ReviewGhrelin and cachexia: Will treatment with GHSR-1a agonists make a difference for patients suffering from chronic wasting syndromes?☆
Introduction
Cachexia is a wasting syndrome that accompanies a wide array of chronic diseases including cancer, chronic kidney disease, chronic heart disease and chronic obstructive pulmonary disease (COPD) (Tisdale, 1997, Evans et al., 2008). While these diseases are varied in their underlying pathophysiology, they each result in a loss of lean and fat mass that is in part fueled by an increase in resting energy expenditure. Perhaps the most striking characteristic of cachexia, however, is on-going anorexia at a time when energy stores are depleted. Thus far, no definitive treatment has been shown to be effective for use in humans with cachexia.
One agent that has gained attention as a potential treatment for cachexia syndromes is the gut hormone ghrelin (Kojima et al., 1999, Tschop et al., 2000, Nakazato et al., 2001). Given its properties of increasing appetite and increasing fat mass accumulation—that is, the opposite of processes observed during cachexia—ghrelin has been investigated in a growing number of animal models and human trials testing its efficacy in treating cachexia. As we will see in this review, ghrelin and other agonists of the growth hormone secretegogue receptor (GHSR-1a) also exhibit additional properties that may further benefit specific underlying diseases associated with cachexia.
Section snippets
Physiology of ghrelin
Ghrelin is a 28-amino acid hormone whose discovery was based on the ability for ghrelin to bind to the GHSR-1a in the hypothalamus and stimulate growth hormone release (Kojima et al., 1999). Ghrelin contains a unique n-octylation of serine residue ser-3 catalyzed by ghrelin-O-acyltransferase (GOAT) prior to its secretion (Gutierrez et al., 2008, Yang et al., 2008). In acylating ghrelin, GOAT utilizes fatty acids absorbed from the diet, including C6–C10 fatty acids, with a strong preference for
Cancer cachexia
Cachexia is a feature that complicates the course of multiple different malignancies. In certain kinds of cancer—particularly gastrointestinal cancers—up to 85% of patients experience cachexia, and cachexia contributes to at least 20% of cancer deaths overall (Tisdale, 2002). The weight loss experienced by patients can be severe, including loss of up to 75% of muscle mass (Fearon, 1992), though even subtle amounts of weight loss and anorexia are associated with a worsened prognosis, poorer
Renal cachexia
Similar to what is seen in cancer cachexia, in the setting of chronic kidney disease cachexia involves a loss of lean body mass, increased energy expenditure and decreased appetite. This constellation of symptoms affects up to 60% of patients on hemodialysis (Kalantar-Zadeh and Balakrishnan, 2006). Given a prominent decrease in serum protein levels in this setting, this syndrome is also referred to as protein energy wasting (Muscaritoli et al., 2009, Naufel et al., 2010). Inflammation—which is
Chronic heart failure
Chronic heart failure (CHF) as a result of myocardial infarction and dilated cardiomyopathy is a relatively common cause of cachexia, as 5.7 million people in the United States have CHF and up to 15% of these will develop cachexia (Anker et al., 1997a, American_Heart_Association, 2005). Individuals with CHF who develop unintended weight loss, decreased lean and fat mass and a decrease in appetite exhibit tripling of mortality rate over an 18-month period, from 17% to 50% (Anker et al., 1997a,
Pulmonary cachexia
Chronic respiratory diseases also can result in a cachexia syndrome, including chronic obstructive pulmonary disease and recurrent pneumonias. Each of these results in increased inflammatory cytokines, and as in other syndromes, the presence of cachexia is linked to increased mortality (Andreas et al., 2005). Levels of total ghrelin are elevated in COPD (Itoh et al., 2004); nevertheless, treatment with ghrelin as a twice-daily IV infusion resulted in increased food intake as well as increases
Cachexia or anorexia from other underlying diseases
Treatment with ghrelin has also been show to be of benefit in other animal models of cachexia or anorexia, including radiation injury (Shah et al., 2009), chemotherapy (Liu et al., 2006, Garcia et al., 2008) and burn injury (Balasubramaniam et al., 2006). Interestingly, in the case of cisplatin-induced anorexia, ghrelin secretion is blunted (Yakabi et al., 2010), underscoring potential differences in etiology of anorexia among various conditions and—thus far—the ability of ghrelin to stimulate
Safety
While the trials reported here have not had significant side effects associated with ghrelin treatment, potential continues for pharmacologic effects of ghrelin that might limit its application in cachectic patients. Tolerability has not seemed to be a significant effect, though one blinded trial revealed a trend toward increased undesirable gastrointestinal effects among subjects receiving ghrelin (Strasser et al., 2008). These gastrointestinal effects included abdominal pain, dry mouth and an
Conclusion
Ghrelin has received significant attention for the treatment of cachexia. This is particularly important because no effective treatments have been shown to have such consistent effects in animal models and human trials. Moreover, the additional systemic effects in improved cardiovascular function particularly raise the potential for application in cachectic states involving heart failure. Questions persist including whether ghrelin's effects will be sustained past the 8–12 week time points that
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2014, Brain, Behavior, and ImmunityCitation Excerpt :Ghrelin expression by T cells is also reduced in ageing mice and ghrelin infusion in this model has been shown to reduce levels of IL-6, TNF-α and IL-1β (Dixit et al., 2009). Ghrelin infusion to improve lean body mass and appetite and decrease circulating inflammatory cytokines has had positive outcomes in patient populations with inflammation–related cachexia including cachetic cancer, cardiovascular disease, chronic obstructive pulmonary disease and chronic kidney disease (DeBoer, 2011; DeBoer et al., 2008; Nagaya et al., 2004, 2005; Strasser et al., 2008). Our finding of increased GHS-R1a availability after exercise and a higher circulating proportion and concentration of GHS-R1a+ lymphocytes in active compared with sedentary individuals suggests that exercise prescription should be explored further as a tool to enhance the effectiveness of ghrelin therapy.
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Funding: 5K08HD060739-02.