Journal of the American College of Nutrition, Vol. 26, No. 1, 49-56 (2007)
Published by the American College of Nutrition
Post-Therapy Profile of Serum Total Cholesterol, Retinol and Zinc in Pediatric Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma
Chanda D. Gokhale, PhD,
Shobha A. Udipi, PhD,
Ramkrishna Y. Ambaye, PhD,
Suresh K. Pai, MD and
Suresh H. Advani, MD
University Department of Food Science and Nutrition, S.N.D.T. Women's University (C.D.G., S.A.U.)
Research Projects in Pharmacology, Department of Pharmaceutical Sciences and Technology, University of Mumbai Institute of Chemical Technology (R.Y.A.)
Department of Medical Oncology, Tata Memorial Hospital (S.K.P.)
Jaslok Hospital, Mumbai, INDIA (S.H.A.)
Address correspondence to: Dr. C. D. Gokhale, Dept of Food Science and Nutrition, Dept of Postgraduate Studies and Research in Home Science, S.N.D.T. Women's University, Juhu, Mumbai—400049, INDIA. E-mail: agashechanda{at}rediffmail.com
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ABSTRACT
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Objective: To assess serum albumin, total cholesterol, retinol, zinc and hemoglobin in children who had completed treatment for acute lymphoblastic leukemia (ALL) and Non-Hodgkin's lymphoma (NHL).
Methods: The above parameters were analyzed in 105 ALL and NHL and 108 age and sex-matched controls. Serum albumin, serum cholesterol and hemoglobin were estimated by colorimetric methods. Serum retinol was estimated by HPLC and serum zinc was estimated by atomic emission spectrophotometer (ICP-AES). Comparisons were made to stage of treatment (maintenance 6 with post-therapy), type of treatment (chemotherapy and radiation with only chemotherapy) and type of malignancy (ALL with NHL).
Results: Only serum albumin in patients included at Maintenance6 was significantly higher (t = 2.31, p = 0.05) than post-therapy patients. No significant difference in serum values was observed by type of treatment. Only total cholesterol was significantly higher in NHL patients than in ALL patients (t = 1.954, p = 0.05). Patients had comparable serum levels to that of controls. However, in patients and controls more than 75% children had deficient serum retinol levels, (< than 0.6989 µmol/l, or 20 µg/dl). Further, 75% patients and 54.7% controls had serum retinol levels less than 0.3439 µmol/l or 10 µg/dl.
Conclusion: The results of the present study indicate that cancer and its treatment did not have any long-lasting effect on serum albumin, total cholesterol, retinol, zinc and hemoglobin. Majority of subjects had low serum retinol suggestive of depleted liver reserves. The deficient serum retinol levels (< than 0.6989 µmol/l, or 20 µg/dl) in at least 75% of the patients and controls probably reflect poor dietary intake. A higher percentage of patients with low serum retinol levels may also be attributed to the possibility of urinary losses of retinol that occur during episodes of infection while on immunosuppressive anti-cancer drug therapy.
Key words: acute lymphoblastic leukemia, Non-Hodgkin's lymphoma, children, India
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INTRODUCTION
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Cancer is frequently associated with a combination of metabolic abnormalities leading to a complex abnormal biochemical state in the tumor-bearing host.
Several investigators have reported hypoalbuminemia at the time of diagnosis of malignancy in children and attributed it to reduced protein intake coupled with hypermetabolic state [1–5]. The hypermetabolic state in children at diagnosis is attributed to incipient infection present without overt signs of infection, as two thirds of patients were febrile and half had hypoalbuminemia. The febrile conditions may lead to elevated secretion of IL-1, which may be associated with altered protein metabolism in muscle and liver. The elevation in energy expenditure was closely associated with accelerated rates of whole body protein turn over [1]. Besides this, the proinflammatory cytokines like IL-6, TNF-
, and IL-2 contribute to a catabolic state, and are clearly implicated in the hypermetabolism and weight loss associated with cancer-associated cachexia [6–7].
Alteration in lipid metabolism at time of diagnosis of pediatric leukemia and lymphoma was observed [8–11]. The researchers found hypertriglyceridemia, reduction in HDL—Cholesterol and hypocholesterolemia in their cancer patients [8–9]. However, in one recent study it was observed that at time of diagnosis of leukemia in children, serum total cholesterol was not lowered unlike that found in adult leukemias. The researchers further stated that the return of serum lipids and lipoproteins towards normal limits during remission confirms correlation of lipid abnormalities with primary disease activity [11].
Unlike abnormalities in protein and lipid metabolism, which are associated with tumor pathogenesis and tumor—host interactions, reductions in circulating vitamins like retinol are not associated with tumor growth and metabolism. Plasma levels of vitamins like retinol, B2, B6, C and E were not affected by underlying disease [12]. Low levels of circulating vitamins observed in children at diagnosis of cancer when compared to normal children are not the effect of disease but due to chronically low intake [4].
Among abnormalities of mineral metabolism, elevation of circulating copper, reduction in circulating zinc, with significantly low serum zinc level at diagnosis compared to controls and consequently an alteration in copper: zinc ratio have been reported [13–16]. Magnesium deficiency has also been reported and it is likely that zinc and magnesium deficiency might be associated with development of malignancy [16].
Further, chemotherapy also affects these parameters. L-asparginase-induced impairment of hepatic protein synthesis is implicated in low serum albumin [5] and an altered lipid: protein ratio in HDL-Cholesterol [10,17].
Elevation in serum total cholesterol levels during therapy has been reported and the researchers attributed it to the effect of corticosteroids, rather than effect of L-asparginase. Corticosteroids alter lipids and lipoprotein synthesis by increasing hepatic cholesterol synthesis [10].
In contrast to abnormalities in protein and lipid metabolism, plasma levels of most vitamins except vitamin A are not affected by chemotherapy; a significant increase in serum retinol during early phase of induction followed by subsequent reduction was observed [12]. In other studies an increase in circulating retinol is reported with commencement of therapy [18,19].
Similarly, with chemotherapy decrease in serum zinc level has been reported. This reduction in circulating zinc was attributed to low dietary intake [12,15,18].
With increasing number of survivors of childhood leukemia and lymphoma, it becomes important to assess the status of these parameters in order to determine whether disease or treatment have any long lasting effect, especially among the survivors of developing countries where undernutrition is more prevalent. Also, these parameters are indicators of nutritional status and play an important role in promoting growth. In view of paucity of data from developing countries, it was deemed worthwhile to study these parameters in pediatric acute lymphoblastic leukemia (ALL) and Non-Hodgkins lymphoma (NHL) patients in remission and on completion of therapy.
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MATERIALS AND METHODS
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The study was approved by the authorities of Tata Memorial Hospital, and the Research Committee of S.N.D.T. Women's University. The patient group was identified from Tata Memorial Hospital, Mumbai. Children treated for ALL and NHL (diffuse lymphoblastic or Burkitt type) when attended OPD clinic for follow-up on completion of treatment were recruited over a period of 11/2 years after completion of treatment. Some ALL patients undergoing last treatment phase the Maintainance6 (M6) phase were also recruited in the present study. Patients with ALL or NHL were treated with anti-cancer drugs protocol and radiation therapy or only chemotherapeutic drug protocol. Dosage modifications were done according to body surface area (BSA) of the patient. The drug protocol—MCP 841 for ALL and MCP 842 used for NHL was designed in collaboration with National Cancer Institute (NCI), Bethesda, USA [20]. The protocol is summarized in Table 1.
The Patient Group
The patient group consisted of 134 ALL or NHL patients. Parental consent was obtained before recruiting the child in the study. Height and weight was recorded for 122 out of 134 patients as 12 patients who were included at last treatment phase (M6) did not come to the clinic on completion of treatment, while blood sample was collected for 105 ALL/NHL patients. The profile of the patient group is presented in Table 2.
The Control Group
The control group consisted of 137 age and sex-matched children. Blood collection was carried out for 108 children, whereas height and weight measurements were carried out for all 137 controls. The children were recruited by approaching the authorities of three schools in the city of Mumbai after taking due permission. The parents were contacted through children for data collection. They were comparable according to nutritional status as well as socio-economic background.
All children were healthy with no evidence of any minor or major ailments including infections at time of recruitment in the study.
Blood Collection and Analysis.
Blood Collection: A written parental consent was obtained for each child, from the patient as well as from the control group. 10 ml of venous blood in fasting state in the morning was drawn from the antecubital vein. The biochemical parameters that were analyzed included albumin, retinol, total cholesterol, zinc and hemoglobin. On collection of blood sample a small aliquot was kept aside for estimation of hemoglobin. The remaining blood was transferred to polypropylene trace element-free centrifuge tube wrapped with aluminum foil. Direct exposure to sunlight was avoided and serum was separated and stored frozen at –20° C in trace element-free storage vials. The centrifuge tubes and storage vials were made trace element-free by rinsing in acids and washing with deionised water [21]. The deionised water was periodically checked for zinc content on Inductively Coupled Plasma Atomic Emission Spectrophotometer (ICP-AES).
Analysis: Aliquots of stored serum were analyzed for albumin, total cholesterol, retinol and zinc. Serum albumin was estimated by using bromocresol green (BCG) dye-binding method [22]. Commercial Cholesterol reagents kit from Pointe Scientific Inc, U.S.A. and marketed by Ranabaxy was used for the estimation of cholesterol. The estimation of serum retinol was estimated by using High-Pressure Liquid Chromatography (HPLC) [23]. Serum zinc was estimated on Inductively Coupled Plasma Atomic Emission Spectrophotometer (ICP-AES) [24]. Hemoglobin was estimated by the cyanomethmoglobin method [25]. Quality Control/Calibration—Commercial reference control serum Humatrol Normal (N) and Humatrol Pathological (P) were used for albumin, total cholesterol and zinc. The reference controls with known normal and elevated values were used to ensure adequate quality control. Quality Control/Calibration were also applied to Hemoglobin.
Height and Weight.
Height and weight measurements were recorded using standard techniques [26].
Statistical Analysis
Student's t test was carried out to determine whether there were significant differences between: The mean values of all parameters by stage of inclusion, by type of malignancy and by type of treatment. Also the mean values of all parameters were compared between the patient group and control group.
Chi-square test was applied to assess the difference between the distribution of patients and controls as categorized according to cut-off values for deficient, low and acceptable levels for retinol, zinc and hemoglobin. The p value = or < than 0.05 was considered as significant.
All analyses were performed using the programs available in the Statistical Package for Social Sciences (SPSS), Versions 6 and 10 for Windows.
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RESULTS
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The mean serum levels of albumin of patients at M6 were significantly different than the mean values of post-therapy patients (t = 2.31, p = 0.05), whereas mean serum levels of total cholesterol, retinol, zinc and hemoglobin of ALL patients at M6 were not significantly different from the patients who had completed therapy (Table 3). The mean values of the patient group did not differ significantly by the type of treatment they had received (Table 4). Further, mean values for the biochemical parameters were examined by the type of malignancy (Table 5). It was observed that only mean serum total cholesterol value of NHL patients was significantly higher than mean values of ALL patients (t = 1.954, p = 0.05).
Age-group wise comparisons of mean height and weight of patients and controls indicated significant difference in mean height of patients and controls only in the age-range of 12.1 to 15 years (t = –2.60, p = 0.01) (Tables 6 and 7). Also, comparison of means of all biochemical parameters of patient group with those of controls indicated no significant difference (Table 8).
Serum retinol less than 0.6989 µmol/l (20 µg/dl) has been considered deficient according to the recommendation of International Vitamin A Consultative Group, 2001 [27]. The subjects in the present study were categorized based on these criteria (Table 9).
The distribution indicates that majority of children from control and patient group had deficient levels, the percentage being marginally higher in the patient group. No significant difference was observed in the distribution. However, 67 out of 88 patients (75.0%) patients had serum retinol less than 0.3491 µmol/l (10 µg/dl), whereas, 41 out of 75 controls (54.7%) had serum less than 0.3491 µmol/l (10 µg/dl). Although, a higher percentage of children from the patient group had extremely low levels of retinol compared to the controls the difference was not significant.
Similarly, categorization of patient and control group was done for serum zinc levels (Table 10). Fasting zinc levels below 9.0 µmol/l is considered deficient and zinc levels between 11.5 to 13 µmol/l are considered low [28].
More than 30% of children from patient and control group had serum levels in the acceptable range. 36.3% controls had low values (9.0–13.0 µmol/l), the percentage being higher than patient group (31%). However, the percentage of controls with deficient levels (17.0%) was slightly but not significantly higher than controls (12.1%). The percentage of patients with values above 22.0 µmol/l was higher than controls (11.0% vs. 3.4%).
Hemoglobin levels in children (Table 11) were classified according to WHO criteria for diagnosis of anemia [29] (Table 12).
The majority of children from both groups had acceptable hemoglobin status, the percentage of patients in this category being slightly higher than controls. Only around 3% of children had deficient levels, whereas 14% and 17% of children from both groups had low status, the percentage being marginally higher in controls.
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DISCUSSION
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Serum levels of albumin, total cholesterol, retinol, zinc and hemoglobin were estimated in 105 patients treated for ALL or NHL. Their values were matched with age and sex-matched controls in order to determine whether these biochemical parameters are affected by the type of disease and treatment, and also to find out the status of the patients who have completed therapy since there are very few reports in the literature.
These indicators of nutritional status are not affected by type of malignancy and the type of treatment administered. Also the drugs administered did not affect any parameters as the profile of patients at last treatment phase was comparable to the profile of the patients in post-therapy stage. The significant difference that was observed in serum albumin levels at M6 being higher than those observed post-therapy may be due to blood and blood components that are administered during therapy. The mean total cholesterol of NHL patients was significantly higher than mean total cholesterol values of ALL patients (t = 1.954, p = 0.05). Malvy et al (1997) reported that mean serum total cholesterol levels in NHL patients was higher than that of ALL patients, however the difference in the mean values in that study was not significant [18].
Further, patients did not differ significantly from matched controls in the examined parameters. Hence the most significant finding of the present study is that cancer and its treatment did not have any long-lasting effect on these selected biochemical parameters. Also the nutritional status of patients was comparable to that of controls as indicated by height and weight data. Moschovi et al (2004) reported that 79% of ALL patients who were in remission had normal total cholesterol levels [11]. On the contrary, in another study ALL survivors had significantly higher levels of total cholesterol [10]. In the present study, the total cholesterol of the patient group was comparable to the values reported for normal Indian children and Pakistani children [30,31]. The variation in cholesterol values in different studies and between different childhood sample populations may be attributed to varied dietary patterns that are followed in different geographical areas of the world. Saturated fat is an important determinant of cholesterol levels. Like adults, even in children the major nutritional determinant of differences in serum total cholesterol levels between countries appears to be the proportion of saturated fat in the diet [31,32]. It has been reported that with reduction in amount of saturated fat in diet the serum cholesterol values in 12–17 year old American children were reduced by 7 mg/dl or 0.181 µmol/l [33].
The results of the present study indicate that nearly 87% patients and 81% controls had deficient levels (< than 0.6989 µmol/l or 20 µg/dl), the low circulating level of serum retinol indicates depleted liver stores [27]. Hence, both patients and controls appear to have low liver reserves. Liver stores of vitamin A accumulate as a function of the absorbed intake, basal requirements and catabolic losses of the vitamin. Dietary intake depends on the volume and vitamin A content of the foods consumed and the percentage absorbed from each source. Basal requirements are primarily influenced by age and body size. Catabolic loss of vitamin A is proportional to existing vitamin A liver stores and the catabolic rate of the vitamin. Illness may affect vitamin A stores by reducing intake, reducing absorption and increasing catabolic rate [34].
It was not possible to compare serum retinol status of the subjects of present study with other studies because there are very few reports on Indian children. The studies that are carried out are mainly on infants and preschool children but not on school children. Nevertheless, these findings highlight the sub-optimal Vitamin A status of school children, especially during the period of rapid growth.
A higher percentage of patients had extremely low levels of serum retinol (0.3491 µmol/l (10 µg/dl). Leukemic patients are immunocompromised and so various infections during therapy are frequent. It may be speculated that low retinol in leukemic patients be attributed urinary losses during the episodes of infection or may be a consequence of decreased synthesis or increased utilization of vitamin A during the episodes of infection [35,36]. It was not possible to correlate the incidence of episodes of infections during therapy with serum retinol levels of the patients as the morbidity data was not recorded during the study and later the hospital data is inaccessible. Hence, a speculation is made about the possible consequence of frequent infections during therapy on low serum retinol levels. Also nutrient intake of the patients during therapy was not examined in the present study. It would be worthwhile to examine the extent to which infections influence serum retinol levels of leukemic children especially in the context of intakes in the developing countries.
Low serum zinc levels in patients compared to matched controls at diagnosis and during treatment has been reported by various researchers [13–16,18]. Most authors have attributed this to low dietary intake. However, the post-therapy profile of the patients studied herein, indicated that mean serum zinc levels were comparable to controls and majority of the patients had acceptable levels of zinc with a substantial number (11.0%) having values greater than 22.0 µmol/l. It is possible that blood components which are administered as supportive care to the patients during therapy may have contributed to maintaining serum zinc levels in optimal or in higher range, even after completion of therapy. In the present study 98% of patients had received blood components as supportive care. On an average 6 units of packed cells and 7 units of platelets were administered during treatment. 4.6 to 26.3 µg of platelet zinc is present in 100 ml of whole blood and 32.7 µg of zinc is present in a single sample of RBC hemolyzate containing 1 gm of hemoglobin [37].
The administered blood components during therapy may also have helped to maintain hemoglobin status in patients on completion of therapy.
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CONCLUSION
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The results of the present study indicate that cancer and its treatment did not have any long-lasting effect on serum albumin, total cholesterol, retinol, zinc and hemoglobin. Majority of subjects had low serum retinol suggestive of depleted liver reserves. The low serum retinol levels (0.3439 µmol/l or 10 µg/dl) in at least 50% of the patients and controls probably reflect poor dietary intake. A higher percentage of patients with low serum retinol levels may also be attributed to the possibility of urinary losses of retinol that occur during episodes of infection while on immunosuppressive anti-cancer drug therapy.
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ACKNOWLEDGMENTS
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The authors are grateful to Talwar Research Foundation, New Delhi, for providing fellowship to Chanda Gokhale.
Authors are also grateful to Dr. Padmini Ghugre, Reader, University Department of Food Science and Nutrition, S.N.D.T. Women's University, for extending her advice in this work.
Received October 28, 2004.
Accepted May 2, 2006.
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ABSTRACT
INTRODUCTION
