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Serum Ferritin Levels Correlation With Heart and Liver MRI and LIC in Patients With Transfusion-Dependent Thalassemia

AUTHORS

Zahra Majd 1 , Sezaneh Haghpanah 2 , Gholam Hossein Ajami 3 , Sara Matin 1 , Hamid Namazi 4 , Marzieh Bardestani 5 , Mehran Karimi 2 , *

1 Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, IR Iran

2 Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran

3 Department of Pediatrics, Division of Pediatric Cardiology, Shiraz University of Medical Sciences, Shiraz, IR Iran

4 Department of Orthopaedic Surgery, Shiraz University of Medical Sciences, Shiraz, IR Iran

5 Department of Library and Information Science, College of Humanities, Khouzestan Sciences and Research Branch, Islamic Azad University, Ahvaz, IR Iran

How to Cite: Majd Z, Haghpanah S, Ajami G H, Matin S, Namazi H, et al. Serum Ferritin Levels Correlation With Heart and Liver MRI and LIC in Patients With Transfusion-Dependent Thalassemia, Iran Red Crescent Med J. 2015 ; 17(4):e24959. doi: 10.5812/ircmj.17(4)2015.24959.

ARTICLE INFORMATION

Iranian Red Crescent Medical Journal: 17 (4); e24959
Published Online: April 25, 2015
Article Type: Research Article
Received: October 28, 2014
Revised: February 19, 2015
Accepted: March 20, 2015
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Abstract

Background: 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.

Objectives: 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.

Patients and Methods: 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.

Results: 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).

Conclusions: 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.

Keywords

Beta-thalassemia Ferritin Magnetic Resonance Imaging Liver Heart

Copyright © 2015, Iranian Red Crescent Medical Journal. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

1. Background

Thalassemia, which is an inherited disorder, is associated with anemia caused by impaired synthesis of globin chain and has a range of complications such as extra medullary hematopoiesis, cardiac failure, arrhythmia, leg ulcer and gall stones (1-3). Cardiac failure, secondary to iron over-load, remains the essential cause of mortality in these patients (4, 5). Early diagnosis and precise measurement of myocardial iron deposition would allow better treatment and reduction of cardiac mortality. The principal methods of iron loading measurement are assessment of Liver Iron Concentration (LIC) and serum ferritin (6, 7). Also, non-invasing modalities are increasingly used as an alternative to biopsy and ferritin level assessment, although T2* Magnetic Resonance Imaging (MRI) is currently the gold standard approach (8, 9). However, T2* MRI is expensive, not widely available, and its interpretation needs an expert radiologist. The current study aimed to investigate the correlation of serum ferritin levels with LIC, T2* MRI of heart and liver inpatients with thalassemia.

2. Objectives

The current study aimed to detect whether the serum ferritin levels could be considered a reliable alternative test or not, also to evaluate cardiac function by echocardiography and investigate the association of systolic ejection fraction with iron over-load.

3. Patients and Methods

In the current cross sectional study, 90 patients with Thalassemia Major (TM) and Thalassemia Intermedia (TI) participated from January 2013 to January 2014 in Shiraz, Iran. All patients attended the thalassemia clinic located at the referral state hospital, the only referral hospital with 45 beds for such patients, in Southern Iran. Subject selection was based on systematic random sampling method from a sampling frame (about 720 patients with thalassemia) available at this center. List of the patients was reviewed and medical details including the drug and transfusion histories were obtained. Also, patients or their parents signed consent letters. The study was approved in the Medical Ethics Committee of Shiraz University of Medical Sciences (approval code: 3663 date: 92/9/3). The diagnosis of TM and TI in patients was based on complete blood count and hemoglobin electrophoresis tests, and clinical history evaluated by an expert hematologist. Inclusion criteria were patients with TM when the age of the first blood transfusion was less than two years old, and in patients with TI it was above two years old. All patients have been on regular blood transfusion. Patients with any infections, fever, or positive history of viral hepatitis during checking serum ferritin levels as well as overt heart and liver failure were excluded from the study. Finally five patients were excluded. Blood samples were obtained to assess fasting serum ferritin levels (electrofluorescentassay method, mini VIDAS machine, France) at the beginning of the study by calibrated equipments. All of the patients were assessed by T2* MRI of liver and heart (Zimmence, Germany, Avanta, 1.5 Tesla), echocardiography (GE VIVID 3, U.S.A, probe 3 MHz), and serum ferritin at the beginning of the research. Conventional echocardiography including the measurement of Ejection Fraction (EF) was done for each patient by an expert cardiologist. All radiographic findings were evaluated by one expert radiologist. According to the type of chelator therapy, patients were categorized into five groups: Group1, used only deferroxamine (Desferal, Novartis) 50 mg/kg/day; group 2 used combination therapy with deferiprone 75 mg/kg/day and deferoxamine 50 mg/kg/day, two days a week; group 3, used only deferasirox 20 - 40 mg/kg/day; group 4 used combination of deferasirox and deferroxamine, and group 5 did not receive any treatment. The duration of iron chelation therapy was at least six months before the study. Myocardial and hepaticiron loading and LIC were classified as normal, mild, moderate, and severe according to T2* MRI of heart and liver (Table 1).

3.1. Statistical Analysis

Data were analyzed by SPSS v. 17. Test of normality was done by Shapiro-Wilk test. Due to small sample size in subgroups exact methods were used (bootstrap and Monte Carlo) to report P values and confidence interval. Serum ferritin levels did not show normal distribution. Descriptive data were presented as mean, standard deviation, median, inter quartile range (IQR), and boxplots. Student t-test or Mann-Whitney test were used to compare quantitative variables between two groups, and Kruskal-Wallis test was used for the comparison among three or more groups of patients. Qualitative variables were compared by Chi-square test. Spearman correlation test was done to find the correlation between serum ferritin levels and values of T2* MRI and LIC. All tests considered two-sided and P values < 0.05 were considered statistically significant. Sample size calculation: Considering α = 0.05, power = 90% and correlation between serum ferritin levels and T2* MRI of liver: r = -0.44 (10), 49 patients with thalassemia were acceptable. Finally, 90 patients were enrolled for more accuracy, and five patients were excluded from the study.

4. Results

Patients with thalassemia consisted of 63, and 22 patients with TM, and TI respectively. The demographic and clinical features of patients with thalassemia are presented in Table 2. There are no statistically significant differences between the two groups of patients with thalassemia regarding gender, age, Body Mass Index (BMI) or serum ferritin levels (P > 0.05). Serum ferritin levels showed a statistically significant positive correlation with LIC (rs = 0.718, P < 0.001), and statistically significant negative correlation with T2* Heart (rs = -0.329, P = 0.002), and T2 Liver (rs = -0.698, P < 0.001), in patients with thalassemia (Table 3). However, Ejection fraction was not significantly correlated with serum ferritin levels in the patients (P = 0.399). Also, comparison results of serum ferritin levels among the four groups of patients with thalassemia based on T2 MRI heart and liver, and LIC are presented in Table 4 and Figures 1-3. Median serum ferritin levels were significantly associated with the values of T2* heart (P = 0.004) and T2 liver (P < 0.001), and LIC (P < 0.001). Abnormal myocardial iron load (T2* MRI < 20 ms) was detected in 58% of the patients among whom 36% had severe myocardial iron load (T2* MRI < 10 ms).

Table 1. Classification of Hepatic and Cardiac iron Loading and Liver Iron Concentration a
GroupCardiac T2* MRIHepatic T2* MRILIC
1, Normal> 20> 6.3< 2
2, Mild14 - 202.8 - 6.32 - 5
3, Moderate10 ≤ 141.4 - 2.75 - 10
4, Severe< 10< 1.4< 10

aAbbreviations: LIC, Liver Iron Concentration.

Table 2. Comparison of Demographic and Paraclinical Data Between the Two Groups of Patients With Thalassemia a
GroupAge, Mean ± SDBootstrap 95% CIBMI, Mean ± SDBootstrap 95% CIFerritin, Median, IQRBootstrap 95% CIMale/Female
Thalassemia major (n = 63)22.79 ± 7.121.06-24.6521.15 ± 3.520.32-21.991700, 34281312-297030/33
Thalassemia intermedia (n = 22)22.77 ± 6.220.24-25.1721.13 ± 3.219.7-22.41094, 1119935-143411/11
Bootstrap P value0.9940.9740.085> 0.9999

aAbbreviations: IQR, Interquartile Range; CI, Confidence Interval.

Table 3. Correlation of Serum Ferritin Level With T2* MRI, liver Iron Concentration and Ejection Fraction in Patients With Thalassemia a
VariablesValues Boot strap P Value
T2* MRI Heart0.002 b
Correlation coefficient-0.329
Bootstrap 95% CI-0.532 - 0.122
T2* MRI Liver
Correlation coefficient-0.698< 0.001 b
Bootstrap 95% CI-0.804 - 0.545
LIC< 0.001 b
Correlation coefficient+ 0.718
Bootstrap 95% CI0.58 - 0.817
EF0.399
Correlation coefficient+0.093
Bootstrap 95% CI-0.116 - 0.294

aAbbreviations: LIC, liver iron concentration; EF, ejection fraction.

bStatistically significant.

Table 4. Comparison of Median of Serum Ferritin Levels Among Different Groups of Thalassemia Patients Based on T2 Heart, T2 Liver, and LICa
Serum Ferritin Median, IQRSerum Ferritin Bootstrapped 95% CI for MedianMonte Carlo Significant
T2 heart0.004b
> 20 (n = 35)1207, 1049809 - 1434
14-20 (n = 14)2995,42571403 - 5013
10 ≤ 14 (n = 18)1425,3014933 - 3232
< 10 (n = 18)4245,48461198 - 5520
T2 liver
> 6.3 (n = 35)1020, 743699 - 1259
2.8 - 6.3 (n = 15)1168, 1541819 - 2319< 0.001b
1.4 - 2.7 (n = 30)3345, 32672086 - 4304
< 1.4 (n = 5)5724, 42515072 - 12491
LIC< 0.001b
< 2 (n = 35)976, 743697 - 1257
2 ≤ 5 (n = 16)1225, 1501935 - 2319
5-10 (n = 29)3397, 32122377 - 4304
> 10 (n = 5)5724, 42515072 - 12491

aAbbreviations: LIC, liver iron concentration; IQR, inter quartile range.

bStatistically significant.

Comparison of Serum Ferritin Levels Among the Four Groups of Patients With Thalassemia Regarding T2* MRI of Heart
Figure 1. Comparison of Serum Ferritin Levels Among the Four Groups of Patients With Thalassemia Regarding T2* MRI of Heart
Comparison of Serum Ferritin Levels Among the Four Groups of Patients With Thalassemia Regarding T2* MRI of Liver
Figure 2. Comparison of Serum Ferritin Levels Among the Four Groups of Patients With Thalassemia Regarding T2* MRI of Liver
Comparison of Serum Ferritin Levels Among the Four Groups of Patients With Thalassemia Regarding LIC
Figure 3. Comparison of Serum Ferritin Levels Among the Four Groups of Patients With Thalassemia Regarding LIC

5. Discussion

Cardiac problems such as heart failure and arrhythmias are the main cause of mortality in patients with thalassemia. Although, cardiac complications in patients with thalassemia are multifactorial, they are mainly related to iron loading toxicity (11, 12). The current study focused on whether the serum ferritin levels could be considered as a parameter to detect cardiac and liver iron loading in patients with thalassemia or not. On the other hand, there was a direct relationship between serum ferritin levels and T2* MRI of heart and liver. The obtained results showed strong correlation between T2* MRI of heart relaxation times and serum ferritin indicating that serum ferritin can estimate the cardiac iron loading. Other studies found different correlation strengths, ranging from no correlation to moderate correlation (13, 14). Also, a significant correlation between T2* MRI of liver and serum ferritin levels was observed in the current study. This is in line with the findings of the study by Zamani et al. who reported that serum ferritin is a good parameter to detect hepatic iron loading (15). In the literature, several studies showed significant relationship between serum ferritin and LIC. The findings of the current study were in accordance with these studies (16, 17). The current study did not find any statistically significant relationship between the ejection fraction and serum ferritin levels to predict the complications of iron loading. Butsome reports such as those of Montazare et al. and Bosi et al. demonstrated significant correlation between serum ferritin and left ventricular EF (18, 19). The current study was limited due to small sample size in subgroups of patients resolved by performing exact methods of statistical analysis. However, the strong point of the current study was that it found that serum ferritin levels can be used as an alternative method of T2* MRI in the areas where T2* MRI is not available. The serum ferritin levels had a significant relationship with liver and heart iron burden. Therefore, it can be used to evaluate iron over-load in areas where access to T2* MRI is limited.

Acknowledgements

References

  • 1.

    Taher A, Isma'eel H, Cappellini MD. Thalassemia intermedia: revisited. Blood Cells Mol Dis. 2006; 37(1) : 12 -20 [DOI][PubMed]

  • 2.

    Cappellini MD, Robbiolo L, Bottasso BM, Coppola R, Fiorelli G, Mannucci AP. Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia. Br J Haematol. 2000; 111(2) : 467 -73 [DOI]

  • 3.

    Atichartakarn V, Likittanasombat K, Chuncharunee S, Chandanamattha P, Worapongpaiboon S, Angchaisuksiri P, et al. Pulmonary arterial hypertension in previously splenectomized patients with beta-thalassemic disorders. Int J Hematol. 2003; 78(2) : 139 -45 [PubMed]

  • 4.

    Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR, et al. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood. 2006; 107(9) : 3733 -7 [DOI][PubMed]

  • 5.

    Wood JC, Enriquez C, Ghugre N, Otto-Duessel M, Aguilar M, Nelson MD, et al. Physiology and pathophysiology of iron cardiomyopathy in thalassemia. Ann N Y Acad Sci. 2005; 1054 : 386 -95 [DOI][PubMed]

  • 6.

    Ludwig J, Batts KP, Moyer TP, Baldus WP, Fairbanks VF. Liver biopsy diagnosis of homozygous hemochromatosis: a diagnostic algorithm. Mayo Clin Proc. 1993; 68(3) : 263 -7 [PubMed]

  • 7.

    Fischer R, Harmatz PR. Non-invasive assessment of tissue iron overload. Hematology Am Soc Hematol Educ Program. 2009; : 215 -21 [DOI][PubMed]

  • 8.

    Wood JC, Enriquez C, Ghugre N, Tyzka JM, Carson S, Nelson MD, et al. MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood. 2005; 106(4) : 1460 -5 [DOI][PubMed]

  • 9.

    Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001; 22(23) : 2171 -9 [DOI]

  • 10.

    Leung AW, Chu WC, Lam WW, Lee V, Li CK. Magnetic resonance imaging assessment of cardiac and liver iron load in transfusion dependent patients. Pediatr Blood Cancer. 2009; 53(6) : 1054 -9 [DOI][PubMed]

  • 11.

    Marsella M, Borgna-Pignatti C, Meloni A, Caldarelli V, Dell'Amico MC, Spasiano A, et al. Cardiac iron and cardiac disease in males and females with transfusion-dependent thalassemia major: a T2* magnetic resonance imaging study. Haematologica. 2011; 96(4) : 515 -20 [DOI][PubMed]

  • 12.

    Koonrungsesomboon N, Chattipakorn SC, Fucharoen S, Chattipakorn N. Early detection of cardiac involvement in thalassemia: From bench to bedside perspective. World J Cardiol. 2013; 5(8) : 270 -9 [DOI][PubMed]

  • 13.

    Kirk P, Roughton M, Porter JB, Walker JM, Tanner MA, Patel J, et al. Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major. Circulation. 2009; 120(20) : 1961 -8 [DOI][PubMed]

  • 14.

    Azarkeivan A, Hashemieh M, Akhlaghpoor S, Shirkavand A, Yaseri M, Sheibani K. Relation between serum ferritin and liver and heart MRI T2* in beta thalassaemia major patients. East Mediterr Health J. 2013; 19(8) : 727 -32 [PubMed]

  • 15.

    Zamani F, Razmjou S, Akhlaghpoor S, Eslami SM, Azarkeivan A, Amiri A. T2* magnetic resonance imaging of the liver in thalassemic patients in Iran. China Natl J New Gastroenterol. 2011; 17(4) : 522 -5 [DOI]

  • 16.

    Taher A, El Rassi F, Isma'eel H, Koussa S, Inati A, Cappellini MD. Correlation of liver iron concentration determined by R2 magnetic resonance imaging with serum ferritin in patients with thalassemia intermedia. Haematologica. 2008; 93(10) : 1584 -6 [DOI][PubMed]

  • 17.

    Pakbaz Z, Fischer R, Fung E, Nielsen P, Harmatz P, Vichinsky E. Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients. Pediatr Blood Cancer. 2007; 49(3) : 329 -32 [DOI][PubMed]

  • 18.

    Montazare Lotfe Elahi S, Hashemi AS, Behjati SM, Zaolfaghari F, Dehghani A. The relation between left ventricular function and serum ferritin in major β-thalassemia. Iran J Pediatr Hematol Oncol. 2011; 1(3) : 94 -7

  • 19.

    Bosi G, Crepaz R, Gamberini MR, Fortini M, Scarcia S, Bonsante E, et al. Left ventricular remodelling, and systolic and diastolic function in young adults with beta thalassaemia major: a Doppler echocardiographic assessment and correlation with haematological data. Heart. 2003; 89(7) : 762 -6 [PubMed]

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