Ghrelin and Anorexia Nervosa

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Anorexia nervosa is a psychiatric disorder characterised by patient-induced and maintained weight loss that leads to progressive malnutrition and specific pathophysiological signs (disturbance of body image and fear of obesity). Based on the presence or not of bulimic symptoms, anorexia nervosa appears in two specific subtypes, restricting and binge-eating/purging [70]. Complications in many organ systems can occur, including cardiovascular, gastrointestinal, haematological, renal, skeletal, endocrine and metabolic systems. These alterations are not only related to the state of malnutrition, but also to the behaviour of these patients to control their weight. The endocrine disturbances include hypothalamic amenorrhoea, hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis, low T3 syndrome and alterations in the activity of the GH/IGF-1 axis [71-73]. Exaggerated GH secretion coupled with reduced IGF-1 levels are common findings in anorexia nervosa as well as in other catabolic states, reflecting malnutrition-induced peripheral GH resistance and implying reduced IGF-1 feedback action on somatotropic secretion [73, 74]. Primary or secondary alterations in the neuroendocrine control of GH secretion have also been hypothesised and are likely to include GHRH hyperactivity coupled with reduced somatostatin-

ergic tone [71-73]. Accordingly, an exaggerated GH response to GHRH has been reported by many studies [58,71-73,75].

As anticipated, ghrelin levels in anorexia nervosa have been reported to be clearly high, in agreement with evidence showing that ghrelin levels are inversely related to BMI [18, 34, 76-78]. A difference in ghrelin levels between restricting or purging-type anorectic patients has been reported by some studies [79], but not others [80].

Interestingly, however, despite the elevated plasma ghrelin levels, in anorexia nervosa, the sensitivity of ghrelin secretion to the inhibitory effect of glucose seems to be preserved, although some differences among the different subtypes of anorexia have been reported [80-82].

In fact, oral glucose load has been reported to reduce circulating total and acylated ghrelin levels in women with anorexia nervosa to a similar extent as in normal subjects, despite absolute ghrelin levels in anorexia nervosa persisting higher than in controls [81,82].

Another study showed that while the inhibitory effect of oral glucose load is preserved in patients with anorexia of purging type, although with delayed nadir, such effect seems to be markedly blunted in women with anorexia of restricting type, thus suggesting that differences in eating behaviour may influence the metabolic control of ghrelin secretion [80].

Interestingly, previous reports showed that, differently from normal subjects, in patients with anorexia nervosa, ghrelin secretion is not inhibited by food intake [83]. The reasons for these discrepant data are at present unexplained and may reflect a different sensitivity to different types of nutrient intake [84]. One hypothesis is that, due to the chronic food restriction and the consequent adaptation, a single physiological meal could be insufficient to suppress the drive to eat, in order to regain a normal weight and replenish energy stores [83]. However, weight gain in anorectic patients is associated with decreased plasma ghre-lin levels [78]. It is therefore possible that in these patients the correction of the abnormal feeding behaviour over a prolonged period of time may restore the normal acute response of plasma ghre-lin to single meals [78].

Notably, though the reduced food intake in anorexia nervosa might seem discordant with a ghrelin hypersecretory state, it has to be emphasised that this condition is not characterised by lack of appetite; on the contrary, appetite is often increased, leading to a stressful condition [85].

The possibility that ghrelin hypersecretion could play a major role in GH hypersecretion in anorexia nervosa has been hypothesised. To support this hypothesis, there is evidence that fasting -induced GH hypersecretion is anticipated by an increase in ghrelin levels, at least in humans [86]. Interestingly, however, anorexia nervosa shows a selective reduction of the GH response to ghrelin administration and, differently from normal women, in anorectic patients ghrelin does not significantly increase glucose levels [87].

Evidence of a blunted GH response to ghrelin is remarkable considering that anorexia nervosa is associated with elevated circulating ghrelin levels coupled with both basal and GHRH-induced GH hypersecretion.

Notably, the GH hyporesponsiveness to ghrelin administration in anorexia nervosa represented an unexpected finding. In fact, several common hormonal alterations in anorexia nervosa, such as enhanced endogenous GHRH activity, reduced IGF-1 feedback action and reduced somatostatin-ergic tone, could have induced an enhanced GH responsiveness to ghrelin [71,73,88,89].

However, the possibility that in anorexia nervosa chronic exposure to elevated circulating ghrelin levels may induce desensitisation to the GH-releasing effect of ghrelin itself has also to be taken into account [90,91].

On the other hand, the absence of a hypergly-caemic effect of ghrelin in anorexia nervosa, which in normal subjects has been suggested to reflect a direct or indirect glycogenolytic effect, might simply reflect exhaustion of glycogen stores in the liver due to chronic starvation [92].

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