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ORIGINAL ARTICLE
Year : 2021 | Volume
: 46
| Issue : 4 | Page : 249-254
Alterations in body composition in survivors of childhood acute lymphoblastic leukemia
Eman S Hamama, Marwa S El-Sherif, Mohamed A El-Asrar, Sara M Makkeyah MD
Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Correspondence Address:
Sara M Makkeyah
Lecturer of Pediatrics, Department of Pediatrics, Ain Shams University Childrens Hospital, Faculty of Medicine, Ain Shams University, Abbassiya, Cairo 11566
Egypt
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ejh.ejh_38_21
Introduction We studied the body composition among survivors of childhood acute lymphoblastic leukemia (ALL) as compared to healthy controls.
Methods Twenty-nine survivors of childhood ALL and 35 age- and sex-matched healthy controls were evaluated for anthropometric measurements, including weight, height, body mass index (BMI), and waist-to-hip ratio. Body composition was analyzed using Tanita SC-330P scale. Measurement of fasting insulin, glucose, lipids, and serum leptin was done for all participants.
Results BMI-standard deviation score (SDS) was significantly higher among the survivor group (mean±SD 0.79±1.2) versus controls (0.25±0.85, P=0.041). Obesity/overweightness were more prevalent among survivors than the control group (34.5% and 17.6%, respectively); however, the difference did not reach statistical significance (P=0.215). There was no difference between both the groups when comparing waist-to-hip ratio, body fat %, fat-free mass %, muscle mass %, and total body water % as well as serum leptin and lipid profile. Among ALL survivors, the overweight/obese group had higher total cholesterol and low-density lipoprotein-cholesterol than survivors with normal BMI-SDS (P=0.0127 and 0.025, respectively), while other variables, including gender, median time from diagnosis, cranial irradiation, serum leptin, were comparable for both the groups.
Conclusion ALL survivors are more prone to obesity and altered body composition. Incorporating preventive strategies early into treatment regimens is needed to prevent the development of these metabolic abnormalities.
Keywords: body composition, childhood ALL, leptin, obesity, survivors
Recent improvements in the management and outcomes of childhood acute lymphoblastic leukemia (ALL) have shed the lights on long-term effects of the disease and its related treatment. Unfortunately, long-term survivors of childhood cancer are at risk of developing a spectrum of late adverse effect, such as reduced growth, obesity, decreased fertility, high blood pressure (BP), cardiovascular diseases, impaired glucose metabolism, and secondary malignancy [1].
Obesity is a well-recognized problem for children treated for ALL and is present in roughly one-fourth of children by end of therapy. It may lead to immediate health issues such as increased risk for cancer relapse or may cause future health issues, such as diabetes mellitus (DM), metabolic syndrome (MS), hypertension, cardiovascular diseases, or additional cancers [2]. Obesity is a modifiable risk factor; primary and secondary prevention can decrease the associated morbidity and mortality [3]. The mechanisms underlying has been hypothesized to the use of steroids, effect of chemotherapy, and cranial irradiation on the hypothalamic–pituitary axis. However, the mechanisms of obesity in ALL survivors seem to be interplay of many factors [4].
Body mass index (BMI) is an indicator of body fat mass; however, the amount and the distribution of fat are more important risk factors for prediction of cardiovascular disease and type 2 diabetes [5]. The body composition of childhood cancer survivors (CCS) should be considered even if they are not overweight or obese [6]. Lipid partitioning is more related to the metabolic phenotype of obese children and adolescents rather than the degree of obesity. Thus, lipid partitioning is a major determinant of peripheral insulin sensitivity and is strongly associated with other metabolic biomarkers [7].
Leptin, a hormone secreted mainly by adipocytes, regulates appetite and energy expenditure by acting in the hypothalamus. Leptin and leptin resistance has been hypothesized to play a role in the development of obesity or weight gain in ALL survivors [8],[9]. Leptin is also an important nutritional marker and adiposity index during and after ALL therapy and is strongly correlated with BMI [8],[10]. We aimed to study the alterations in body composition of ALL survivors in comparison to healthy controls and to assess the relationship to serum leptin and lipid profile.
Patients and methodsStudy participants
Twenty-nine children, adolescents, and young adults aged 10–23 years with cured ALL were enrolled in the study. They were recruited from attendants of the Pediatric Oncology Clinic at Ain Shams University Children’s Hospital during the period from December 2016 to December 2017. All patients were treated according to the Children’s Cancer Group (CCG) protocol for ALL (CCG-1991 for standard risk ALL and CCG-1961 for high-risk group) [11],[12]. Thirty-five age- and sex-matched participants served as the control group. An informed consent was obtained from each participant or their legal guardian before participation. The procedures applied in this study were approved by the Ethics Committee for Human Experimentation at Ain Shams University and are in accordance with the Helsinki Declaration of 1975. Patients with pre-existing (before diagnosis of ALL) diagnosis of hypertension, DM of hyperlipidemia as well as patients with associated chronic disorders affecting weight (for example, thyroid disease eating disorders, and chromosomal disorders) were excluded from the study.
Anthropometric assessment and body composition analysis
Using the Tanita SC-330P scale (Tanita, Japan) and with the participant bare foot and in minimal clothing, the following measurements were estimated: weight (Kg), Body fat mass (Kg), body fat percent (%), fat-free mass (Kg), muscle mass (Kg), total body water (Kg), and total body water percent (%) (Tanita SC 330, Japan).
Height was measured by portable stadiometer with the participants’ feet placed together with heels, buttocks, and shoulder blades against the stick and head positioned in the Frankfurt horizontal plane.
BMI was defined as weight (in kg) divided by height (in m2). Waist and hip circumferences (WC and WC, respectively) were measured twice using inextensible anthropometric tape with the participant standing erect and relaxed with arms at the sides and feet positioned close together. WC was measured midway between the lowest border of rib cage and the upper border of iliac crest at the end of normal expiration. HC was measured at the widest part of the hip at the level of the greater trochanter.
Measurement of BP
BP measurement was done using sphygmomanometer by the same person. With the participant in a relaxed sitting position, BP was measured in the right arm using auscultatory method.
Laboratory investigations
Laboratory investigations were done for all participants, including complete blood count, fasting glucose, fasting insulin with calculation of insulin-to-glucose ratio, lipid profile (triglycerides (TG), total cholesterol, low-density lipoprotein-cholesterol (LDL-cholesterol), high-density lipoprotein-cholesterol (HDL-cholesterol)), and serum leptin.
Diagnostic criteria
Patients were categorized according to their BMI into obese if BMI is more than +2 SD for age (equivalent to BMI 30 kg/m2 at 19 years), overweight if more than +1 SD (equivalent to BMI 25 kg/m2 at 19 years), normal weight between greater than or equal to −2 SD and less than or equal to +1 SD, and thin if less than −2 SD for age [13],[14].
Hypertension
Hypertension was defined as systolic BP (SBP) and/or diastolic BP (DBP), that is, on repeated measurement, >95th percentile. BP between the 90th and 95th percentile in childhood is termed ‘prehypertensive’ [15].
Metabolic syndrome
Patients were defined as having the MS when they had central obesity >90th percentile as assessed by WC [16], plus any 2 of the following four factors: raised TG level more than 150 mg/dl, or specific treatment for this lipid abnormality; reduced HDL-cholesterol less than 40 mg/dl in males and less than 50 mg/dl in females, or specific treatment for this lipid abnormality; raised BP: SBP >130 or DBP >85 mmHg, or treatment of previously diagnosed hypertension; raised fasting plasma glucose: more than 100 mg/dl or previously diagnosed type 2 diabetes if above 100 mg/dl [17].
Statistical analysis
Data were analyzed using the Statistical Program for Social Science version 17 (SPSS Inc., Chicago, IL, USA). Quantitative data were described as mean±SD for parametric variables and median (interquartile range (IQR)) for non-parametric variables. Qualitative data were described as number and percentage. Independent Student’s t-test was used for comparison of parametric quantitative variables among two independent groups. Qualitative variables were compared using Chi-square (χ2) test or Fischer’s exact test when frequencies were below five. Pearson correlation coefficient was used for testing association between different parametric variables. A P value less than 0.05 was considered significant in all analyses.
ResultsStudy population
The study included 29 ALL survivors (14 males and 15 females) with a male-to-female ratio 1 : 1.1 and mean age 14.0±3.3 years (range: 10–21 years), and 35 healthy control participants (11 males and 24 females with male-to-female ratio 1 : 2.2) and mean age 12.5±3.5 (range 10–23 years). The median (IQR) time from diagnosis was 65.1 (46–106) months while median (IQR) duration from end of therapy was 25.2 (12–70.8) months. Other demographic and clinical characteristics are shown in [Table 1].
Table 1 Some clinical and laboratory characteristics of the ALL survivor groupSurvivors versus control group
Body mass index
BMI-standard deviation score (SDS) was significantly higher among ALL survivors (mean±SD 0.79±1.2, range ‑1.14 to −2.92) when compared to the control group (mean±SD 0.25±0.85, range: −1.44 to −2.72, P=0.041). Ten out of the 29 ALL survivors (34.5%) and 6/34 (17.6%) controls were overweight/obese; however, the difference between the two groups did not reach statistical significance (P=0.106). None of the study participants had lower than normal BMI. No significant difference was found between the two groups when comparing the waist-to-hip ratio (P=0.121).
Body composition
Compared to participants in the control group, ALL survivors had comparable body fat percent (P=0.415), fat-free mass % (P=0.217), muscle mass % (P=0.478), and body water % (P=0.075) ([Table 2]).
Table 2 Blood pressure, anthropometric measurements, and body composition of the studied groupsLipid profile and serum leptin
Serum levels of TG, total cholesterol, LDL-C, and HDL-C were comparable between both the groups (P=0.274, 0.220, 0.417, and 0.549, respectively). There was no difference between both groups when comparing serum leptin, although lower median levels were noticed among the survivor group, median (IQR) 3 ng/ml (0.5–9) for survivors and 5.5 ng/ml (1.9–8) for control participants ([Table 3]).
Metabolic syndrome
None of the study participants fulfilled the criteria for the diagnosis of MS as characterized by the International Diabetes Foundation.
Survivors
Overweight/obese versus normal BMI survivors
Among the ALL survivor group, there was no significant difference between the overweight/obese group and the normal BMI group when comparing sex (P=0.517), mean age at diagnosis (P=0.260), age at study entry (P=0.322), time from diagnosis (P=0.284.), time from end of therapy (P=0.203).
Overweight/obese survivors had significantly higher serum total cholesterol with mean±SD 157±33 versus 127.5±31, P=0.012 and LDL-C with mean±SD 97.8±25 versus 77.3±26, P=0.025. However, HDL-C, serum TG, insulin:glucose ratio, and serum leptin did not differ between both the groups (P=0.086, 0.396, 0.275, and 0.256, respectively).
BMI SDS positively correlated with waist-to-hip ratio (r=0.737, P<0.01) and body fat percent (r=0.816, P<0.01), while it negatively correlated with muscle mass percent (r=−0.820, P<0.01) and body water % (r=−0.828, P<0.01). BMI-SDS also positively correlated with total cholesterol (r=0.472, P=0.010) but not with LDL-C (r=0.292, P=0.124), TG (r=0.04, P=0.838), or serum leptin (r=−0.01, P= 0.959). There was no significant correlation between BMI-SDS and age at diagnosis (r=−0.065, P=0.743), age at study entry (r=−0.092, P=0.643), median time from diagnosis (r=0.063, P= 0.743), and median time from end of therapy (r=0.042, P=0.831).
Cranial irradiation
From the 29 ALL survivors, 6 patients (4 males and 2 females) had received chemoradiotherapy (CRT) as a part of their treatment regimens but none of them had higher than normal BMI. BMI-SDS in the CRT group was significantly lower than the non-CRT group (mean±SD −0.13±0.63 for the former and 1.03±1.2 for the latter, P=0.032).
Serum leptin
We did not find any correlation between serum leptin and any of the studied anthropometric measurements, including weight-SDS, height-SDS, BMI-SDS, or waist-to-hip ratio (r=−0.114, P=0.56; r=−0.211, P=0.28; r=−0.010, P=0.95, and r= 0.097, P=0.62, respectively). Similarly, no significant correlation was found between serum leptin and body composition analysis, including body fat % (r=0.124, P=0.47), fat-free mass % (r=−0.216, P=0.270), muscle mass % (r=−0.119, P=0.55), and total body water % (r=−0.162, P=0.41).
DiscussionWe found that around one-third of ALL survivors had increased BMI (10.3% overweight and 24% obese) as compared to only 17.6% for the control group (11% overweight and 6% obese), and BMI-SDS were significantly higher in ALL survivors. Mixed data regarding the prevalence and risk factors of obesity exist in literature. In one study, 26/68 (38.2%) of ALL survivors were overweight/obese with BMI-SDS significantly higher than the control group [18]. A recent study comparing 3 groups: patients with leukemia/lymphoma, patients with solid tumors, and healthy controls, reported a higher rate of obesity/overweightness among leukemia lymphoma group (34.5 during treatment and 43.7% after treatment) as compared to patients with solid tumors (25% during treatment and 13.7% after treatment) and healthy controls (24.8%) [19]. In contrast, Jahnukainen et al. [20] found no difference in the number of overweight participants between very long-term adult male ALL survivors and controls participants. In their meta-analysis, Zhang and colleagues examined the prevalence and risk factors of obesity among childhood survivors. The mean BMI z-score in 1742 pediatric ALL survivors from the 47 studies was 0.83 (95% confidence interval: 0.60–1.06), corresponding to the 80th BMI percentile, a significantly higher BMI than the reference population [21].
Obesity in ALL survivors is multifactorial and might include the effect of therapy itself, mainly cranial irradiation and corticosteroid use. In this work, we could not identify specific risk factors for overweightness/obesity related to ALL and its treatment. Cranial radiation is often cited as an independent risk factor for obesity and MS [22],[23],[24], and hypothalamic damage leading to growth hormone deficiency or leptin insensitivity, or both, have been suggested as causative factors [8],[25]. Out of the 29 ALL survivors in our study, 6 patients (4males and 2 females) had received CRT as a part of their treatment regimens but none of them had higher than normal BMI. Moreover, BMI in the non-CRT group was significantly higher than in the CRT group. We were unable to demonstrate a significant effect of central nervous system irradiation, perhaps because of a low number of patients receiving CRT. Also, we could not identify a correlation between serum leptin and BMI-SDS or body composition features.
In a recent meta-analysis, CCS had a significantly higher BMI regardless of treatment type, sex, or the length of time from the completion of treatment [21]. Moreover, recent ALL treatment protocols do not involve cranial irradiation, yet we still noted high prevalence of obesity among survivors, suggesting a higher risk of obesity/overweightness in ALL survivors regardless of the use of CRT. Other reports found that among males there was no difference between cranially irradiated and nonirradiated survivors, but females who had received cranial irradiation had a significantly higher BMI SDS than females who had not been cranially irradiated [18].
Some authors report increased body fat percent in their study cohort despite normal BMI-SDS [6] and hence suggesting that the body composition of CCS should be considered even if they are not overweight or obese. However, in our work BMI-SDS correlated well with body composition features being positively correlated with body fat percent and negatively correlated with fat-free mass percent and muscle mass percent, which signifies that BMI can still be a surrogate indicator to body fat.
ConclusionSurvivors of ALL in childhood are at an increased risk of obesity/overweightness with BMI-SDS representing a simple tool for assessment of body fat. As this may increase their future risks of MS and cardiovascular disease, incorporating preventive strategies into the treatment regimens of this group may be needed.
This work has been previously presented in the Society of Hematologic Oncology (SOHO) Annual Meeting in 2018, Texas, USA under the title ‘Obesity and Altered Body Composition in Childhood ALL Survivors‘.
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Conflicts of interest
There are no conflicts of interest.
References
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