2. The Evolving Concept of Cachexia

Cachexia is a multifactorial syndrome occurring during both acute and persistent catabolic events such as malnutrition and chronic degenerative diseases. The concept of “chronic degeneration” can create confusion when associated with a complex syndrome like cachexia. By definition, chronic degeneration determines the progressive loss of function or deterioration of a tissue or organ in the absence of a single causing event (e.g., an acute trauma) and is responsible for premature disability, mortality, and morbidity. This picture highlights the clinical relevance of cachexia. Nevertheless, the progression of degeneration may be faster or slower in absolute terms. In healthy aging, for example (without the presence of any disease), these processes are significantly slower and occur significantly later than those observed in degenerative diseases. By contrast, cachexia arising from acute events (i.e., nondegenerative events in the long term), such as trauma, burn, acute infection, or toxicity, can be reversed by therapy interventions aimed at the primary cause of cachexia, even though the signs of cachexia often last for a long time following the recovery of the patient.

Indeed, cachexia is associated with a plethora of chronic diseases, which, for their nature, can be all considered degenerative diseases, including cancer, organ failure (COPD), heart or kidney failure, infectious (AIDS), autoimmune (rheumatoid arthritis), metabolic (diabetes) diseases, etc. All these conditions share several underlying mechanisms and ultimately have a similar output, i.e., severe muscle wasting. However, the multifactorial origin of cachexia and its multisystem involvement made the study of this syndrome in the context of underlying chronic diseases complicated and, consequently, difficult to develop a definition of cachexia. Therefore, the current definition of cachexia is the result of a prolonged effort and continuous evolution; the major advances toward a definition of cachexia, which would be both accurate at the molecular level and clinically exploitable are summarized in Table 1.

Overall, the efforts to reach an accurate and clinically-sound definition of cachexia are important for several reasons: (1) to heighten the awareness of conditions potentially inducing cachexia; (2) to improve the staging of cachexia, thus helping in the identification of novel diagnostic/prognostic markers; and to (3) speed up the diagnosis of cachexia. Each “new” definition of cachexia presented in Table 1 amended the previous definition, ameliorating and, somehow, replacing it. These guidelines definitely helped to deal with the diagnosis and management of cachexia. An important issue that still awaits clarification is the relationship between cachexia and malnutrition ^[3]. Indeed, while not all malnourished patients are cachectic, all cachectic patients are invariably malnourished ^[4].

Table 1. The evolving concept of cachexia. Listed here are the criteria for the diagnosis of malnutrition, precachexia, and cachexia, including its severity with (from left to right): the corresponding reference, the definition of the cachectic status, and highlights of the main diagnostic criteria used. Cachexia was initially distinguished from anorexia or malnutrition, and, over the years, the progressive nature of muscle wasting (and its relevance to survival) has been highlighted. Ultimately, a staging was proposed for the severity of cachexia depending on the initial status of the patients.