Investigation of the mechanisms of therapy‐related hypoglycaemia in children with acute lymphoblastic leukaemia

Aim : To determine the mechanisms of fasting hypoglycaemia occurring during maintenance therapy (MT) for childhood acute lymphoblastic leukaemia (ALL). Methods : Thirty‐five children and adolescents with ALL, aged 2.4–17.4 y, were fasted for up to 16 h during MT. Nineteen of the children developed hypoglycaemia after 11 to 16 h of fasting. Blood samples for determination of metabolic changes were taken on completion of fasting. Nineteen patients underwent a glucagon stimulation test after 4 to 16 h of fasting during MT. Erythrocyte concentrations of the metabolites of methotrexate (E‐MTX) and 6‐mercaptopurine (E‐TGN) were measured at the time of fasting. Fifteen out of 19 patients who became hypoglycaemic were re‐studied 3 to 4 mo after cessation of therapy. Results : In the hypoglycaemia group, plasma levels of gluconeogenic amino acids alanine and glutamine were lower (medians 117 vs 190 μmol L −1 , p = 0.009, and medians 396 vs 448 μmol L −1 , p = 0.031, respectively) than in the normoglycaemia group. Serum levels of free carnitine were lower (medians 20.3 vs 29.8 μmol L −1 , p = 0.027), free fatty acids higher (medians 3.09 vs 1.23 mmol L −1 , p < 0.001) and marked dicarboxylic aciduria was more common in the patients with hypoglycaemia (in 14/16 vs in 2/14, p < 0.001). Impaired responses to glucagon stimulation occurred in 36% (4/11) in the hypoglycaemia group and in 12.5% (1/8) in the normoglycaemia group ( p = 0.243). No significant differences were detected in E‐MTX and E‐TGN between the groups. Most of the metabolic abnormalities returned to normal after cessation of chemotherapy. Conclusions : Low levels of gluconeogenic amino acids, especially of alanine, are associated with hypoglycaemia. Reduced hepatic glycogen stores may also be involved in the aetiology.