Beta-thalassemia major is a hereditary genetic disorder of hemoglobin which leads to hemolysis; an effect makes these patients need repeated blood transfusions that lead to iron overloading including the liver, heart, spleen, bone marrow, pancreas, and endocrine system [1, 16, 17].
Iron deposition in the heart follows a characteristic pattern; it is greater in the epicardium and more in the ventricles than the atria [3, 5, 9, 10, 16, 17]. Cardiac dysfunction depends on the quantity of the deposited iron and the extent of fibers involvement. Despite the reversible nature of siderotic cardiomyopathy, the heart is still considered the target lethal organ as 71% of deaths in TM patients are caused by cardiac complications such as iron-induced acute myocarditis and acute heart failure [9,10,11,12,13,14,15,16,17,18,19].
The magnetic resonance signal of the hepatic and cardiac tissues depends on the T1 and T2 relaxation times (TR) of their iron content (Fig. 2). T2* is inversely related to intracellular iron, increased tissue iron displays a moderate decrease in T1 signals and extreme decrease in T2 signal intensities [10, 20, 21].
T2* is a simple, non-invasive and rapid technique that is gained in a single breath-hold [1, 8, 9, 11, 14]. Owing to the late development of the clinical findings and echocardiographic abnormalities, MR-T2* has become the strongest biomarker for simultaneous evaluation of liver and heart iron burden [1, 19] plus prediction of iron-induced cardiac complications such as heart failure and arrhythmia in TM patients [18,19,20].
Measuring serum ferritin level remains the primary screening test and is still used in monitoring the efficacy of chelation therapy. It has been reported that serum ferritin level greater than 2500 ng/ml is considered an important risk factor for developing iron-induced complications such as liver cirrhosis, heart failure, arrhythmias, impaired growth, and delayed puberty [22,23,24,25].
In this study, the level of serum ferritin ranged from 1000 to 7000 ng/ml.
A significant mild positive correlation has been observed between the level of serum ferritin and liver iron loading (Fig. 3); however, no significant correlation was found between the level of serum ferritin and heart iron content based on T2* (Fig. 4), LIC and MIC (Table 4). Also Eghbali et al. [26] studied the association between liver and heart T2* and levels of serum ferritin in TM patients and he reported a correlation between serum ferritin level and liver T2*, but not cardiac T2*. However, Puliyel M et al. 2014 [27] reported that ferritin cannot predict the total body iron changes with a little relevance between cardiac and hepatic iron content and levels of serum ferritin. Anderson et al. 2001 [21] also reported a non-significant correlation between cardiac T2* and levels of serum ferritin while Tanner et al. 2005 [7] reported a weak correlation between them.
Wood et al. 2005 [8] and Papakonstantinou et al. 2009 [9] reported that MR-R2* mapping could accurately estimate LIC in transfusion-dependent TM patients. Previous studies found that the frequency of MR-T2* relies on the iron concentration and chelation therapy used [11,12,13, 18]. In this study, a high statistical significance was found regarding the association between LIC and liver T2* (p = 0.000) (Table 5) and between MIC and cardiac T2* (p = 0.000) (Table 6).
Previous literatures reported that cardiac T2* of 52 ± 16 ms is the reference range and 20 ms is the minimum value for normal myocardium T2* [13]. Cardiac siderosis cannot be predicted from the hepatic iron load because liver iron normalizing within 3–6 months which is much faster than the heart [12,13,14, 18].
We found that although iron-loaded liver was detected in 95% of cases with moderate to severe affection in 67.5% (27/40) of cases, yet the myocardial iron was still normal in (90%) of cases (Fig. 5). However, a significant but weak correlation (r = 0.3) has been observed between hepatic and cardiac T2* (p = 0.02). But no significant correlation was found (r = 0.1) between MIC and LIC (p = 0.5) (Table 7). In agreement with our results, Anderson [12] reported that a marked discordance was observed between hepatic and cardiac iron concentration. Also Di Tucci et al. [28], Tanner et al. [29], Perifanis et al. [30], and Wood et al. [17] reported that no correlation was found among liver T2*, cardiac T2*, and iron concentration levels.
In this study, only 10% of studied cases (4/40) developed iron-loaded heart with either mild (5%; n = 2) or moderate (5%; n = 2) cardiac siderosis which is much less than those reported by Majd et al. [31] and Leung et al. [32] who described abnormal cardiac MR-T2* findings in 58% and 50% of patients respectively. This may be attributed to the different chelation regimens used and a better efficacy of ferriprox in removing excess cardiac iron; however, further prospective RCTs on a larger number of patients are needed to confirm this hypothesis.
Josep et al. [33] stated that using echocardiography to measure the diastolic parameters can distinguish early cardiac involvement before the appearance of clinical signs of heart failure. In our study, 10% of cases had excess cardiac iron; however, they presented with normal echocardiographic findings.
Auger and Pennelle [20] reported that assessment of cardiac iron loading should be started between the age of 6 and 10 years and that cardiac siderosis may present at the age of ten by acute heart failure. In this study, the youngest subject who developed cardiac siderosis based on abnormal cardiac T2* results was an 8-year-old female (Fig. 6). No significant correlation was found between patient age and the development of hepatic or cardiac siderosis (p = 0.6).
This study faced some limitations: first lack of regular follow-up of the patients, second is the inability to perform functional cardiac analysis using MRI owing to unavailable software of the equipment to accomplish that task in our institution, third is the lack of reference standard. Also the large percentage of cases with liver iron overload detected in this study raises the need to re-evaluate the iron chelation strategy used.
Overall, myocardial iron assessment from the assessment of serum ferritin, liver iron, or echocardiography is not reliable enough to adjust the iron chelation strategy in TM patients with risk for cardiac siderosis.