MRI evaluation of hepatic and cardiac iron burden in pediatric thalassemia major patients: spectrum of findings by T2*
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Iron deposition distorts the local magnetic field exerting T2* signal decay. Biopsy, serum ferritin, echocardiography are not reliable to adjust iron chelation therapy. Quantified MRI signal decay can replace biopsy to diagnose iron burden, guide treatment, and follow up. The objective of this study is to evaluate the role of T2* in quantification of the liver and heart iron burden in thalassemia major patients. This cross-sectional study included 44 thalassemia patients who were referred to MRI unit, underwent T2* MRI.
Twenty-one male (47.7%) and 23 female (52.3%) were included (age range 6–15 years, mean age 10.9 ± 2.9 years). Patients with excess hepatic iron show the following: 11/40 (27.5%) mild, (13/40) 32.5% moderate, and (14/40) 35% severe liver iron overload. High statistical significance regarding association between LIC and liver T2* (p = 0.000) encountered. Cardiac T2* values showed no relationship with age (p = 0.6).
T2* is a good method to quantify, monitor hepatic and myocardial iron burden, guiding chelation therapy and prevent iron-induced cardiac complications.
KeywordsThalassemia major (TM) Liver iron concentration T2*
- TM patients
Thalassemia major patients
Institutional review board
Field of view
- E/A ratio
Early (E) to late (A) ventricular filling velocity
The gradient echo (the inverse of T2*)
Turbo field echo sequence
Randomized clinical trials
Liver iron concentration
Myocardial iron concentration
Thalassemia major (TM) patients require regular blood transfusions which may lead to iron overload. Excess iron is accumulated in the liver, heart and endocrine organs. Intracellular free iron can cause tissue damage, leads to arrhythmias, heart failure accounting for 71% of deaths in TM patients [1, 2, 3, 4].
Significant cardiac iron load can be encountered, although the hepatic iron concentration is kept low, an issue urges the need to quantify this burden, especially in a non-invasive manner in the pediatric age group .
Instead of measuring the serum ferritin level (a metalloprotein found in the cells) to take a tissue biopsy to diagnose iron overload, T2* can be used as a non-invasive method . T2* is useful in tailoring the iron chelation strategies [7, 8].
Assessing the T2 and T2* relaxation parameters is the gold standard in cases of iron overload. Iron is not directly imaged, instead, water protons are imaged so long they diffuse near iron deposits in the tissue of interest. Those iron particles with their characteristic ferromagnetic effects act as small magnets, destroying the homogeneity of the magnetic field in iron-laden tissues, so moving water protons significantly exhibit different magnetic momentum and desynchronized from each other. A consequence yields a black image by a rate proportional to the iron load [3, 4]. The objective of this work is to evaluate the role of T2* in detection and quantification of cardiac and hepatic iron concentration in pediatric TM transfusion-dependent patients.
Study design and population
This prospective cross-section study included 44 thalassemia pediatric patients from 6 to 15 years old. They were referred from the pediatric department to radio-diagnosis department from February 2015 to January 2019 after getting a local institutional review board (IRB) approval and informed consents from all patients' parents before the study.
Inclusion criteria were pediatric TM patients receiving a regular blood transfusion and iron chelation agent (Ferriprox). Cases of siderotic cardiomyopathy or have potential contraindications to MRI examination including claustrophobia, metallic objects, and pacemakers were excluded. Patients were subjected to MRI examination after thorough history taking (regarding patient’s chelation regimen, serum ferritin level and echocardiographic findings).
MRI examinations were done using a 1.5 Tesla superconducting magnet (Achieva, Philips Medical System, Best, Netherlands). Fasting and sedation were not needed prior to the exam. Respiratory triggering was applied to ensure minimal movement and lessen respiratory motion artifact. In cases of free-breathing, increased signal averaging number to 3 was used (instead of 1 at breath-holding technique).
Scan protocol and parameters
Cardiac gating MRI exam was performed in a supine position with head first using torso phased-array body coil. The field of view (FOV) extends from the carina caudally to the lower renal pole.
3-plane localizer. (Ensure the heart at the center of the field).
Cardiac T2* (Table 1): scanned at 8 different echo times (TE 1.5, 4, 6.4, 8.8, 11.2, 13.6, 16, and 18.5 ms).
The following two sequences were used: single breath-hold multi-echo gradient echo sequence (white blood) and double inversion recovery ‘black blood’ sequence where TI should be set to extend into diastole and the blood signal should be adequately nulled thus reducing the blood flow artifact and motion artifact.
Mid ventricular imaging plane using 2 chamber, 4 chamber, and short-axis images (usually mid papillary muscle level) was selected not encroaching on the outflow tract. To minimize the breath-hold time we used in plane rotation and reduced the field of view in phase encoding direction.
Liver T2* (Table 2): the acquisition consists of 5 slices collected through the center of the liver in a single breath-hold at 16 different echo times (TE 1, 1.9, 2.7, 3.6, 4.4, 5.3, 6.1, 7, 7.8, 8.7, 9.5, 10.4, 11.3, 12.2, and 13.1 ms) with a gradient-echo sequence (Turbo field echo: TFE) to ensure accurate measurement of liver T2* in cases with light liver iron burdens.
We used large voxels to improve the signal to noise ratio and so decreased echo time. Voxels are 4–5 mm in-plane resolution. According to body habitus FOV was adjusted (FOV < 32 cm may prolong the echo time).
Thin slice axial T2 (Table 3)*: provides a finer sampling of the entire abdomen extending from diaphragm dome to the lower renal poles. Slice positioning should have some slop to account for variable breath-hold position. Voxel size should have 2–3 mm in-plane resolution. It takes five stacks to span the target region. TR was reduced to increase coverage to five slices per breath-hold.
Parameters for cardiac T2* imaging
128 × 256
1.5–18.5 with 2.4 ms increments
Parameters for liver T2* imaging
#Slices/#slices per BH
FOV (F × Ph)
40 × 24
1–13.1 ms with 0.9 ms increments
Min water-fat shift
Parameters for axial T2* imaging
#Slices/#slices per BH
FOV (F × Ph)
32–36 × 24–27
1–13.1 ms with 0.9 ms increments
Min water-fat shift
Before the patient’s departure. The MRI technician must review the image data after scans are completed to avoid recalling the patient later for a repeat MRI.
Cardiac MR-T2* values were quantified with the region of interest in the ventricular septum to avoid susceptibility artifact. The region of interest was copied automatically to identical positions on images from different TEs (Fig. 1). Patients with iron-loaded heart showed rapid signal loss with increasing TE with both black and white blood sequences and T2* measures were less than 20 ms. They were categorized as mild (15–20 ms), moderate (10–15 ms), and severe (T2*; < 10 ms) .
Myocardial iron concentration (MIC) was also calculated from R2* using the equation (0.0254 × R2*) + 0.202 (R2*, the reciprocal of T2*, 1000/T2*), according to carpenter JP et al. formula  where values from 1.16 to 1.65 indicate light, 1.65 to 2.71 indicate moderate, and more than 2.71 mg/g indicate severe cardiac siderosis.
Liver-T2* values below 11.4 ms indicate iron overload: mild (3.8–11.4), moderate (1.8–3.8), and severe (> 1.8 ms).
Liver iron concentration (LIC) using Garbowski MW et al. formula  was calculated where 2–7 mg/g indicates light, 7 to 15 indicate moderate, and <15 mg/g severe iron burden.
It was performed within 1 week from MRI by a pediatric cardiologist who was blinded to the clinical data and imaging results to evaluate the cardiac function owing to the unavailability of MRI software for cardiac function assessment in our department. The parameters tested were diastolic and systolic functions. An ejection fraction > 55% and > 27% fraction shortening was considered as normal systolic function; while E/A ratio less than 1 was considered as normal diastolic function.
Serum ferritin level
It was performed as a primary screening test to evaluate the iron overload.
The data analysis was performed using SPSS 20 (Chicago SPSS, SPSS Inc., Chicago, IL). Comparison of cardiac T2*, MIC, and hepatic T2* and LIC values was performed with Kruskal-Wallis test. We used the Spearman test to correlate between serum ferritin level and T2*, MIC, and LIC. A p value of < 0.05 reflects a statistical significance.
This study included 44 pediatric TM patients (21 male; 47.7 % and 23 female; 52.3 %). Only 40 (18 males; 45% and 22 females; 55%) patients performed cardiac MRI and completed the study, their age ranges from 6 to 15 years with a mean 10.9 ± 2.9 years. Remaining 4 patients were excluded due to poor quality cardiac images from motion artifact. All patients received Ferriprox as iron chelator agent.
All subjects had a high serum ferritin (ranging from 1000 to 7000 ng/ml) with a mean 3141.2 ± 1967.5. Only 35/40 patients performed echocardiography and all patients had normal or accepted echocardiographic results regarding the diastolic and systolic functions.
Cardiac T2* values showed no relationship with age (p = 0.6). An 8-year-old female was the youngest who developed cardiac siderosis.
Correlation between serum ferritin, hepatic, and cardiac investigations of the studied group
Association between LIC and hepatic T2* in the studied group
mean ± SD
mean ± SD
Mann-Whitney U test
18.4.1 ± 1
4.3 ± 4.2
Association between MIC and cardiac T2* in the studied group
mean ± SD
mean ± SD
36.1 ± 7.9
13.9 ± 2.9
Correlation between hepatic and cardiac investigations of the studied group
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].
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.
Wood et al. 2005  and Papakonstantinou et al. 2009  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* . 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].
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.  and Leung et al.  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.  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.
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.
T2* MRI is nowadays the method of choice to early detect, quantify and monitor the hepatic and myocardial iron burden and guiding the chelation therapy to prevent the iron-induced cardiac complications and reduce patients’ mortality.
We would like to express our gratitude to Dr. Dudley Pennell, Dr. John C. Wood, and Dr. Gillian Smith for their assistance in interpreting our findings and Dr. Ahmed Samir for supplying us with the liver and heart spreadsheets thus enabled us to interpret the results ourselves.
MI carried out the study concept and design, participated in the sequence alignment, and drafted the manuscript. SM carried out the process of literature search. ZE participated also in the sequence alignment and participated in the design of the study. SM performed the statistical analysis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This study was approved by the Institutional Review Board (IRB) of Zagazig University. A written informed consent from all patients’ parents before the study were filled and signed, which are also approved by the Institutional Review Board (IRB) of Zagazig University with reference number 3186.
Consent for publication
All patients included in this research gave written informed consent to publish the data contained within this study by their parent.
The authors declare that they have no competing interests.
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