Introduction

Beta thalassemia major (β-TM) is a hereditary anemia resulting from the absence or severe deficiency of β-globin chain production, which leads to chronic hemolytic anemia [1]. These patients are in need of regular blood transfusion to improve oxygen carrying capacity and their overall wellbeing. However, such treatment might lead to iron overload and its related morbidities, such as cardiac, liver, and endocrine system damages [2]. In recent decades, combination of blood transfusion and iron-chelating therapies has improved the life expectancy and quality of life of β-TM patients [3].

While β-TM patients’ survival has improved, there are growing concerns about long-term complications of this disease and its related therapies [2]. One important complication can be metabolic syndrome, which is accompanied by hyperglycemia, dyslipidemia, abdominal obesity, and hypertension. Metabolic syndrome can increase cardiovascular atherosclerotic risks and diabetes mellitus [4]. Hyperinsulinemia and insulin resistance are well documented in β-TM patients [1, 4,5,6,7]; however, its association with metabolic syndrome has not been investigated. Furthermore, there are some sporadic reports about hypertension [8], hypertriglyceridemia [9, 10], and obesity [11]. To the best of our knowledge, there has been no report about the prevalence of metabolic syndrome in β-TM patients. Consequently, we aimed to investigate the prevalence of metabolic syndrome in β-TM patients in southern Iran.

Material and methods

The present cross-sectional study was conducted in thalassemia clinics affiliated to Shiraz University of Medical Sciences, Fars Province, Iran, in 2015. All patients were registered in these clinics after the clinical diagnosis and peripheral blood evaluation and hemoglobin electrophoresis. We enrolled 100 patients with beta thalassemia major, selected through simple randomized sampling. Diabetes mellitus and secondary hypertension were our exclusion criteria. Also, adolescents, who had any type of disability that would prevent us from measuring their weight, height, and waist circumference, and pregnant women were excluded from the study. Healthy age- and gender-matched adolescents were enrolled in the control group. Controls were randomly selected from a cohort study in Kavar, located in south of Fars Province, which include 478 normal population checked for metabolic syndrome.

The patients were transfusion-dependent before the age of 2. All patients were treated with deferoxamine as an iron-chelating therapy. This study was approved by both the local ethics committee and vice-chancellor of research at Shiraz University of Medical Sciences. All patients signed a written informed consent.

Anthropometric data and blood pressure

Weight and height of patients were assessed by a single trained physician. While the patient was standing without shoes; height was measured using an Altura Exata portable stadiometer and the number was rounded to the nearest 0.5 cm. Weight was evaluated using a standard scale (Seca, Germany), while the patient wore light clothes, which was rounded to the nearest 0.1 kg. Body mass index (BMI) was calculated through the standard formula:

$$ \mathrm{BMI}\ \left(\mathrm{kg}/{\mathrm{m}}^2\right)=\mathrm{Weight}\ \left(\mathrm{kg}\right)/{\left[\mathrm{height}\ \left(\mathrm{m}\right)\right]}^2 $$

We classified the patients according to the World Health Organization (WHO) BMI curves specified by age and gender into four categories [12]: underweight, BMI Z score < − 2; normal, − 2 ≥ Z < +1; overweight, + 1 ≥ Z < +2; and obese adolescents, BMI Z score more than + 2.

Waist circumference (WC) was measured with a Sanny inelastic measuring tape at the midpoint between the last rib and the iliac crest, while the patient was standing relaxed.

Blood pressure (BP) was assessed with a mercury sphygmomanometer (Riester, Germany) using a standard method [13]. The recorded blood pressure was the mean of two BP readings with a 5-min interval in a sitting position.

Biochemical measurements

Serum triglyceride (TG), total cholesterol (Chol), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and fasting plasma glucose (FPG) were assessed on a Dirui-T-240 auto-analyzer with an enzymatic method (New and high Tec, Jilin, China), in Shiraz endocrinology and metabolism research center.

Metabolic syndrome definition

We used the International Diabetes Federation (IDF) consensus worldwide definition to define metabolic syndrome [14]. According to these criteria, presence of at least three of the below components was classified as metabolic syndrome:

  1. (1)

    Central obesity (< 16 years: WC ≤ 90th percentile and ≤ 16 years: WC ≤ 94 cm in males and ≤ 80 cm in females), which is defined for Eastern Mediterranean and Middle East population.

  2. (2)

    Raised TG level: ≤ 150 mg/dL

  3. (3)

    Reduced HDL cholesterol: < 40 mg/dL in males and < 50 mg/dL in females

  4. (4)

    Raised blood pressure: systolic BP ≤ 130 mmHg or diastolic BP ≤ 85 mmHg

  5. (5)

    Raised FPG: FPG ≤ 100 mg/dL

Statistics

Statistical analysis was conducted using Statistical Package for Social Sciences (SPSS) software version 18.0. Numerical data was mentioned as mean ± SD. p value less than 0.05 was considered as significant. Normality of data distribution was evaluated using Kolmogorov-Smirnov test. We compare normally distributed data by Student’s t test and not-normal ones by Mann-Whitney test. Qualitative data comparisons were carried out using chi-square test.

Results

One hundred patients with beta thalassemia major aged 23.7 ± 5.9 years and their age- and gender-matched controls were enrolled in this study (Table 1). Patients with thalassemia included 24 males and 76 females, and controls included 36 males and 64 females (p value = 0.07). General characteristics and biochemical studies of our patients were defined by gender shown in Table 2. Male patients had higher diastolic blood pressure (p = 0.018), higher serum ferritin level (p = 0.002), and lower HDL level (p = 0.024). Prevalence of underweight, overweight, and obesity in our patients was 28, 5, and 1%, respectively. BMI categories according to WHO classification in both genders of our patients and controls are shown in Table 3. BMI of thalassemia patients is lower than that of the controls (p < 0.001). We also did not observe any significant difference between prevalence of overweight or obesity among both genders (p = 0.23).

Table 1 General characteristics and the biochemical studies of beta thalassemia major patients and their healthy controls (mean ± SD)
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Table 2 General characteristics and the biochemical studies of beta thalassemia major patients in both sexes
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Table 3 WHO BMI categories in the beta thalassemia major patients, in both sexes
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Prevalence of hyperglycemia, abdominal obesity, low HDL, hypertriglyceridemia, and hypertension in patients with thalassemia was 32, 32, 90, 23, and 4%, respectively. Figure 1 and Table 4 reveal that metabolic syndrome was more prevalent in thalassemia patients (p < 0.001). Table 5 shows that there was no significant difference between the prevalence of these criteria in males and females with thalassemia major, except for abdominal obesity, which was more prevalent in females (p < 0.001). Data revealed that 22% of our patients had metabolic syndrome, which was more prevalent in females (26.3% in females vs. 8.3% in males), (p = 0.045). Metabolic syndrome in our patients was associated with BMI (p = 0.001). However, it was not associated with age (p = 0.217), ferritin (p = 0.702), hemoglobin (p = 0.734), and transfusion intervals (p = 0.215). Serum ferritin was associated with abdominal obesity (p = 0.028) and hypertriglyceridemia (p = 0.017), but it was not associated with hyperglycemia (p = 0.381), hypertension (p = 0.33), and low HDL (p = 0.073).

Fig. 1
figure 1

Frequency of positive IDF criteria of metabolic syndrome comparisons between beta thalassemia patients and their controls

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Table 4 Frequency of positive IDF criteria of metabolic syndrome in controls compared to beta thalassemia major patients
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Table 5 Frequency of positive IDF criteria of metabolic syndrome in beta thalassemia major patients classified by sex
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Discussion

The present study revealed that 6% of our thalassemic patients were either overweight or obese. Also, it was shown that 22% of our β-TM patients had metabolic syndrome, and low HDL was the most frequent positive criterion. The present study showed that metabolic syndrome was more prevalent in females. Furthermore, it was shown that metabolic syndrome was associated with BMI; whereas, abdominal obesity and hypertriglyceridemia were associated with serum ferritin.

Prevalence of metabolic syndrome in adults is 26–29% (16–20% in males and 30–37% in females) in Iran [13, 15,16,17,18,19,20], and abdominal obesity is the most prevalent positive criterion. We showed that 2% of healthy adolescents (aged 22.6 ± 5.8 years) in southern Iran have metabolic syndrome, and also low HDL was the most common criterion. However, there is no validated data about the prevalence of metabolic syndrome in β-TM patients. Hence, it was revealed that 8.3% of males and 26.3% of females with β-TM have metabolic syndrome, which is in a similar range of the normal population. However, low HDL was the most prevalent criterion in β-TM patients. Gozashti et al. revealed that prevalence of metabolic syndrome in minor β-TM patients was lower than that in the normal population, and they proposed that minor thalassemia might act as a protective factor for metabolic syndrome [21].

Abnormal glucose tolerance and insulin resistance were previously reported in multi-transfused β-TM patients [5,6,7, 22]. Also, it was shown that insulin resistance was associated with metabolic syndrome [19, 20]. In β-TM patients, hyperglycemia might be due to early impairment of β cell function and insulin resistance. Iron overload and chronic hepatitis C (HCV) could play a significant role in this regard [6]. Some previous studies reported the relationship between serum ferritin levels and insulin resistance in non-diabetic women [23], in over weight and obese population [24], and in Korean men [25]. These results suggest that iron overload is associated with insulin resistance even in non-thalassemic populations [25]. Our result revealed that there is a high prevalence of hyperglycemia (32%) in major thalassemic patients; however, it was not associated with serum ferritin. Also, Kirim et al. revealed that there was no association between β-TM minor and metabolic syndrome criteria, regardless of insulin resistance [26]. Other possible explanation could be liver damage or HCV infection that might play an important role in hyperglycemia of β-TM patient that needs to be investigated in future studies.

Fung et al. reported that 26.5% of non-transfused thalassemia in Canada had BMI of more than 25. This was more than that of non-transfused thalassemia, and females had higher body fat index in comparison to men [11]. It was shown that 6% of our β-TM patients had BMI of more than 25, while, 32% of β-TM patients had abdominal obesity, which was significantly higher in women. The differences between the Fung et al. study and our report could be attributed to the differences in culture and lifestyle [27]. They also revealed that abdominal obesity was associated with serum ferritin. Fung et al. suggested that hypogonadism and growth hormone deficiency secondary to iron overload in β-TM patient played an important role in abdominal obesity [11].

Low level of total cholesterol accompanied with low serum HDL, low serum LDL, and hypertriglyceridemia was well shown in β-TM patients [10, 28,29,30,31,32]. This might be due to increased erythropoiesis that could result in increased cholesterol requirement for cell membrane formation in these patients [29, 33]. Some studies have found a link between serum ferritin and changes in lipid profile of β-TM patients [34, 35]. Khera et al. also reported on a syndrome called hypertriglyceridemia thalassemia in four β-TM patients [9]. Even though pathogenesis of such syndrome is still unclear, it might be associated with high risk of developing atherosclerosis and acute pancreatitis at a young age [9]. Bordbar et al. revealed a genotype-phenotype correlation between lipid profile and different β-globin gene mutations [10]. The most severe gene mutation (β°/β°) in thalassemia patients is accompanied with high reduction in serum lipids [10]. In the present study, we found a high prevalence of low HDL (90%). Also, 23% of our β-TM patients had hypertriglyceridemia, associated with their serum ferritin.

Prevalence of hypertension in β-TM patients was previously reported at 6.7% [36]. In our study, 4% of our β-TM patients had hypertension, which was close to the prevalence in the normal population [13]. However, heart rate variability was reduced in β-TM patients due to early autonomic neuropathy in their hearts [37]. Similar to our results, Tabatabaie et al. revealed that serum ferritin, hemoglobin, and transfusion intervals did not affect the abnormal changes in blood pressure [36].

Although there are several novelties in the present research, such as being the first to evaluate the metabolic syndrome prevalence in β-TM patients, it was also the first to evaluate the prevalence of abdominal obesity and hypertension in β-TM patients of southern Iran. However, there were some limitations. We did not check the fasting insulin level to estimate the Homeostatic Model Assessment (HOMA) index. We suggest considering the evaluation of the HOMA index in β-TM patients in future researches to find out a more accurate estimation of the metabolic syndrome in β-TM patients and its association with insulin resistance.

Conclusion

This study revealed that 22% of β-TM patients had IDF criteria of metabolic syndrome and low HDL was the most frequent positive criterion. Metabolic syndrome was more prevalent in female patients. Abdominal obesity and hypertriglyceridemia were associated with serum ferritin. Further studies should be performed to find the related factors, to reduce the cardiovascular morbidities associated with metabolic syndrome in β-TM patients.