Biology of Cachexia
Abstract
About half of all cancer patients show a syndrome of cachexia, characterized by loss of adipose tissue and skeletal muscle mass. Such patients have a decreased survival time, compared with the survival time among patients without weight loss, and loss of total body protein leads to substantial impairment of respiratory muscle function. These changes cannot be fully explained by the accompanying anorexia, and nutritional supplementation alone is unable to reverse the wasting process. Despite a falling caloric intake, patients with cachexia frequently show an elevated resting energy expenditure as a result of increases in Cori cycle (i.e., catalytic conversion of lactic acid to glucose) activity, glucose and triglyceride-fatty acid cycling, and gluconeogenesis. A number of cytokines, including tumor necrosisfactor-α, interleukins 1 and 6, interferon γ, and leukemia-inhibitory factor, have been proposed as mediators of the cachectic process. However, the results of a number of clinical and laboratory studies suggest that the action of the cytokines alone is unable to explain the complex mechanism of wasting in cancer cachexia. In addition, cachexia has been observed in some xenograft models even without a cytokine involvement, suggesting that other factors may be involved. These probably include catabolic factors, which act directly on skeletal muscle and adipose tissue and the presence of which has been associated with the clinical development of cachexia. A polyunsaturated fatty acid, eicosapentaenoic acid, attenuates the action of such catabolic factors and has been shown to stabilize the process of wasting and resting energy expenditure in patients with pancreatic cancer. Such a pharmacologic approach may provide new insights into the treatment of cachexia.
The word “cachexia” is derived from the Greek “kakos” meaning “bad” and “hexis” meaning “condition.” It occurs in a number of disease states, including cancer, acquired immunodeficiency syndrome (AIDS), major trauma, surgery, malabsorption, and severe sepsis. Cachexia is characterized by weight loss involving depletion of host adipose tissue and skeletal muscle mass. Weight loss in cancer patients differs from that found in simple starvation. During the first few days of starvation, glucose utilization by the brain and erythrocytes necessitates depletion of liver and muscle glycogen and an increased glucose production by the liver, using gluconeogenic amino acids derived from catabolism of muscle. This early phase is replaced in long-term starvation by the use of fat as a fuel, in which free fatty acids released from adipose tissue are converted into ketone bodies, which are utilized for energy by peripheral tissues and eventually to a great extent by the brain. This leads to conservation of muscle mass. In anorexia nervosa, more than three quarters of the weight loss arises from fat and only a small amount from muscle. In contrast, in cancer cachexia, there is equal loss of both fat and muscle, so that for a given degree of weight loss there is more loss of muscle in a patient with cachexia than in a patient with anorexia nervosa ( 1 ). Thus, although anorexia is common in cancer patients, with reports of occurrence in 15%–40% of subjects at presentation ( 2 ), the body composition changes suggest that anorexia alone is not responsible for cachexia. Also, in malnourished cancer patients, the measured food intake fails to correspond with the degree of malnutrition ( 3 ), and loss of both muscle and adipose tissue has been reported to precede the fall in food intake ( 4 ). In contrast to simple starvation, it is not possible to reverse the body composition changes seen in patients with cancer cachexia by the provision of extra calories. Attempts to increase energy intake in cancer patients through dietary counseling failed to reverse the cachexia ( 5 ). Trials of total parenteral nutrition in cachectic cancer patients also failed to show benefit in terms of increased median survival time or long-term weight gain ( 6 ). Although a short-term weight gain was observed, this weight was subsequently lost, suggesting the retention of water ( 7 ). Analysis of body composition indicated that patients receiving total parenteral nutrition temporarily maintained body fat stores, but there was no evidence for preservation of lean body mass. Thus, the cause of wasting in cancer cachexia is more complex than that in simple starvation.
https://academic.oup.com/jnci/article/8 ... 63/2526545