Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukemia in childhood

Acute lymphoblastic leukemia ( ALL) is the most common childhood malignancy, and until recently prophylactic cranial radiotherapy (CRT) was important for achieving long-term survival. Hypothalamic-pituitary hormone insufficiency is a well-recognized consequence of CRT for childhood cancer. Another problem is increased cardiovascular risk, which has been shown in long-term survivors of other childhood cancers. In the only previously reported study on cardiovascular risk after childhood ALL, obesity and dyslipidemia were recorded in a small subgroup treated with CRT, compared with patients treated with chemotherapy. The mechanisms behind the increase in cardiovascular risk in survivors of childhood cancer are not clarified. The aim of the present study was to elucidate mechanisms of increased cardiovascular risk in former childhood ALL patients. A group of 44 ALL survivors ( 23 males, median age 25 yr, range 19 - 32 yr at the time of study) treated with CRT ( median 24 Gy, 18 - 30 Gy) at a median age of 5 yr ( 1 - 18 yr) and chemotherapy were investigated for prevalence of GH deficiency and cardiovascular risk factors. Comparison was made with controls randomly selected from the general population and individually matched for sex, age, smoking habits, and residence. All patients and controls underwent a GHRH-arginine test, and patients with a peak GH 3.9 mug/liter or greater were further investigated with an additional insulin tolerance test. Significantly higher plasma levels of insulin ( P = 0.002), blood glucose ( P = 0.01), and serum levels of low-density lipoprotein cholesterol, apolipoprotein (Apo) B, triglycerides, fibrinogen, and leptin ( all P less than or equal to 0.05) were recorded among the ALL patients, compared with controls. Furthermore, the serum levels of high-density lipoprotein cholesterol ( P = 0.03) and Apo A1 ( P = 0.005) were significantly lower among the patients. Compared with controls, the patients had higher body mass index and waist to hip ratio, and body composition measured with dual-energy x-ray absorptiometry showed significantly higher fat mass and lower lean mass ( P < 0.001). Forty of 44 ALL patients (91%) were considered GH deficient according to the insulin tolerance test and/or the GHRH-arginine test, and the rest were considered GH insufficient. In patients, peak GH during GHRH-arginine was significantly negatively correlated to total body fat mass measured with dual-energy x-ray absorptiometry ( r = -0.48, P = 0.001), waist to hip ratio ( r = - 0.32, P = 0.03), plasma insulin ( r = - 0.49, P = 0.001), and leptin ( r = - 0.46, P = 0.002). Moreover, a significantly positive correlation was recorded with high-density lipoprotein cholesterol ( r = 0.38, P = 0.012). Using Doppler echocardiography, a marked reduction in cardiac dimensions and performance ( ejection fraction P < 0.001 and fractional shortening P = 0.01), compared with controls, was recorded. In conclusion, at a median 17 yr after treatment with CRT and chemotherapy in former childhood ALL patients, a significant increase in cardiovascular risk factors was recorded. We suggest that GH deficiency, induced by CRT, is a primary cause for this because strong correlations between the stimulated GH peak and several of the cardiovascular risk factors were observed.