Cachexia Related to Multiple Causes

Giovanni Mantovani, Clelia Madeddu

Despite the long and widespread interest in this topic, there is not an univocal definition for cachexia [1]. The term derives from the Greek kakos, which means 'bad,' and from hexis, meaning 'condition.' The clinical syndrome of cachexia is characterised by anorexia, tissue wasting, loss of body weight accompanied by a decrease in muscle mass and adipose tissue, and poor performance status that often precedes death [2-5]. Cachexia can occur as part of many chronic or end-stage diseases, such as infections, cancer, AIDS, congestive heart failure, rheumatoid arthritis, tuberculosis, chronic obstructive pulmonary disease, cystic fibrosis, and Crohn's disease. It may develop also in a proportion of elderly persons without obvious diseases. A literature search using the term 'cachexia' yielded more than 1000 articles published over the past 5 years [1].

Multiple mechanisms appear to be involved in the development of cachexia, including anorexia, decreased physical activity, decreased secretion of host anabolic hormones, and altered host metabolic response with abnormalities in protein, lipid, and carbohydrate metabolism [6]. Anorexia, one of the main features of the cachectic syndrome, may be so significant that spontaneous nutrition is totally inhibited. The pathogenesis of anorexia is most certainly multifactorial but is not yet well-understood. It seems to be attributable, in part, to intermediary metabolites (e.g. lactate, ketones, oligonucleotides) that accumulate along an abnormal metabolic pathway, or to other substances released, such as acute phase response proteins [3], by normal body cells. Indeed, nutritional supplementation alone is not able to effectively reverse the process of cachexia. An increased resting energy expenditure may contribute to the loss of body weight in cachectic patients and may explain the increased oxidation of fat tissue. Futile energy-consuming cycles, such as the Cori cycle, may also play a role in the increased energy demand. Unlike starvation, body-weight loss in cachectic patients arises equally from loss of muscle and fat, characterised by increased catabolism of skeletal muscle and decreased protein synthesis [7]. Catabolic factors capable of direct breakdown of muscle and adipose tissue appear to be secreted in cachexia and may play an active part in tissue degeneration [7].

The degree of wasting is an important prognostic factor, with a loss to 66% of ideal body weight being predictive of death regardless of the specific cause of the weight loss [8]. Therefore, a more thorough understanding of the pathogenesis of cachex-ia may lead to further therapeutic options that theoretically could improve survival. Neither the infective burden nor the tumour size correlate with the degree of wasting; rather, the host response, via endogenous mediators, appears to affect the cachectic response in diseased patients. Much research has focused on possible mediators of cachexia induced by disease [6].

The causes of cachexia are multiple and differ, at least in part, in different diseases, but some of them are common and they constitute the main background on which the symptoms of cachexia are based. Among the common causes of cachexia, the most well-recognised are: (1) proinflammato-ry cytokines with related metabolic symptoms and hypermetabolism; (2) neurotransmitters, (3) hormone changes, and (4) anorexia.Proinflam-matory cytokines certainly play a central role in non-cancer-related cachexia, but more particularly in cancer cachexia. Neurotransmitters are represented mainly by neuropeptide Y and an endogenous antagonist of a-MSH, the agouti-related protein (AgRP). The hormones that play the most significant role in weight maintenance and homeostasis are leptin, also referred to as a satiety signal hormone, which is released from white adipose tissue, and ghrelin, a hunger signal hormone that is released from the stomach [9]. Both neurotransmitters and hormones, and their abnormalities, may be involved in cachexia.

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