Chapter 24 Weight Loss and Cachexia
Healthy animals typically maintain their body weight within a remarkably stable range given the differing levels of caloric intake and energy expenditure that may occur daily. Significant, unintentional weight loss is usually a sign of disease. In patients who tend to mask early signs of disease, it may be the first clue of pathology. Loss of greater than 5% body weight should prompt diagnostic evaluation. Weight loss is considered a negative predictor in the outcome of many chronic diseases; therefore, it must be recognized and addressed.1
Weight loss occurs when energy expenditures and caloric loss exceed caloric intake. The main controllers of these processes, appetite and metabolism, are regulated by an intricate network of neural and hormonal factors. These signals are primarily integrated in the arcuate nucleus of the hypothalamus, which maintains homeostatic control over food intake, levels of activity, and basal energy expenditure.2 This area of the brain is relatively accessible to circulating signals and can respond to peripheral and central inputs. Peripherally secreted hormones, primarily insulin and leptin, give information relating to long-term energy stores in the body. Insulin, secreted by the pancreatic B cells, regulates storage of absorbed nutrients and acts as an adiposity signal to the brain.3 Adiposity signals are cytokines produced and secreted by adipose tissue in proportion to the body fat content. Leptin secreted by adipocytes informs the brain of adipose energy reserves, and appetite is adjusted accordingly.4 Signals relating to recent nutritional condition are provided by the vagal neural system that relates information about gastric distention and nutrients in the portal circulation.5
Enteroendocrine cells in the gut produce numerous hormones that are also integrated in the hypothalamus to control metabolism. These include satiety peptides cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and oxyntomodulin that are produced in the small intestine in response to food in the gut lumen.6–8 Peptide YY (produced in ileum and colon) and pancreatic polypeptide (produced by pancreatic cells) are released in response to feeding and signal satiety as well.9–11 Ghrelin, produced primarily in the stomach, is secreted during fasting and stimulates appetite.12
When faced with a decrease in caloric intake, otherwise normal animals respond with a corresponding decrease in energy expenditure. Although body weight is lost, muscle protein is preserved while adipose tissue is broken down providing energy. The net result is fat loss over muscle loss. If adequate calories are later ingested, normal body weight and condition should be restored.
The terms weight loss and cachexia are often used interchangeably with cachexia usually referring to more severe weight loss that is associated with disease. Cachexia is technically different than simple weight loss, being a metabolic disorder of increased energy expenditure that cannot be resolved by merely providing extra calories.13 It differs from simple weight loss in that the normal physiologic mechanisms supporting muscle preservation despite increased energy demands are lost.14 Thus, protein and adipose tissue provide energy in the cachexic animal resulting in disproportionate muscle wasting in the animal. Cachexia occurs with severe debilitating disease, including malignancy, renal failure, heart failure, and chronic inflammatory diseases.15 Cachexia is a significant predictor of mortality in human medicine.16
Although the pathogenesis of cachexia is not fully understood, cytokines have been implicated as major mediators.17 Systemic inflammation from cell injury or activation of the immune system can trigger release of cytokines into circulation. Proinflammatory cytokines (e.g., interleukin [IL]- 1 and -2, interferon-γ, tumor necrosis factor [TNF]-α) are commonly implicated in the pathogenesis of cachexia.18–20 These cytokines can activate proteolytic systems that cause hypercatabolism as well as activate tissue factors (e.g., IL-1, TNF-α) responsible for decreased protein synthesis and enhanced lipolysis.20–22 The result of these processes is negative energy balance, muscle wasting, and weight loss. Other hormones implicated in cachexia are testosterone, insulin-like growth factor 1, myostatin, glucocorticoids, and catecholamines.23–27
The list of differential diagnoses for weight loss and cachexia is extensive. Major causes of weight loss include inadequate caloric ingestion, absorption, or digestion; caloric loss; increased metabolic rate; or cachexia. Inadequate calories available for ingestion occurs when animals are underfeeding or eat nutritionally incomplete diets. Dental pain, prehension or swallowing abnormalities, regurgitation, vomiting, or gastrointestinal obstructions can prevent adequate calories from being digested. Malabsorption, maldigestion, and diabetes mellitus are examples of weight loss as a result of an inability to absorb or process adequate calories. Caloric loss can occur from protein-losing diseases (e.g., protein-losing nephropathy, exudative skin lesions). Hyperthyroidism, extreme exercise, cold weather, lactation, and cachexia caused by chronic illness can produce weight loss from increased metabolism causing excess calorie usage.