What Therapeutic Strategies Are Effective in Improving Anorexia and Weight Loss in Nonmalignant Disease?

Introduction and Scope of the Problem

Cachexia is a term commonly understood by health care professionals. It describes a condition characterized by the presence of involuntary weight loss and culminating in a state of emaciation. Until recently, no agreement had been reached on an operational definition of and diagnostic criteria for cachexia; this lack of definition motivated international groups of experts to develop a uniformly accepted definition, diagnostic criteria, and classification to advance clinical practice. Clearly defined diagnostic criteria are also essential for development and approval of potential therapeutic agents. The definition provided by an international consensus group chaired by Evans and colleagues is as follows: cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance, and increased muscle protein breakdown are frequently associated with cachexia. Cachexia is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption, and hyperthyroidism and is associated with increased morbidity.

This definition makes several key distinctions. Although cachexia is often associated with reduced food intake, it differs from simple malnutrition by the presence of underlying disease; involuntary weight loss does not occur in healthy individuals and conversely is associated with a host of chronic conditions, including cancer, diabetes, untreated acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), chronic heart failure, chronic renal failure, and rheumatoid arthritis. Chapter 22 discusses cancer cachexia, the most well studied cachexia in chronic diseases. It should be noted that several acute conditions, such as trauma, burn, and sepsis, are associated with acute and sometimes severe weight loss. In all of these conditions the underlying disease or injury can add to the development of weight loss through inflammation, insulin resistance, increased catabolism of skeletal muscle, and increased overall energy expenditure.

Von Haehling and Anker described cachexia as a major underestimated and unmet medical need. According to the estimated prevalence of cachexia in patients affected by chronic diseases, this ranges from a low of 5% to 15% in advanced COPD or chronic heart failure to as much as 60% to 80% in advanced cancer. Those authors calculated the population prevalence of cachexia, concluding that the most frequent cachexia subtypes are, in order of frequency, COPD cachexia, cardiac cachexia, cancer cachexia, and cachexia of chronic renal failure. In higher-income countries (e.g., North America, Europe, Japan), the overall prevalence of cachexia (resulting from any disease) is thought to be growing and to currently be about 1%, that is, affecting about 9 million patients. Notably, older people develop multiple comorbid conditions, and it is not unusual for a person over 70 years of age to have more than one condition associated with cachexia. For example, atherosclerotic disease, depression, chronic kidney disease (CKD), cognitive impairment, obstructive sleep apnea syndrome, lung cancer, osteoporosis, diabetes, heart failure, sarcopenia, aortic aneurysm, arrhythmias, and pulmonary embolism are all highly prevalent among older COPD patients.

Cachexia is associated with mortality. Large degrees of weight loss and low body mass index are poor prognostic factors in chronic heart failure. Perhaps not surprisingly, higher BMI can be protective, and longer survival has been documented in patients with initially heavy body weights across a range of cachexia-associated conditions.

Cachexia is a source of psychological distress. The evident physical wasting and loss of appetite that patients commonly experience, particularly in advanced stages of the progression of cachexia, impart a substantial burden of distress on the patient and their family. Psychological distress associated with cachexia has been most studied in the context of cancer. Often, family members hold a strong belief that increased caloric intake can enhance patient quality of life and prolong survival, and patients often feel significant distress when family members insist on offering food. Thus the progression of cancer cachexia and its associated physical wasting can have profound effects on the family environment, including distress and frustration and heightened anxiety regarding outcomes of the disease.

Relevant Pathophysiology

Cachexia is a complex multidimensional problem, and several points of its pathophysiology are important for the diagnosis and treatment of the condition. The following five key points mirror the phenomenon of cancer cachexia in many ways and serve as the foundation for therapeutic strategies to treat anorexia and cachexia in the setting of nonmalignant diseases:

• 1.

  The specific erosion of skeletal muscle (i.e., lean tissue) is the physiologically and nutritionally important element of weight loss. As described earlier, cachexia is “characterized by loss of muscle with or without loss of fat mass.” It is important to note that many patients whose body weight is normal, overweight, or even obese may harbor very significant muscle wasting. As in the case of cancer, severe muscle wasting (or sarcopenia) can be obscured by adipose tissue and is nonetheless related to reduced physical function and survival. The presence of occult muscle wasting brings into view the need for objective measures of skeletal muscle mass in clinical assessment, and this is accessible simply by anthropometry or image-based technologies such as dual energy X-ray. The perceived importance of muscle explains the emphasis on treatments with essential amino acid supplementation and anabolic agents. The clinical importance of sarcopenia and its impact on patients’ ability to receive disease-modifying treatments and their outcomes is gaining increasing attention in fields such as liver transplant, pulmonology, and cardiology.

• 2.

  The pathophysiology is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The degree to which food intake is decreased and metabolism increased is a characteristic of a given patient, disease type, and stage. Quantification of protein and calorie intake is useful. Several micronutrients that are essential in the diet for humans, such as n-3 polyunsaturated fatty acids and vitamin D, have been proposed to contribute to the wasting of skeletal muscle and loss of physical function in cachexia.

• 3.

  Reduced food intake is attributable to primary anorexia and other symptoms affecting oral intake. A clinical distinction is to be made between alterations occurring in the brain, such as decreased central drive to eat, and secondary causes of impaired food intake, such as constipation, decreased upper gastrointestinal motility (causing early satiety and nausea), dyspnea, pain, and individual dietary habits. These secondary causes should be recognized early because they may prove reversible.

• 4.

  Hypercatabolism aggravates weight loss. This is provoked by disease, systemic inflammation, and other catabolic factors. Increased resting energy expenditure per kilogram of fat-free (lean) body mass has been characterized in COPD, chronic heart failure, and chronic renal failure; other physiological changes may occur as well, such as increased lipolysis and proteolysis or resistance to the normal anabolic actions of insulin that underlie weight loss. A feature of cachexia is the activation of the host immune system, involving proinflammatory cytokines. Increased production of interleukin (IL)-1β, IL-6, interferon-γ, and tumor necrosis factor (TNF)-α may be the primary catabolic triggers of skeletal muscle loss in addition to anorexia. Of importance, these metabolic changes define the reason that cachexia, unlike simple malnutrition, cannot be fully reversed by conventional nutritional support. Some of these metabolic changes are potentially reversible with suitable anti-inflammatory therapy.

• 5.

  The clinical progression of malnutrition and wasting occurs over time. The need exists to apply a staging system to what is essentially a progressive and cumulative problem of depletion. This is an important point in relation to therapy and in recognition of cachexia as a continuum. Fearon and colleagues proposed three clinical stages of cachexia: precachexia, cachexia, and refractory cachexia. Because the underlying metabolic abnormalities responsible for the eventual clinical manifestations of cachexia are likely present before overt weight loss, it seems reasonable to identify cachexia in its earliest stages (precachexia) with the goal of early treatment to prevent or delay the onset. Compared with the relatively rapid course of metastatic cancer and cancer cachexia, the evolution of cachexia in some chronic diseases is slower, giving much opportunity for preemptive treatments. The concept of refractory cachexia is relatively new and has arisen in discussion of cancer cachexia and the lack of efficacy of cachexia therapy in the end stages of disease. It can be clinically refractory as a result of advanced disease that is unresponsive to treatment, such as in end-stage renal failure. This stage is associated with profound anorexia and active catabolism or the presence of factors that render active management of weight loss no longer possible or appropriate. Refractory cachexia is characterized by a low performance status and life expectancy of less than 3 months. Thus cachexia may be viewed as an end-of-life condition that is managed primarily through palliative approaches in the refractory phase, whereas cachexia may be present early in the progression of disease and approachable by nutritional and pharmacological treatment.