Review
Ghrelin and cachexia: Will treatment with GHSR-1a agonists make a difference for patients suffering from chronic wasting syndromes?

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Abstract

Cachexia is a syndrome of wasting and anorexia that worsens the prognosis of many chronic diseases including cancer, chronic kidney disease, chronic heart disease and chronic obstructive pulmonary disease. Properties of the orexigenic hormone ghrelin-including appetite-stimulation, weight-gain production and increased cardiac output make it a logical treatment for cachexia. While endogenous ghrelin levels are increased in the setting of cachexia, treatment with ghrelin and other GHSR-1a agonists in animal models of cachexia and in humans with cachexia has demonstrated consistent effects of increased appetite and improved weight gain. These positive effects occur in multiple underlying diseases associated with cachexia and appear to be sustained over treatment duration of up to 12 weeks. The mechanism of action in producing these effects is likely related to stimulation of central appetite centers such as the central melanocortin system and to increased growth hormone release, though ghrelin's effects may also relate to decreased systemic inflammation and other direct and indirect actions. Questions regarding the long-term safety of ghrelin treatment are still unanswered, as is the important question of whether successful treatment of cachexia will improve the prognosis of the underlying disease itself.

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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    Funding: 5K08HD060739-02.

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