Early cardiac iron overload in children with transfusion-dependent anemias

Quantitative magnetic resonance imaging (MRI) heart iron assessment has been an important advance in the follow-up of patients with transfusion-dependent anemias.1 Few longitudinal data are available on the natural history of cardiac iron overload.2 We refer this letter to the manuscript by Wood et al.3 in which they recently reported that in pediatric patients with thalassemia major (TM) no detectable cardiac iron overload was observed in children under the age of 9.5 years. Another study showed that cardiac iron loading in patients with increased transfusion requirements occurred only after at least 13 years of chronic transfusion therapy.4 These facts are important in determining the appropriate age at which to start screening for increased iron in the heart with an expensive technique such as MRI. However, as published in recent guidelines,5 it has been hypothesized that these observations should only be true if chelation therapy has started early and been received regularly as well as there having been no increases in transfusion needs. To evaluate if cardiac iron overload might occur in younger children who do not satisfy these requirements, we assessed pediatric patients from 7–18 years of age with chronic transfusion therapy undergoing MRI to detect cardiac iron loading. Cardiac T2* assessment was performed on a 1.5T Siemens Symphony scanner using previously described validated techniques.6

A total of 23 patients were scanned (61% male, mean age 12.6±3.1 years) with thalassemia major being the most frequent diagnosis (78%), followed by thalassemia intermedia (13%), sideroblastic anemia (4%), and sickle cell disease (4%). In this cohort, there were 4 patients diagnosed with cardiac iron overload, 3 of them males under the age of ten (Table 1). The fourth patient was 17 years of age (older than the age reported for the first findings of cardiac iron overload in previous studies) and was not included in the analysis (heart T2* of 17.2msec). All other patients had normal heart T2* with no other cardiac findings (27.3±6.5msec).

In common, the 3 patients under the age of ten with cardiac iron overload reported suboptimal chelation therapy prior to the MRI scans, either due to irregular use of the prescribed chelator or late access to chelation early in the course of the disease. Chelation history for these patients included late start for patients 1 and 2 (17 and 28 months gap between transfusions and desferrioxamine use, respectively) and irregular use for patient 3. All patients had adequate prescriptions for subcutaneous desferrioxamine at the time of cardiac iron overload diagnosis, with deferiprone added after heart involvement diagnosis. It is interesting to note that the mean transfused iron input for these patients was 189.1±98.5 mg/kg/y, a total iron dose similar to that previously reported.3 Moreover, in all these patients the degree of cardiac iron overload was always severe with only one patient already showing symptoms of heart failure (patient 3). This patient in particular already showed signs of heart failure (shortness of breath while playing with other children and premature ventricular complexes in the ECG) at the age of three with no other etiologies besides cardiac siderosis being found.

Regarding the other 20 patients in the cohort, chelation therapy included subcutaneous desferrioxamine only in 15 patients, desferrioxamine plus deferiprone in one patient and deferasirox in the remaining 4. Compared to the 3 patients described, all these patients reported good adherence to chelation therapy, defined as correct intake of the prescribed medication more than 90% of the time.

Table 1.Characteristics of study patients.

In this letter, we showed that increased cardiac iron deposition can occur even at a younger age then predicted by previous studies. The main reason for this occurrence seems to be inadequate compliance with chelation therapy as has been reported in unchelated adult patients with myelodysplastic syndromes.7 Other reasons for the results observed, such as anemia as a potential factor for iron overload, were not assessed in this study. Although chelation therapy is mentioned in previous reports with young patients, the compliance status of the population described was not portrayed,3 leaving the possibility that all patients were well chelated or that poorly compliant subjects were not included. Nevertheless, it seems prudent to recommend starting MRI screening as early as 7-years of age if poor chelation is assumed, even in the absence of symptoms of heart disease. Cardiac MRI can be performed with no need for sedation in children at this age and normal reference ranges have been extensively studied for comparisons of heart function.8 While cost and availability should be considered, especially if one assumes that patients with difficult access to chelation will also have the same problems with MRI, these are the patients that should benefit most from precocious screening.

Footnotes

• Funding: this work was supported by a grant from Fundaçao de Amparo a Pesquisa do Estado de SP (FAPESP).