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Human Nutrition and Metabolism

Hyperphagia Contributes to the Normal Body Composition and Protein-Energy Balance in HIV-Infected Asymptomatic Men¹

Department of Medicine, Infectious Diseases and Clinical Nutrition, Raymond Poincaré Hospital (AP-HP), Garches, Versailles-Saint-Quentin en Yvelines University and ^* Hepatogastroenterology and Nutritional Support, Lariboisière Hospital (AP-HP) and INSERM U290, Paris, France

²To whom correspondence should be addressed. E-mail: pascal.crenn{at}rpc.ap-hop-paris.fr.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Wasting can occur at an early stage of HIV infection. Both reduced energy intake and increased resting energy expenditure (REE) have been considered as factors in wasting with predominant lean body mass loss, suggesting disturbances of protein metabolism. Our aim was to study protein-energy metabolism in relation to body composition and oral energy intake in asymptomatic patients with HIV infection but receiving no active antiretroviral therapy. Stable-weight asymptomatic male patients (n = 8) at stage A of HIV infection with a detectable viral load were compared with 9 healthy control men. Protein metabolism was studied in the postabsorptive state using a primed constant infusion of L-[1-¹³C]leucine and L-[2-¹⁵N]glutamine. REE was studied by indirect calorimetry, body composition by bioelectrical impedance, and energy intake by dietary records. BMI and lean body mass did not differ between patients and controls. In HIV-infected subjects, energy intake, protein breakdown, protein synthesis, and REE were 57% (P < 0.05), 18% (P < 0.05), 22% (P < 0.05) and 14% (P < 0.05) greater than in controls, respectively. REE and protein breakdown were correlated (r = 0.73, P < 0.05). The hormonal profile was normal in HIV-infected subjects with the exception of low urinary C-peptide and plasma reverse triiodothyronine. Plasma interleukin-6 and tumor necrosis factor- were greater than in controls, but energy intake was 1.53 times the REE in the HIV-infected men. Thus, at the asymptomatic stage of HIV infection, increased protein turnover contributes to the increase in the REE. Moderate hyperphagia, which occurred despite increased levels of cytokines, in conjunction with increased protein synthesis maintains a normal body composition, without significant loss of lean body mass.

KEY WORDS: • HIV • body composition • energy expenditure • hyperphagia • protein metabolism

Wasting syndrome, i.e., malnutrition related to HIV infection (1), has not disappeared despite a decrease in Western countries due to highly active antiretroviral therapy (HAART).³ Wasting syndrome remains a major cause of morbidity and mortality (2) especially in developed countries, which account for >90% of the estimated 40 million AIDS patients in the world but in which fewer than 2% of HIV-infected patients receive HAART (3). Weight loss is associated with an accelerated disease progression in HIV infection (4), and malnutrition without HIV infection promotes immunodeficiency (5). At an early stage of HIV infection, patients can present progressive weight loss characterized by a greater depletion of lean than fat body mass (6). This observation suggests that protein metabolism may be disturbed. Among investigations using [¹³C]leucine as an isotopic tracer for protein metabolism, 3 studies showed that rates of protein turnover were higher in HIV-infected patients (7–9); in asymptomatic stage A patients, 1 study showed an increase in protein turnover (9), whereas it was reported as normal in 2 other studies (7,10).

There are different metabolic situations in spontaneous HIV infection. The first situation, associated with opportunistic infections, is acute infection syndrome, which is accompanied by an increase in both resting energy expenditure (REE) and protein turnover (11,12), contributing to rapid weight loss (12,13). In chronic HIV infection with no opportunistic infection, 20% of HIV-infected patients develop wasting syndrome (14), attributed mainly to a negative energy balance due to reduced energy intake, with increased REE reaching 15%, whatever the level of immunodeficiency (12,15,16). Other patients constitute a third category because they do not exhibit weight loss and are asymptomatic, despite chronic viral infection. Host metabolism disturbances at this asymptomatic stage of HIV infection are characterized by increased de novo lipogenesis (17), insulin hypersensitivity (18), and fat oxidation (16). It has not been clearly determined why at this asymptomatic stage of HIV infection, most HIV-infected patients in the absence of protease inhibitor therapy and HAART can sustain a normal body composition, and no study has addressed the interplay among protein-energy balance, body composition, and oral energy intake. The aim of this study was therefore to explore this question by performing an in vivo postabsorptive metabolic study in asymptomatic HIV-infected patients who did not receive active antiretroviral therapy.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Subjects

Approval was given by the Ethics Committee of the Saint Louis Hospital (Paris, France). Each subject gave written informed consent. Subjects were recruited among patients attending the consultation for infectious diseases at Bichat-Claude Bernard Hospital, Paris and from the Action Traitement association. All subjects were positive in an ELISA and Western blot for antibody against HIV-1. We selected 8 asymptomatic male patients with stable weight during the previous year, no opportunistic infection, and who had not received antiretroviral treatment, especially by protease inhibitors, due to refusal, absence of indication or arrest, in the 6 mo before the metabolic study. Only patients with CD4 lymphocytes < 200/mm³ were treated by the association sulfamethoxazole-trimetoprime as primary prophylaxis. All patients had a detectable HIV viral load. Patients were sedentary, i.e., no physical exercise, and free from diarrhea, known endocrine disease (thyroid disease or diabetes mellitus), impaired kidney or liver function, malignancy, and hepatitis C or B infection. No patients had lipodystrophy syndrome. The HIV-infected group was compared with an age and sex-matched control group of 9 healthy uninfected men with normal clinical nutritional status and stable weight during the previous year.

Experimental methods

    Nutritional assessment and body composition analysis. The metabolic study included a weighted dietary record over a 1-wk period to estimate usual macronutrient intake. Body composition was measured using a 2-frequency (5 kHz, 1 MHz) bioelectrical impedance analyzer (IMP B01) to estimate fat-free mass (FFM), i.e., lean body mass (19,20). Indeed, we previously found a close correlation (r = 0.97) between bioelectric impedance and anthropometric determination (skinfold measurements) in HIV-infected patients (12).

    Energy expenditure assessment. REE was measured in a postabsorptive state after an overnight fast by indirect calorimetry with a ventilated hood and metabolic monitor (Deltratrac II MBM-200, Datex Instrumentarium). REE was calculated from O₂ consumption, CO₂ production, and urinary nitrogen excretion using the Ben Porat equations (21). The calorimeter was calibrated before each measurement (atmospheric pressure, O₂, and CO₂ analyzers) and checked regularly by burning methanol under standard conditions.

    Whole-body leucine and glutamine kinetics and estimation of protein turnover. Whole-body leucine and glutamine kinetics were measured in a postabsorptive state after an overnight fast and were calculated as described previously (22,23). At steady state, fluxes were calculated as the measured rate of tracer infusion divided by the plateau plasma tracer enrichment. Isotopic steady state was defined by a satisfactory plateau of plasma isotopic enrichments (CV < 10%). Leucine oxidation was the product of the rate of carbon dioxide production and breath ¹³CO₂ enrichment at plateau divided by serum enrichment of [¹³C]-ketoisocaproic acid (KIC). The estimated fraction of carbon recovered in expired air was 0.70. For leucine oxidation, [¹³C]KIC enrichments were used because KIC is the immediate intracellular precursor of irreversible leucine decarboxylation (22). In the model used, there are only 2 possible fates for the labeled carbon of [¹³C]leucine (leucine flux), i.e., incorporation into body protein (protein synthesis or nonoxidative leucine disposal) or decarboxylation and release as ¹³CO₂ (oxidation). Thus, the rate of incorporation of leucine into body protein was calculated from the difference between rate of oxidation and leucine flux. The rate of release of leucine from protein breakdown was calculated from the difference between flux and dietary intake (equal to zero in the postabsorptive state). Protein balance was taken as the difference between the rate of protein synthesis and the rate of protein breakdown, measured by leucine kinetics as described above (22). Protein fluxes were expressed as µmol/(kg · h). Isotopic enrichments of tracers and [¹³C]KIC in serum were measured by GC-MS (DELSI DI 700, NERMAG R1010T, Nermag). Isotopic enrichment of ¹³CO₂ was measured by gas isotope ratio MS (Tracer Mass, Europa Scientific). Breath ¹³CO₂ enrichment was calculated as the variation compared with preinfusion values. Sodium [¹³C]bicarbonate, L-[2-¹⁵N]glutamine (99 mol% excess) and L-[1-¹³C]leucine (99 mol% excess) were purchased from Mass Trace.

    Blood hormone levels and metabolic and immunovirological function assessment. The following postabsorptive plasma or serum analyses were performed: insulin and C-peptide by RIA (Phadeseph); albumin, prealbumin, triglycerides, C-reactive protein (CRP; Dade Behring); cortisol (VIDAS); thyroid stimulating hormone, triiodothyronine (T3), thyroxin (T4), free T3, reverse T3, and free T4 (VIDAS), full blood CD4 and total lymphocyte count, glucagon, adrenaline, interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor- (TNF-) (Immunotec). The HIV viral load was measured by PCR (Monitor Roche).

Experimental protocol

Isotopes were dissolved in saline solution, passed through a 0.22-µm filter, and stored in sealed vials at 4°C. A test sample of isotope solution was found to be sterile and pyrogen-free. Two venous catheters were inserted, one into a forearm vein to inject labeled amino acids, the other into a superficial vein of the contralateral hand to withdraw "arterialized" venous blood samples using a ventilated box heated to 70°C (23), which permits an opening in the arteriovenous shunt. Subjects were studied after an overnight fast and continued to fast (postabsorptive state). REE was assessed during the first 45 min. After a primer dose of [¹³C]bicarbonate (0.2 mg/kg), [¹³C]leucine (4 µmol/kg) and [¹⁵N]glutamine (6 µmol/kg), continuous infusion of [¹³C]leucine [4 µmol/(kg · h)] and [¹⁵N]glutamine [6 µmol/(kg · h)] was begun and continued for 3 h 40 min. Blood and breath samples were collected before every infusion to determine baseline values (T0 min) and at 20-min intervals during the last hour of the isotopic plateau (from T160 to T220 min). Blood samples were centrifuged at 3000 x g for 15 min at 4°C and the plasma obtained was stored at –60°C. Breath samples were collected in 50-L latex Douglas bags and kept in 10-mL evacuated containers (Vacutainer, Becton Dickinson) to determine expired ¹³CO₂. The urine produced in 6 h during the postabsorptive state was pooled to estimate urinary nitrogen flow and urinary C peptide. Total CO₂ production and O₂ consumption were recorded at steady state.

Statistical analysis

All data are expressed as means ± SD. Results were analyzed using the unpaired Student’s t test or the paired Student’s t test when indicated. Correlation was determined by linear regression and tested for significance by ANOVA. P-values < 0.05 were considered significant.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Subject characteristics. The 8 selected HIV-infected men were homosexual and classified at stage A according to 1993 CDC criteria (24), i.e., A1 (n = 1), A2 (n = 2), and A3 (n = 5). The median HIV infection was recorded as 4 y (range: 1–8). Lymphocyte CD4 count was 153 (68–578) x 10⁹/L and HIV viral load was 135 (21–890) x 10³ copies/mL. The control group and HIV-infected groups did not differ in body weight, BMI, FFM, or body fat content (Table 1).

Plasma concentrations of glucagon, T4, T3, catecholamine, and cortisol were within the normal range. Postabsorptive insulinemia and glycemia were 108 ± 30 pmol/L (normal value < 108 pmol/L) and 4.9 ± 0.6 mmol/L respectively. Postabsorptive urinary C-peptide and plasma reverse T3 levels were lower than the normal range: 5.1 ± 3.1 mmol/d (normal value > 8 mmol/d) and 0.15 ± 0.05 µg/L (normal range: 0.35–0.9 µg/L), respectively.

    REE and dietary records. For comparison of REE adjusted to the FFM, we used the method proposed by Ravussin et al. (25). The prediction equation for REE in control subjects was REE (kJ/d) = 51 x FFM (kg) + 3520. In the asymptomatic HIV-infected men, a theoretical value for each patient’s REE was obtained by applying the actual FFM to the regression equation of the control group (Fig. 1). This theoretical value was significantly lower than the measured REE (paired t test: t = 8.25, P < 0.001). Energy intake by the HIV-infected group was higher than that of the control group (P = 0.02) and protein intake tended to be greater (P = 0.07) (Table 2). The energy intake/REE ratio was higher in HIV-infected patients than in control subjects (1.53 ± 0.10 vs. 1.12 ± 0.07, respectively, P < 0.01). Moreover, energy intake/weight and energy intake/fat-free mass were higher (P < 0.01) in HIV-infected men than in controls. Plasma albumin and prealbumin concentrations in the HIV group were 44 ± 6 g/L and 310 ± 50 mg/L, respectively, within normal ranges. Triglyceridemia was slightly high in the HIV group at 1.66 ± 0.55 mmol/L (normal range: 0.7–1.66 mmol/L).

View larger version (16K): [in this window] [in a new window]   FIGURE 1 REE relative to fat-free body mass in men at the asymptomatic stage of HIV infection and their matched controls.

View larger version (19K): [in this window] [in a new window]   FIGURE 2 Correlation between REE and leucine flux in men at the asymptomatic stage of HIV infection and their matched controls. The correlation was significant in the HIV-infected subjects: r = 0.73, r2 = 0.53, P = 0.04, and the equation is as follows: resting energy expenditure = 5.32 x whole-body leucine flux + 1179. The correlation was not significant in control subjects (P = 0.14).

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

The factors responsible for increased protein breakdown and energy expenditure during chronic infection and inflammation have not yet been fully defined, but cytokines may be the host mediators. Feingold et al. (32) reported stimulation of hepatic lipid synthesis in vivo by cytokines. Elevated circulating concentrations of cytokines such as TNF-, IL-6 and IL-1ß were reported during HIV infection (33). These data probably explain the energetic needs for maintaining hepatic acute-phase protein synthesis and immune function in HIV infection. TNF- may (34) or may not (35) be responsible for the cachexia of AIDS, whereas other studies suggest that weight loss is potentially due to the effect of elevated levels of cytokines in plasma (36). We showed high plasma concentrations of TNF- and IL-6 without correlation with protein flux or REE, but plasma concentrations may not correspond exactly to the activation of local cytokines. Nevertheless, it would appear that these increases were not the single cause of anorexia or wasting during HIV infection because our patients maintained a normal body composition associated with hyperphagia. Our patients had low reverse T3 with normal T3 levels as reported previously (37). It was suggested that these abnormalities during HIV infection might be an inappropriate response to energy deprivation resulting from a cytokine effect (38). Our study ruled out this hypothesis because our patients were not lacking in energy. We observed low urinary C peptide associated with normal insulinemia and glycemia, which suggests the existence of insulin hypersensitivity, an effect first described by Hommes et al. (16). Such insulin hypersensitivity was not associated with a disturbed body composition; on the contrary, this could explain the preservation of lean body mass as a result of increased whole-body protein turnover with a parallel increase in protein synthesis. The insulin hypersensitivity may also explain the favorable response to parenteral nutrition with net positive protein balance and rapid lean body mass repair after wasting syndrome in HIV-infected patients who are not receiving protease inhibitor therapy or HAART (39). At the asymptomatic stage of HIV infection, increased energy intake could compensate for disturbances in protein-energy metabolism. Protein balance in the HIV group did not differ from that of the control group. Thus, increased protein synthesis compensates for increased protein breakdown. This result is consistent with the lack of significant lean body mass loss in our HIV-infected subjects.

The protein-energy disturbances we found agree with previous studies in asymptomatic HIV-infected patients, showing that even at the asymptomatic stage, HIV infection per se disturbs protein-energy balance. The 14% increase in REE observed in our study is in agreement with the results in literature for the asymptomatic stage of HIV infection (12,16,40). We showed a good correlation between leucine flux and REE (r = 0.73); therefore acceleration of protein turnover could explain in part the increase in REE. Protein turnover may be the most energy-requiring part of the macronutrient cycle because many steps, especially for protein synthesis, require ATP. In fact, our HIV population had a 22% significant increase in protein synthesis. Mulligan et al. (41) suggested a possible correlation between increased REE and HIV viral load, independent of immunocompetence. However, the decreased viral load observed during HAART treatment does not seem to lead directly to a decrease in REE (42), and we did not find significant correlations between HIV viral load and protein turnover or energy expenditure.

To examine the parameters of protein kinetics, Macallan et al. (7) conducted a study assessing protein metabolism using [¹³C]leucine in asymptomatic HIV-infected subjects at stages A and C. They reported a significant increase in protein breakdown and synthesis without an increase in leucine oxidation in asymptomatic stage C subjects and a tendency for increased protein turnover early on. On the other hand, Berneis et al. (10) did not find an increase in protein turnover in stable HIV-infected patients with BMI < 21 kg/m² or CD4 < 500 x 10⁹/L. Yarasheski et al. (9) found that whole-body breakdown and synthesis rates in fasting subjects were greater than controls in asymptomatic HIV-infected patients and in cases of AIDS wasting. Our study, which used the same [¹³C]leucine methodology, confirmed a significant acceleration in whole-body protein breakdown and synthesis in subjects at asymptomatic stage A presenting a detectable HIV viral load. However, few data were available on glutamine metabolism in HIV-infected patients. Yarasheski et al. (9) found that glutamine flux was significantly increased in AIDS-wasting patients but did not differ between controls and asymptomatic HIV-infected patients. In our study, glutamine flux, 11% higher in the HIV group than in the control group, did not differ significantly. Nevertheless, plasma concentrations of glutamine were significantly lower (26%) in HIV-infected subjects than in control subjects (Table 3). Glutamine, together with glucose, is a preferred fuel for immune cells, providing both an energy source and nucleic acid precursors for new cell synthesis. In our study, the low plasma glutamine concentration possibly resulted from a higher utilization by the immune system rather than short supply because protein intake, slightly higher in the HIV group than in the control group, was 1.6 g/(kg · d). We speculate therefore that 1 of the factors that accounts for the lean body mass loss in HIV infection is a chronic need for an increased glutamine supply to support the rapidly dividing cells of the immune system. This hypothesis is supported by studies reporting that in normal subjects and in bone marrow transplant patients, supplemental glutamine both increases protein synthesis and improves nitrogen balance (43,44).

In summary, these results show that HIV-infected sedentary patients at the asymptomatic stage of the disease can compensate an increased energy expenditure and protein turnover through hyperphagia, leading to protein-energy balance equilibrium and a normal body composition despite their proinflammatory cytokine profile.

	ACKNOWLEDGMENTS

 
We thank M. C. Morin for dietary assessments, O. Rigal for plasma cytokine measurements, C. Rouzioux for HIV viral load assessments, B. Beaufrère for technical comments, and Auvergne Traduction Technique for careful review of the English language content of the manuscript. We also thank the subjects who participated in this study.

	FOOTNOTES

 
¹ Supported in part by the Agence Nationale de Recherche sur le SIDA (ANRS) and the Fondation pour la Recherche Médicale.

³ Abbreviations used: CRP, C-reactive protein; FFM, fat-free mass; HAART, highly active antiretroviral therapy; IL, interleukin; KIC, [¹³C]-ketoisocaproic acid; REE, resting energy expenditure; T3, triiodothyronine; T4, thyroxin; TNF, tumor necrosis factor.

Manuscript received 6 February 2004. Initial review completed 23 March 2004. Revision accepted 3 June 2004.

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TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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