|Ahead of print
Assessment of metabolic syndrome parameters in pediatric acute lymphoblastic leukemia survivors
Omer Kartal, Orhan Gürsel
Gülhane Training and Research Hospital, Division of Pediatric Hematology and Oncology, Ankara, Turkey
|Date of Submission||27-Sep-2020|
|Date of Decision||31-Jan-2021|
|Date of Acceptance||17-Apr-2021|
|Date of Web Publication||22-Jun-2022|
Gülhane Training and Research Hospital, Division of Pediatric Hematology and Oncology, Ankara
Source of Support: None, Conflict of Interest: None
Objective: This study aims to demonstrate the prevalence of metabolic syndrome parameters and to investigate their relationship with body mass index in pediatric acute lymphoblastic leukemia survivors.
Methods: The cross-sectional study was conducted between January and October 2019 at the Department of Pediatric Hematology and comprised acute lymphoblastic leukemia survivors who had been treated between 1995 and 2016 and had been off treatment for at least 2 years. The control group included 40 healthy participants who were matched for age and gender. The two groups were compared in terms of various parameters (BMI [body mass index], waist circumference, fasting plasma glucose, HOMA-IR [Homeostatic Model Assessment–Insulin Resistance], etc.). Data were analyzed using Statistical Package for the Social Sciences (SPSS) 21.
Results: Of the 96 participants, 56 (58.3%) were survivors and 40 (41.6%) were controls. Among the survivors, there were 36 (64.3%) men, whereas the control group had 23 (57.5%) men. The mean age of the survivors was 16.67 ± 3.41 years, whereas the mean age of the controls was 15.51 ± 4.2 years (P > 0.05). Multinomial logistic regression analysis showed that cranial radiation therapy and female gender were associated with overweight and obesity (P < 0.05). A significant positive correlation was found between BMI and fasting insulin, in survivors (P < 0.05).
Conclusion: Disorders of the metabolic parameter were found to be more common among acute lymphoblastic leukemia survivors than among healthy controls.
Keywords: Leukemia, metabolic syndrome, obesity, pediatric, survivors
| » Introduction|| |
With advances in the treatment of acute lymphoblastic leukemia (ALL), the survival rates have gradually increased., Today, it is expected that more than 85% of children with ALL will be long-term survivors. However, along with these improving survival rates, some long-term life-threatening complications, such as cardiovascular diseases (CVDs), secondary malignancies, and metabolic and endocrine problems, have been observed.
Metabolic syndrome (MS) occurs due to the association of insulin resistance (IR), dyslipidemia, obesity, hypertension (HTN), and high blood sugar level. Because of this, the risk of heart disease, stroke, and diabetes increases in these patients. However, based on existing evidence, these risk factors are preventable with the help of some measures, such as close monitoring of ALL survivors at follow-up and regulation of their lifestyle and diet.
The current study was planned to demonstrate the prevalence of MS parameters and to investigate their relationship with body mass index (BMI) in ALL survivors.
| » Materials and Methods|| |
The cross-sectional study was conducted between January and October 2019 at the Department of Pediatric Hematology and comprised ALL survivors who had been treated between 1995 and 2016 and had been off treatment for at least 2 years. The control group was selected from the matched (similar age and gender) healthy siblings of ALL survivors.
After approval from the institutional ethics review committee, an electronic medical recording system was used to detect ALL survivors. Those included had been treated according to the ALL Berlin–Frankfurt–Münster (BFM) protocol. Patients with any other disease or who were using any drugs known to affect BMI, lipid/glucose metabolism, and blood pressure (BP) were excluded.
Those who met the criteria were contacted by telephone and were requested to visit the Department of Pediatric Hematology.
After taking written informed consent from the ALL survivors, controls, and their parents, waist circumference (WC), weight, height, and BP were measured according to the recommendations of the World Health Organization. Harpenden Stadiometer was used for height measurement, and the participants were weighed in lightweight clothing. The precision of Harpenden Stadiometer and weighing scale had been routinely checked. HTN was defined as BP ≥95th percentile for age, gender, and height. BMI was calculated as weight/square of height. Being underweight, normal weight, overweight, and obese were defined for all the children as BMI <18.5, ≥18.5, <25.0, ≥25, and ≥30.0 kg/m2, respectively. High WC was defined as ≥90th percentile for age and gender. National charts were used to evaluate anthropometric measurements.
Blood samples were obtained after overnight fasting for analysis of lipid profile, fasting insulin (FI), and fasting plasma glucose (FPG). Insulin resistance was calculated using Homeostatic Model Assessment–Insulin Resistance (HOMA-IR = FPG × FI/405). Serum high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels were evaluated using enzymatic colorimetric assay. Serum low-density lipoprotein (LDL) cholesterol levels were evaluated using Friedewald's formula.
The participants were categorized as having IR if fasting insulin (FI) levels were >15 μU/mL during prepuberty, 30 μU/mL during puberty, and >20 μU/mL after puberty, or if HOMA-IR index were ≥3.16 during puberty and ≥2.5 during pre- and postpuberty.
Impaired glucose tolerance (IGT) was defined as FPG ≥100 mg/dL. Dyslipidemia was defined as hypertriglyceridemia ≥150 mg/dL, low HDL level <40 mg/dL in men, and <50 mg/dL in women, or elevated LDL level ≥130 mg/dL.
Data were analyzed using SPSS 21. The groups were compared by using independent-sample t test and multinomial logistic regression analysis. The correlation of the groups was evaluated using Pearson's r formula. P < 0.05 was taken as statistically significant.
| » Results|| |
Of the 96 participants, 56 (58.3%) were ALL survivors and 40 (41.6%) were controls. Among the ALL survivors, six (10.7%) patients had received cranial radiation therapy (CRT) during their course of treatment. There were 36 (64.3%) men among ALL survivors and 23 (57.5%) in the control group. The mean age of ALL survivors was 16.67 ± 3.41 years, whereas the mean age of the controls was 15.51 ± 4.2 years (P > 0.05).
In ALL survivors, the prevalence of underweight, normal weight, overweight–obese was 5 (8.9%), 32 (57.1%), and 19 (33.9%), respectively. In the control group, all (100%) participants were of normal weight. The mean BMI of ALL survivors and controls at the last evaluation were 23.78 ± 6.87 and 20.33 ± 1.62, respectively (P < 0.05), and the mean BMI z scores of the groups were 1.31 ± 0.99 and 0.59 ± 0.36, respectively (P < 0.05) [Table 1].
There was a significant positive correlation of BMI with TG and LDL (P < 0.05), but not with HDL (P = 0.17) [Table 2]. In the control group, none of the participants had dyslipidemia.
|Table 2: Correlation between BMI and metabolic parameters in overweight and obese survivors|
Click here to view
In 10 (17.8%) ALL survivors, there was IR compared with none in the control group (P < 0.05) [Figure 1].
|Figure 1: Correlation between body mass index and metabolic parameters in overweight and obese survivors|
Click here to view
There was a significant positive correlation of BMI with systolic BP (SBP) and diastolic BP (DBP) levels (P < 0.05).
Multinomial logistic regression analysis showed that CRT and female gender were associated with overweight and obesity [Table 3].
|Table 3: Multinomial logistic regression of acute lymphoblastic leukemia (ALL) survivors associated with weight status|
Click here to view
| » Discussion|| |
ALL survivors are more likely to die of noncancer causes, especially CVDs, than the general population. Early cardiovascular deaths mostly happen because of leukemia therapy, and according to some studies, Metabolic syndrome (MS) parameters, including obesity, can enhance the risk of cardiovascular death about 40-fold in ALL survivors.
The prevalence of overweight and obesity among ALL survivors (5–9 years posttreatment) ranges from 11% to 69% and varies according to the research method and patient characteristics., Belle et al. reported that with a mean of 15 years after diagnosis after diagnosis (AD), 26% ALL survivors were overweight and obese. Additionally, a study in Athens showed that 44% ALL survivors were overweight and 25% were obese with a mean of 5.9 years after the completion of therapy after the completion of therapy (ACT). The present study revealed that at a mean of 11.2 years AD, 33.9% ALL survivors were overweight and obese. Despite the different prevalence rate, the result is in line with the previous studies.,
The potential late effects of treatment-related obesity are a significant challenge to ALL survivors and clinicians. Till date, although several studies explored the risk factors that lead to treatment-related obesity, uncertainty related to etiology still remains.,
Multinomial logistic regression analysis in the current study identified two significant risk factors of overweight and obesity: CRT and female gender. Similar results have been reported earlier.,, Contrary to some studies, we were unable to demonstrate a significant association between age at diagnosis and overweight–obesity. It was perhaps because of the small sample size or a shorter duration of follow-up., Additionally, we did not find any statistically significant difference between underweight status and age at diagnosis, CRT, and gender.
Some studies have advocated that exposure to CRT increases the risk of overweight–obesity. A lifetime cohort study showed that 44.9% ALL survivors who were exposed to CRT had a BMI ≥30 kg/m2 at a mean of 26.1 years ACT. Another study found that patients receiving CRT had a higher prevalence of overweight (2.9-fold) and obesity (2.4-fold) compared with those who did not receive CRT at a mean of 11 years ACT. Our findings are consistent with these reports. ALL survivors receiving CRT have a higher prevalence of overweight–obesity (2.4-fold) compared with those who did not receive CRT at follow-up. However, contrary to these studies, some studies did not find any association between CRT and obesity.,
Steroids and l-asparaginase are important chemotherapeutic drugs for ALL treatment, but they increase the risk of glucose metabolism disorders and IR., Additionally, in obese patients, adipocytes secrete inflammatory mediators and adipokines, which may cause IR.
A prospective study in Italy revealed that 69% ALL survivors had IR, and 28% of them had IGT 1 year ACT. In another study, IR rate was found as 30.5% in ALL survivors 21 months ACT. In contrast, one study did not find any significant difference between ALL survivors and healthy controls, and it also did not find any correlation between FI and BMI at a mean 8.6 years ACT. The present study found an IR rate of 17.8%, and there was a significant positive correlation between HOMA-IR and BMI. Case selection and sample size could explain these different rates between the studies.
The prevalence of dyslipidemia in ALL survivors was reported differently by previous studies., One study in Montreal showed that 50% ALL survivors had dyslipidemia, which was characterized by increased TG and decreased HDL levels at a mean of 12.4 years ACT. Another study found 38% with dyslipidemia at a mean of 10.5 years ACT. The current study found the prevalence of dyslipidemia as 14.2%, and it was more prevalent than in the control group.
There are different observed rates related to the prevalence of HTN in the literature., The current study did not observe HTN in ALL survivors. This discrepancy may be explained by different dietary habits, lifestyle, or treatment methods.
The cross-sectional design and a small sample size are the limitations of the current study, whereas the incorporation of a control group and long-term follow-up are its strengths.
| » Conclusion|| |
Disorders of metabolic parameter are more common in ALL survivors than in healthy individuals. To protect these children from future CVD disorders and other possible late effects, clinicians should pay attention to the risk factors of MS and establish a screening program.
This study was conducted in accordance with the declaration of Helsinki. This study was conducted with approval from the Ethics Committee of the University of Health Sciences.
Declaration of patient consent
Written informed consent was obtained from all participants.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Tonorezos ES, Vega GL, Sklar CA, Chou JF, Moskowitz CS, Mo Q, et al
. Adipokines, body fatness, and insulin resistance among survivors of childhood leukemia. Pediatr Blood Cancer 2012;58:31-6.
Özdemir ZC, Düzenli Kar Y, Demiral M, Sırmagül B, Bör Ö, Kırel B. The frequency of metabolic syndrome and serum osteopontin levels in survivors of childhood acute lymphoblastic leukemia. J Adolesc Young Adult Oncol 2018;7:480-7.
Oudin C, Simeoni MC, Sirvent N, Contet A, Begu-Le Coroller A, Bordigoni P, et al
. Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia. Blood 2011;117:4442-8.
Saultier P, Auquier P, Bertrand Y, Vercasson C, Oudin C, Contet A, et al
. Metabolic syndrome in long-term survivors of childhood acute leukemia treated without hematopoietic stem cell transplantation: An L.E.A. study. Haematologica 2016;101:1603-10.
Zareifar S, Haghpanah S, Shorafa E, Shakibazad N, Karamizadeh Z. Evaluation of metabolic syndrome and related factors in children affected by acute lymphoblastic leukemia. Indian J Med Paediatr Oncol 2017;38:97-102.
] [Full text]
Belle FN, Weiss A, Schindler M, Goutaki M, Bochud M, Zimmermann K, et al
. Overweight in childhood cancer survivors: The Swiss childhood cancer survivor study. Am J Clin Nutr 2018;107:3-11.
Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, et al
. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010;24:265-84.
World Health Organization. WHO AnthroPlus for Personal Computers Manual: Software for Assessing Growth of the World's Children and Adolescents. Geneva, Switzerland: World Health Organization; 2009. Available from: http://www.who.int/growthref/tools/en/
. [Last accessed 2009 Mar 12].
Neyzi O, Saka HN, Kurtoğlu S. Anthropometric studies on the Turkish population--a historical review. J Clin Res Pediatr Endocrinol 2013;5:1-12.
Sampath KA, Maiya AG, Shastry BA, Vaishali K, Ravishankar N, Hazari A, et al
. Exercise and insulin resistance in type 2 diabetes mellitus: A systematic review and meta-analysis. Ann Phys Rehabil Med 2019;62:98-103.
Knopfholz J, Disserol CC, Pierin AJ, Schirr FL, Streisky L, Takito LL, et al
. Validation of the friedewald formula in patients with metabolic syndrome. Cholesterol 2014;2014:261878.
Bruzzi P, Bigi E, Predieri B, Bonvicini F, Cenciarelli V, Felici F, et al
. Long-term effects on growth, development, and metabolism of ALL treatment in childhood. Expert Rev Endocrinol Metab 2019;14:49-61.
Armstrong GT, Oeffinger KC, Chen Y, Kawashima T, Yasui Y, Leisenring W, et al
. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 2013;31:3673-80.
Zhang FF, Kelly MJ, Saltzman E, Must A, Roberts SB, Parsons SK. Obesity in pediatric ALL survivors: A meta-analysis. Pediatrics 2014;133:704-15.
Trimis G, Moschovi M, Papassotiriou I, Chrousos G, Tzortzatou-Stathopoulou F. Early indicators of dysmetabolic syndrome in young survivors of acute lymphoblastic leukemia in childhood as a target for preventing disease. J Pediatr Hematol Oncol 2007;29:309-14.
Karakurt H, Sarper N, Gelen SA, Zengin E. Screening survivors of childhood acute lymphoblastic leukemia for obesity, metabolic syndrome, and ınsulin resistance. Pediatr Hematol Oncol 2012;29:551-61.
Garmey EG, Liu Q, Sklar CA, Meacham LR, Mertens AC, Stovall MA, et al
. Longitudinal changes in obesity and body mass index among adult survivors of childhood acute lymphoblastic leukemia: A report from the childhood cancer survivor study. J Clin Oncol 2008;26:4639-45.
Oeffinger KC, Mertens AC, Sklar CA, Yasui Y, Fears T, Stovall M, et al
. Obesity in adult survivors of childhood acute lymphoblastic leukemia: A report from the childhood cancer survivor study. J Clin Oncol 2003;21:1359-65.
El-Rashedy FH, El-Hawy MA, El Hefnawy SM, Mohammed MM. Assessment of obesity and hepatic late adverse effects in the egyptian survivors of pediatric acute lymphoblastic leukemia: A single center study. Mediterr J Hematol Infect Dis 2017;9:5-11.
Nottage KA, Ness KK, Li C, Srivastava D, Robison LL, Hudson MM. Metabolic syndrome and cardiovascular risk among long-term survivors of acute lymphoblastic leukaemia-From the St. Jude lifetime cohort. Br J Haematol 2014;165:364-74.
Siviero-Miachon AA, Spinola-Castro AM, Tosta-Hernandez PD, de Martino Lee ML, Petrilli AS. Leptin assessment in acute lymphocytic leukemia survivors: Role of cranial radiotherapy? J Pediatr Hematol Oncol 2007;29:776-82.
Hwangbo Y, Lee EK. Acute hyperglycemia associated with anti-cancer medication. Endocrinol Metab (Seoul) 2017;32:23-9.
Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006;116:1793-801.
Mohn A, Di Marzio A, Capanna R, Fioritoni G, Chiarelli F. Persistence of impaired pancreatic beta-cell function in children treated for acute lymphoblastic leukaemia. Lancet 2004;363127-8.
Surapolchai P, Hongeng S, Mahachoklertwattana P, Pakakasama S, Winaichatsak A, Wisanuyothin N, et al
. Impaired glucose tolerance and ınsulin resistance in survivors of childhood acute lymphoblastic leukemia: Prevalence and risk factors. J Pediatr Hematol Oncol 2009;32:383-9.
Papadia C, Naves LA, Costa SS, Vaz JA, Domingues L, Casulari LA. Incidence of obesity does not appear to be increased after treatment of acute lymphoblastic leukemia in Brazilian children: Role of leptin, insulin, and IGF-1. Horm Res 2007;68:164-70.
Bielorai B, Pinhas-hamiel O. Type 2 diabetes mellitus, the metabolic syndrome, and ıts components in adult survivors of acute lymphoblastic leukemia and hematopoietic stem cell transplantations. Curr Diab Rep 2018;18:32.
Malhotra J, Tonorezos ES, Rozenberg M, Vega GL, Sklar CA, Chou J, et al
. Atherogenic low density lipoprotein phenotype in long-term survivors of childhood acute lymphoblastic leukemia. J Lipid Res 2012;53:2747-54.
Morel S, Leahy J, Fournier M, Lamarche B, Garofalo C, Grimard G, et al
. Lipid and lipoprotein abnormalities in acute lymphoblastic leukemia survivors. J Lipid Res 2017;58:982-93.
Kourti M, Tragiannidis A, Makedou A, Papageorgiou T, Rousso I, Athanassiadou F. Metabolic syndrome in children and adolescents with acute lymphoblastic leukemia after the completion of chemotherapy. J Pediatr Hematol Oncol 2005;27:499-501.
[Table 1], [Table 2], [Table 3]