Hyperghrelinemia in Prader-Willi syndrome begins in early infancy long before the onset of hyperphagia

Abstract

Circulating total ghrelin levels are elevated in older children and adults with Prader-Willi syndrome (PWS). However, the presence or absence of hyperghrelinemia in young children with PWS remains controversial. We hypothesized that a more robust way to analyze appetite-regulating hormones in PWS would be by nutritional phases rather than age alone. Our objectives were to compare total serum ghrelin levels in children with PWS by nutritional phase as well as to compare total ghrelin levels in PWS (5 weeks to 21 years of age) to normal weight controls and individuals with early-onset morbid obesity (EMO) without PWS. Fasting serum total ghrelin levels were measured in 60 subjects with PWS, 39 subjects with EMO of unknown etiology, and in 95 normal non-obese sibling controls of PWS or EMO subjects (SibC) in this 12 year longitudinal study. Within PWS, total ghrelin levels were significantly (P < 0.001) higher in earlier nutritional phases: phase 1a (7,906 ± 5,887); 1b (5,057 ± 2,624); 2a (2,905 ± 1,521); 2b (2,615 ± 1,370) and 3 (2,423 ± 1,350). Young infants with PWS also had significantly (P = 0.009) higher total ghrelin levels than did the sibling controls. Nutritional phase is an important independent prognostic factor of total ghrelin levels in individuals with PWS. Circulating ghrelin levels are elevated in young children with PWS long before the onset of hyperphagia, especially during the early phase of poor appetite and feeding. Therefore, it seems unlikely that high ghrelin levels are directly responsible for the switch to the hyperphagic nutritional phases in PWS.

Keywords: Prader-Willi; ghrelin; hyperghrelinemia; hyperphagia; nutritional phase; obesity.

Figure 1

Total fasting ghrelin levels at the various nutritional phases in PWS. A) Box plot of serum ghrelin at each nutritional phase (ages 0–36 years); The lower and upper whiskers in the boxplots represent the 10^th and 90^th centiles, the bars from bottom to top represent the 25^th, 50^th and 75^th centiles respectively, while the plus (+) sign represents the mean. The sample sizes (n) represent repeated measures. The only significant transition in nutritional phases is from phase 1b to 2a (P=0.0032). B) Scatter plot of nutritional phase ghrelin by age in PWS (cut off at 21 years for illustrative purposes). Note that in the 2–4.99 year age range (denoted by the hashed red lines) individuals in four different nutritional phases (i.e., 1b, 2a, 2b and 3) can be found.

Figure 2

Ghrelin levels of children and young adults belonging to the PWS, sibling control and EMO groups using repeated measures (cut off at 21 years for illustrative purposes).

Figure 3

Comparisons of PWS with sibling controls (SibC) within age group 0 – 1.99 years for A) weight-for-length centiles, B) body fat centiles, and C) fasting plasma leptin levels. P-values derived from mixed model analysis and the sample sizes (n) represent observations.