In this study, in subjects who received supplements, total daily energy intake increased, but total energy expenditure with time increased also. Thus, nutritional supplementation alone was not associated with greater benefits in height-SDS, weight-SDS, lean body mass accrual, or growth velocity compared with the observation group. Furthermore, combining nutritional supplementation with GH therapy was not associated with improved linear or ponderal growth compared with GH therapy alone.
Children with CDGM are short, grow poorly (particularly prior to puberty), tend to be thin, and seem to utilize energy at an accelerated pace. The use of the doubly labeled water method allows the calculation of total energy expenditure under free-living conditions with minimal intrusion to daily activities, making it ideally suited for studies in children. Using this technique and indirect calorimetry to assess resting energy expenditure, we had previously reported similar resting metabolic rate in boys with CDGM compared with age- and size-matched controls, but much higher TEE in those with CDGM [6
]. Underlying differences in metabolic pathways of substrate utilization (e.g., mitochondrial uncoupling proteins and homologues [22
] or increase in non-exercise activity thermogenesis (NEAT) [25
], may explain these differences in TEE. We hypothesize that a similar increase in TEE may have occurred in the subjects reported here who received added nutrition, essentially canceling any putative benefit of the added nutrition on growth. We had previously studied the effects of combined nutritional supplements (glutamine – a non-essential amino acid) alone and in combination with GH in another condition of relative under nutrition, children with cystic fibrosis, on rates of whole body protein synthesis [26
]. Although the metabolic tools used were different, we also observed in this previous study that the combination of supplemental nutrition and GH was not any better at enhancing protein synthesis rates than GH alone. It is possible that the potent anabolic actions of GH override any added benefit from nutrition supplementation, although a dose effect of much higher nutrition supplementation cannot be excluded.
Compliance among our subjects was very good with estimated intake of 87% of prescribed supplemental calories. However, it is possible that the subjects may have compensated for the additional calories by downregulating intake at other times during the day, a phenomenon that would reflect energy homeostatic mechanisms observed in normal children and adults [27
]. An imbalance between energy intake and utilization likely contributes to the spectrum of failure-to-thrive [32
] and obesity [29
]. Although energy intake increased within the Nutrition group, there was no difference between the group Nutrition and Observation groups with regard to energy intake over time, suggesting that the frequent clinical visits with weight assessments in the Observation group and the subsequent initiation of GH therapy may have diminished differences between the groups. Still, the findings of this study are clinically meaningful, as the subjects had high compliance with aggressive nutritional therapy (on average, >2 cans of nutritional supplement each day for 18 months) – whether this failed due to lack of increased total intake or because increased nutrition does not affect growth in boys with CDGM may not be ascertainable from this study. Inpatient admission to a metabolic unit to ensure increased total daily intake would be the only way to address this question, but such an approach would not be practical from either a research or clinical standpoint. Because only prepubertal boys were studied, the diagnosis of CDGM was based on delayed skeletal maturation rather than delayed puberty; we would anticipate, but cannot be certain, that their entry into puberty will be delayed. Furthermore, whether supplemental nutrition might promote peripubertal growth in contrast with prepubertal growth was not addressed by this study. However, the findings of this study would suggest that in the absence of true nutritional deficiency, supplemental nutrition would not be expected to be a particularly effective strategy to promote linear growth.
There were no quantifiable differences in a host of nutritional and hormonal measures over time between the 2 groups, despite the additional nutrition supplements, suggestive that at least at this level of extra supplement, these excess calories were not enough to alter these markers significantly, especially IGF-1, the ultimate mediator of linear growth, which is both GH- and nutrition-dependent. Of note, this is a preliminary study and the original study design was powered to assess the primary outcome measures, height-SDS and lean body mass accrual. However, examination of our findings indicates that our sample size permitted 80% power to detect an increase in IGF-1 of 150 ng/mL at a one-tailed significance of 5%. Such a difference is the equivalent of less than half the effect observed with GH therapy in our study. Thus, although our study may have not been designed to detect small differences in IGF-1 in response to nutrition, it was adequately powered to detect clinically significant changes in IGF-1, i.e., increases typically associated with improved growth.