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Effect of Glucocorticoid Therapy on Energy Intake in Children Treated for Acute Lymphoblastic Leukemia

Departments of Human Nutrition (J.J.R., C.M., F.R., A.K.) and Hematology and Oncology (M.B., B.E.S.G.), University of Glasgow, Yorkhill Hospitals, Glasgow, Scotland G3 8SJ

Address all correspondence and requests for reprints to: Dr. John Reilly, University Department of Human Nutrition, Yorkhill Hospitals, Dalnair Street, Glasgow, Scotland G3 8SJ. E-mail: jjr2y{at}clinmed.gla ac.uk.

Abstract

Despite a widespread belief that glucocorticoid therapy is associated with positive energy balance and excess weight gain there is a dearth of quantitative evidence about its effects and the underlying mechanisms of any effects. The primary aim of the present study was to quantify the effect of dexamethasone and prednisone treatment on energy intake in children treated for childhood acute lymphoblastic leukemia. A secondary aim was to test for differences in excess weight gain between patients treated using the 2 glucocorticoids. We measured energy intake in 26 patients (mean ± SD age, 6.3 ± 2.3 yr) during a 5-d period "on" steroids and again in the week before steroid treatment. Changes in body mass index from diagnosis to 1 and 2 yr postdiagnosis were expressed as SD scores. Steroid treatment was associated with a significant increase in energy intake of approximately 20% (mean paired difference, 1.7 MJ/d; SD, 2.8; 95% confidence interval, 0.7–2.8 MJ/d), with no significant difference between the 2 steroids. The mean change in body mass index SD score was +0.38 (SD, 1.10; P < 0.05) to 1 yr and +0.68 (SD, 1.38; P < 0.05) to 2 yr, with no significant difference between the 2 groups of patients. Glucocorticoid treatment in childhood acute lymphoblastic leukemia increases energy intake markedly, and this effect contributes to the excess weight gain and obesity characteristic of patients being treated for acute lymphoblastic leukemia.

DESPITE A WIDESPREAD belief that glucocorticoid therapy has a marked effect on energy balance and body weight control, there is surprisingly little quantitative evidence on the effect of treatment with corticosteroids on energy balance in humans. Effects of glucocorticoid therapy on body weight, and the underlying mechanisms, are only poorly described at present. A literature search (on glucocorticoids and the following variables: weight gain, appetite, energy intake, energy expenditure, and substrate oxidation), revealed only 8 published studies (1, 2, 3, 4, 5, 6, 7, 8) (see Table 2). All of these studies involved adults, not children. Many were small (10 subjects or less). Few focused on energy intake; those that did took place in experimental settings such as metabolic wards, and their design involved healthy adults offered buffet-type menus and asked to eat ad libitum. Of the few clinical studies, most did not measure energy intake or body weight change. None of the studies definitively identified underlying mechanisms for any steroid effects, such as increased appetite or alterations in energy intake, energy expenditure, or substrate oxidation. None identified the magnitude or dose dependence of any effects. A large number of studies have indicated a role for corticosteroids in the regulation of energy balance in man (9, 10, 11, 12), but these do not permit simple predictions about likely effects in clinical use or the mechanisms of any such effects. In summary, clear evidence for the influence of glucocorticoid therapy on energy balance in humans is lacking at present. Obtaining empirical data on such putative effects in clinical settings would be of relevance to the treatment of many diseases.

Subjects and Methods

Study design and subjects

As part of their maintenance therapy, children treated for ALL on MRC-97, which has been used in the United Kingdom since 1997, receive either dexamethasone (6.5 mg/m²) or prednisone (40 mg/m²) for 5 d every 28 d. The present study was designed as a paired comparison, with each child acting as his/her own control. Energy intake was measured during the 5-d steroid treatment period ("on" steroids) and in the week before steroid treatment ("off") as described below. Children were eligible for entry into the study if they were in the maintenance phase of treatment, in first remission, and clinically well with no comorbid conditions that might influence energy balance. We also tried to avoid recruiting patients who were severely obese because our primary interest was in abnormalities of energy balance in the preobese state. We used a combination of two criteria to define severe obesity: the presence of obesity-related morbidity, body mass index (BMI) above the 98th percentile on United Kingdom 1990 BMI charts (a definition used to refer patients for specialist treatment in the United Kingdom) (22). Patients were measured at a range of stages of therapy (from 8–20 months postdiagnosis), but we avoided measurements within 1 month of the end of a period of intensification to reduce possible carry-over effects on intake from intensification and focused the study on effects during the maintenance phase of treatment.

For the study of excess weight gain in patients treated according to MRC-97, patients were considered eligible for inclusion if they were being treated at Yorkhill Hospitals in Glasgow, the main Scottish treatment center for ALL. Inclusion required that patients were in continuous complete remission to at least 1 yr postdiagnosis and had no comorbid conditions relevant to energy balance. All patients who met these criteria were entered into the study.

Measurement procedures

Energy intake was measured over a 4-d period on two occasions in each patient, once when on and again when off steroids. We used the multiple-pass 24-h recall, a technique previously described and validated for use in children (23). The 4 d consisted of 2 weekdays and 2 weekend days in the same week. During the on steroid phase, steroid treatment commenced on Tuesday afternoon and was continued for 5 consecutive days. Energy intake assessment during the on phase began on the second full day of treatment (Thursday). Energy intake assessments were made by two dietitians blind to the steroid treatment status of patients. Each patient was allocated to one or the other dietitian, so that on vs. off comparisons were not only made within each child but also within each investigator. Patients were not informed of the hypothesis being tested and were told in general terms that this was a study of nutrition in children treated for ALL. Food intake data were quantified using a combination of a photographic atlas of food portion sizes for the UK (24), parental descriptions of portion sizes reported in household measures, and guide weights for portion sizes in UK children (25). We converted food intake data to energy intake using nutritional analysis software (Compeat release 4.0, Grantham, UK) based on the database of the chemical composition of foods in the United Kingdom (Royal Society of Chemistry, Cambridge, UK).

For the study of excess weight gain, heights (to 0.1 cm) and weights (to 0.1 kg) of all patients were measured, and BMI was calculated and expressed as an SD score relative to United Kingdom 1990 reference data (22).

Statistical analysis and power

Differences in energy intake between on and off periods were tested for significance using paired t test. The power of the study was unclear at the design stage, but we carried out an interim analysis after data collection was complete for 12 patients. This analysis was not made known to the dietitians collecting the data, but revealed statistically significant differences in energy intake between the two periods and suggested that inclusion of an additional 10–12 patients would be adequate to detect significant differential effects between patients randomized to dexamethasone vs. those randomized to prednisone. We also tested for significance of differences in age, gender, weight, height, and BMI between patients allocated to the two glucocorticoids.

For study of excess weight gain, changes in BMI SD scores relative to United Kingdom reference data were calculated using simple descriptive statistics for those patients who had reached 1 and 2 yr postdiagnosis in first remission. The significance of differences in changes in BMI SD scores within patients was assessed using paired t tests. An unpaired t test was used to test the significance of differences in change in BMI SD score between patients treated with dexamethasone and those using prednisone.

Results

Of the 36 eligible patients treated in our center, 2 were not invited to participate because they were experiencing social/family problems at the time of the study. Of the remaining 34, 28 consented. Of these, 26 successfully completed the procedures in both periods. Characteristics of the 26 subjects are described in Table 1. Eleven patients were allocated to dexamethasone and 15 to prednisolone. We found no significant differences between the 2 groups of patients for age, gender distribution, height, weight, BMI, or BMI SD score. We found no significant difference in the change in energy intake between on-off periods between patients allocated to prednisone and those allocated to dexamethasone (by t test, P > 0.05). Changes in energy intake between on and off steroid periods within patients were highly significant. The mean paired difference in energy intake was 1.7 MJ/d [SD, 2.8; 95% confidence interval (CI), 0.7–2.8 MJ/d; 1 MJ = 239 kcal]. When expressed per kg BW, the mean paired difference was 74 kJ/kg·d (SD, 12; 95% CI, 24–124 kJ/kg·d). Energy intake was consistently higher while on steroids, but the difference was of variable magnitude (Fig. 1). There was an increase when on steroids in 20 of the 26 patients, a decrease in 4 of 26, and negligible changes in 2.

View larger version (25K): [in this window] [in a new window]   Figure 1. Difference (on-off steroids) in energy intake (kilojoules per kg/d) in patients treated for ALL.

Discussion

The present study showed that energy intakes increased significantly when patients were treated with glucocorticoids during the long-term maintenance phase of therapy. The magnitude of the effect (a mean increase of 20% of habitual intake) was sufficiently large that it would be generally regarded as clinically/biologically significant. It is widely believed that a relatively small energy imbalance can lead to obesity as long as it is sustained over a prolonged period. For example, Goran (26) estimated that an energy imbalance of as little as 1–2% of energy requirement is of biological significance. In the present study the apparent effect of steroids on energy intake was variable in magnitude, but with our estimated 95% CI for the size of the effect (0.7–2.8 MJ/d), and a daily energy intake of 7.1 MJ/d (mean of the two measurement periods), our estimate suggests an effect on daily energy intake ranging from about 10–40%. It is therefore likely that glucocorticoid therapy contributes to excess weight gain in children treated for ALL and so has a role in the development of obesity in these patients. Although this might not seem unexpected, there is a dearth of empirical evidence about the effect of steroids on energy intake (Table 2) (1, 2, 3, 4, 5, 6, 7, 8), no evidence on the magnitude of any likely effects, and very limited evidence about possible mechanisms for any effects (i.e. relative importance of alterations in energy intake, energy expenditure, or substrate oxidation and fat deposition). To our knowledge, the present study was the first to demonstrate an effect of glucocorticoid therapy on energy intake in a clinical setting. It should also be noted that it is possible that glucocorticoids might have other important effects on energy balance and obesity risk independent of their effects on food intake. These might include effects on substrate oxidation (2, 4, 5, 8) and resting energy expenditure (6, 8), although marked differences in resting energy expenditure between patients treated for ALL and healthy controls have not been observed (15, 20).

It is important to note that other abnormalities in energy balance contribute to excess weight gain and the development of obesity in patients treated for ALL. The most notable is reduced habitual physical activity: children treated for ALL are much less active than their healthy peers both during and after therapy (20, 21). The relative importance of steroid treatment to obesity in ALL is therefore difficult to assess because of the contribution of factors other than steroid effects, the possibility that steroid effects may extend beyond an influence on appetite, and because the time course of the effect on food intake is unknown. In the present study energy intakes of patients were measured during maintenance therapy, but at a range of times postdiagnosis. We were unable to detect differences in the magnitude of any effect on appetite associated with time from diagnosis, but our study was not designed to test this. It could be argued that our study design might have maximized the differences in intake between on and off therapy, because the on period consisted of the week when the 5-d treatment with steroids took place, and the off period was the week before. However, the use of dexamethasone and prednisone in treatment protocol MRC-97 during maintenance therapy is short term (5-d course). Both glucocorticoids are used at the same dose, but for much longer periods at other stages of therapy (e.g. the 4-wk period of induction treatment), so steroid effects on energy balance might be even greater at other times.

The present study found a trend for a more marked increase in energy intake during glucocorticoid therapy for those patients randomized to dexamethasone compared with those treated with prednisone, but this difference was not statistically significant. The trend was present in our interim analysis (n = 12), and a power calculation suggested that recruitment of an additional 10–12 patients with a paired study design would provide adequate power to detect a significant difference between the two steroids. Such a difference remains possible, although it was not observed in the present study when data collection was completed on an additional 14 patients. As treatment protocol MRC-97 has only been underway since 1997, it is difficult to provide a definitive test for differences in rates of excess weight gain between patients randomly allocated to the two steroids. However, the absence of differences in the magnitude of excess weight gain in the present study provides tentative support for the conclusion that differential effects on excess weight gain between the two steroids are likely to be small. We also found no significant difference in the rate of excess weight gain between patients treated in our center with protocol MRC-97, which included dexamethasone during maintenance, and the previous protocol, which did not (by two-sample t test) (14). This tentative conclusion must be confirmed by larger studies with longer term follow-up. Differences in excess weight gain between the two steroids may be clinically unimportant, possibly because differential effects on appetite are small and/or because of the important contributions of other factors to excess weight gain in these patients, notably reduced habitual physical activity. As a great deal of emphasis is now placed on the avoidance of long-term adverse consequences of therapy for ALL (27), any possible differences between steroids on energy balance are potentially important. The present study suggests that differences between dexamethasone and prednisone on energy balance are minor.

In conclusion, despite a widespread clinical impression that glucocorticoid therapy produces excess weight gain, probably via increased appetite, such observations have not hitherto been supported by empirical evidence. The magnitude of any such effect was unknown, and the mechanisms were unclear. We conclude that glucocorticoid treatment increases energy intake substantially in patients with ALL, and this contributes to the development of obesity that is characteristic of these patients.

Acknowledgments

We thank Diane Henderson for her support in patient identification/recruitment, and Sheila Fairweather for her assistance with the literature search. We also thank the children and families for their enthusiastic cooperation.

Footnotes

This work was supported by Schiehallion Unit Research Funds.

Abbreviations: ALL, Acute lymphoblastic leukemia; BMI, body mass index; CI, confidence interval; MRC-97, Medical Research Council Protocol 97.

Received February 2, 2001.

Accepted April 20, 2001.

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