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Cachexia
Donald P. Kotler, MD

Cachexia represents the clinical consequence of a chronic, systemic inflammatory response, and its manifestations differ considerably from those of starvation. Although cachexia is classically associated with chronic infections and malignant conditions, some of its elements have been identified in a wide variety of chronic diseases and in aging persons. Cachexia has repeatedly been associated with adverse clinical outcomes.

Recent studies have demonstrated the ability of anabolic and anticatabolic agents to mitigate the loss of skeletal muscle and to improve clinical outcomes in selected circumstances.

Ann Intern Med. Oct. 17, 2000;133:622-634.
 

Cachexia is now seen as a multidimensional adaptation encompassing a variety of alterations that range from physiologic to behavioral (Table 1 ).

Adverse consequences of cachexia
have been documented in patients with cancer, congestive heart failure, AIDS, and other diseases. The presence of cachexia also confounds attempts at nutritional support through hypercaloric feeding.

Despite long and widespread interest in the topic, there is no standard definition for cachexia, which means simply "poor condition" in Greek. Accelerated loss of skeletal muscle in the context of a chronic inflammatory response is a characteristic feature of cachexia and will be considered its definition in this review.

Many chronic or end-stage diseases, such as infections, cancer, AIDS, congestive heart failure, rheumatoid arthritis, tuberculosis, chronic obstructive pulmonary disease, cystic fibrosis, Crohn disease, and others, demonstrate some nutritional changes of cachexia. Cachexia may develop in a proportion of elderly persons without obvious disease. Even pure starvation may evolve to cachexia in clinical situations because malnutrition-induced immune dysfunction predisposes to infection.

Paradigms of Malnutrition
Cachexia and starvation are the two major paradigms of malnutrition.
Starvation is characterized by pure caloric deficiency. The organism adapts metabolically to conserve lean mass and increase fat metabolism (4), and the changes can be reversed by appropriate feeding.
Intestinal disease with malabsorption is a form of starvation characterized by excess fecal losses of ions and water, in addition to nutrients.
In contrast, cachexia is associated with inflammatory or neoplastic conditions that evoke an acute-phase response, and feeding does not reverse the macronutrient changes.
A third paradigm of malnutrition is sarcopenia, which is characterized by subnormal contents of skeletal muscle in the absence of weight loss. The term sarcopenia is most commonly used to refer to body composition changes in elderly persons but can also apply to patients who have repeatedly tried to lose weight by dieting, patients with growth hormone deficiency, and patients with very limited physical activity, such as those debilitated by painful arthritis. Clinically, the situation may be complicated because cachectic patients are often anorectic and others may have sarcopenia.

Detection of Malnutrition
The diagnosis of malnutrition is complicated because nutritional alterations may involve macronutrients or micronutrients and the depletion may be stable or progressive. Most clinicians rely on body weight as the major measure of nutritional status, using usual adult weight as a reference.

Rates of change beyond these limits can be considered abnormal. However, rates of change within these limits may also be abnormal if divergent changes are seen in different body compartments (for example, depletion of skeletal muscle plus fluid overload caused by cardiac, hepatic, or renal disease; hypoalbuminemia; or intravenous hydration). In addition, measurement of weight cannot differentiate between lean tissues or fat, and, as noted, some debilitated patients have sarcopenia (5). Because of these limitations, nutritional analysis is now done by using body compartment analysis, a process in which fat is distinguished from fat-free mass and fat-free mass is further separated into body cell mass and extracellular mass.

Changes in Body Composition in Patients with Cachexia
Moore and coworkers reported the results of body composition studies in healthy persons, obese persons, and persons with acute and chronic injury. The studies they examined were performed by using isotope dilution techniques during the first 20 years after World War II. The authors showed that patients with cachexia lose roughly equal amounts of fat and fat-free mass but maintain extracellular water volume. Losses of fat-free mass are centered in skeletal muscle and reflect decreases in both cellular mass and intracellular potassium concentration; the latter indicates a bioenergetic deficit.  Weight loss is common but not universal. Experimental studies have used the technique of pair-feeding to distinguish cachexia from starvation.

Pathogenesis of Cachexia
Tissue damage is a threat to well-being because it is self-promoting; that is, hydrolases released from inflammatory or injured cells cause further injury and provide substrate for formation and propagation of free radicals. For this reason, the body must localize and limit the injury and clear tissue debris. To perform these functions, the organism has developed an acute-phase response. The acute-phase response includes the hepatic synthesis of large quantities of proteins. The functions of the acute-phase proteins vary widely and include binding proteins (opsonins), protease inhibitors, complement factors, apoproteins, fibrinogen, and others. For example, a cycle involving C-reactive protein, complement, and interleukin-6 has been described. C-reactive protein, which was named for its ability to bind to a specific bacterial lipopolysaccharide, circulates in low quantities in healthy persons; however, its levels increase in response to inflammatory or neoplastic processes. C-reactive protein is an opsonin that binds to denatured proteins, lipopolysaccharides, and nucleic acids. Binding leads to local complement activation and phagocytosis by macrophages through their complement receptors. The complement-split products stimulate release of interleukin-6 by macrophages, which in turn stimulates the synthesis and secretion of more C-reactive protein in the liver. This completes a positive feedback loop. The intensity of this response is quantitatively related to the amount of tissue debris; the response extinguishes itself after tissue debris is cleared.

The acute-phase response has nutritional implications. It is energy-intensive with high rates of hepatic protein synthesis and requires large quantities of essential amino acids. The need for essential amino acids drives the loss of skeletal muscle. The survival value is obvious: An injured animal has an impaired ability to obtain exogenous protein, and skeletal muscle, which represents approximately 40% of body weight in men and approximately 33% in women, is the largest available pool of protein. The tradeoff may be viewed as a shift in the body's priorities from offensive to defensive. The adaptation is effective over the short term because skeletal muscle is replaced rapidly as recovery is completed. Problems ensue when the process is chronic because skeletal muscle depletion contributes increasingly to morbidity and mortality.

Cachexia is also characterized by changes in fat metabolism, including hypertriglyceridemia, increased hepatic secretion of very-low-density lipoproteins, decreased lipoprotein lipase activity, increased de novo triglyceride synthesis and esterification, increased release of free fatty acid from the periphery, and a futile cycle of fatty acids between the liver and adipose tissue beds. These changes, which are promoted by a variety of cytokines, maintain serum lipid concentrations despite the presence of anorexia (19).

Alterations in carbohydrate metabolism include peripheral insulin resistance, which is also mediated by proinflammatory cytokines. This adaptation redirects glucose to the liver and other viscera and away from skeletal muscle because hepatic glucokinase is not affected by insulin, unlike hexokinase in myocytes and elsewhere. The energy needs of muscle are met by oxidation of nonessential amino acids, which contributes to negative nitrogen balance.

Alterations in Energy Balance in Patients with Cachexia: Anorexia Compared with Hypermetabolism
Hypermetabolism, defined as an elevation in resting energy expenditure, is a cardinal feature of cachexia but not of starvation (Table 2 ). It was commonly believed that hypermetabolism is the direct cause of weight loss in cachexia. Several recent studies using two experimental approaches have successfully challenged that notion. In the first approach, statistical comparisons of correlations among resting energy expenditure, food intake, and weight changes are made. Studies in HIV infection (22, 23) and Crohn disease without malabsorption (24), among other diseases, showed that short-term weight change is more closely related to decreased caloric intake than to increased resting energy expenditure. In the second approach, total energy expenditure was measured by using the doubly-labeled water technique. Total energy expenditure involves resting energy expenditure (approximately 70%), voluntary energy expenditure (25%), and energy expended in digestion (5%). Studies in congestive heart failure (11), chronic obstructive pulmonary disease (25), and HIV infection (23) all showed that weight loss was associated with a decrease in total energy expenditure despite an elevation in resting energy expenditure. This is accomplished by a decrease in voluntary energy expenditure, which manifests clinically as apathy and lethargy. The decrease in voluntary energy expenditure, although very significant clinically, does not compensate quantitatively for the combined increase in resting energy expenditure and decrease in caloric intake.

Cytokine Regulation of the Acute-Phase Response
The realization that the response to illness and injury is an endogenous, not exogenous, process was a milestone in the understanding of cachexia. Our understanding that cytokines regulate the acute-phase response and cachexia resulted from several observations. The responsible protein was sought, isolated, and named cachectin, and its sequence was found to be identical to that reported for TNF (26). These studies concluded that this molecule was the mediator of cachexia.

Cytokines do mediate systemic effects, however. Of the proinflammatory cytokines, interleukin-6 has the longest serum half-life and may have important endocrine effects. Circulation of mononuclear cells that secrete cytokines in a target organ is an alternate way to achieve a classic endocrine effect. Such a mechanism might be especially important in transmission of cytokine signals through the blood-brain barrier.

Proinflammatory cytokines exert a variety of behavioral and physiologic effects in addition to their immunologic and nutritional functions. Anorexia results from proinflammatory cytokine activity and has both central and peripheral elements. The central effect is at the level of the hypothalamic nuclei, which control feeding behavior. Several cytokines affect food intake directly or through other mediators, such as corticotrophin-releasing hormone, serotonin, or leptin. Leptin, a cytokine secreted from adipocytes that has prominent effects on feeding behavior and energy balance, is believed to be a major peripheral regulator of long-term body composition. It is also thought to be responsible for self-correcting changes in energy intake and expenditure that can be demonstrated after voluntary overfeeding and underfeeding (31). However, animal studies demonstrated that endotoxin leads to a dose-dependent increase in plasma leptin and white fat leptin mRNA (32-34), which implies that leptin might be a mediator of anorexia in cachexia. There is a normal relationship between plasma leptin concentration and body fat content in healthy persons as well as in patients with AIDS, cancer, and chronic obstructive pulmonary disease (35-39). Leptin does not mediate the metabolic changes of the acute-phase response (40).

Several alterations in gastrointestinal function that indirectly affect nutritional status have been ascribed to proinflammatory cytokines, including altered gastric emptying. Decreases in intestinal blood flow, changes in small bowel motility, changes in cellular proliferation, and altered ion fluxes have also been described.

Cachexia in Clinical Diseases
A broad spectrum of clinical disease fits this paper's definition of cachexia. Cachexia due to cancer or infection has been recognized for many years. Recent studies have demonstrated elements of the acute-phase response of various types of cancer, including cancer of the pancreas, stomach, prostate, esophagus, and colon and rectum (41-47). In cancer cachexia, levels of fibrinogen, an acute-phase reactant (48), were elevated; levels of albumin synthesis, however, were not (49). These elevated levels of fibrinogen are associated with shortened survival (50). Cachexia in cancer may be due to endogenous or tumor-associated factors. Several laboratories have extracted lipid or protein-mobilizing factors from tumors (51, 52).

Infection with HIV and AIDS are also characterized by cachexia. Early studies of body composition demonstrated depletion of body cell mass (9). Metabolic alterations include elevations in resting energy expenditure and changes in lipid metabolism (53). Endocrine alterations include hypogonadism in both men and women (53), consistent with a hypoanabolic state (54, 55). Many studies have documented cytokine activation and its association with malnutrition (56) in HIV-infected persons. Studies of protein turnover demonstrate elevated plasma glutamine concentration as well as leucine oxidation in patients with weight loss, implying increased protein breakdown (57, 58). A poor response to hypercaloric feeding in patients with AIDS, in which fat accumulation occurs without changes in lean mass, is also consistent with cachexia.

Rheumatologic disease is a useful model with which to study cachexia associated with chronic inflammation. Depletion of body cell mass has been reported in patients with rheumatoid arthritis, who also have increased resting energy expenditures. Malnutrition in rheumatic disease increases morbidity.

Cardiac cachexia is a classic clinical entity that is seen in about 20% of patients with congestive heart failure (60) and is an independent risk factor for death.

Malnutrition is common in end-stage renal disease, in which depletion of skeletal muscle mass may be masked by an increase in total-body water volume. Malnutrition in end-stage renal disease is associated with increased mortality rates. Anorexia is a prominent clinical symptom.  In addition, metabolic acidosis, which is prominent in end-stage renal disease, increases protein degradation as well as degradation of essential branched-chain amino acids, which prevent adaptation to decreased protein intake.

Malnutrition can be documented in up to 50% of patients with chronic obstructive pulmonary disease, in whom circulating TNF levels are associated with unintentional weight loss independent of measures of pulmonary function. Although patients with this disease may have a low caloric intake, increased breathing difficulty also contributes to malnutrition.

Malnutrition is a serious problem in elderly persons. Weight loss and hypoalbuminemia are more frequently associated with adverse outcomes than chronologic age is. Aging is associated with progressive increases in serum levels of glucocorticoids and catecholamines and decreases in levels of growth hormone and sex hormones. Elevated levels of proinflammatory cytokines may also be found. In one study of aging persons, serum levels of interleukin-6 were significantly associated with serum concentrations of C-reactive protein.

A few studies have identified cachexia in other diseases, such as alcoholic hepatitis, chronic pancreatitis, cystic fibrosis, and active inflammatory bowel disease. A recent study of children with protein energy malnutrition demonstrated proinflammatory cytokine activity, possibly as a result of infectious or other complicating factors.

Treatment of Cachexia
As noted above, starvation and cachexia are overlapping but independent phenomena. Decreased physical activity may exacerbate the loss of skeletal muscle through deconditioning. The changes are presumably additive and provide rationale for the use of hypercaloric feeding and exercise to treat the changes of cachexia.

Hypercaloric Feeding
The inability of hypercaloric feeding to increase lean mass, and especially skeletal muscle mass, has been shown repeatedly.  Older studies of hypercaloric feeding by total parenteral nutrition in patients with AIDS and lymphoma showed that weight gain may occur but leads almost solely to fat accumulation. The reason for this outcome is that the increase in protein degradation in cachexia is greater in magnitude than the possible increase in protein synthesis during hypercaloric feeding. However, some studies document objective benefits of caloric feeding on certain end points, which suggests that poor food intake and metabolic alterations may have independent adverse effects on outcome.

Appetite Stimulants
Appetite stimulants are an alternative way to increase caloric intake and are better tolerated than tube feeding, especially in an outpatient ambulatory setting. Megestrol acetate (Megace) promotes caloric intake in patients with cancer and HIV infection. However, the increase in weight is due to increases in fat, not fat-free mass.

[Mantovani G, Maccio A, Bianchi A, Curreli L, Ghiani M, Santona MC, et al. Megestrol acetate in neoplastic anorexia/cachexia: clinical evaluation and comparison with cytokine levels in patients with head and neck carcinoma treated with neoadjuvant chemotherapy. Int J Clin Lab Res. 1995;25:135-41. | PubMed |

Megestrol acetate 320 mg/day was dministered at a dose of in the interval between chemotherapeutic cycles for a total of three consecutive cycles; 9 of the 11 patients could be evaluated (81.8%). Except for the performance status according to Karnofsky, all parameters were increased after megestrol acetate treatment. The average weight increased by 6.3 kg (13.2%), appetite by a score of 2.4 (38.6%) and the Spitzer's quality of life index by a score of 2.4 (36.2%). ] 

Tetrahydrocannabinol has also been evaluated for its ability to stimulate appetite and promote weight gain. Dronabinol was significantly less effective than megestrol acetate in a comparative study in HIV-infected persons.

If feeding alone is insufficient to replete lean mass, then pharmacologic or other means are required. At present, few therapies have proven nutritional benefit in patients with cachexia. Clinical and experimental therapies can be divided into those available clinically and those whose efficacy is hypothetical and whose supporting studies are preclinical (Tables 4 and Table 5 )

Anabolic Therapies
The most logical pharmacologic therapy for cachexia is an agent that promotes protein synthesis or inhibits protein breakdown. Both approaches have been tried. Recombinant human growth hormone was shown to promote nitrogen retention in short-term studies of HIV infection and lean mass accrual in a double-blind, placebo-controlled clinical trial; in the latter, functional improvement was also shown. The use of growth hormone to mitigate losses of lean mass during acute illnesses in patients with AIDS has been reported.  In contrast, improvements in lean mass without concomitant functional improvements were seen in sarcopenia associated with aging and in chronic obstructive pulmonary disease.  Growth hormone has also been applied in patients with cardiomyopathy.  Although use of growth hormone in patients with cancer is worrisome because of a theoretical positive anabolic effect on the tumor itself, the results of an animal study demonstrated that its combination with protein restriction led to increased growth of skeletal muscle at the expense of the tumor.  Use of growth hormone could have a negative effect in some situations by diverting excess essential amino acids and energy to skeletal muscle and away from use in the acute-phase response, thereby thwarting a basic function of host defense. This situation could explain the substantial increase in mortality rates reported with use of growth hormone in critically ill patients.  There is no evidence that concomitant administration of growth hormone with insulin-like growth factor I or other agents improves its effectiveness.

The other major anabolic agents available for clinical use are the anabolic steroids.   In a small randomized trial of patients in the recovery phase after 30% to 50% full-thickness burns, Demling and DeSanti (88) showed that oxandrolone (20 mg/d) plus high protein intake and active physical therapy doubled weight gain compared with a treatment program that lacked the anabolic agent. An increasing number of studies are evaluating the use of testosterone and anabolic steroids in HIV-infected patients and have shown increases in fat-free mass (89-94).

Anabolic steroids have been widely used in end-stage renal disease because of their documented effects on erythropoiesis; in addition, they increase renal release of erythropoietin and increase protein synthesis in hematopoietic cells. Gaughan and coworkers (95) showed that the combination of erythropoietin and nandrolone increased hemoglobin concentration more than erythropoietin alone. Johansen and colleagues (96) demonstrated that nandrolone decanoate significantly increased fat-free mass compared with placebo and baseline levels. Positive effects have also been reported with the use of oxandrolone in patients with alcoholic hepatitis (98). Those studies also demonstrated strong associations between shortened survival and the extent of malnutrition, as well as the severity of liver disease.

Exercise Training
Several studies have evaluated resistance exercise training in various clinical diseases, among them rheumatology, HIV infection, and others. Nutritional benefits have been documented in patients with congestive heart failure and HIV infection. Benefits have been reported for combination therapy in elderly patients (resistance exercise training and growth hormone) and HIV-infected patients (resistance exercise training and anabolic steroids).

Anticytokine Therapies
The other means of improving protein balance is through the inhibition of protein breakdown. However, it must once again be noted that excess breakdown of skeletal muscle protein may be life-sustaining in cases of serious acute illness or injury. Inhibition of proinflammatory cytokine activity can be shown to decrease protein breakdown in vitro. Some agents in current use have anticytokine properties in vitro, including the appetite stimulants megestrol acetate, medroxyprogesterone, and 9-tetrahydrocannabinol.  Pentoxifylline has documented anti-TNF effects, although no significant beneficial effects have been seen in clinical studies. Thalidomide has been evaluated for nutritional benefits related to its anti-inflammatory properties, which may be due, at least in part, to an increase in the degradation rate of TNF mRNA. Adjunctive use of thalidomide in HIV-infected patients receiving treatment for tuberculosis has been shown to promote weight gain.

Anti-Inflammatory Agents
Anti-inflammatory therapies are an alternative way to moderate proinflammatory cytokine activity, since signal transduction may involve arachidonic acid metabolites. Lundholm and coworkers showed that indomethacin and prednisolone maintained Karnofsky index and prolonged survival compared with placebo in patients with cancer cachexia. A combination of megestrol acetate and indomethacin led to accrual of fat (but not lean tissue) and decreased C-reactive protein concentration in patients with cancer cachexia. In another study, anti-inflammatory agents plus erythropoietin improved nutritional status, blood counts, and exercise capacity.  -3 fatty acids have been proposed as therapy for cachexia because of their ability to alter cytokine release; in addition, they have had documented physiologic effects in animal and human studies. However, these benefits in cancer are not uniform in the literature. Anti-inflammatory agents may have a greater impact in nonmalignant cachectic conditions, such as rheumatologic diseases.

Conclusion
Ultimately, the strongest predictor of outcome is the severity of the underlying illness. Advances in prevention and treatment of the primary disease may improve overall health but are not likely to abolish cachexia. Further understanding of the mediators of cachexia, especially at the molecular level, will guide the development of treatment strategies. The development of nutritional therapies will continue and will be aimed increasingly at the preservation of skeletal muscle mass and functional capabilities. More widespread application of nutritional therapies will require demonstration of their safety and efficacy.

From Columbia University, New York, New York.

Requests for Single Reprints: Donald P. Kotler, MD, Gastrointestinal Division/S&R 1301, St. Luke's-Roosevelt Hospital Center, 421 West 113th Street, New York, NY 10025; e-mail, dpkotler@aol.com.