‐up of 13·6 years (range 2·3–14·8 years) after biopsy, nine patients died and an additional three patients developed heart failure. Hypothyroidism developed in five, hypoparathyroidism in four, and diabetes mellitus in seven patients. Cirrhosis developed in four of 10 evaluable patients. The clinical end‐point of death or cardiac failure was significantly associated with increasing iron load using all three means of assessment. Although numbers were insufficient for statistical analysis, MSF or TSF were more closely associated with complications of iron overload than LI. There was no clear additional value in combining LI with MSF or TSF. The data show that quantitation of liver iron from a single liver biopsy has little value in long‐term monitoring of iron stores. Most complications can be avoided if ferritin levels can be brought down to <1500 μg/l.

In a proportion of transfusion-dependent patients iron chelation with daily doses of deferiprone of 75 mg/kg body weight (b.w.) is inadequate. The effects on iron status of increasing the daily oral dose of deferiprone and/or combining deferiprone therapy with subcutaneous infusions of desferrioxamine have been studied in 13 transfusion-dependent patients. Raising the daily dose of deferiprone in nine patients from 75 mg/kg to 83-100 mg/kg resulted in a fall in serum ferritin in all nine patients (t test for paired samples, P = 0.0022). Combined therapy of daily deferiprone with subcutaneous desferrioxamine on 2-6 d each week in five patients (with an increased dose of deferiprone in three patients) resulted in a fall in serum ferritin in all five patients studied after 7-15 months (P=0.0791). No toxic side-effects attributable to either drug occurred in these five patients or in the nine patients in whom the dose of deferiprone was increased. The effects of the drugs given on the same day on urine iron excretion were additive. These results suggest that increasing the dose of deferiprone or combining subcutaneous desferrioxamine with deferiprone therapy are two methods by which efficacy of iron chelation with deferiprone can be improved in patients inadequately chelated by a daily dose of deferiprone of 75 mg/kg b.w. More extensive trials including full metabolic balance studies are needed to establish the safety and efficacy of long-term combined therapy.