Possible mechanisms underlying the development of cachexia in COPD

About 25% of patients with chronic obstructive pulmonary disease (COPD) will develop cachexia (fat-free body mass index <17 kg(.)m(-2) (males) or <14 kg(.)m(-2) (females)). This is associated with similar to 50% reduction in median survival. The pathogenetic mechanism has been variously suggested to result from the following: 1) energy imbalance; 2) disuse atrophy; 3) tissue hypoxia from arterial hypoxaemia; 4) systemic inflammation; and 5) anabolic hormonal insufficiency. Genetic polymorphisms implicate inflammatory cytokines, especially interleukin (IL)-1 beta, but IL-6 and tumor necrosis factor (TNF)-alpha do not show polymorphisms in these patients. Early reports of elevated TNF-alpha levels suggested a role for inflammation, but recent studies have not shown elevated levels of either IL-6 or TNF-a. Therapeutic trials of nutritional support, hormonal supplementation, anti-TNF-alpha immunotherapy, ghrelin and antioxidants have been conducted, but only a few have shown any benefits in muscle structure and function. Considerably more mechanistic knowledge is needed before therapeutic recommendations can be made. At this time, it is not possible to attribute cachexia in COPD unequivocally to inflammation or any other cause, and much more research is needed. To date, studies have been predominantly cross-sectional, with measurements made only after cachexia has developed. Future research should target prospective observation, studying patients as cachexia progresses, since once cachexia is established, inflammatory cytokine levels may not be abnormal.