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The wasting syndrome, defined as the unintentional loss of more than 10 percent of body weight, is a devastating complication of AIDS, other infections, and cancer. (1) Because weight loss is an independent contributor to death, (2,3) reversing it could theoretically both extend life and improve its quality.
Unfortunately, nutritional supplementation is not uniformly effective in patients with the wasting syndrome. (1) Such supplementation does improve the nitrogen balance in patients with carcinoma of the esophagus and stomach in whom food intake is decreased. In patients with lymphoma or patients with AIDS who have active infections, hyperalimentation increases fat mass but not lean body mass. However, in critically ill patients with sepsis, total parenteral nutrition does not reverse the negative nitrogen balance and may not even prevent the loss of weight. (1)
Many efforts have been made to understand the wasting syndrome. (1) Although it is at one extreme of the spectrum of wasting, sepsis has served as the model for studying the mechanisms involved. Sepsis is a markedly hypermetabolic state characterized by increased resting energy expenditure, negative nitrogen balance, and disturbances in metabolism that waste energy. For example, futile cycling occurs when fatty acids are mobilized from fat and, rather than being oxidized, are re-esterified into triglyceride, secreted from the liver, and stored again in fat. Inappropriate use of substrate occurs when glucose is converted to fatty acid and ultimately stored as fat, a normal event when energy intake is excessive but an inappropriate one when it is not.
Human immunodeficiency virus (HIV) infection causes an increase in resting energy expenditure and disturbances in metabolism similar to those in sepsis. (1,4,5,6,7) Given the difficulty of reversing the wasting syndrome with alimentation, it has been tempting to attribute wasting in patients with AIDS to hypermetabolism. However, the quantitative contribution of these metabolic pathways to the increase in resting energy expenditure is small. Indeed, the role of increased resting energy expenditure in wasting is unknown, and theoretically, increased intake of calories could replenish any energy expended.
Recent studies of HIV-infected patients indicate that these disturbances in lipid metabolism and even the increase in resting energy expenditure do not suffice to cause wasting, for several reasons. First, such patients can usually sustain their weight and lean body mass for prolonged periods. (4) Second, resting energy expenditure is increased in patients at all stages of HIV infection, (5,6,7) even asymptomatic patients with normal CD4 cell counts. (5) (It should be noted that since the metabolic changes are due to the host response, these studies indicated that HIV infection was not latent but contained.) Yet increased resting energy expenditure was not enough to cause wasting. (5,6,7) Instead, the change in weight in patients with HIV infection was proportional to their caloric intake. (7) Patients who were losing weight had anorexia induced by secondary infection. Thus, it seemed unlikely that hypermetabolism in itself was the driving force behind their wasting.
The true measure of hypermetabolism, however, is total energy expenditure, which consists of resting energy expenditure plus diet-induced thermogenesis plus energy expended in activity. Until total energy expenditure was measured, the relative roles of hypermetabolism and decreased caloric intake remained uncertain. In this issue of the Journal, Macallan et al. report the results of a study of the wasting syndrome in patients with HIV infection in which total energy expenditure was measured by the doubly-labeled-water technique. (8) These investigators studied patients who were losing weight, had stable weight, or were gaining weight. None of these groups had an increase in total energy expenditure, and indeed, this value decreased in the group with the most rapid weight loss. Thus, even in terms of total energy expenditure, hypermetabolism does not cause wasting. Instead, as in the earlier study, (7) caloric intake was the chief determinant of weight change. (8)
What, therefore, is the role of energy expenditure in the wasting process of AIDS? Increased resting energy expenditure is not sufficient to cause wasting in AIDS; the body has mechanisms to compensate for this small increase. In uninfected persons, caloric restriction causes a decrease in resting energy expenditure that blunts the loss of weight, preserving lean body mass. During HIV infection, in contrast, the elevation in resting energy expenditure persists despite decreased caloric intake. (7,8) Thus, failure to compensate with a decrease in resting energy expenditure during decreased caloric intake accelerates the negative energy balance.
Macallan et al. present evidence for another compensatory response: patients with rapid weight loss had a decrease in physical activity, which decreased their total energy expenditure, in turn reducing the energy deficit. (8) Thus, the lethargy and fatigue that accompany infection help maintain energy balance and weight. Yet physical activity is important for maintaining lean body mass. Furthermore, the HIV-infected men with stable weight had normal total energy expenditure and caloric intake, despite their increased resting energy expenditure. To retain stable weight, such patients too must decrease the amount of energy they expend in activity; maintaining normal activity may lead to more subtle defects in energy balance, as the data of Macallan et al. suggest. (8)
If metabolic disturbances are not enough to cause wasting and decreased caloric intake does cause it, what is the role of increasing energy intake to reverse the wasting syndrome, and why is increased intake of calories stored mostly as fat? Rapid weight loss due to decreased caloric intake is usually caused by secondary infection, whereas weight gain resulting from increased caloric intake usually occurs during a recovery from such infection. (7,9) The recovery of weight is often incomplete, however, and lean body mass may not be regained as efficiently as fat. (1,2) The decrease in physical activity due to lethargy and fatigue from illness that Macallan et al. describe (8) may contribute to the failure to rebuild lean body mass. Whether increasing caloric intake during wasting can blunt the loss of lean body mass remains unknown.
The clinical implications of these studies are important. Despite metabolic disturbances and increased resting energy expenditure, most HIV-infected patients maintain their weight. Wasting predicts impending complications. Rapid weight loss (more than 4 kg in less than four months) accompanied by anorexia is a sign of secondary infection. (7,9) Slower weight loss (more than 4 kg in more than four months) is often due to gastrointestinal disease with diarrhea, (9) with less marked decreases in caloric intake. (8) Because successful treatment of secondary infection is the best way to increase weight and lean body mass, early diagnosis is critical. Thus, keeping a graphic record of the weight of each patient with AIDS will provide an early warning of infections. (10)
Carl Grunfeld, M.D., Ph.D.
University of California,
San Francisco
San Francisco, CA 94121