Page 108 - Haematologica-April 2018

C. Oudin et al.
able socio-economic conditions (e.g. higher level of educa-
tion, higher rates of employment) than IPC patients. Indeed, it is well known that lower socio-economic status is associated with a higher risk of metabolic syndrome.24,35 As the control group (IPC population) was characterized by particularly unfavorable social and economic condi- tions (unemployed: 52.7%, no higher education: 59.8%), the relative risk of metabolic syndrome in the LEA group may be underestimated. Due to these unfavorable socio- economic conditions, the IPC group is probably at higher risk of metabolic syndrome than the general French popu- lation, which makes the risk described in the LEA patients even higher. Moreover, LEA patients had a lower mean BMI, and were less frequently smokers than controls, which could contribute to their relative risk of developing a metabolic syndrome being underestimated.
Few studies on metabolic syndrome in AL survivors consider socio-economic factors,36 whereas studies about metabolic syndrome in the general population have shown this to be very important. Given the impact of socio-economic status on the development of the meta- bolic syndrome, further studies are needed to investigate a potential correlation between lifestyle (e.g. sedentary behavior), eating habits, and the occurrence of metabolic syndrome in AL survivors.
Our findings concerning metabolic syndrome preva- lence in the LEA cohort (10.3%) is difficult to compare with studies from other countries, as metabolic syndrome prevalence in the general population varies from one country to another. Furthermore, metabolic syndrome prevalence is lower in France than in many other industri- alized countries.25,37 Previous reports of metabolic syn- drome prevalence among AL survivors range from 4.2% to 49%,11,16,32,38-40 with prevalence depending mainly on the treatment type (chemotherapy, HSCT or CNS irradiation), follow-up duration and metabolic syndrome definition. In several studies, HSCT was associated with a high preva- lence of metabolic syndrome, ranging from 31% to 49%.16,39,40 The study by Nottage et al. reported a higher metabolic syndrome prevalence among non-transplanted patients (33.6%) than that found in our study, and this can partly be explained by the number of patients who received CNS irradiation (507 of 784 patients) and the older age of the patients.11
The risk of developing metabolic syndrome was even higher among patients who received CNS irradiation (OR: 2.32, 95%CI: 1.36-3.97; P=0.002), which confirms the results of previous studies.15,17,38 Interestingly, those patients had a much larger waist circumference compared with the IPC group. This highlights the impact of CNS irradiation on the development of obesity, an observation which has been previously described11,41,42 and debated.43,44
The highest risk of metabolic syndrome was observed among transplanted patients (prevalence: 18.8%, OR: 4.87, 95%CI: 3.4-6.99; P<0.001), especially those who received TBI (OR: 6.26, 95%CI: 4.17-9.36; P<0.001). The deleterious impact of TBI on the development of the metabolic syndrome has previously been reported by our group13 and others;18,32 here, these data are confirmed with a larger number of patients. Apart from TBI, so far addi- tional risk factors for metabolic syndrome in HSCT patients have not been clearly documented: some authors have suggested that graft-versus-host disease would increase this risk,18 but this remains controversial.
Several studies, including ours, have also shown an
association between metabolic syndrome and growth hor- mone deficiency,14,18,33,45 particularly in patients who received CNS irradiation or TBI. However, the precise mechanism by which growth hormone deficiency could induce a metabolic syndrome remains unclear.
We also aimed to determine whether the metabolic pro- file among patients who had a metabolic syndrome was different between LEA patients and controls. This is why we only selected patients with a metabolic syndrome from among LEA and IPC patients in order to study this metabolic profile (Figures 1 and 2). Interestingly, we found that, compared with metabolic syndrome controls, patients with metabolic syndrome who received HSCT after TBI had a specific metabolic profile: they had more elevated triglycerides and fasting glucose levels, as well as higher blood pressure. This suggests that these patients develop a metabolic syndrome with more severe features than that of controls, which could lead to higher rates of cardiovascular morbidity, as suggested for the general population.46
Patients who developed metabolic syndrome after TBI had a smaller waist circumference than IPC patients with metabolic syndrome. Altogether, these results suggest that obesity is not a key factor after TBI, in contrast to the gen- eral population. Different hypotheses can be made con- cerning the pathophysiology in those patients. Irradiation of the pancreas during TBI can induce diabetes47 and there- fore metabolic syndrome. Furthermore, some authors have found that, in patients treated with TBI, insulin resistance was not associated with obesity but rather with abnormal fat mass repartition.48,49 Modification of adipose tissue metabolism has been recognized as a fundamental mechanism behind metabolic syndrome development.50 Therefore, TBI exposure may induce adipose tissue abnor- malities, as suggested by animal models,51 and contribute to the development of metabolic syndrome. Our previous studies indicated that high-dose corticosteroids do not have an impact on metabolic syndrome,11,15 and, therefore, this hypothesis remains controversial.11,15
Patients with metabolic syndrome who received only chemotherapy displayed higher systolic blood pressure and increased triglyceride levels compared with metabolic syndrome controls, thus suggesting a more severe form of metabolic syndrome.
The waist circumference of patients who received CNS irradiation was markedly larger than that of the controls. Obesity caused by CNS irradiation, as previously described,41 is probably linked to the metabolic syndrome development. As the hypothalamus exerts central neu- roendocrine functions that control hunger and satiety, hypothalamic irradiation could lead to modifications in food intake and energy balance.
One limitation of our study involved the fact that some important metabolic syndrome factors such as physical activity, eating habits and lifestyle have not been docu- mented in our population. However, those factors are known to be very important in the metabolic syndrome genesis. A reduction in physical activity in LEA patients, as well as unhealthy eating habits could worsen the risk of developing metabolic syndrome. Another bias is linked to the control population, which includes only people from the Ile de France region, whereas LEA patients are recruit- ed from throughout France. Some regional differences in the metabolic syndrome prevalence could be found, which might make it difficult to extrapolate the results
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haematologica | 2018; 103(4)