Survivors of childhood acute lymphoblastic leukaemia, with radiation‐induced GH deficiency, exhibit hyperleptinaemia and impaired insulin sensitivity, unaffected by 12 months of GH treatment

Abstract

Summary OBJECTIVE Adult survivors of childhood acute lymphoblastic leukaemia (ALL) often exhibit GH deficiency (GHD), due to prophylactic cranial radiotherapy (CRT). It is not known whether the observed risk for adiposity in these patients is associated with impaired insulin sensitivity and whether the insulin sensitivity is affected by GH replacement therapy. SUBJECTS AND DESIGN Eleven patients with GHD (median age 29 years), previously given prophylactic CRT for ALL, and 11 sex‐, age‐ and body mass index (BMI)‐matched controls were investigated with bioimpedance analysis (BIA) and analysis of serum leptin, serum free fatty acids (FFA) and serum insulin. Insulin sensitivity was measured by a euglycaemic–hyperinsulinaemic clamp technique (IS‐clamp). Moreover, the effects of 12 months of individually titrated GH treatment (median dose 0·5 mg/day) on these parameters were investigated. RESULTS At baseline, the patients had lower fat free mass (FFM) (P = 0·003), higher percentage fat mass (FM) (P = 0·05), serum insulin (P = 0·02) and serum leptin/kg FM (P = 0·01) than controls. The patients had a tendency towards impaired IS‐clamp (P = 0·06), which disappeared after correction for body composition (IS‐clamp/kg FFM; P > 0·5). In the patients, time since CRT was positively correlated with percentage FM (r = 0·70, P = 0·02), and there was an independent negative association between serum FFA and IS‐clamp (P = 0·05). Twelve months of GH treatment increased serum IGF‐I (P = 0·003) and FFM (P = 0·02) and decreased percentage FM (P = 0·03), but no significant changes were seen in serum leptin/kg FM, serum FFA, FFA‐clamp, serum insulin or IS‐clamp (all, P ≥ 0·2). CONCLUSIONS Young adult survivors of childhood ALL with GHD had increased fat mass, hyperleptinaemia and impaired insulin sensitivity, which could be a consequence of radiation‐induced impairment of GH secretion or mediated by other hypothalamic dysfunctions, such as leptin resistance or other unknown factors, affected by CRT. Twelve months of individualized GH replacement therapy led to positive effects on body composition, but the hyperleptinaemia, hyperinsulinaemia and the impaired insulin sensitivity remained unchanged.

Body composition in young adult survivors of childhood acute lymphoblastic leukaemia

“…Bulow et al (40) found higher leptin/kg in patients (predominantly women) than controls and this difference remained after 1 year with GH treatment. Bulow et al (40) also found impaired glucose tolerance in GHdeficient young adult survivors of ALL and this impairment remained after 1 year with GH treatment (40). Using the less-sensitive HOMA index for investigating glucose metabolism, we did not detect similar abnormalities.…”

Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia

“…13,23,44,45 The risk profile for diabetes that we observed in ALL survivors with GH deficiency is notable. Whether or not GH treatment is advisable for GH-deficient ALL survivors 19,46 is beyond the scope of our study, but assessment of hypothalamus and pituitary functioning and GH secretion among ALL survivors appears warranted, even in those who did not receive cranial irradiation, given that 20% of those subjects were found to be GH-deficient.…”

“…4 Although currently limited to high-risk ALL, about 10% to 20% of patients, 18 whole-brain irradiation at 18 grays (Gy) or 24 Gy was historically used as prophylactic treatment against central nervous system (CNS) involvement of leukemia. Long-term hypothalamic-pituitary hormone insufficiency, a potential consequence of cranial irradiation, [19][20][21][22] may also be related independently to cardiovascular disease. 23,24 Growth hormone (GH) deficiency has emerged as a likely contributor to central obesity and its related metabolic disorders, including insulin resistance and dyslipidemia.…”

Metabolic syndrome in long-term survivors of childhood acute leukemia treated without hematopoietic stem cell transplantation: an L.E.A. study

“…47 Other investigators have examined the interest of growth hormone supplementation in a select population of patients. 48,49 A group of American investigators has shown that preventive therapeutic interventions limiting the increase in BMI and insulin resistance may be particularly important during maintenance therapy. 50 These therapeutic interventions will however require more expensive prospective studies for accurate evaluation.…”