Relationship between T2* magnetic resonance imaging-derived liver and heart iron content and serum ferritin levels in transfusion-dependent thalassemic children

T2* magnetic resonance imaging (MRI) is being increasingly used for the assessment of organ iron content in thalassemics, but cost is a major prohibitive factor for repeated measurements. If serum ferritin correlates well with the T2* MRI liver and heart, it will be economical and more simple tool to assess organ iron deposition.  The aim of this study was to find out the relationship between serum ferritin level and T2* MRI-derived liver and heart iron content in transfusion-dependent thalassemic children Settings: Thalassemia day-care center of a teaching hospital Design: This was a cross-sectional study Subjects  Seventy-three transfusion-dependent beta thalassemic children belonging to 2–18 years of age were subjected to T2* MRI of heart and liver to assess their iron content. Values obtained here were related to serum ferritin.  Keeping the correlation between serum ferritin and T2* MRI as primary outcome, spearman's correlation coefficient was calculated.  We found poor (negative) correlation between serum ferritin level and T2* MRI liver (r = -0.448, P = 0.000) but no correlation between serum ferritin and T2*MRI heart (r = -0.221, P = 0.060).  Serum ferritin cannot reliably predict the liver and heart iron content in Indian children with β thalassemia.

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title: Iron chelators for the treatment of iron overload disease: Relationship between structure, redox activity, and toxicity
abstract: The success of the iron (Fe) chelator desferrioxamine (DFO) in the treatment of β‐thalassemia is limited by its lack of bioavailability. The design and characterization of synthetic alternatives to DFO has attracted much scientific interest and has led to the discovery of orally active chelators that can remove pathological Fe deposits. However, chelators that access intracellular Fe pools can be toxic by either inhibiting Fe‐containing enzymes or promoting Fe‐mediated free radical damage. Interestingly, toxicity does not necessarily correlate with Fe‐binding affinity or with chelation efficacy, suggesting that other factors may promote the cytopathic effects of chelators. In this review, we discuss the interactions of chelators and their Fe complexes with biomolecules that can lead to toxicity and tissue damage.  2003.

title: Monitoring chelation therapy to achieve optimal outcome in the treatment of thalassaemia.
abstract: Effective management of iron overload in thalassaemia requires monitoring both for iron toxicity and the effects of excessive chelation. Careful monitoring together with adherence to established regimens using desferrioxamine (DFO) results in a 78% survival rate at 40 years of age at UCLH, with steadily improving survival as progressive cohorts receive chelation earlier in life. By contrast, survival is considerably below this in non-specialist centres. The prognostic significance of the measures being used in monitoring should be known so that decisions about chelation management are evidence-based. Serum ferritin measurement, although easy to perform frequently, is subject to variability and falsely high or falsely low values in relation to body iron are frequently obtained. However, there is evidence that persistently high ferritin values above 2500 microg/l have poor prognostic significance in patients treated with DFO. Liver iron predicts total body iron in a more predictable way than serum ferritin in thalassaemia. Liver iron concentrations of 15 mg/g dry weight appear to predict those patients who develop heart failure in subjects treated with DFO. The prognostic significance of this measurement or indeed other measurements of iron overload in patients treated with other chelation regimens is not known. Recent advances with MRI imaging have aroused interest in its use for monitoring patients with thalassaemia. A recent publication suggests a relationship between left ventricular ejection fraction and cardiac T2*, the value of which shortens with increasing iron concentrations in the liver and hence by inference in the heart. The prognostic value of this technique has not yet been demonstrated in prospective studies and hence changes in therapy based on this measurement alone should be considered with caution at this time. The value of monitoring to decrease morbidity from iron overload is also discussed, particularly with reference to the estimation of iron deposition in the pituitary.

title: Non-invasive assessment of hepatic iron stores by MRI
abstract: MRI has been proposed for non-invasive detection and quantification of liver iron content, but has not been validated as a reproducible and sensitive method, especially in patients with mild iron overload. We aimed to assess the accuracy of a simple, rapid, and easy to implement MRI procedure to detect and quantify hepatic iron stores.



Of 191 patients recruited, 17 were excluded and 174 studied, 139 in a study group and 35 in a validation group. All patients underwent both percutaneous liver biopsy with biochemical assessment of hepatic iron concentration (B-HIC) and MRI of the liver with various gradient-recalled-echo (GRE) sequences obtained with a 1.5 T magnet. Correlation between liver to muscle (L/M) signal intensity ratio and liver iron concentration was calculated. An algorithm to calculate magnetic resonance hepatic iron concentration (MR-HIC) was developed with data from the study group and then applied to the validation group.



A highly T2-weighted GRE sequence was most sensitive, with 89% sensitivity and 80% specificity in the validation group, with an L/M ratio below 0.88. This threshold allowed us to detect all clinically relevant liver iron overload greater than 60 micromol/g (normal value <36 micromol/g). With other sequences, an L/M ratio less than 1 was highly specific (>87%) for raised hepatic iron concentration. With respect to B-HIC range analysed (3-375 micromol/g), mean difference and 95% CI between B-HIC and MR-HIC were quite similar for study and validation groups (0.8 micromol/g [-6.3 to 7.9] and -2.1 micromol/g [-12.9 to 8.9], respectively).



MRI is a rapid, non-invasive, and cost effective technique that could limit use of liver biopsy to assess liver iron content. Our MR-HIC algorithm is designed to be used on various magnetic resonance machines.

title: T2* Magnetic Resonance and Myocardial Iron in Thalassemia
abstract: Magnetic resonance T2* values of the myocardium are directly related to tissue iron levels. Minor effects from myocardial oxygenation and fibrosis are overwhelmed by the highly dominant iron effect in clinically relevant levels of myocardial iron overload. Myocardial T2* values less than 20 ms indicate iron overload, and this is considered severe when T2* is less than 10 ms. Decreasing myocardial T2* levels are associated with systolic and diastolic ventricular dysfunction. Most recorded cases of heart failure in thalassemia to date have occurred in patients with very low T2* values (in the severe range). Exceptions to this have occurred in patients with other causes of heart failure such as concomitant congenital heart disease. In patients presenting with heart failure who undergo aggressive chelation with continuous intravenous deferoxamine, longitudinal studies show that myocardial T2* increases, and this is accompanied by increases in ejection fraction and relief of heart failure. In cross‐sectional studies, the myocardial T2* and ejection fraction of patients on deferiprone was superior to that of patients on deferoxamine. Randomized controlled prospective trials comparing these two drugs for their action in clearing myocardial iron, as measured by myocardial T2*, are under way and should report in 2005/2006. These trials will clarify the role of different chelators in the management of myocardial iron overload and may be valuable in reducing the toll of death in thalassemia from heart failure.

title: Non-invasive assessment of tissue iron overload.
abstract: In recent years, there has been increasing interest in non-invasive iron measurement, especially of the liver and heart, in patients with iron overload. Serum ferritin still remains an essential monitoring parameter in intervals between liver iron measurements; however, confounding factors such as inflammation, chelation treatment changes and the specific disease have to be taken into account. Liver iron measurements can now routinely be performed in clinical applications either by quantitative magnetic resonance imaging (MRI) using the transverse magnetic relaxation rate R(2) or R(2)* (1/T(2)*) or by biomagnetic liver susceptometry. For iron measurements in the heart, the single-breathhold multi-echo MRI-R(2)* method has become a standard modality and is now applied in clinical settings beyond research studies. In other tissues like the pancreas, pituitary, and brain, different MRI methods are employed, but their clinical benefit has yet to be proven.

title: MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients.
abstract: Measurements of hepatic iron concentration (HIC) are important predictors of transfusional iron burden and long-term outcome in patients with transfusion-dependent anemias. The goal of this work was to develop a readily available, noninvasive method for clinical HIC measurement. The relaxation rates R2 (1/T2) and R2* (1/T2*) measured by magnetic resonance imaging (MRI) have different advantages for HIC estimation. This article compares noninvasive iron estimates using both optimized R2 and R2* methods in 102 patients with iron overload and 13 controls. In the iron-overloaded group, 22 patients had concurrent liver biopsy. R2 and R2* correlated closely with HIC (r2 > or = .95) for HICs between 1.33 and 32.9 mg/g, but R2 had a curvilinear relationship to HIC. Of importance, the R2 calibration curve was similar to the curve generated by other researchers, despite significant differences in technique and instrumentation. Combined R2 and R2* measurements did not yield more accurate results than either alone. Both R2 and R2* can accurately measure hepatic iron concentration throughout the clinically relevant range of HIC with appropriate MRI acquisition techniques.

title: A comparison of magnetic resonance imaging and cardiac biopsy in the evaluation of heart iron overload in patients with β‐thalassemia major
abstract: To apply magnetic resonance imaging (MRI) for the assessment of myocardial iron deposition in patients with β‐thalassemia and compare the results with cardiac biopsy data.  Myocardial iron accumulation is the main cause for cardiac complications in β‐thalassemia.  Twenty‐five consecutive thalassemic patients were studied using a 0.5‐T (Tesla) system, ECG‐gated, with echo time (TE) = 17–68 ms. T2 relaxation time of the interventricular septum was calculated assuming simple monoexponential decay. A heart T2 relaxation time value of 32 ms was used for the discrimination between high and low iron deposition. Heart biopsy was performed within a week after the MRI study. Patients with stainable iron in more than 50% of the myofibrils were graded as having severe iron deposition. A serum ferritin level below 2000 ng/mL was considered as an indication of successful chelation.  Seven of the 25 patients had heart biopsy indicative of low iron deposition (Group L) and the remaining 18 patients had heart biopsy indicative of high iron deposition (Group H). T2 relaxation time of the heart (T2H) was lower in Group H compared to Group L (31.5 ± 3.9 (range: 28–40) ms vs. 35.7 ± 3.7 (range: 29–40) ms, P = 0.026). The T2H was in agreement with heart biopsy in 86% of the patients in Group L and in 78% of the patients in Group H (overall agreement 80%). Similarly, serum ferritin levels were in agreement with heart biopsy in 28% and 88%, respectively (overall agreement 72%). In Group L, MRI was in better agreement with biopsy compared to serum ferritin (86% vs. 28%, P < 0.05). A receiver operating characteristic curve (ROC) analysis confirmed that a T2 relaxation time of 32 ms had the highest discriminating ability for the corresponding biopsy outcome.  Heart T2 relaxation time appears in agreement with cardiac biopsy, both in high and low iron deposition, and may become a useful non‐invasive index in β‐thalassemia.

title: Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload.
abstract: To develop and validate a non-invasive method for measuring myocardial iron in order to allow diagnosis and treatment before overt cardiomyopathy and failure develops.



We have developed a new magnetic resonance T2-star (T2*) technique for the measurement of tissue iron, with validation to chemical estimation of iron in patients undergoing liver biopsy. To assess the clinical value of this technique, we subsequently correlated myocardial iron measured by this T2* technique with ventricular function in 106 patients with thalassaemia major. There was a significant, curvilinear, inverse correlation between iron concentration by biopsy and liver T2* (r=0.93, P<0.0001). Inter-study cardiac reproducibility was 5.0%. As myocardial iron increased, there was a progressive decline in ejection fraction (r=0.61, P<0.001). All patients with ventricular dysfunction had a myocardial T2* of <20 ms. There was no significant correlation between myocardial T2* and the conventional parameters of iron status, serum ferritin and liver iron. Multivariate analysis of clinical parameters to predict the requirement for cardiac medication identified myocardial T2* as the most significant variable (odds ratio 0.79, P<0.002).



Myocardial iron deposition can be reproducibly quantified using myocardial T2* and this is the most significant variable for predicting the need for ventricular dysfunction treatment. Myocardial iron content cannot be predicted from serum ferritin or liver iron, and conventional assessments of cardiac function can only detect those with advanced disease. Early intensification of iron chelation therapy, guided by this technique, should reduce mortality from this reversible cardiomyopathy.

title: Future challenges in the use of magnetic resonance imaging for the diagnosis of iron overload.
abstract: Dear Editor, 
 
the review by Mavrogeni on the evaluation of myocardial iron overload using magnetic resonance imaging (MRI) provides important information on recent developments in this area both with respect to diagnosis of cardiac iron overload and the effect of chelation therapy1. 
 
The evaluation of cardiac iron overload using the MRI T2* and T2 relaxation time measurements appears to be the only reliable method for the diagnosis of the iron-overloaded heart. Patients with excess cardiac iron load are thought to be in danger of congestive cardiac failure, which until recently was the main cause of mortality of patients with thalassaemia major1,2. No other invasive or non-invasive methods, including the superconducting quantum interference device (SQUID) or serum ferritin, can be used for determining excess cardiac iron deposition2,3. 
 
It is now clear from MRI T2* and T2 relaxation time estimates and recent studies that, in contrast to previously accepted theories, cardiac iron load is not related to serum ferritin levels or liver iron concentration and that the latter two parameters are unreliable for estimating excess cardiac iron concentration2,3. This explains why in the past many thalassaemia patients suffered congestive cardiac failure and some died despite having a low serum ferritin ( 80 mg/kg/day) as monotherapy or in combination with deferoxamine, excess iron in the heart can be removed and the incidence of iron-induced congestive cardiac failure diminished or abolished1–4. 
 
New physiological mechanisms of iron deposition and removal have been identified following the introduction of MRI T2* and T2 for the diagnosis of iron overload. For example, it was found that the organ distribution of excess iron load differs between the heart and the liver of iron-loaded thalassaemia patients. Furthermore, the distribution within each organ also differs and in some cases focal points of excess iron deposition could be identified in the heart or mosaic iron distribution in the liver1,3,5. The heterogeneity of iron distribution within each organ suggests that liver biopsies and other techniques monitoring sections of organs, may not provide accurate estimates of excess iron load and new diagnostic criteria may be needed for more accurate iron load estimations3. Moreover, the heterogeneity in the deposition of excess iron in various parts of the heart, liver and other organs may be relevant to the degree of iron toxicity and the level of malfunction of each of these organs. A determination of total excess iron load by using, for example, multislice, multiecho T2* techniques could minimise errors in the estimation of excess iron load deposition caused by heterogeneous iron distribution in the various organs1,3,5. In this context further studies are needed to clarify the physiological and pharmacological mechanisms involved in iron deposition, organ distribution and removal, as well as the toxicological mechanisms of iron overload affecting organ function4,5. 
 
Despite the fact that any form of excess iron is potentially toxic, it is now apparent that not all the patients with excess iron are in danger of congestive cardiac failure and that only those patients with deposits of iron of about T2* < 9 ms are likely to be at higher risk4. Ultrastructural pathology studies using electron microscopy of cardiac biopsy samples from patients with congestive heart failure indicated extensive iron deposition and damage in myocytes, including disruption of lysosomes, damage to other intracellular components and loss of myofibres4. This potential mechanism of iron overload toxicity in congestive heart failure could lead to death but may also be reversible, especially if effective dose protocols of deferiprone and deferiprone/deferoxamine combination therapies are used4. In the latter cases excess cardiac iron load would be cleared and the patient would become asymptomatic with no further need for anti-arrhythmic and other drugs previously used for the treatment of the cardiomyopathy4. 
 
Although the diagnosis of iron overload of the heart and other organs by MRI T2* is generally very reliable, further standardisation is required for the methodology, techniques and the equipment to be used worldwide3,5. In recent studies some variability between MRI T2* and T2 in cardiac iron load estimation has been identified, suggesting that, ideally, both techniques should be used for the most accurate estimation of iron overload3. It has also been suggested that the factors contributing to the differences in iron load estimation between MRI T2* and T2 include the ferritin and haemosiderin composition of the excess deposited iron, which lead to signal variation between the two methods1,3. In general, T2* relaxation time is preferred over T2 for estimating iron overload in the heart and other organs because of the former’s shorter monitoring time, ease of scanning on many scanners, lower cost and better validation of the results3. 
 
The high cost of the use of MRI T2* and T2 for monitoring excess iron load precludes its widespread application for the vast majority of thalassaemia and other transfusion iron-loaded patients, most of whom live in the developing countries. In developed countries, MRI for monitoring excess iron load is usually carried out once a year. The intervals of monitoring can be extended to 2 or 3 years for patients who have achieved and maintained normal range serum ferritin, as well as normal cardiac and liver MRI T2* and T2 relaxation times following the effective use of the deferiprone/deferoxamine combination or deferiprone monotherapy4. 
 
Future challenges in the use of MRI are the diagnosis and standardisation of iron overload in other organs such as the pancreas and pituitary gland, affecting the production of insulin and other hormones. Similarly, iron deposition in the knees, which may be related to the arthropathy observed in iron-loaded patients, and localised excess toxic iron in the brain, kidneys or other organs, which affects many other important physiological functions, may also be considered for future investigations. 
 
Overall, MRI T2* and T2 relaxation times could be used as a diagnostic method for monitoring excess iron load in the heart and other organs in regularly transfused and other iron-loaded patients3,5. These techniques could also be used for monitoring the ferrokinetic profile of iron deposition and iron removal during chelation therapy. This approach could help in the adjustment of dose protocols and the selection of appropriate chelation regimens for the optimisation of chelation therapy and the reduction of iron overload toxicity as well as the associated morbidity and mortality observed in thalassaemics and other transfused patients.

title: R2* magnetic resonance imaging of the liver in patients with iron overload.
abstract: R2* magnetic resonance imaging (R2*-MRI) can quantify hepatic iron content (HIC) by noninvasive means but is not fully investigated. Patients with iron overload completed 1.5T R2*-MRI examination and liver biopsy within 30 days. Forty-three patients (sickle cell anemia, n = 32; beta-thalassemia major, n = 6; and bone marrow failure, n = 5) were analyzed: median age, 14 years, median transfusion duration, 15 months, average (+/-SD) serum ferritin 2718 plus or minus 1994 ng/mL, and average HIC 10.9 plus or minus 6.8 mg Fe/g dry weight liver. Regions of interest were drawn and analyzed by 3 independent reviewers with excellent agreement of their measurements (intraclass correlation coefficient = 0.98). Ferritin and R2*-MRI were weakly but significantly associated (range of correlation coefficients among the 3 reviewers, 0.41-0.48; all P < .01). R2*-MRI was strongly associated with HIC for all 3 reviewers (correlation coefficients, 0.96-0.98; all P < .001). This high correlation confirms prior reports, calibrates R2*-MRI measurements, and suggests its clinical utility for predicting HIC using R2*-MRI.

title: On T2* Magnetic Resonance and Cardiac Iron
abstract: Measurement of myocardial iron is key to the clinical management of patients at risk of siderotic cardiomyopathy. The cardiovascular magnetic resonance relaxation parameter R2* (assessed clinically via its reciprocal, T2*) measured in the ventricular septum is used to assess cardiac iron, but iron calibration and distribution data in humans are limited.  Twelve human hearts were studied from transfusion-dependent patients after either death (heart failure, n=7; stroke, n=1) or transplantation for end-stage heart failure (n=4). After cardiovascular magnetic resonance R2* measurement, tissue iron concentration was measured in multiple samples of each heart with inductively coupled plasma atomic emission spectroscopy. Iron distribution throughout the heart showed no systematic variation between segments, but epicardial iron concentration was higher than in the endocardium. The mean±SD global myocardial iron causing severe heart failure in 10 patients was 5.98±2.42 mg/g dry weight (range, 3.19 to 9.50 mg/g), but in 1 outlier case of heart failure was 25.9 mg/g dry weight. ] was strongly linearly correlated with ln[Fe] (R2=0.910, P<0.001), leading to [Fe]=45.0×(T2*)−1.22 for the clinical calibration equation with [Fe] in milligrams per gram dry weight and T2* in milliseconds. Midventricular septal iron concentration and R2* were both highly representative of mean global myocardial iron.  These data detail the iron distribution throughout the heart in iron overload and provide calibration in humans for cardiovascular magnetic resonance R2* against myocardial iron concentration. The iron values are of considerable interest in terms of the level of cardiac iron associated with iron-related death and indicate that the heart is more sensitive to iron loading than the liver. The results also validate the current clinical practice of monitoring cardiac iron in vivo by cardiovascular magnetic resonance of the midseptum.

title: Relation between serum ferritin and liver and heart MRI T2* in beta thalassaemia major patients.
abstract: There is a need for higly accurate non-invasive methods for assessing organ iron content in thalassaemia patients. This study evaluated the relation between serum ferritin level, liver enzyme levels and hepatitis C antibody and liver and heart iron deposition assessed by MRI T2*. Data were obtained from the medical records of 156 thalassemia major patients in Tehran. There was a moderate negative correlation between serum ferritin and liver MRI T2* relaxation time (r = -0.535) and a weak negative correlation between serum ferritin and heart MRI T2* relaxation time (r = -0.361). Hepatitis C infection and liver enzyme levels did not confound or modify the relation between ferritin and liver or heart MRI T2*. Liver and heart MRI T2* readings were poorly correlated (r = 0.281). Routine evaluation of liver and heart iron content using MRI T2* is suggested to better evaluate the haemosiderosis status in thalassemia patients.

title: Association between serum ferritin level, cardiac and hepatic T2-star MRI in patients with major β-thalassemia
abstract: Frequent blood transfusion is often associated with iron overload. Proper use of iron chelators to treat iron overload requires an accurate measurement of iron levels. Magnetic resonance T2-star (T2* MRI) can measure iron level in the heart and liver. Our goal was to see whether an association exists between serum ferritin level and T2* MRI in patients with major beta thalassemia.  Sixty patients with a diagnosis of major beta thalassemia were enrolled in the study. They were older than five years old and needed regular transfusion. Cardiac and hepatic T2*MRI and mean serum ferritin levels were measured within 3 months.  No significant correlation was observed between serum ferritin level and cardiac T2*MRI (p=0.361, r=-0.120).However, a significant correlation was observed between serum ferritin and liver T2*MRI (p=0.021, r=-0.297).  Our results showed an association between hepatic T2*MRI and serum ferritin level.

title: Liver iron and serum ferritin levels are misleading for estimating cardiac, pancreatic, splenic and total body iron load in thalassemia patients: factors influencing the heterogenic distribution of excess storage iron in organs as identified by MRI T2*
abstract: A comparative assessment of excess storage iron distribution in the liver, heart, spleen and pancreas of β-thalassemia major (β-ΤΜ) patients has been carried out using magnetic resonance imaging (MRI) relaxation times T2*. The β-ΤΜ patients (8–40 years, 11 males, 9 females) had variable serum ferritin levels (394–5603 μg/L) and were treated with deferoxamine (n = 10), deferiprone (n = 5) and deferoxamine/deferiprone combination (n = 5). MRI T2* assessment revealed that excess iron is not proportionally distributed among the organs but is stored at different concentrations in each organ and the distribution is different for each β-ΤΜ patient. There is random variation in the distribution of excess storage iron from normal to severe levels in each organ among the β-ΤΜ patients by comparison to the same organs of ten normal volunteers. The correlation of serum ferritin with T2* was for spleen (r = –0.81), liver (r = −0.63), pancreas (r = −0.33) and none with heart. Similar trend was observed in the correlation of liver T2* with the T2* of spleen (r = 0.62), pancreas (r = 0.61) and none with heart. These studies contradict previous assumptions that serum ferritin and liver iron concentration is proportional to the total body iron stores in β-ΤΜ and especially cardiac iron load. The random variation in the concentration of iron in the organs of β-ΤΜ patients appears to be related to the chelation protocol, organ function, genetic, dietary, pharmacological and other factors. Monitoring of the iron load for all the organs is recommended for each β-ΤΜ patient.

title: T2* magnetic resonance imaging of the liver in thalassemic patients in Iran.
abstract: To investigate the accuracy of T2*-weighted magnetic resonance imaging (MRI T2*) in the evaluation of iron overload in beta-thalassemia major patients.



In this cross-sectional study, 210 patients with beta-thalassemia major having regular blood transfusions were consecutively enrolled. Serum ferritin levels were measured, and all patients underwent MRI T2* of the liver. Liver biopsy was performed in 53 patients at an interval of no longer than 3 mo after the MRI T2* in each patient. The amount of iron was assessed in both MRI T2* and liver biopsy specimens of each patient.



Patients' ages ranged from 8 to 54 years with a mean of 24.59 ± 8.5 years. Mean serum ferritin level was 1906 ± 1644 ng/mL. Liver biopsy showed a moderate negative correlation with liver MRI T2* (r = -0.573, P = 0.000) and a low positive correlation with ferritin level (r = 0.350, P = 0.001). Serum ferritin levels showed a moderate negative correlation with liver MRI T2* values (r = -0.586, P = 0.000).



Our study suggests that MRI T2* is a non-invasive, safe and reliable method for detecting iron load in patients with iron overload.

title: Myocardial iron overload assessed by magnetic resonance imaging (MRI)T2* in multi-transfused patients with thalassemia and acquired anemias.
abstract: Cardiac complications secondary to iron overload remain a significant matter in patients with transfusion dependent anemias.



To evaluate cardiac siderosis, Magnetic resonance imaging T2* (MRI T2*) was performed in 3 cohorts of transfusion dependent patients: 99 with thalassemia major (TM), 20 with thalassemia intermedia (TI), and 10 with acquired anemias (AA). Serum ferritin was measured and all patients underwent echocardiographic evaluation.



In TM patients cardiac T2* pathologic values (below 20 ms) were found in 37 patients. Serum ferritin was negatively associated with age (r=-0.32, p=0.001) and weakly with T2* values (r=-0.19, p=0.057). A positive correlation was found between T2* and LVEF (r=0.27, p=0.006). Out of 37 patients with T2*<20 ms, 18 (48%) had serum ferritin values<1000 ng/ml. In TI cohort, 3 patients had cardiac T2* pathologic values. In AA cohort, pathologic T2* values were found in 2 patients, who received 234 and 199 PRBC units, respectively, and were both on chelation therapy (in one patient ferritin value was 399 ng/ml). T2* values were negatively associated, but not significantly, with the number of PRBC transfused (r=-0.53, p=0.07).



In our experience, 37% of TM patients had a myocardial iron overload assessed by MRI T2*; this value is higher than in TI patients. Serum ferritin measurement was a poor predictor of myocardial siderosis. In patients with AA, more than 200 PRBC units transfused were required to induce cardiac hemosiderosis, in spite of chelation therapy and, in one patient, of normal ferritin values.

title: Serum Ferritin Levels Correlation With Heart and Liver MRI and LIC in Patients With Transfusion-Dependent Thalassemia
abstract: Iron-loaded cardiac complication is the essential cause of mortality in patients with thalassemia. Early detection and treatment of cardiac over-load can reduce mortality.  The current study aimed to evaluate the relationship between serum ferritin levels and T2* magnetic resonance imaging (MRI) of heart and liver and liver iron concentration (LIC) to diagnose iron over load in countries with limited access.  In the current cross-sectional study, 85 Iranian patients with thalassemia with the mean age of 22.7 ± 7 years were randomly selected. All patients were on regular blood transfusion. Echocardiography of heart and liver T2* MRI, determination of serum ferritin levels, and LIC were performed in all subjects at the same time. The correlation of serum ferritin levels with T2*MRI of heart and liver, and LIC was assessed. P value < 0.05 was considered statistically significant.  Abnormal myocardial iron load (T2* MRI < 20 ms) was detected in 58% of the patients and among whom, 36% had severe myocardial iron load (T2* MRI < 10 ms). Median and interquartile range of serum ferritin levels were 1434 and 2702 respectively in patients with thalassemia. Serum ferritin levels showed a statistically significant positive correlation with LIC (rs = 0.718, P < 0.001) and significant negative correlation with T2* Heart (rs = -0.329, P = 0.002), and T2* Liver (rs = -0.698, P < 0.001). However, Ejection fraction was not significantly correlated with serum ferritin levels in the patients (P = 0.399).  Serum ferritin levels can be used to diagnose iron over-load in patients with thalassemiaas an alternative method in areas where T2* MRI is not available.

title: Correlative Study of Iron Accumulation in Liver, Myocardium, and Pituitary Assessed With MRI in Young Thalassemic Patients
abstract: Clinical complications resulting from unevenly iron accumulation in individual organs of patients with β-thalassemia major can affect both expectancy and quality of life. Magnetic resonance imaging (MRI) offers a quantitative, noninvasive, accurate method for estimating iron levels in various tissues, not easily accessible with other techniques. The aim of this study was to evaluate and correlate the level of iron accumulation in different organs (anterior pituitary, myocardium, and liver) assessed with MRI, in children and young adults with β-thalassemia major. Thirty children and young adults (13 female and 17 male patients) with homozygous β-thalassemia, treated conventionally, were studied with hepatic, myocardial, and hypophyseal MRI. For liver and myocardium, we calculated the natural logarithm of the signal-to-air ratio in flash 2-dimensional sequences with electrocardiogram gating, whereas for anterior pituitary, the signal intensity was measured in sagittal T2 sequences. All scans were performed within 3 months. In 13 patients, data regarding liver iron concentrations (LIC) assessed by percutaneous liver biopsy were available. The mean of serum ferritin concentrations for 1 year before scans was calculated for each patient. MRI values in myocardium and liver showed a significant negative correlation to age (r=−0.73 and −0.69, respectively). For pituitary MRI, a linear regression with age was recorded in patients over 14 years of age (r=−0.67), whereas a relatively increased signal intensity reduction was recorded in pubertal subjects. Mean serum ferritin concentrations ranged from 252 to 5872 μg/L with an average of 1525±1047 μg/L. No statistical significant correlation was noted between mean ferritin levels versus liver, pituitary, and cardiac MRI values (r=−0.49, −0.28, and −0.1, respectively). Mean LIC values assessed by percutaneous biopsy were 13.76±11.6 mg/g of dry tissue. A statistically significant negative correlation was observed between liver MRI readings and LIC determined by biopsy (r=−0.89). None of the 3 organs studied with MRI were significantly correlated to each other. Pituitary to liver MRI values and liver to myocardial MRI values were moderately correlated (r=0.34 and 0.42, respectively). Pituitary MRI was not correlated at all to myocardial MRI (r=−0.001). In conclusion, iron accumulation in thalassemic patients is a procedure progressing with age, which seems to act independently in different organs. MRI represents a reliable, noninvasive method for assessing iron overload in various tissues, noneasily accessible with other techniques. Regular scanning, to recognize preclinically excessive iron deposits and intensified chelation therapy, can prevent serious and fatal complications.