Assessment of Obesity and Hepatic Late Adverse Effects in the Egyptian Survivors of Pediatric Acute Lymphoblastic Leukemia: a Single Center Study
1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt.
2 Department of Biochemistry, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt.
3 Department of Pediatrics, Benha Educational Hospital, Benha, Egypt.
Received: September 9, 2016
Accepted: March 27, 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017026 DOI 10.4084/MJHID.2017.026
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Childhood acute lymphoblastic leukemia (ALL) with current cure rates
reaching 80% emphasizes the necessity to determine treatment-related
long-term effects. The aim of this study is to estimate the prevalence
of overweight, obesity, and hepatic late adverse effects in a cohort of
ALL survivors treated at the Hematology and Oncology Unit, Pediatrics
Department, Menoufia University, Egypt.
Fortunately, improvements in treatment, including multimodal therapy and hospital care, have improved survival such that over 80% of children diagnosed with ALL survive at least five years.[2,3]
However, childhood cancer survivors are at increased risk of developing chronic health conditions, some of which manifest during or soon after treatment whereas others emerge years after therapy. Obesity is a particularly significant problem among ALL survivors, which can intensify cardiovascular outcomes and place these individuals at greater risk for other chronic health conditions.
Evidence from the Childhood Cancer Survivor Study (CCSS) suggests that survivors of ALL (who lived 5ys after treatment) experience a higher rate of obesity than their same-sex siblings, especially for female survivors (ALL: 31.7% vs. siblings: 22.2%). Obesity may further compound the risk of other late effects, such as increased rate of cardiovascular diseases observed in childhood cancer survivors.
Previous studies have attributed obesity to the cranial irradiation (CRT) patients received to prevent central nervous system (CNS) relapse, However, since the 1990s, CNS prophylaxis with CRT protocols has gradually been replaced with intrathecal and systemic chemotherapy by several consortia. A study of the Children’s Oncology Group (COG) found excessive weight gain also occurred in children receiving chemotherapy alone. Treatment with glucocorticoids has been implicated in the physiology of adiposity, and there is data that dexamethasone may act more potently than prednisone. Prolonged use of corticosteroids has shown effects on body composition associated with increases in the percentage of body fat in pediatric ALL survivors.
Also, Hepatic abnormalities are well documented in survivors of childhood malignancies. A spectrum of liver diseases has been described including hepatitis B and C, iron overload, hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Less commonly reported hepatobiliary complications include cholelithiasis, focal nodular hyperplasia (FNH), nodular regenerative hyperplasia, hepatic microvesicular fatty change and siderosis. The Childhood Cancer Survivor Study (CCSS) noted an almost two-fold excess risk of gallbladder disease among childhood cancer survivors compared to sibs (1.9 95 % 1.7–2.2).
Acute or sub-acute hepatobiliary injury is recognized with varying incidence following radiation, multiple chemotherapies, or hematopoietic stem cell transplantation (HSCT). Additionally, hepatobiliary toxicity is associated with supportive care measures, such as transfusion-acquired hepatitis, transfusion-associated iron overload or cholestatic disease from total parenteral nutrition (TPN). These conditions may predispose to clinically significant liver disease in aging childhood cancer survivors. In this study, we aimed to estimate the prevalence of overweight, obesity, and hepatic late adverse effects in pediatric ALL survivors who lived 5 years after treatment.
Patients and Methods
None of those survivors received radiotherapy. The study was done in the period between March 2015 and December 2015. A control group of 35 healthy children with matched age and sex was selected from volunteers from a local school. They were apparently healthy with no history of chronic illnesses or previous history of steroid intake. A written informed consent was obtained from the parents of all children, and oral assent was obtained from children of both groups. This study was approved by the ethical committee of the Faculty of Medicine, Menoufia University.
The survivors and controls were subjected to anthropometric measurements and laboratory investigations:
Anthropometric measurements (weight, height, and body mass index), BMI was assessed by Z-score. Body Mass Index = Weight in Kilograms/ (Height in meters) ² was plotted on age and gender-specific percentile charts (for 2 to 20-year-olds). BMI over the 95th percentile indicates obesity, between 85th and 95th, indicates risk of overweight. We evaluated longitudinal changes in obesity rate and BMI Z scores in survivors of pediatric ALL as for survivors of childhood cancer aged <20 y. The BMI Z-score or percentile is often used to evaluate weight status, rather than the absolute BMI because an increased BMI is part of the normative/adolescent development and also varies by sex. The BMI Z-score or percentile can be calculated on the basis of age and sex-specific mean BMI of a reference population. 7 ml of venous blood were withdrawn from every child then transferred into a plain tube, centrifuged for 10 min at 4000 r.p.m. The serum obtained was kept frozen at - 20 ºC till analysis (Liver, kidney function tests, iron profile and HCV antibodies detection). Serum ALT & AST were estimated by enzymatic colorimetric method using Randox kit, United Kingdom. Serum total and direct bilirubin were estimated by enzymatic colorimetric method using Diamond Diagnostics kit, Germany. Serum urea was determined by Mod Berthelot enzymatic colorimetric method using Diamond Diagnostics Kit, Germany. Serum creatinine was determined by the fixed rate kinetic chemical method, using Diamond Diagnostics Kit, Germany. Serum iron and total iron binding capacity (TIBC) were determined by a colorimetric method using SPECTRUM diagnostics kit (Germany).[23,24] Transferrin saturation index (TSI) was calculated by the following formula: iron concentration divided by TIBC and multiplied by 100. The TSI > 16% values were regarded as correct ones. Serum ferritin levels were measured to assess the iron status of our patients by Enzyme Linked Immune Sorbent Assay (ELISA) technique using (RAMCO LABORATORIES kit, INC., USA), and HCV antibodies were detected by ELISA using (AUTOBIO DIAGNOSTICS, China) kit on microplate reader (Bio-Rad 680 Hercules, California, USA).
|Table 1. Z-score of anthropometric measures of studied groups|
|Table 2. Multivariate analysis of predicting risk factors for obesity.|
|Table 3. Laboratory investigations of studied groups.|
|Table 4. HCV Antibodies in studied groups.|
|Table 5. Correlation between risk of liver abnormalities in patients and higher asparaginase cumulative dosage.|
|Table 6. Correlation between liver abnormalities and increased ferritin level.|
Fang et al. indicated a significantly higher BMI in pediatric ALL survivors than the reference population. However, a study by Murphy et al. found that on-treatment and survivor groups had a significantly lower body cell mass index than matched controls, and 53% of the survivors were considered undernourished.
In a study done on 56 adolescent, ALL survivors in Saudi Arabia, with a mean age of 13.4 years an average of 9.1 years post-diagnosis who did not receive CRT, the prevalence of BMI for age defined overweight, and obesity (combined 28.5%) were lower than in the general population in Saudi Arabia. The authors supposed that overweight and obesity observed were probably not an ALL specific problem.
Our results demonstrated that the survivors who had high BMI z-score at diagnosis also had increased risk of being overweight /obese after treatment completion. This result was in line with Fang et al. study which is a retrospective cohort of 83 pediatric patients with ALL; they examined BMI status at several key time points: diagnosis; end of induction; end of consolidation; every 6 months during maintenance; and yearly for up to 5 years post-treatment. At diagnosis, 21% were overweight (BMI = 85–94.9th percentile) or obese (BMI ≥95th percentile). At the end of treatment and 5 years post-treatment, approximately 40% were overweight or obese. Weight gain during treatment was associated with being overweight/obese 5 years post-treatment (OR = 3.8, 95% CI: 1.1–12.5).
All of the involved survivors had received dexamethasone with the mean cumulative dose of 927 ± 135 mg/m2 which may be the cause of weight gain. It is not entirely understood why ALL survivors gain excess fat mass. One theory is that, during glucocorticoid treatment, ALL patients have an increased energy intake and reduced energy expenditure on habitual physical activity and that this effect continues after treatment ceases. Other theories are that glucocorticoid treatment causes increased adiposity by suppressing growth hormone secretion or that it causes resistance to leptin.
The second aim of this study was to assess the hepatic late adverse effects in pediatric ALL survivors. At our study, there was a significant increase in D. Bilirubin, T. Bilirubin, ALT, serum ferritin and soluble transferrin saturation in the survivors’ group more than the control group. Ten of our survivors (28.6 %) have HCV positive antibodies detected by ELISA. These results go with the previous findings of Mulder et al. who concluded that abnormal high ALT level was detected in survivors of childhood cancer. Also, Schempp et al. found elevated levels of serum ferritin and soluble transferrin (iron overload) in survivors of childhood cancer and attributed this to Transfusion volume. This iron overload causes tissue damage through the chronic formation of free radicals leading to liver dysfunction.
In a study of 118 children (with standard-risk leukemia) receiving native E. coli asparaginase or PEG-asparaginase, abnormal liver function (grade 3/4), including elevated transaminases and hyperbilirubinemia, was found in 8% of patients receiving native E. coli asparaginase and in 5% of patients receiving PEG-asparaginase.
There are no clear pediatric guidelines for the management of asparaginase in patients with hepatic toxicity, and treatment recommendations vary across protocols. In the DCOG ALL-11 pediatric protocol, patients are required to display aspartate aminotransferase/alanine aminotransferase < 10×ULN and no signs of jaundice with bilirubin < 3× ULN before starting asparaginase treatment.
Patients with hematologic malignancies were at a very high risk of HCV infection due to the large transfusional support they often needed. The previously immunocompromised status of the leukemia survivors may have promoted more rapid viral replication or impaired host viral clearance and led to rapidly progressive liver disease.
Moreover, it is known that chemotherapeutic drugs (methotrexate and 6-mercaptopurine) increase the risk of liver toxicity during or soon after cancer treatment.
- Shalaby R, Ashaat N, El-Wahab N, El-Hamid M, El-Wakeel S. Bcl-2 expression and chromosomal abnormalities in childhood acute lymphoblastic leukemia. Academic Journal of Cancer Research 2010; 3(2):34-43.
- Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer Incidence in Egypt: Results of the National Population-Based Cancer Registry Program. J Cancer Epidemiol. 2014; 2014: 437971. doi:10.1155/2014/437971. https://doi.org/10.1155/2014/437971
- Tantawy AA, El-Rashidy FH, Ragab IA, Ramadan OA, El-Gaafary MM. Outcome of childhood acute Lymphoblastic leukemia in Egyptian children: a challenge for limited health resource countries. Hematology. 2013; 18(4):204-210. https://doi.org/10.1179/1607845412Y.0000000061 PMid:23394310
- Hudson MM, Ness KK, Gurney JG, Mulrooney DA, Chemaitilly W, Krull KR, et al. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 2013; 309, 2371-81. https://doi.org/10.1001/jama.2013.6296 PMid:23757085 PMCid:PMC3771083
- Zhang F, Liu S, Chung M, Kelly M. Growth patterns during and after treatment in patients with pediatric ALL: A meta-analysis. Pediatr Blood Cancer. 2015;62(8):1452-1460 https://doi.org/10.1002/pbc.25519 PMid:25808413 PMCid:PMC4482769
- 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. https://doi.org/10.1200/JCO.2008.16.3527 PMid:18824710 PMCid:PMC2653124
- Oeffinger KC. Are survivors of acute lymphoblastic leukemia (ALL) at increased risk of cardiovascular disease? Pediatr Blood Cancer. 2008; 50(2 Suppl):462-7; discussion 468. [PubMed: 18064658]. https://doi.org/10.1002/pbc.21410 PMid:18064658
- Oeffinger KC, Mertens AC, Sklar CA, Yutaka Yasui, Thomas Fears, Marilyn Stovall, et al. Obesity in adult survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study. J Clin Oncol 2003; 21(7):1359-65. https://doi.org/10.1200/JCO.2003.06.131 PMid:12663727
- Withycombe JS, Post-White JE, Meza JL, Hawks RG, Smith LM, Nancy Sacks et al. Weight patterns in children with higher risk ALL: a report from the Children's Oncology Group (COG) for CCG 1961. Pediatr Blood Cancer 2009; 53(7):1249- 54. https://doi.org/10.1002/pbc.22237 PMid:19688832 PMCid:PMC3044478
- Tonorezos ES, Vega GL, Sklar CA, Chou JF, Moskowitz CS, Qianxing Mo, et al. Adipokines, body fatness, and insulin resistance among survivors of childhood leukemia. Pediatr. Blood Cancer 2012; 58: 31-6. https://doi.org/10.1002/pbc.22964 PMid:21254377 PMCid:PMC3520427
- Chow EJ, Pihoker C, Hunt K, Wilkinson K, Friedman DL. Obesity and hypertension among children after treatment for acute lymphoblastic leukemia. Cancer 2007; 110: 2313-20. https://doi.org/10.1002/cncr.23050 PMid:17896787
- Bano G, Chong H, Vlahos I. A new long term hepatic complication in survivors of childhood haematological malignancy. Med Hypotheses 2012; 79(5):663-6. https://doi.org/10.1016/j.mehy.2012.08.004 PMid:22951417
- Goldsby R, Chen Y, Raber S, Linda Li, Diefenbach K, Shnorhavorian M, et al. Survivors of childhood cancer have increased risk of gastrointestinal complications later in life. Gastroenterology 2011; 140: 1464-71. https://doi.org/10.1053/j.gastro.2011.01.049 PMid:21315721 PMCid:PMC3081911
- Rodriguez-Frias EA, Lee WM. Cancer chemotherapy II: atypical hepatic injuries. Clin Liver Dis. 2007; 11(3):663-76. https://doi.org/10.1016/j.cld.2007.06.012 PMid:17723925
- Castellino S, Muir A, Shah A, Shope S, McMullen K, Ruble K, et al. Hepato-Biliary Late Effects in Survivors of Childhood and Adolescent Cancer: A Report from the Children's Oncology Group. Pediatr Blood Cancer 2010; 54(5):663-9. PMid:19890896 PMCid:PMC2838980
- Pui CH, Sandlund JT, Pei D. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 2004; 104:2690-6. https://doi.org/10.1182/blood-2004-04-1616 PMid:15251979
- Zhang FF, Rodday AM, Kelly MJ, Must A, Macpherson C, Roberts SB, et al. Predictors of being overweight or obese in survivors of pediatric acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer 2014; 61:1263-9. https://doi.org/10.1002/pbc.24960 PMid:24482072 PMCid:PMC4435552
- Barlow SE. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics 2007; 120(Suppl 4):S164-92. https://doi.org/10.1542/peds.2007-2329C PMid:18055651
- Centers for Disease Control and Prevention. CDC Growth Chart Training Modules: Overweight Children and Adolescents: Recommendations to Screen, Assess and Manage. Available at: http://www.cdc.gov/nccdphp/dnpa/growthcharts/training/modules/module3 /text/page4a.htm. Accessed: 26 February 2006.
- Tietz NW, 1995. Clinical Guide to Laboratory Tests. 3rd Edn., W.B. Saunders Co, Philadelphia, PA. PMCid:PMC228439
- Tobacco A; Meiathini F; Moda E and Tarli P (1979): Simplified enzymic/colorimetric serum urea nitogen determination. Clin Chem 25:336-337.
- Bowers L and Wong E (1980): kinetic serum creatinine assays. A critical evaluation and review. Clin Chem; 26:555-561. PMid:7020989
- Stookey L. (1970): Ferrozine – a new spectrophotometric reagent for iron. Anal chemistry 42: 779-781. https://doi.org/10.1021/ac60289a016
- Fairbanks V and Klee G. (1987): Biochemical aspects of hematology In: Tietz NW, ed. Fundamentals of clinical chemistry 3rd ed. Philadelphia WB saunders. 789-824.
- Kamer B et al. (2012): The usefulness of soluble transferrin receptor (sTfR) in differentiating anemia occurring in young children. FOLIA HISTOCHEMICA ET CYTOBIOLOGICA,Vol. 50: 473–479. https://doi.org/10.5603/FHC.2012.0066
- Salazar-Martinez E, Allen B, Fernandez-Ortega C,Torres-Mejia G, Galal O, Lazcano-Ponce E. Overweight and obesity status among adolescents from Mexico and Egypt. Arch Med Res, 2006; 37 (4):535-42. https://doi.org/10.1016/j.arcmed.2005.10.014 PMid:16624655
- Asner S, Ammann RA, Ozsahin H, Beck-Popovic M, von der Weid N.X. Obesity in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia. Pediatr Blood Cancer 2008; 51:118-22. https://doi.org/10.1002/pbc.21496 PMid:18338394
- Fang F. Zhang, Michael J. Kelly, Edward Saltzman, Aviva Must Susan B. Roberts, Susan K. Parsons. Obesity in Pediatric ALL Survivors A Meta-Analysis. Pediatrics 2014;133 :e704-e15.
- Murphy AJ, White M, Elliott SA, Lockwood L, Hallahan A, Davies PSW. Body composition of children with cancer during treatment and in survivorship. Am J Clin Nutr. 2015 Oct; 102(4):891-6. https://doi.org/10.3945/ajcn.114.099697 PMid:26269368
- Aldhafiri F, Al-Nasser A, Al-Sugair A, Al-Mutairi H, Young D, Reilly JJ. Obesity and metabolic syndrome in adolescent survivors of standard risk childhood acute lymphoblastic leukemia in Saudi Arabia Pediatr Blood Cancer. 2012; 59 (1):133-7
- Fang Fang Zhang, Angie Mae Rodday, Michael J. Kelly, Aviva Must, Cathy MacPherson, Susan B. Roberts, Edward Saltzman, and Susan K. Parsons (2014): Predictors of Being Overweight or Obese in Survivors of Pediatric Acute Lymphoblastic Leukemia (ALL). Pediatr Blood Cancer. 2014 July ; 61(7): 1263–1269. doi:10.1002/pbc.24960. https://doi.org/10.1002/pbc.24960
- Reilly JJ, Brougham M, Montgomery C, Richardson F, Kelly A, Gibson BE. Effect of glucocorticoid therapy on energy intake in children treated for acute lymphoblastic leukemia. J Clin Endocrinol Metab 2001; 86:3742-5. https://doi.org/10.1210/jcem.86.8.7764 PMid:11502805
- Warner JT, Bell W, Webb DK, Gregory JW. Daily energy expenditure and physical activity in survivors of childhood malignancy. Pediatr Res 1998;43:607-13 https://doi.org/10.1203/00006450-199805000-00008 PMid:9585006
- Davies JH, Evans BAJ, Jones E, Evans WD, Jenney MEM, Gregory JW. Osteopenia, excess adiposty and hyperleptinaemia during 2 years of treatment for childhood acute lymphoblastic leukemia without cranial irradiation. Clin Endocrinol 2004;60:358-65 https://doi.org/10.1111/j.1365-2265.2003.01986.x
- Mulder RL, Kremer LC, Koot BG, Benninga MA, Knijnenburg SL, van der Pal HJ, et al. Surveillance of hepatic late adverse effects in a large cohort of long-term survivors of childhood cancer: prevalence and risk factors. Eur J Cancer. 2013 Jan; 49(1):185-93. Epub 2012 Aug 15. https://doi.org/10.1016/j.ejca.2012.07.009 PMid:22901831
- Schempp A, Lee J, Kearney S, Mulrooney DA, Smith AR. Iron Overload in Survivors of Childhood Cancer. J Pediatr Hematol Oncol. 2016 Jan; 38(1):27-31. https://doi.org/10.1097/MPH.0000000000000444 PMid:26422286
- Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM. Ferritin for the clinician. Blood Rev. 2009 May; 23(3):95-104. https://doi.org/10.1016/j.blre.2008.08.001 PMid:18835072 PMCid:PMC2717717
- Dinndorf PA, Gootenberg J, Cohen MH, et al. FDA drug approval summary: pegaspargase (Oncaspar_) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). Oncologist 2007; 12: 991–998. https://doi.org/10.1634/theoncologist.12-8-991 PMid:17766659
- Dutch Childhood Oncology Group. Treatment study protocol of the Dutch Childhood Oncology Group for children and adolescents (1–19 year) with newly diagnosed acute lymphoblastic leukemia; April 10, 2013. Accessed December 1, 2014 from: https:// www.skion.nl/workspace/uploads/Onderzoeksprotocol-ALL11-version-4-1-april-2013.pdf
- Kebudi R, Ayan I, Y´ilmaz G, Akící F, Görgün O, Badur S. Seroprevalence of hepatitis B, hepatitis C and immunodeficiency virus infections in children with cancer at diagnosis and following therapy in Turkey. Med Pediatr Oncol.2000;34: 102-5. https://doi.org/10.1002/(sici)1096-911x(200002)34:2<102::aid-mpo5>3.0.co;2-#
- Paul IM, Sanders J, Ruggiero F, Andrews T, Ungar D, Eyster ME. Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease. Blood. 1999 Jun 1;93(11):3672-7 PMid:10339473
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