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Studies of body composition in patients with the acquired immunodeficiency syndrome

Donald P. Kotler, Jack Wang, and Richard N. Pierson, Jr.

The acquired immunodeficiency syndrome (AIDS)is the most serious worldwide public health problem of the current generation. While knowledge of the disease has advanced rapidly, no effective means of halting its spread through the population or of halting its progression in the body have been identified. Treatment of people affected with this multi-system disorder is limited by incomplete knowledge of its pathogenesis. Elucidation of the mechanisms of the disease's progression should lead to improvements in treatment and in the length and quality of life of AIDS patients.

Protein-energy malnutrition (PEM) is a common complication of AIDS [1, 2] and contributes significantly to its morbidity and mortality. Our laboratory has studied PEM in AIDS patients since 1981 with the aims of characterizing the alterations in body composition that occur, identifying the pathogenetic mechanisms underlying PEM, demonstrating the functional consequences of PEM, and determining the efficacy of nutritional support in promoting body mass repletion. In this review, we will summarize the status of our studies of body composition in patients with AIDS and attempt to establish a framework for future investigations of the nature and treatment of PEM in AIDS.

The core of our nutritional assessments has been the estimation of body composition. These studies, performed in the Body Composition Laboratory at St. Luke's Hospital, involve measurement of total body potassium (TBK) content by whole body counting of 40K, as well as determination of total body water and extracellular water volumes by isotope dilution techniques, and body fat content by anthropometric measurements [2-6]. Total body potassium content is a well accepted measure of body cell mass, and its measurement correlates well with calculations of intracellular water volume, another valid parameter of body cell mass.

1. Our initial studies demonstrated that malnutrition in AIDS is common, severe, and progressive [1]. A group of 33 AIDS patients was shown to have diminished TBK and intracellular water volume compared to homosexual and heterosexual controls, indicating body cell mass depletion (table 1) [2]. The depletion of TBK in the AIDS group was greater than expected from analysis of body weight because of the relative expansion of the extracellular water volume and the ratio of extracellular to intracellular water. Variably severe hypoalbuminaemia was found in the AIDS patients. The depletion of TBK was shown not to be related to overt adrenal dysfunction. The severity of depletion was related to length of survival, as patients surviving less than three months were significantly more depleted than those who survived more than six months after study. On the other hand, body fat content was quite variable and patients with significantly decreased TBK were seen who had subnormal or elevated body fat contents. These findings are consistent with studies of body composition in other models of PEM [7-9] and provide an adequate cross-sectional description of body composition in AIDS.

TABLE 1. Cross-sectional study of body composition in AIDS patients

Data expressed as mean ± SE.
Measured values of TBK and body waters normalized as described previously [2].
TBK = total body potassium; ICW = intracellular water volume;
E/I = ratio of extracellular to intracellular water volume.

2. To further explore the relationship between malnutrition and survival, we reviewed retrospectively the results of 43 body composition studies performed in patients not receiving parenteral nutritional support who died of a wasting illness within three months of study, including seven done as part of a postmortem examination [10, 11]. TBK was plotted as a function of days before death and the points resolved to a straight line with an intercept at 0 days survival of 54% of normal (fig. 1). Normalized body weight had a similar relationship with time from death with an extrapolated value at death of 67% of ideal body weight (fig. 2). In contrast, body fat content bore no identifiable relationship to the time from death.

FIG. 1. The relationship between total body potassium content and survival. A progressive depletion of TBK expressed as percentage of normal until death was noted. The extrapolated TBK at death was 54% of normal.

FIG. 2. Total body potassium content and body weight (expressed as percentage of ideal body weight-IBW) had similar relationships to time before death

We concluded that the magnitude of depletion rather than its cause determines the timing of death from wasting in AIDS. These results indicate that an unsustainably low level of body cell mass may develop in patients with AIDS, which links this illness to other chronic debilitating diseases [12]. The finding that death from wasting in patients with AIDS occurs at a body weight approximately one-third below ideal values is similar to other observations of semi starvation, such as those documented by Soviet physicians during the siege of Leningrad and by the physicians of the Warsaw ghetto [13, 14] during the Second World War. The similar degrees of body mass depletion at death due to wasting in AIDS and due to starvation stands in contrast to the usual view of AIDS as an aggressive fulminating disease. The results also imply that effective nutritional therapy, which could slow the rate of body cell mass depletion, might prolong survival.

3. Most clinical investigations in AIDS patients, including nutritional investigations, have involved studies of patients with acute or ongoing illnesses. Such studies may not provide an accurate view of the effect of the HIV infection, or of the immue deficiency itself, on nutritional status. For this reason, we studied short-term energy balance in five clinically stable outpatients with AIDS who had no known untreated or untreatable complications, six HIV-seronegative homosexual controls, and five seronegative heterosexuals [15,16]. Body composition studies were performed twice, six weeks apart; food intake was analysed from a three-day food diary using a computerized database of dietary constituents (Nutritionist III); resting energy expenditure was determined using indirect calorimetry; and intestinal absorption was determined using the D-xylose and C triolein breath tests.

The AIDS patients had significantly decreased values of TBK compared to controls at the beginning of the study (table 2). They lost body weight over the six-week period, but had no significant changes in TBK or intracellular water volumes, indicating preservation of body cell mass. Nutrient intakes were similar in all groups. Malabsorption of xylose and triolein was documented in the AIDS group. The AIDS group was hypometabolic compared both to the controls and to predicted values. Energy balance, which was calculated as intake minus expenditure. was significantly abnormal in AIDS (approximately -850 kcal/day) compared to controls. The difference was related, at least in part, to nutrient malabsorption.

TABLE 2. Body energy balance in clinically stable patients with AIDS

Data expressed as mean ± SE.
N = 5 AIDS, 6 homosexuals, 5 heterosexuals.
*p <.05.

We concluded that AIDS patients with no serious complications can maintain body cell mass, at least during a short-term follow-up. The hypometabolism seen is an appropriate response to malabsorption in the absence of a compensatory increase in food intake. Nutritional balance in clinically stable AIDS patients differs markedly from those suffering from severe systemic illnesses, where rapid and progressive depletion of body cell mass occurs.

4. To further explore the nutritional differences between clinically stable patients and those with serious ongoing systemic complications of the disease, we studied patients who were treated for serious cytomegalovirus (CMV) infections. Disseminated CMV infection is a frequent complication of AIDS [17] and often is associated with rapid and progressive wasting.

The experimental agent ganciclovir effectively suppresses CMV infection in more than 80% of patients with serious disease [18], and its use may prolong survival [19]. Thus, successful treatment of serious cytomegalovirus infection with ganciclovir provides a unique opportunity to examine the nutritional consequences of a systemic infection in AIDS. For this reason, we reviewed retrospectively the results of body composition studies in patients with serious CMV infections who had had at least two body composition studies performed, and compared four patients not treated with ganciclovir with eight patients who received ganciclovir [20, 21]. The average daily changes in body weight, TBK, body fat content, and serum albumin concentration were calculated by regression analysis.

The results documented a fall in weight, TBK, fat, and serum albumin concentration in the untreated group. In contrast, a rise in these values was noted in the treated group (table 3). The differences between groups were statistically significant. The caloric values of the average daily changes in TBK and body fat in the two groups were estimated by conversion of the average daily changes in body cell mass and body fat content to energy equivalents and a difference of more than 600 kcal/day between the groups was found. This value represents the increase in the body's daily energy balance that could be ascribed to ganciclovir therapy.

We concluded that disseminated CMV infection promotes wasting and that ganciclovir therapy may reverse wasting in AIDS patients with serious CMV infections by decreasing the intensity of viral infection. The precise mechanism by which ganciclovir therapy exerts its beneficial nutritional effect remains to be determined.

TABLE 3. Effect of ganciclovir therapy on body mass in AIDS patients with cytomegalovirus infections

Data expressed as mean ± SE.
N = 4 untreated patients, 8 treated patients.
*p < .05. ** p < .01. *** p < .001.

5. Clinical observations indicate that may AIDS patients are hypertriglyceridaemic. The finding of hypertriglyceridaemia without hypercholesterolaemia is common to many systemic illness [22], while it is an unusual finding in uncomplicated starvation. Its presence has been ascribed to the inhibitory effect of cytokines such as tumour necrosis factor (TNF) on lipoprotein lipase activity [23], though other pathogenetic mechanisms also are possible. Cytokines have a wide variety of physiologic functions. including effects on cell metabolism, proliferation, and viability [24, 25]. The role of cytokines in metabolic regulation is complex and the focus of considerable current investigation.

The observation that hypertriglyceridaemia occurs in patients with AIDS is intriguing and implies a metabolic derangement. For this reason, we studied, retrospectively, fasting serum lipid concentrations in patients undergoing body composition analysis between July 1985 and December 1986, in collaboration with Dr. Carl Grunfeld at the San Francisco Veterans Administration Hospital and the University of California, San Francisco [26, 27]. Triglyceride concentrations were significantly higher in 32 AIDS patients than in 17 heterosexual controls (table 4). The results in eight HlV-seropositive subjects without AIDS were intermediate, though the prevalence of hypertriglyceridaemia was similar in the HIV+ subjects with and without AIDS (approximately 50%).

While 50% of the AIDS group had significantly decreased values for TBK, the presence or degree of depletion did not correlate with fasting serum triglyceride concentrations. Hypertriglyceridaemia also did not correlate with hypercholesterolaemia, with ongoing acute complications, or with a wasting course. The only common factor correlated with hypertriglyceridaemia was the presence of HIV infection. The results, thus, suggest that hypertriglyceridaemia might be a direct consequence of HIV infection. The pathogenetic mechanism for the hypertriglyceridaemia is uncertain, though the likelihood is that it results from altered cytokine secretion. No correlation between the presence of fasting hypertriglyceridaemia and the presence of circulating HIV p24 antigen, a putative marker of HIV production [28], was found in a recent preliminary study from our laboratory, indicating that there is no simple relationship between these parameters.

The results of the triglyceride studies are provocative and support a large body of data indicating that the chronic infectious processes in AIDS have nutritional effects similar to those found in other chronic wasting illnesses (29]. Since HIV can infect macrophages [30] and modulate gene expression [31] a direct role for HIV in wasting is quite possible.

6. Early observations indicated that PEM in AIDS is a progressive process. The ability to replete body mass in AIDS may be important since repletion may increase physical performance, enhance a patient's sense of well-being, and improve the response to other medical therapies. As noted above, body cell mass repletion might prolong survival. Furthermore, since PEM is associated with specific immune deficits [32], it also is possible that nutritional repletion might improve immune function.

In an ongoing longitudinal study, patients receiving nutritional support by total parenteral nutrition (TPN) at home are being examined to determine whether body cell mass repletion occurs and how these changes are related to the precise clinical conditions [33]. Eleven patients have been followed for 832 weeks. Four of these patients had significant increases in TBK, body weight, and body fat content, while seven patients increased body weight and body fat content alone.

Analysis of disease complications revealed that all the patients with significant increases in body mass after TPN had abnormalities in food intake or absorption (and presumably appropriate metabolic responses). The patients who increased body weight and body fat content without increasing TBK had serious systemic diseases such as disseminated Mycobacterium avium intracellulare infection or cytomegalovirus infection (and presumably deranged metabolic responses). Several of the latter patients also were extremely debilitated and immobilized, which also would inhibit repletion of body cell mass. These results would suggest that the response to parenteral nutritional support in patients with AIDS varies depending on the precise clinical circumstances.

The nutritional studies, thus, have defined two general classes of nutrition-related problems in AIDS patients. One type is related to intestinal dysfunction with malabsorption, while the other appears to be related more to systemic diseases and deranged metabolism. The specific cause of energy imbalance in a patient as well as the approach to nutritional therapy depends on the relative contribution of these two separate processes.

Several tasks remain before the role of PEM in AIDS can be fully understood. The presence and composition of body mass depletion must be correlated with changes in caloric intake and metabolic rate. The pathogenetic mechanisms underlying PEM must be more clearly defined. Specifically, the role of enteric infections in PEM must be determined, the mechanisms of intestinal nutrient malabsorption elucidated, the pathogenesis of hypertriglyceridaemia defined, and the metabolic alterations associated with HIV and other systemic infections identified. The impact of PEM on immune function in AIDS patients is an extremely important question, as the deficits related to PEM potentially are reversible. Finally, the efficacy of nutritional support must be identified and such therapies optimized. As the nutritional problems vary with the stage and precise characteristics of the disease, guidelines must be established that take into consideration the specific problems that might be encountered in an AIDS patient.

TABLE 4. Serum triglyceride concentrations in AIDS patients

N = 32 AIDS. 8 HIV+, 17 controls.
a. Mean ± SE.
*p<.05. **p<.01.

Acknowledgements

These studies were supported by grants from the New York State AIDS Institute and the National Institutes of Health (AI 21414).

References

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