Cardiac MRI for Iron Overload in pediatric thalassemia patients– Right Age to Start in a Resource Constrained Environment

Abstract

The aim of this article is to assess the prevalence and severity of myocardial iron overload in thalassemia patients who present for the first time for cardiac MRI and to define the right age to start screening, in a resource—constrained environment. All MRI scans done at our institute for myocardial iron overload assessment in thalassemia patients, between 2015 and 2018 were analysed. Patients up to the age of 30 years were included. There were a total of 600 patients, (Age group between 2 and 30 years). All these scans were retrospectively analysed and severity of myocardial iron overload was categorized as normal, mild, moderate and severe based on the bright blood T2* equivalent values at 1.5 T. Overall prevalence of myocardial iron overload was 32.3%, while the prevalence of myocardial iron overload in patients in the age group 0–10 was 10.2%.There were 40 patients in the age group 0–6 years, of whom, only 2 had myocardial iron overload. In patients less than or equal to 6 years of age, the number of patients with iron overload was very small and this may be used to decide the optimal age for scanning.

Introduction

Thalassemia major patients require blood transfusions from infancy to maintain adequate haemoglobin. The exogenous iron transfused daily is nearly 50 times the physiologic rate of iron absorption [1–3]. This causes increased iron accumulation in various organs, viz. liver, heart, pancreas, pituitary, bone marrow, spleen, endocrine organs and lymph nodes.

Cardiac failure secondary to Fe [iron] overload is a common cause of death in patients with thalassemia major [4–6]. There is also variable damage to the rest of the organs where the transfused iron has a propensity to deposit.

Starting chelation therapy promptly can avoid irreversible end organ damage [1, 7]. Chelation therapy however requires close monitoring of iron levels [1, 8].

There are various means to assess the total body iron burden which include monitoring transfusion burden, serum markers of iron overload, measurement of liver iron concentration (LIC), liver biopsy, computed tomography, magnetic detectors and MRI [9].

Amongst these, MRI has emerged as a standard of care. This is because of its non-invasive nature, increasing availability, higher sensitivity and reproducibility [1, 10, 11]. At the same time it also offers the advantage to image multiple organs in the body during a single imaging session. T2* measurements are the most commonly used parameter [9, 12].

Data regarding the prevalence of myocardial iron overload in paediatric population is scarce [13–15]. There are no clear guidelines regarding the age at which myocardial iron overload monitoring should be started. Patients as young as two years of age have started presenting for cardiac MRI for iron overload assessment. Defining an age cut off is important, especially in a resource constrained environment like India.

This study is a retrospective analysis of the prevalence and severity of myocardial iron overload in a cohort of thalassemia patients who presented for the first time for MRI assessment of iron overload status and includes 386 paediatric patients (< 18 years of age).

Materials and Methods

From 2015 to 2018, all iron overload scans done in thalassemia patients who presented for the first time for myocardial iron overload assessment, were retrospectively analysed. There were 621 patients in total, 21 of whom were above the age of 30 and hence were excluded.

The final cohort of thalassemia patients, up to the age of 30 years, who presented for the first time for iron overload assessment consisted of 600 patients (363 male and 237 female). The youngest patient was 2 years of age (median age 14 years).

Gender-wise prevalence and severity of cardiac iron overload was assessed. The patients were sub-grouped into three age-based categories viz, 0–10 years, 10–20 years and 20–30 years. Prevalence and severity of cardiac iron overload in each age subgroup was also assessed separately.

The status of iron overload in the heart was categorized as normal, mild, moderate and severe based on the bright blood T2* equivalent values at 1.5 T.

Conversion Formula used: 2000/R2*[3 T] = T2* equivalent value at 1.5 T [16]

T2* MRI scans used to be done on 1.5 T scanners, something we have been doing since 2005. In 2015 we shifted to 3 T after speaking to the Brompton group that pioneered the technique and gave us a conversion formula and since then we have scanned more than 2000 plus patients.

3 T is not a contraindication nor is 1.5 T necessary. Multiple studies have shown that T2* is reproducible on both 1.5 T and 3 T.

Alam et al. [16], discussed at length the relative merits of iron quantification at 3 T vs 1.5 T and also demonstrated that heart and liver T2* and R2* at 3 T showed close association with 1.5 T values.

Storey et al. [17], established this relationship between R2* at 3 T and 1.5 T over a range of tissue iron concentrations in 2007.

MR Imaging and Analysis Technique

Myocardial T1, T2, bright blood T2* and black blood T2* maps were obtained on a 3.0 T MRI (Ingenia CX, Philips, Eindhoven) scanner.

The quantitative cardiac imaging protocol included standard ECG gated, multi-transmit RF enabled single breath-hold Modified Look-Locker Inversion recovery (MOLLI) sequence (5 s(3 s)3 s) for native T1 quantification, a double inversion recovery (DIR) prepared multi-echo gradient echo black blood sequence for T2* quantification, DIR prepared GraSE for T2 & a multi-echo gradient echo bright blood sequence for T2* quantification. T1,T2,bright blood T2* and black blood T2* values were measured by manually selecting ROIs in the cardiac septum in a single mid-cavity short axis slice.

The severity of cardiac iron overload was categorized as follows:

Cardiac

• Normal: T2* > 20 ms

• Mild: 12 ms > T2* > 20 ms

• Moderate: 8 ms > T2* > 12 ms

• Severe: 8 ms > T2*

Results

Median myocardial T2* value was 3.63 ms (range, 2.97–105.2 ms).

Overall prevalence of iron overload was 32.3% (194 of 600 patients); mild, 11% (66 patients); moderate, 10.6% (64 patients); severe, 10.6% (64 patients) (Table 1).

Table 1.

Gender wise prevalence and severity of iron overload

Category	Overall prevalence of iron overload (%)	Mild (%)	Moderate (%)	Severe (%)
Total population	32.3	11	10.6	10.6
Males	31.4	11.5	9.9	9.3
Females	33.7	10.1	11.3	12.2

Prevalence of iron overload in males was 31.4% (114 of 363 patients); mild, 11.5% (42 patients); moderate, 9.9% (37 patients); severe, 9.3% (35 patients) (Table 1).

Prevalence of iron overload in females was 33.7% (80 of 237 patients); mild, 10.1% (24 patients); moderate, 11.3% (27 patients); severe, 12.2% (29 patients) (Table 1).

Amongst the patients with severe myocardial iron overload (67 of 621 patients) 37 were men, 30 were women. Majority of these patients were in the age group, 16–30 years (50 of 67 patients).

Prevalence of iron overload in patients in the age group 0–10 was 10.2% (18 of 175 patients), in the age subgroup 10–20 was 40.4% (119 of 294 patients) and in the age subgroup 20–30 years was 43.5% (57 of 131 patients) (Table 2).

Table 2.

Age wise prevalence and severity of iron overload

Age group	Overall prevalence of iron overload (%)
0–10 years	10.2
10–20 years	40.4
20–30 years	43.5

Prevalence of iron overload in males in the age group 20–30 years was 41.8% (31 of 74 patients), and in females in the same age group was 45.6% (26 of 57 patients).

Prevalence of iron overload in males in the age group 10–20 was 38.7% (71 of 183 patients), and in females in the same age group was 43.2% (48 of 111 patients).

The patients in the age group 10–20 were further sub-grouped into 10–15 and 15- 20 years. The prevalence of iron overload in patients in the age group 10–15 years was 33.7% (50 of 148 patients) and in the age subgroup 15–20 years was 47.2% (69 of 146 patients).

Prevalence of iron overload in males in the age group 0–10 was 11.3% (12 of 106 patients), and in females in the same age group was 8.6% (6 of 69 patients). Only 4 (0.02%) of 175 patients, in the age group 0–10 years had moderate or severe myocardial iron overload. There was only 1 patient (0.005%) in the age group 0–10 years with severe myocardial iron overload.

There were 40 patients in the age group 0–6 years, of which only 2 had myocardial iron overload [one male and one female, and one had mild and another moderate iron overload].

Discussion

Myocardial MRI is an established technique for Fe overload in the heart. However, there are no clear-cut guidelines that help establish the minimum age at which scanning should be done and children as young as 2 years of age are currently being sent for scanning.

The prevalence of any Fe overload in the age group 0–10 years was just 10.2%, suggesting that routine scanning in this age group may not be necessary in a resource-constrained environment. Further stratification of the data also revealed that only two (5%) of the 40 patients less than or equal to 6 years had cardiac iron overload (Figs. 1, 2).

Fig. 1.

Bar chart shows age-wise incidence and severity of cardiac iron overload. In the age group 0–10, 90% of the patient have no cardiac Fe overload when they present for the first time for iron overload assessment

Fig. 2.

Scatter Diagram—Cardiac T2* value versus Age. The data shows a downhill pattern indicating a negative relationship between Cardiac T2* value and Age. As age increases the Cardiac T2* values tend to decrease i.e. the cardiac iron overload tends to increase

Multiple studies in past have also attempted to establish the age at which this parameter should be first measured in paediatric patients.

Wood et al. [18], in their study of 77 thalassemia major patients between the ages of 2.5 and 18 years found abnormal levels of cardiac iron to be present only in patients older than 9.5 years.

In yet another previous study by Wood et al. [19], directed towards assessment of age of onset of cardiac iron overload in patients with transfusion dependent thalassemia and sickle cell disease, cardiac iron loading occurred only after at least 13 years of chronic transfusion therapy, which means that the youngest patient would be at least 13 years of age. Their cohort included 19 patients with thalassemia major between 7 and 26 years of age of which 8 had iron overload.

The Italian Society of Haematology practice guidelines for the management of iron overload in thalassemia major and related disorders [20], also stated that both serum ferritin and liver iron concentrations need to be determined for planning iron chelation therapy in patients over 5 years of age and with an unknown previous transfusion history and/or inappropriate chelation therapy. There was no recommendation for cardiac MRI for iron overload assessment in this age group and no recommendation for iron overload assessment in general in patients below 5 years of age.

In a retrospective study on paediatric patients with thalassemia [15], the youngest patient with heart iron overload was 7.9-years-old. Their cohort consisted of 107 patients in the age group between 4.2 and 17.9 years. In another retrospective study on 35 thalassemia patients below 10 years of age, four patients had cardiac iron overload, of which the youngest was 6 years of age. No patient below the age of 6 years showed cardiac iron overload [13]. Another study on 23 chronically transfused patients aged 7–18 years also showed that cardiac iron was present only in four of the 23 patients, of which the youngest was 7.4 years of age [21]. Three patients were less than 10 years and the fourth was 17 years of age and they concluded that it was prudent to recommend MRI screening at 7 years of age if poor chelation is assumed.

The results of our study are thus in concordance with these studies on assessment of myocardial iron overload in paediatric thalassemia patients and reinforce that the prevalence of cardiac iron overload in patients less than or equal 6 years is very low.

At the same time, the overall percentage of prevalence of any Fe overload was 32.3% in our study. In the age group of 20–30, it was 43.5%, meaning that many patients are being scanned very late for the first time.

The prevalence of cardiac iron overload in the age group 6–10 years was 11.85% (16 of 135 patients), in the age group 10–15 years, it was 33.7% (50 of 148 patients) and in the age subgroup, 15–20 years, it was 47.2% (69 of 146 patients). There is a progressive and significant increase in the prevalence of cardiac iron overload between these age groups with a dramatic increase in cardiac iron overload seen in patients above 10 years of age who present for the first time for cardiac iron overload assessment.

Hence, MRI screening for cardiac iron overload should ideally be done between 6 and 10 or 10–15 or 6–15 years of age. Screening before or up to the age of 6 seems to be an unnecessary financial burden given the low prevalence of iron overload in that age group and delaying beyond 15 years of age may delay the initiation of the chelation therapy and lead to irreversible damage to the heart tissue.

Limitations

No attempt has been made to correlate with transfusion status and other clinical data. While these would make a difference in an individual patient sometimes, the aim was to see if the use of MRI data alone can give us an idea of the appropriate age-group thresholds for scanning.

Conclusion

Patients less than or equal to 6 years of age are unlikely to benefit from MRI evaluation of myocardial Fe. Scanning patients for the first time after the age of 15 years may risk delaying the diagnosis and management of patients with Fe overload. The appropriate time for the first scan should be beyond 6 years but not greater than 15 years of age', depending on the clinical situation.

Abbreviations

Fe

Iron

Authors' contributions:

KP: Analysis and interpretation of data, Review of articles, Drafting the article, Final approval of the version to be published, and Agree to be accountable for all aspects of the work if questions arise related to its accuracy or integrity. BJ: Conception and design, and acquisition of data. Revising it critically for important intellectual content, Final approval of the version to be published, and Agree to be accountable for all aspects of the work if questions arise related to its accuracy or integrity. AK: Acquisition of data. Drafting the article. Final approval of the version to be published, and Agree to be accountable for all aspects of the work if questions arise related to its accuracy or integrity.

Funding

None.

Availability of data and material

Data transparency.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.