|Year : 2016 | Volume
| Issue : 2 | Page : 45-49
Ischemia modified albumin in children with transfusion-dependent β-thalassemia: a new marker for an old problem
Suzan M Omar Mousa MD 1, Mohamed F Afifi1, Ahmed A Saedii2, Alaa A El-Setohy1
1 Department of Pediatrics, Faculty of Medicine, Minia University, Minia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Minia University, Minia, Egypt
|Date of Submission||01-Sep-2015|
|Date of Acceptance||13-Sep-2015|
|Date of Web Publication||15-Jul-2016|
Suzan M Omar Mousa
Department of Pediatrics, Faculty of Medicine, Minia University, Minia, 61111
Source of Support: None, Conflict of Interest: None
Background Thalassemia is associated with the generation of labile iron in the red blood cells, which promotes the formation of reactive oxygen species, leading to cumulative cell damage. Ischemia modified albumin (IMA) is now suggested to reflect generalized oxidative stress.
Objectives The aim of this study was to evaluate IMA in children with transfusion-dependent (TD) β-thalassemia and its relation with serum ferritin and iron chelation therapies.
Patients and methods A total of 60 children with TD thalassemia were divided into three groups on the basis of the type of iron chelation therapy received: group A received oral deferiprone (DFP), group B received effervescent deferasirox (DFX), and group C did not receive any type of iron chelation therapy. A total of 20 age-matched and sex-matched healthy children were included as controls. Serum ferritin and IMA were determined for all participants.
Results There were significant increases in serum ferritin and IMA levels in thalassemic children than in controls (P < 0.001 for each). Children on DFP and DFX had significantly lower IMA levels compared with children not receiving any iron chelation therapy (P < 0.001 and 0.01, respectively). Serum ferritin had a positive significant association with IMA (r = +0.27 and P = 0.03).
Conclusion IMA was higher in children with TD thalassemia than in controls. Moreover, its level in thalassemic children on either DFP or DFX was significantly lower than its level in children not receiving any chelation therapy. Therefore, IMA may be a possible marker of iron-induced oxidative stress in β-thalassemia.
Keywords: ischemia modified albumin, oxidative stress, transfusion-dependent thalassemia
|How to cite this article:|
Omar Mousa SM, Afifi MF, Saedii AA, El-Setohy AA. Ischemia modified albumin in children with transfusion-dependent β-thalassemia: a new marker for an old problem. Egypt J Haematol 2016;41:45-9
|How to cite this URL:|
Omar Mousa SM, Afifi MF, Saedii AA, El-Setohy AA. Ischemia modified albumin in children with transfusion-dependent β-thalassemia: a new marker for an old problem. Egypt J Haematol [serial online] 2016 [cited 2020 Feb 22];41:45-9. Available from: http://www.ehj.eg.net/text.asp?2016/41/2/45/186397
| Introduction|| |
Secondary iron overload in transfusion-dependent (TD) β-thalassemia patients is commonly caused by increased dietary iron absorption and repeated blood transfusions . This leads to the generation of labile iron at the inner and outer cell surfaces of the red blood cell. Consequently, the excessive active iron catalyzes the production of a variety of reactive oxygen species (ROS), leading to cumulative cell damage  and inflammatory changes .
Many studies have reported increased blood levels of the redox active fractions of non-transferrin-bound iron and labile plasma iron in patients with β-thalassemia . It has also been demonstrated that such patients experience decreased antioxidant capacity and increased products of peroxidative damage .
Therefore, effective iron chelators are required to remove the toxic irons to prevent oxidative damage in the vital organs, particularly the heart and liver. Chelators can act upon different iron pools, including transferrin-bound iron, non-transferrin-bound iron and labile plasma iron in plasma compartment, and labile plasma iron in cytoplasm to form iron-chelate (s), which will then be excreted in the urine and feces .
Ischemia modified albumin (IMA) is currently used as an early marker for myocardial ischemia and acute coronary syndrome . However, IMA is not a signal protein and not generated in proinflammatory state alone. Recently, it was found that it is an end product of oxidative stress . Accordingly, it has been suggested that elevated levels of IMA may reflect a generalized rather than organ or tissue-specific state of oxidative stress .
This study aimed to evaluate IMA in TD β-thalassemic children and its relation with different iron chelators.
| Patients and methods|| |
The present study was carried out on 60 children with TD β-thalassemia major, recruited from the Hematology Clinic, Department of Pediatrics, Children's University Hospital, Minia University. A total of 20 age-matched and sex-matched healthy children were included as controls. The control group was selected from the outpatient clinic in the same hospital. None had any history of blood transfusion, anemia, or liver disease.
There were 38 male and 22 female patients; their ages ranged from 5 to 16 years. They were divided into three groups:
- Group A included 20 β-thalassemic children on oral DFP chelation therapy (at a dose of 75 mg/kg/day for at least 6 months).
- Group B included 20 β-thalassemic children on effervescent deferasirox (DFX) chelation therapy (at a dose of 20 mg/kg/day for at least 6 months).
- Group C included 20 β-thalassemic children not receiving any iron chelation therapy.
A total of 20 age-matched and sex-matched healthy children were included as controls.
Written informed consent was obtained from the legal guardians of the participants, and approval was obtained from the ethical committee in Minia University Medical School.
Thalassemic children with heart diseases (even associated congenital anomalies), obesity, hepatitis, chronic kidney disease or elevated renal function, or diabetes mellitus were excluded.
All children included in our study were subjected to the following:
- Thorough history taking and clinical examination, with emphasis on the type and duration of chelation therapy in the patients (age of onset, type, and compliance to it).
- Both twelve-lead ECG and Echocardiography were done to exclude cardiac disease.
Echocardiography (stressing on normal left ventricular function and ejection fraction) was performed.
A volume of 5 ml of venous blood was drawn from each child, from both patients (before their regular blood transfusion) and controls, under complete aseptic conditions and divided into two tubes. The first tube contained EDTA for evaluating Hb% level (0.5 ml) using an automated cell counter, sysmex NE (TAO, Medical Incorporation, Ono, Japan), and the second tube (4-5 ml) was left in the incubator for 30 min, centrifugated at 3000 rpm for 10 min and then the separated serum was collected and divided into two Eppendorf. The contents of the first Eppendorf were used for routine laboratory investigations of liver function test [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, and albumin (Konelab 20i; Finland)] and renal function test [serum urea and creatinine (Konelab 20i)], and the second Eppendorf was stored at −20°C for serum ferritin assay using enzyme-linked immunosorbent assay (Accubind; Lake Forest, CA 92630, USA) and serum IMA assay using enzyme-linked immunosorbent assay (ElAab; China).
The collected data were coded, tabulated, and statistically analyzed using SPSS program for Windows (Statistical Package for Social Sciences, Developer Armonk, NY: IBM Corp.) software, version 20. Descriptive statistics for numerical data were analyzed using mean ± SD, and using number and percentage for categorical data. Analyses were carried out for quantitative variables using the Student t-test for normally distributed data between the two groups and Mann-Whitney U-test for not normally distributed data between the two groups. The analysis of variance test was used for analyzing normally distributed quantitative data between three groups, the post-hoc test for analyzing normally distributed quantitative data between two groups, the Kruskal-Wallis test was used for analyzing not normally distributed data between three groups, and the Mann-Whitney U-test for analyzing not normally distributed data between two groups. The χ2 -test was used for qualitative data analysis between groups. Pearson's correlation coefficient was used to estimate the correlation between each two variables. Receiver operating characteristic curve analysis was performed for estimation of area under the curve, sensitivity, specificity, positive predictive value, and negative predictive value. The significance was considered when P value was less than 0.05.
| Results|| |
[Table 1] shows the general demographic and laboratory data of patients and controls. Weight, height, BMI, and Hb% were significantly lower in patients than in controls (P < 0.001 for each). Moreover, there was a significant increase in AST, ALT, serum ferritin, and IMA levels in children with β-thalassemia than in controls (P < 0.001) ([Table 1] and [Figure 1]).
|Figure 1 Serum ischemia modified albumin (IMA) levels in children with thalassemia and controls|
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|Table 1 Comparison of demographic and laboratory data between children with thalassemia and controls |
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[Table 2] shows that children receiving chelation therapy with either DFP or DFX (groups A and B) had significantly lower serum ferritin levels compared with children not receiving iron chelation therapy (group C) (P < 0.001 for each). Moreover, children in (groups A and B) had significantly lower IMA levels compared with children in group C (P < 0.001 and 0.01, respectively).
|Table 2 Difference in serum ferritin and ischemia modified albumin levels in children with thalassemia based on the type of chelation therapy received |
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[Figure 2] shows that serum ferritin had a positive significant association with IMA (r = +0.27 and P = 0.03) ([Table 3]). When serum ferritin is equal to 2500 ng/ml, IMA has a cutoff value greater than 107 ng/ml, with a sensitivity of 68.9%, a specificity of 48.3%, a negative predictive value of 62.5%, and a positive predictive value of 55.6%.
|Figure 2 Correlation between serum ferritin and ischemia modified albumin (IMA) levels in children with thalassemia|
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|Table 3 Validity tests of ischemia modified albumin at serum ferritin = 2500 in thalassemic children |
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| Discussion|| |
In our study, there was a significant decrease in weight, height, BMI, and Hb% level in thalassemic children compared with controls (P < 0.001 for each). Moreover, a significant increase in AST, ALT, and serum ferritin levels were noticed in thalassemic children compared with controls (P < 0.001). The rise in hepatic aminotransferases in the absence of hepatitis was found in the study by Soliman et al.  as well, who reported that impairment of liver function to a certain extent can occur in hepatitis-negative thalassemic patients with iron overload and was attributed to the fact that hepatic iron overload impairs hepatic functions in these patients. In contrast, the thalassemic children showed no significant difference in serum urea (P = 0.9), serum creatinine (P = 0.4), serum albumin (P = 0.8), and total protein (TP) (P = 0.8) compared with the control group, as we excluded all thalassemic children with renal affection .
IMA was significantly increased in our thalassemic children compared with the control group (P < 0.001). In agreement with our results, Awadallah and colleagues reported that serum levels of IMA were significantly higher in thalassemic patients than in controls. They attributed their finding to the increased level of IMA in thalassemic patients that are likely to be a result of iron-induced oxidative stress and hence its potential significance as a new marker of oxidative stress in such patients . In addition, Sbarouni et al.  postulated that overproduction of ROS resulting from conditions related to ischemia, hypoxia, acidosis, free radicals, and free iron plays a major role in the formation of IMA. Generation of ROS can transiently modify the N-terminal region of albumin and produce an increase in IMA levels .
As the blood samples in our thalassemic children were pretransfusional, anemia may contribute to the rise in IMA as it causes mild hypoxia due to low hemoglobin levels, altering the metal-albumin binding. Besides, the reduction in hemoglobin levels could change the tissue oxygen delivery, resulting in hemoglobin-induced variations in arterial O 2 content ,. However, Cichota et al.  (2008) found that lactate, which is an insensitive marker of ischemia, was more sensitive to anemia compared with IMA.
We found that thalassemic children on DFP iron chelation therapy had a significant decrease in IMA levels compared with thalassemic children not on chelation therapy (P < 0.001). Similar to our results, Akrawinthawong et al.  (2011) stated that DFP therapy alone improved iron overload and oxidative stress. This can be attributed to the fact that DFP chelates the excess of iron, reducing the circulating and intracellular free iron that lead to decreased formation of ROS . We found that IMA levels were significantly decreased in thalassemic children receiving DFX chelation therapy compared with thalassemic children not receiving any chelation therapy (P = 0.01). Abdul-Razzak et al.  (2013) stated that oxidative stress in β-thalassemic patients resulted from iron overload can be effectively controlled with DFX chelation therapy. Ghoti et al.  (2010) also confirmed that DFX chelation can act as an antioxidant by decreasing intracellular and extracellular toxic iron species and reducing oxidative stress.
In our study, we noticed a significant positive association between serum ferritin and IMA levels (r = +0.27 and P = 0.03). This is in accordance with the study by Awadallah et al.  (2012), who reported a significant correlation between serum ferritin and IMA in their thalassemic patients. When iron overload exceeds the storage capacity of the cell, free iron start to deposit in the organs  and that in turn leads to overproduction of ROS that plays a major role in the formation of IMA .
As regards the validity tests of IMA, at serum ferritin equal to 2500 ng/ml in thalassemic children, which is the serum ferritin threshold at which iron overload-induced complications duplicate ,, IMA had a cutoff value greater than 107 ng/ml, with a sensitivity of 68.9%, a specificity of 48.3%, a negative predictive value of 62.5%, and a positive predictive value of 55.6%.
| Conclusion|| |
IMA is a new marker of oxidative stress to which thalassemic children are exposed to due to free iron radical production. IMA levels in thalassemic children on either DFP or DFX were significantly lower than its level in children not receiving any chelation therapy, reflecting the rationale to support iron chelation therapy for the elimination of the free-iron species. Further studies are needed on the effect of anemia on IMA.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Hershko C. Iron loading and its clinical implications. Am J Hematol
Rachmilewitz E, Weizer-Stern O, Adamsky K, Amariglio N, Rechavi G, Breda L, et al.
Role of iron in inducing oxidative stress in thalassemia. Can it be prevented by inhibition of absorption and by antioxidants? Ann NY Acad Sci
Scott M, van den Berg J, Repka T. Effect of excess alpha-hemoglobin chains on cellular and membrane oxidation in model beta-thalassemic erythrocytes. J Clin Invest
Cabantchik Z, Breuer W, Zanninelli G, Cianciulli P. LPI-labile plasma iron in iron overload. Best Pract Res Clin Haematol
Walter P, Fung E, Killilea D. Oxidative stress and inflammation in iron overloaded patients with β-thalassaemia or sickle cell disease. Br J Haematol
Porter JB. A risk-benefit assessment of iron-chelation therapy. Drug Safety
Sbarouni E, Georgiadou P, Voudris V. Ischemia modified albumin changes review and clinical implications. Clin Chem Lab Med
Roy D, Quiles J, Gaze D, Collinson P, Kaski J, Baxter G. Role of reactive oxygen species on the formation of the novel diagnostic marker ischaemia modified albumin. Heart
Borderie D, Allanore Y, Meune C, Devaux J, Ekindjian O, Kahan A. High ischemia modified albumin concentration reflects oxidative stress but not myocardial involvement in systemic sclerosis. Clin Chem
Soliman A, Yassin M, Al Yafei F, Al-Naimi L, Almarri N, Sabt A, DeSanctis V. Longitudinal study on liver functions in patients with thalassemia major before and after Deferasirox (DFX) therapy. Mediterr J Hematol Infect Dis
Piva S, Duarte M, Da Cruz I. Ischemia-modified albumin as an oxidative stress biomarker in obesity. Clin Biochem
Awadallah S, Atoum M, Nimer N, Saleh S. Ischemia modified albumin: an oxidative stress marker in β-thalassemia major. Clin Chim Acta
Roach R, Koskolou M, Calbet J, Saltin B. Arterial O 2
content and tension in regulation of cardiac output and leg blood flow during exercise in humans. Am J Physiol
Saltin B, Kiens B, Savard G, Pedersen PK. Role of haemoglobin and capillarization for oxygen delivery and extraction in muscular exercise. Acta Physiol Scand
Cichota L, Moresco R, Duarte M, da Silva J. Evaluation of ischemia-modified albumin in anemia associated to chronic kidney disease. J Clin Lab Anal
Akrawinthawong K, Chaowalit N, Chatuparisuth T, Siritanaratkul N. Effectiveness of deferiprone in transfusion-independent beta-thalassemia/HbE patients. Hematol
Pilo F, Di Tucci A, Dessì L, Angelucci E. Management of transfusional chronic iron overload: focus on deferasirox. Clin Med Ther
Abdul-Razzak A, Al-Shimmary L, Hemid A. The effect of deferasirox on the oxidative stress and inflammation in iron overloaded beta-thalassemic patients. Med J Babylon
Ghoti H, Fibach E, Merkel D, Perez-Avraham G, Grisariu S, Rachmilewitz EA. Changes in parameters of oxidative-stress and free iron biomarkers during treatment with deferasirox in iron-overloaded patients with myelodysplastic syndromes. Haematologica
Cappellini MD, Cohen A, Eleftheriou A, Piga A, Porter J, Taher A. Guidelines for the Clinical Management of Thalassaemia [Internet]. Source 2nd Revised edition. Nicosia (CY): Thalassaemia International Federation; 2008. Bookshelf ID: NBK173968 PMID: 24308075.
Belhoul K, Bakir M, Saned M, Kadhim A, Musallam K, Taher A. Serum ferritin levels and endocrinopathy in medically treated patients with β thalassemia major. Ann Hematol 2012; 91
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]