Longitudinal analysis of heart and liver iron in thalassemia major

Abstract

High hepatic iron concentration (HIC) is associated with cardiac iron overload. However, simultaneous measurements of heart and liver iron often demonstrate no significant linear association. We postulated that slower rates of cardiac iron accumulation and clearance could reconcile these differences. To test this hypothesis, we examined the longitudinal evolution of cardiac and liver iron in 38 thalassemia major patients, using previously validated magnetic resonance imaging (MRI) techniques. On cross-sectional evaluation, cardiac iron was uncorrelated with liver iron, similar to previous studies. However, relative changes in heart and liver iron were compared with one another using a metric representing the temporal delay between them. Cardiac iron significantly lagged liver iron changes in almost half of the patients, implying a functional but delayed association. The degree of time lag correlated with initial HIC (r ‫؍‬ 0.47, P < .003) and initial cardiac R2* (r ‫؍‬ 0.57, P < .001), but not with patient age. Thus, longitudinal analysis confirms a lag in the loading and unloading of cardiac iron with respect to liver iron, and partially explains the weak cross-sectional association between these parameters. These data reconcile several prior studies and provide both mechanical and clinical insight into cardiac iron accumulation. (Blood. 2008; 112:2973-2978) IntroductionDespite availability of iron chelation, iron-mediated cardiac toxicity remains the leading cause of death in thalassemia major patients. 1 Cardiac dysfunction, whether detected by radionuclide angiography, echocardiography, or magnetic resonance imaging (MRI), is often a late finding and carries an ominous prognosis. 2,3 Although intense chelation can rescue many patients, depleting cardiac iron burden often takes years and mortality is high with incomplete compliance. 3 Thus, prevention of cardiac iron accumulation and dysfunction is imperative. Initial studies in this area examined hepatic iron concentration (HIC), as measured by liver biopsy, and serum ferritin levels as potential predictors of cardiac toxicity. [4][5][6] This hypothesis was logical because HIC is an excellent indicator of iron balance and total body iron stores. 6,7 These early studies concluded that elevated liver iron and serum ferritin trends raise prospective risk of cardiac dysfunction, implying a correlation between cardiac and liver iron deposition. [4][5][6] Based upon this work, treatment algorithms for iron removal therapy based primarily on HIC and ferritin levels 8,9 were developed with the goal of minimizing cardiac and endocrine toxicities.However, the use of HIC and ferritin to infer cardiac iron has been challenged by recent MRI studies. 10-13 MRI allows organ iron concentrations to be easily and noninvasively measured and has been validated on both animals and humans. [14][15][16] Crosssectional analysis has demonstrated poor correlation between HIC or ferritin and cardiac iron. [10][11][12]13 In addition, some patients develop cardiac deposition and symptom...

Sustained improvements in myocardial T2* over 2 years in severely iron‐overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine

“…Since the removal of accumulated iron from the heart of transfusion-dependent beta thalassemia major patients is a slow process [5,7], additional long-term controlled studies are needed to strengthen the evidence demonstrating clinical benefits of iron chelation regimens. The 1-year extension to the CORDELIA study generated long-term data on the efficacy and safety of deferasirox or DFO in patients with myocardial siderosis when treated for up to 2 years, adding to the body of evidence supporting a consensus statement on the use of these chelators in the treatment of myocardial siderosis in patients without cardiac decompensation [17].…”

“…The heart is one of the most sensitive organs to iron toxicity [3] and the clinical consequences of iron overload including symptoms of cardiac dysfunction have been observed from an early age, even in children aged less than 10 years [4]. Considerable variation has been observed in the kinetics of iron loading in the heart and liver, which is not completely understood [5]. Iron clears more slowly from the heart than the liver and as such, patients with myocardial siderosis may require a longer duration of iron chelation therapy to achieve a low-risk myocardial iron status (cardiovascular magnetic resonance [CMR]-measured T2* >20 ms) [6,7].…”

“…Longer-term single-arm studies with deferasirox for myocardial iron removal have shown a continuous decrease in Additional Supporting Information may be found in the online version of this article. 1 NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom; 2 Department of Haematology, University College London, London, United Kingdom; 3 Department of Paediatrics, University of Turin, Turin, Italy; 4 Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China; 5 Department of Pediatric Hematology, Cairo University, Cairo, Egypt; 6 Department of Pediatrics, Ain Shams University, Cairo, Egypt; 7 Department of Pediatric Hematology-Oncology, Akdeniz University, Antalya, Turkey; 8 Department of Biochemistry, Cukurova University Medical Facility, Adana, Turkey; myocardial iron with up to 3 years of treatment with a clinically manageable safety profile [7,14,15]. CORDELIA was a large, prospective randomized study comparing deferasirox with DFO in patients with beta thalassemia major who demonstrated, at the end of 1 year, the noninferiority of deferasirox versus DFO for myocardial iron removal, with a trend for superiority (P 5 0.057) [8].…”

Single region of interest versus multislice T2* MRI approach for the quantification of hepatic iron overload

“…Decay curve fitting was performed by the Levenberg-Marquadt method and the T2* value for the ROI was obtained (19,20). First, as common in clinical practice, a single ROI was defined in the medium-hepatic slice.…”

Management of the Thalassemias

“…These conclusions have been challenged by the identification of a calibration error in T2 Ã liver measurements conducted by the London investigators, leading in many studies to repeated underestimation of liver iron concentration Tanner et al 2008). Even if iron within the heart is correctly imaged (Garbowski et al 2008), simple cross-sectional associations between the two organs may have limited usefulness because of delays in loading and removal of cardiac iron, relative to these processes in the liver (Noetzli et al 2008). The influences on CMR T2 Ã of the rate of tissue iron loading, the age at the start of iron loading, the processes of iron absorption and ineffective erythropoiesis, and the particular iron-chelating therapy administered remain poorly understood.…”