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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 39  |  Issue : 3  |  Page : 164-170

Iron overload in transfusion-dependent β-thalassemia patients: defining parameters of comorbidities


Department of Clinical Pathology, Faculty of Medicine, Ain Shams University Hospitals, Cairo, Egypt

Date of Submission22-Oct-2014
Date of Acceptance11-Nov-2014
Date of Web Publication31-Dec-2014

Correspondence Address:
Deena S Eissa
Department of Clinical Pathology, Faculty of Medicine, Ain Shams University Hospitals, Ramses St., Abbasia, Cairo 11566
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.148252

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  Abstract 

Background Iron overload represents a consistent and almost inevitable complication in patients with transfusion-dependent β-thalassemia. The frequently needed erythrocyte transfusions are known to be the leading source of body iron. Increased iron deposition in tissues was strongly suggested to underlie poor growth and development in transfusion-dependent β-thalassemia. This study aimed to investigate the pattern of increase in iron-overload parameters in relation to the therapeutic measures used and explore its effect on the physical growth of patients with transfusion-dependent β-thalassemia.
Patients and methods The study included 60 transfusion-dependent β-thalassemia patients (median age 12.5 years, interquartile range 8-17 years) and 20 age-matched and sex-matched controls; each group was further subcategorized into less than 12-year-old and more than 12-year-old subgroups. The studied clinical parameters comprised weight and height, which were used to calculate the body mass index (BMI). Laboratory assays included complete blood counts for the assessment of pretransfusion hemoglobin, serum iron, total iron-binding capacity, ferritin, and growth differentiation factor 15 (GDF15), and the calculation of the transferrin iron saturation percentage (TISP).
Results Less than one-third (30%) of the patients had a low BMI; no patient was overweight or obese. The median pretransfusion hemoglobin was 7.1 g/dl (interquartile range 6.8-7.2 g/dl). Fifty-two (86.7%) patients were inadequately chelated, showing serum ferritin levels more than 1000 ng/ml. In patients older than 12 years of age, the BMI was significantly lower in comparison with controls of the same age subgroup as well as patients less than 12 years old. Patients with a low BMI had significantly higher median values of TISP, ferritin, and GDF15 than those with a normal BMI. GDF15 values of the more than 12-year-old patients showed significant positive correlations with TISP and ferritin levels. Setting optimal cutoffs at 63% for TISP and 1210 ng/ml for serum ferritin (area under the curve 0.965 and 0.957, respectively) had indicated low BMI with higher certainties compared with GDF15 at a level of 10 000 pg/ml (area under the curve 0.783) in the more than 12-year-old patients.
Conclusion Avoiding iron overload should be warranted for transfusion-dependent β-thalassemia patients to have normal BMI. Although a high GDF15 level is helpful in pointing toward the development of a low BMI, it added no value to TISP or ferritin as indictors of patients' growth retardation.

Keywords: body mass index, growth, growth differentiation factor 15, iron overload, β-thalassemia


How to cite this article:
Eissa DS, El-Gamal RA. Iron overload in transfusion-dependent β-thalassemia patients: defining parameters of comorbidities. Egypt J Haematol 2014;39:164-70

How to cite this URL:
Eissa DS, El-Gamal RA. Iron overload in transfusion-dependent β-thalassemia patients: defining parameters of comorbidities. Egypt J Haematol [serial online] 2014 [cited 2018 Oct 16];39:164-70. Available from: http://www.ehj.eg.net/text.asp?2014/39/3/164/148252


  Introduction Top


In Egypt, β-thalassemia is the most common genetically determined chronic hemolytic anemia: 1000/1.5 million live births per year suffer from thalassemia disease, with an estimated carrier rate of 9-10.5% [1],[2] . Although the disease can be avoided by premarital counseling and prenatal testing, a large number of children are born with thalassemia, and resorting to bone marrow transplantation as a curative treatment is not applicable for the majority of these patients. Such patients require regular transfusions of packed red blood cells and suitable iron-chelation therapy together with careful monitoring and treatment of complications of the disease [3] .

The frequently needed erythrocyte transfusions are identified as the leading source of body iron. Yet, it is now well established that even non-transfusion-dependent thalassemia patients often develop harmful iron overload [4] . Pasricha et al. [5] clearly demonstrated that in β-thalassemia major patients, who are highly iron overloaded, levels of serum hepcidin, the iron-regulatory hormone, are lower than would be expected. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β superfamily, secreted by the erythropoietin-stimulated marrow erythroblasts (specifically late and apoptotic erythroblasts) is known to suppress the synthesis of hepcidin. GDF15 measurement is thought to predict ineffective or apoptotic erythropoiesis [6] . Through lowering hepcidin levels and, hence, increasing intestinal iron absorption, excessive serum GDF15 appears to underlie the paradoxical iron overload seen in patients with β-thalassemia [7] .

As for the iron-chelation therapy, it is meant to minimize iron overload. All guidelines recommend initiating iron chelation after receiving 10 or more transfusions or after reaching a serum ferritin level more than 1000 ng/ml [8],[9],[10],[11],[12],[13] . Poor compliance to chelation treatment was reported as one cause of poor growth [14] .

A group of researchers [15] have earlier shown a significant difference in the mean serum ferritin levels between thalassemia patients with endocrine complications and thalassemia patients without endocrinopathies, referring to iron deposition in the pituitary gland. Others have linked high serum ferritin levels during the first decade of life to a final short stature [16] . These data suggest that a high serum ferritin level during puberty is a risk factor for hypogonadism and growth retardation. In addition to iron-overload-induced endocrinopathies, the affected sexual maturation at puberty was found to be attributed to the association of insufficient body fat with defective growth, altered pubertal development, and poor bone health [17] .

This study presents a profile of transfusion-dependent β-thalassemia patients and investigates the effects of the therapeutic measures used (blood transfusion and iron chelation) on iron overload and growth. The role of GDF15 in the iron-overload status and whether it can help determine the risk of being burdened by poor growth was studied extensively in an attempt to find an additional putative predictor of disease morbidities.


  Patients and methods Top


Patients

This was a cross-sectional study of patients with transfusion-dependent β-thalassemia registered at and being followed up at the Thalassemia Outpatient Clinic, Ain Shams University Hospitals, during the period from September 2012 to April 2013. The study included a test group of 60 patients (36 male and 24 female; male : female ratio 1.5 : 1) with transfusion-dependent β-thalassemia and 20 age-matched and sex-matched healthy individuals as the control group. The mean age of the patients was 11.8 ± 4.3 years [median 12.5; interquartile range (IQR) 8-17 years]. The patients were equally distributed on either side of the age of 12 years. Each of the two groups (patients and controls) was further subcategorized into two subgroups: less than 12-year-old subgroup and more than 12-year-old subgroup. Informed consents were obtained from all participants or guardians before enrollment, and the study was approved by the local research ethical committee.

Exclusion criteria included patients with abnormal liver or kidney function tests, primary skeletal disorders, severe malnutrition, recently splenectomized patients (within the past 6 months), the presence of comorbidities at the time of sampling (inflammation, infection), the presence of other hereditary hemoglobin disorders, and pregnant or lactating women. The state of being Egyptians and not of foreign ancestry was strictly checked for all enrolled patients.

The body mass index (BMI) (weight in kg/height in m 2 ) was calculated for all participants. As all studied individuals were unintentionally 19 years old or younger, the BMI scoring was interpreted as follows:

  1. BMI of less than 5th percentile for age and sex was considered underweight,
  2. BMI of 5th to less than 85th percentile as normal weight,
  3. BMI of 85th to less than 95th percentile as overweight, and
  4. BMI 95th percentile or more as obese [18] .


The frequency of erythrocyte transfusion, the start of iron-chelation therapy, clinical data of body response to chronic anemia or ineffective erythropoiesis (hepatomegaly and/or splenomegaly, hypochondrial pain, bone pains, or specific thalassemic facies), and a family history of β-thalassemia disease were defined carefully for the patients' group.

Methods

Peripheral blood samples were collected immediately before transfusion and tested for complete blood count (Coulter LH 750 Hematology Analyzer; Beckman Coulter Inc., Fullerton, California, USA), serum iron and total iron-binding capacity (TIBC) (UniCel DxC 600 Synchron Clinical Systems; Beckman Coulter Inc.), and serum ferritin (Access 2 Immunoassay System; Beckman Coulter Inc.); the transferrin iron saturation percentage (TISP) was calculated mathematically (serum iron/TIBC × 100).

Quantification of GDF15 in sera was performed using the Quantikine Human GDF15 enzyme-linked immunosorbent assay (R&D Systems Inc., Minneapolis, MN, USA). In brief, serum samples were diluted; 96-well plates were coated with the monoclonal mouse antihuman GDF15 capture antibody. After incubation with the serum, the wells were washed, and the bound GDF15 was detected using a polyclonal antibody against human GDF15 conjugated to horseradish peroxidase. Recombinant human GDF15 protein was used to generate a standard curve. Results are expressed in pg/ml.

Statistical analysis

All statistical procedures were performed using the MedCalc software (v.13.2.2; MedCalc, Ostend, Belgium). Descriptive statistics are expressed as numbers and percentages or medians and IQR. The χ2 -test was used for the comparison of categorical variables, whereas the Mann-Whitney U-test was used to compare medians of continuous variables between the selected groups. Correlations between different parameters were performed using the Spearman rank test. Receiver operating characteristic (ROC) curve analysis was applied to determine the threshold levels for the different assayed parameters, with the highest sum of sensitivity and specificity to discriminate patients with from those without morbidities. The level of significance (P-value) was set at less than 0.05.


  Results Top


The β-thalassemia patients studied were found to have either a low BMI [18 (30%) patients] or a normal BMI [42 (70%) patients]. One or more signs of ineffective erythropoiesis were detected in 36 (60%) patients; none of the patients in this study was identified to suffer from any of the following endocrinopathies: diabetes mellitus, hypothyroidism, or hypoparathyroidism. All patients were receiving regular blood transfusion: 54 (90%) patients were transfused at a rate of twice/month, whereas 6 (10%) patients were receiving one blood transfusion monthly. The median pretransfusion hemoglobin was 7.1 g/dl (IQR 6.8-7.2 g/dl), being less than the internationally desired values (9-10.5 g/dl) [9],[10],[11] ; the median ferritin level was 1180 ng/ml (IQR 1015-1300 ng/ml); 52 (86.7%) patients were inadequately chelated, showing serum ferritin levels more than 1000 ng/ml [8],[9],[10],[11],[12],[13] .

Comparison of clinical and laboratory data between the patient and the control groups

When compared with the control individuals, β-thalassemia patients showed significantly lower values of red cell counts, hemoglobin, and mean corpuscular volume and significantly higher values of red cell distribution width and serum levels of iron, TIBC, TISP, and ferritin. Similarly, the median value of GDF15 was significantly higher in β-thalassemia patients than in controls (14 000 vs. 700 pg/ml; P < 0.001). BMI values showed no significant difference between the two groups. However, when the comparison was conducted between the more than 12-year-old subgroups of both patients and controls, the BMI showed statistically significantly lower values in β-thalassemia patients in comparison with the control individuals (P = 0.047) ([Table 1]).
Table 1 Comparison of clinical and laboratory data between the patient and the control groups

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Comparison of clinical and laboratory data between the two age subgroups within the patients' group

Patients in the more than 12-year-old subgroup showed higher hemoglobin levels, TISP, and serum ferritin concentrations, along with lower BMI values, all of which reached a significant level of difference (P = 0.002, 0.0474, 0.008, and 0.003, respectively). GDF15 showed a nonsignificant difference between the two subgroups ([Table 2]).
Table 2 Comparison of clinical and laboratory data between the two age subgroups within the patients' group

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Comparison of body mass index values with the relevant laboratory and iron-loading parameters

Patients with a low BMI were older than those with a normal BMI (P = 0.006). In addition, patients with a low BMI showed higher concentrations of the studied iron-overload parameters: serum TISP and ferritin (P < 0.001 for each). Low-BMI patients also showed higher GDF15 levels (P = 0.044) ([Table 3] and [Figure 1] and [Figure 2]).
Figure 1 The age o f low-BMI and normal- BMI patients.

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Figure 2 Serum growth differentiation factor 15 (GDF15) values in low-BMI and normal- BMI patients.

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Table 3 Comparison of body mass index values with the relevant laboratory and iron-loading parameters

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Correlations of growth differentiation factor 15 levels with the relevant laboratory and iron-loading parameters

When all β-thalassemia patients were included, none of the tested parameters showed significant correlation with GDF15. Conversely, when the test was performed on the more than 12-year-old subgroup, GDF15 was positively correlated with TISP (r = 0.5608, P = 0.0044) and serum ferritin (r = 0.6456, P < 0.001) ([Table 4] and [Figure 3] and [Figure 4]).
Figure 3 Correlation between growth differentiation factor 15 (GDF15) values and transferrin iron saturation percentage (TISP).

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Figure 4 Correlation between growth differentiation factor 15 (GDF15) values and serum ferritin.

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Table 4 Correlations of growth differentiation factor 15 levels with the relevant laboratory and iron-loading parameters

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Determination of cutoff values for iron-loading parameters to discriminate low from normal body mass index

We ranked the iron-loading determinants studied in terms of their ability to indicate the development of low BMI in the more than 12-year-old subgroup using the ROC analysis ([Figure 5]).
Figure 5 The receiver operating characteristic curve for determining cutoff values for transferrin iron saturation percentage (TISP), ferritin, and growth differentiation factor 15 (GDF15) in relation to a low BMI.

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The best chosen cutoffs for the selected parameters in relation to the development of a low BMI were as follows: 63% for TISP [area under the curve (AUC) 0.965, P < 0.001, sensitivity 96%, specificity 87%], 1210 ng/ml for serum ferritin (AUC 0.957, P < 0.001, sensitivity 96%, specificity 81%), and 10 000 pg/ml for GDF15 (AUC 0.783, P = 0.0028, sensitivity 83%, specificity 67%).


  Discussion Top


β-Thalassemia patients suffer major morbidities, and among the main reported disease features are those related to the failure of proper growth and development. Therapeutic regimens target increasing longevity with the least morbid features, relying mainly on adequate transfusion therapy (to limit ineffective erythropoiesis) and a suitable iron-chelation system (to minimize iron overload) [19] .

Insufficient transfusion therapy permits the persistence of ineffective erythropoiesis, the milestone of β-thalassemia major [20] . All international guidelines have recommended target pretransfusion hemoglobin level ranges between 9 and 10.5 g/dl with minor differences [9],[10],[11] . This hemoglobin range was not a characteristic of any of the patients enrolled in the present study. Considering the generally accepted rate of red cell transfusions received by our patients (once or twice per month), the undesirable low hemoglobin levels may denote inappropriate transfusion therapy used, being of questionable quantity or quality.

Regarding ferritin, only the spot measurement of serum ferritin levels performed in our study was used, as no previous results could be traced for most of the patients. Setting the cutoff limit for serum ferritin at 1000 ng/ml to discriminate adequately from poorly chelated patients [8],[9],[10],[11],[12],[13],[21] , 86.7% of the patients had high serum ferritin levels more than 1000 ng/ml (median 1180 ng/ml), a testimony to inadequate chelation in these patients. Yet, our study has shown lower serum ferritin values when compared with those described in similar studies [3],[16],[17],[22] . One of these studies [3] reported ferritin levels in β-thalassemia patients to be three times (3112 ng/ml) the desired value. Meanwhile, in clear contrast to the patients in our study, their patients were transfused adequately, with pretransfusion hemoglobin maintained at a mean value of 9.2 g/dl. Thus, it seems that the lower ferritin levels obtained in our study are primarily the result of inadequate transfusion received by the enrolled patients. This confirms the fact that direct iron introduction into the body by regular transfusions is the main source of body iron overload, exceeding the effect of iron accumulation caused by the increased ineffective erythropoiesis occurring in inadequately transfused patients.

Our findings have revealed a considerable difference in the results of complete blood counts and iron-overload parameters between the patient and the control groups. These differences can be very well explained by the pathogenetic nature of the disease. The higher TIBC values in the patients' group compared with controls contradict the expected condition of low TIBC, which characterizes iron-overload states. Other researchers have also reported high TIBC values in β-thalassemia major patients [22],[23],[24] .

The well-founded fact that physical growth is affected in transfusion-dependent thalassemic patients [3] was the basis of the comprehensive study of BMI in this work. Our results have revealed that 18 (30%) patients had a low BMI. The BMI was significantly lower in the patients' group compared with the control individuals only when the comparison was conducted between the more than 12-year-old subgroups. This may indicate that the development of a low BMI is highly dependent on disease progression. Our results match with a study from Iran, which specified that 70% of the boys and 73% of the girls over 10 years of age with transfusion-dependent thalassemia had a short stature [25] . Somewhat similar observations were made by Abdulzahra et al. [26] , who found no major impairment of endocrine function in Iraqi thalassemia patients aged 4-12 years with moderate to severe degrees of iron loading.

Our results have shown that older patients (>12-year-old) had a lower BMI, higher TISP and higher ferritin levels as compared with younger patients; patients with a lower BMI had higher TISP, ferritin, and GDF15 levels. These inter-relationships that exist between BMI, age, and serum levels of iron-loading parameters were similar to the findings obtained by Saxena [27] , who found patients to have lower BMI in older ages, with a negative correlation between serum ferritin and BMI. Similar results were also obtained by Hamidah et al. [28] who found serum ferritin levels in thalassemic patients with height less than 3rd percentile to be higher compared with patients with height more than 3rd percentile. Similarly, Pemde et al. [3] correlated physical growth with the status of iron overload. In contrast, a study from India found no relation between physical growth and serum ferritin levels [29] .

Several factors were described to affect mean levels of serum ferritin, including the age at presentation, the age at the beginning of regular transfusion, the age at the starting of iron-chelation therapy, the efficacy of the iron-chelation drug and its compliance, and the age group of the reported series of patients [3] . These are to be added to the more common causes of fluctuation of serum ferritin (e.g. inflammation, abnormal liver function, and metabolic deficiencies) [21] . This led us to investigate the relationship of GDF15 (reflecting ineffective erythropoiesis) with the state of BMI and iron overload, and evaluate its use as a potential substitute or as an adjuvant to ferritin as markers of low BMI. In patients older than 12 years of age, GDF15 levels were positively correlated with TISP and serum ferritin. However, such correlations were absent when the age categorization was ruled out.

To determine the basis for avoiding excessive tissue iron deposition, which might ultimately lead to a retarded growth, we ranked the tested parameters in terms of their ability to determine the development of a low BMI using ROC analysis. Our results showed that the occurrence of a low BMI was best determined by values of 63% for TISP and 1210 ng/ml for serum ferritin (AUC 0.965 and 0.957, respectively); GDF15 was a relatively worse determinant at a level of 10 000 pg/ml (AUC 0.783). A recent study [30] has determined cutoff values of 75% for TISP and 400 ng/ml for serum ferritin at which the appearance of nontransferrin-bound iron (NTBI) in the blood would commence. The noticeably lower cutoff value of serum ferritin, compared with our results, may be explained by the chronological occurrence of the events, as the first appearance of NTBI would be followed by a sustained increase in iron overload, with further increase in NTBI to gain a negative influence over BMI. Yet, the determined cutoff value of ferritin (1210 ng/ml), being greater than that already adopted for starting and monitoring the adequacy of chelation therapy (1000 ng/ml), makes its predictive power for a low BMI debatable. This points toward the importance of relying on a mean value of ferritin instead of accepting a single measurement to estimate the degree of iron overload.


  Conclusion Top


Our study has affirmed that minimizing the iron overload in regularly transfused β-thalassemia patients should be warranted for them to have a rather normal growth and development. Achieving normal BMI levels requires reviewing of the transfusion and chelation regimens used for patients.

While GDF15 represents one root of rise of iron-loading determinants, TISP and serum ferritin seemed to indicate the development of retarded growth with higher accuracy when compared with testing for GDF15. As a consequence, the assay of GDF15 has proved to have no particularly superior implications over the other known tests in the development of a low BMI, limiting its chance to be used as a therapeutic target.

This study needs to be further assessed by larger prospective studies. Also, repeated measurements of ferritin should be taken into account, as this would provide an actual iron status value with higher certainty.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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