169 Leptin, hunger and fat 5 At T1 (before start of the dexamethasone course), we observed a large variation of leptin SDS (range -5.4 to +4.1). We explored possible contributing factors for this variation, and found that a higher age and higher fat mass were associated with increased leptin level at T1, even for leptin values adjusted for age, sex, pubertal stage and BMI. The cause is not known, but could indicate an increased risk of leptin resistance in children during ALL treatment. Possible contributors to this phenomenon could be concomitant asparaginase treatment, which was associated with delta leptin in our study. Asparaginase is known to influence dexamethasone pharmacokinetics as well as to cause hypertriglyceridemia and may therefore mediate the association between higher dexamethasone and increased leptin.53,54 Also, we found that children who were further in their maintenance treatment, had lower leptin levels. This is surprising, since children further in maintenance have had a higher cumulative dose of administered dexamethasone. For some dexamethasoneinduced side effects, such as osteonecrosis, a higher (cumulative) dose is associated with more physical problems.55 Moreover, lipid accumulation in hepatocytes is associated with higher cumulative doses of (endogenous) glucocorticoids.56 The reversed phenomenon in our study may be due to a longer time since asparaginase, which is administered in the beginning of maintenance only. Additionally, physical activity increases in the course of treatment and exercise may assert a protective role on metabolic adverse events and leptin resistance.57 Longitudinal studies that include physical activity in combination with leptin and body composition are needed to get more insight in the effect of multiple dexamethasone courses on these outcomes. The current study is the first, and largest, to evaluate leptin SDS in ALL patients, before and after a dexamethasone course. Furthermore, we were able to study leptin SDS in combination with feeling of hunger, as well as fat mass and sleep and fatigue, which has not been evaluated previously. Some limitations may be worth mentioning. The reference cohort for the leptin SDS values was based on children from the age of 5.8 years. Our study also included younger children, which may have influenced the SDS values. However, the standardized values are calculated based on Tanner stage and BMI, which will not differ greatly for younger children. Additional analyses excluding children <5.8 years did not show dissimilar results. Furthermore, the relatively small number of patients prohibited larger multivariable analyses to investigate associations between leptin and other measurements. To conclude, standardized leptin levels increase significantly after merely five days of dexamethasone, as well as fat mass, hunger scores, fatigue and sleep problems. Our findings suggest a dexamethasone-induced state of acute leptin resistance. Since children with ALL are at increased risk for metabolic adverse events, it is important to understand the underlying mechanisms, and leptin resistance might play a role.
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