Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation.

The cytokines IL-1 beta and TNF-alpha cause cachexia and hypermetabolism in animal models, but their role in human inflammation remains controversial. The relationship between in vitro cytokine production and metabolism was examined in 23 adults with RA and 23 healthy control subjects matched on age, sex, race, and weight. Body composition was measured by multicompartmental analysis of body cell mass, water, fat, and bone mass. Resting energy expenditure (REE) was measured by indirect calorimetry. Cytokine production by PBMC was measured by radioimmunoassay. Usual energy intake, physical activity, disability scores, medication use, and other confounders were also measured. Body cell mass was 13% lower (P < 0.00001), REE was 12% higher (P < 0.008), and physical activity was much lower (P < 0.001) in subjects with RA. Production of TNF-alpha was higher in RA than controls, both before and after stimulation with endotoxin (P < 0.05), while production of IL-1 beta was higher with endotoxin stimulation (P < 0.01). In multivariate analysis, cytokine production was directly associated with REE (P < 0.001) in patients but not in controls. While energy and protein intake were similar in the two groups and exceeded the Recommended Dietary Allowances, energy intake in subjects with RA was inversely associated with IL-1 beta production (P < 0.005). In this study we conclude that: loss of body cell mass is common in RA; cytokine production in RA is associated with altered energy metabolism and intake, despite a theoretically adequate diet; and TNF-alpha and IL-1 beta modulate energy metabolism and body composition in RA.

The relationship between growth hormone kinetics and sarcopenia in postmenopausal women: the role of fat mass and leptin.

Sarcopenia, the decline in body cell mass (BCM) and especially in muscle mass with age, is an important age-related cause of frailty and loss of independence in the elderly. Because the decline in BCM with age parallels a decline in GH secretion from young adulthood to old age, loss of GH secretion has been considered an important contributory cause of sarcopenia in the elderly. To test this hypothesis in a group of healthy postmenopausal women (n = 15; mean +/- SD age, 66.9 +/- 7.8 yr), 24-h GH concentrations and secretory kinetics were correlated with BCM (measured by whole body counting of 40K) and percent body fat (measured by dual energy x-ray absorptiometry or neutron inelastic scattering). Serum leptin levels were determined as a measure of adipocyte mass. Contrary to prediction, GH secretion was lower in women with higher BCM (r = 0.50; P < 0.05), whereas their mean fat mass was higher (r = 0.51, P < 0.05). These data indicate that sarcopenia in postmenopausal women is not associated with reduced GH secretion and is inversely correlated with fat mass. Serum leptin levels were inversely associated with GH secretion (r = -0.67; P < 0.006). Although a causal relationship has not been demonstrated, these data suggest that leptin could modulate GH secretion through its action on the aging hypothalamic-pituitary axis, or that GH regulates leptin secretion.

Total body potassium and body fat: relevance to aging.

Understanding the mechanisms that govern sarcopenia (depletion of muscle mass with age) may suggest ways to preserve lean tissue and functional capacity, and to maintain quality of life in the elderly. We investigated the body-composition changes in normal aging in a cross-sectional study of 188 healthy volunteers aged 20-89 y, which examines the differences in body cell mass and fat as a function of age. In aging, the assumptions of indirect body-composition-measurement techniques, such as the "constant" hydration coefficient of lean body mass or the "constant" density of fat-free mass, may not hold. Therefore, we selected body-composition-measurement techniques that are not sensitive to assumptions about the composition of lean tissue. Cellular mass, lean body mass, and fat were assessed "directly" by total body potassium (TBK) measurements and neutron inelastic scattering. Our results show that TBK content declines at a rate of 7.20 +/- 1.00 mg K.kg body wt-1.y-1 for females (r = 0.601, P < or = 0.001) and 9.16 +/- 0.96 mg K.kg body wt-1.y-1 for males (r = 0.710, P < or = 0.001). Body fat measurements by neutron inelastic scattering have shown a significant increase of percentage body fat with age for female volunteers between the ages of 20 and 50 y and a continuous increase for male volunteers throughout adult life.

In vivo determination of body fat by measuring total body carbon.

Total body carbon (TBC) is measured in vivo by neutron inelastic scattering. The fast neutrons needed for the irradiation are produced by a miniature deuterium-tritium (D-T) neutron generator. Body fat and protein are the main contributors to TBC. Bone ash and carbohydrates contribute less than 3%. Fat is calculated from TBC after the subtraction of the carbon contributions from protein, bone, and glycogen. The technique was applied to 14 normal volunteers (8 females, 6 males) aged 24-94 y who underwent neutron inelastic scattering and neutron activation measurements for body carbon, nitrogen, and calcium. The initial results agree with other techniques. Unlike models that evaluate body fat by subtracting lean body mass from body weight, the TBC technique is not sensitive to assumptions on the composition of lean body; therefore, it is appropriate for studies of adults of any age and health condition.

Dual-photon absorptiometry: comparison of bone mineral and soft tissue mass measurements in vivo with established methods.

This study extended initial observations that indicated the potential of dualphoton absorptiometry (DPA) to measure total-body bone mineral (TBBM) and fat in vivo. DPA-derived TBBM and fat were compared with established methods in 13 subjects (aged 24-94 y) who underwent measurement of body density (Db), total-body water (TBW), potassium (TBK), calcium (TBCa, delayed-gamma neutron activation), and nitrogen (prompt-gamma neutron activation). TBBM was highly correlated with TBCa (r = 0.95, p less than 0.001) and the slope of TBCa vs TBBM (0.34) was similar to Ca content of ashed skeleton (0.34-0.38). DPA-measured fat (means +/- SD, 16.7 +/- 4.9 kg) correlated significantly (r = 0.79-0.94; p less than 0.01-0.001) with fat established by Db (16.3 +/- 5.4 kg), TBW (16.0 +/- 4.3 kg), TBK (17.7 +/- 4.6 kg), combined TBW-neutron activation (17.6 +/- 5.9 kg), and means of all four methods (16.9 +/- 4.8 kg). DPA thus offers a new opportunity to study human skeleton in vivo and to quantify fat by a method independent from the classical assumption that bone represents a fixed fraction of fat-free body mass.

The Boston FICSIT study: the effects of resistance training and nutritional supplementation on physical frailty in the oldest old.

Research indicates that lower extremity muscle weakness in the elderly is consistently related to impaired mobility and fall risk. Reversible components of the muscle weakness of aging include underuse syndromes and undernutrition, both of which are prevalent in nursing home populations. The Boston FICSIT study is a nursing home-based intervention to improve muscle strength through progressive resistance training of the lower extremities and/or multi-nutrient supplementation in chronically institutionalized subjects aged 70-100. Baseline measurements of falls, medical status, psychological variables, functional status, nutritional intake and status, body composition, muscle mass and morphology, muscle function, and gait and balance are taken. The nursing home residents are then randomly assigned to one of four treatment groups for 10 weeks: (1) high intensity progressive resistance training of the hip and knee extensors 3 days per week; (2) multi-nutrient supplementation with a 360-kcal high carbohydrate, low fat liquid supplement every day; (3) a combination of groups (1) and (2); and (4) a control group. Both non-supplemented groups receive a liquid placebo every day, and both non-exercising groups attend three sessions of "leisure activities" every week in order to control for the attentional aspects of the exercise and nutritional interventions. At the end of the 10-week period, all baseline measurements are re-assessed.

The meaning and measurement of lean body mass.

Methods of measuring lean body mass have evolved greatly in the past decade. Because all practical methods of measurement are indirect (i.e., not involving carcass analysis), appropriate models of body composition must be applied. Today's improved precision is due both to better instrumentation and to improved models based on partition of the body into its constituent compartments. With this improved methodology has come the recognition that loss of lean body mass is associated with survival in starvation, acute illness, and aging. In addition, correlations of lean body mass with immune competence and functional status are beginning to emerge. It remains to be proven that changes in lean body mass in aging and disease independently determine outcome. Interventions that preserve or normalize lean body mass could be important for preservation of vigorous functional status.

In vivo elemental partition analysis using fast neutrons. A tool for testing the efficacy of new clinical interventions.

The nutritional status of patients can be evaluated by monitoring changes in body composition, including depletion of protein and muscle; distribution of adipose tissue; and changes in hydration status, and bone or cell mass. Fast neutron activation (for N and P) and neutron inelastic scattering (for C and O) are used to assess in vivo elements characteristic of specific body compartments. Nonbone phosphorus for muscle is measured by the 31P(n,alpha)28Al reaction, and nitrogen for protein via the (n,2n) fast neutron reaction. The carbon-to-oxygen (C/O) ratio is used to measure distribution of fat and lean tissue in the body and to monitor small changes in lean mass and its quality. In addition to evaluating the efficacy of new treatments, the method is used to study the mechanisms of depletion of lean tissue with aging.

The effect of gender and body composition method on the apparent decline in lean mass-adjusted resting metabolic rate with age.

BACKGROUND: Declining resting energy expenditure (REE) is a hallmark of normal aging, but the cause of this decline remains controversial. Some, but not all, studies have shown that the decline in REE with age is eliminated after adjustment for fat-free mass (FFM). METHODS: We examined the effect of four body composition methods used to assess FFM (underwater weighing [UWW], bioimpedance analysis [BIA], tritium dilution, and total body potassium [TBK]) on the relationship between REE and age in 30 healthy men and 101 healthy women aged 18 to 87 years. RESULTS: The decline in REE with age was significant in women (-80.3 kJ/d/y, p < .004) but not in men (-46.9 kJ/d/y, p = .328). After adjustment for FFM, the decline in REE with age persisted when FFM was measured by BIA, UWW, or tritium dilution, but no decline was seen when TBK was used to adjust for FFM. In both women and men, fat mass was significantly associated with REE after adjusting for age and FFM. CONCLUSION: It is the decline in cell mass with age, detectable by TBK but not by other methods, rather than any metabolic alteration, that explains the decline in FFM-adjusted REE with age.

Body composition in children and adults by air displacement plethysmography.

OBJECTIVES: Air displacement plethysmography (ADP) may provide a partial alternative to body density (Bd) and therefore body composition measurement compared to conventional hydrodensitometry (Hd) in children. As there are no evaluation studies of ADP in children, this study had a two-fold objective: to compare Bd estimates by ADP and Hd; and to compare fat estimates by both ADP and Hd to fat estimates by another reference method, dual energy X-ray absorptiometry (DXA). SETTING: Obesity Research Center, St. Luke's/Roosevelt Hospital, New York, USA. SUBJECTS: One hundred and twenty subjects (66 females/54 males) who ranged in age from 6-86 y and in body mass index (BMI, kg/m2) from 14.1-40.0 kg/m2 met study entry criteria. STUDY DESIGN: Cross-sectional study of healthy children (age < or = 19 y) and adult group for comparison to earlier studies. Each subject completed ADP, Hd, and DXA studies on the same day. Only subjects with subjectively-judged successful Hd studies were entered into the study cohort. RESULTS: There was a high correlation between Bd by ADP and Hd (Bd Hd = 0.11 + 0.896 x Bd ADP; r = 0.93, SEE = 0.008 g/cm3, P < 0.0001), although the regression line slope and intercept differed significantly from 1 and 0, respectively. Additional analyses localized a small-magnitude Bd bias in the child (n = 48) subgroup. Both ADP and Hd %fat estimates were highly correlated (r > 0.9, P < 0.0001) with %fat by DXA in child and adult subgroups. Bland-Altman analyses revealed no significant %fat bias by either ADP or Hd vs DXA in either children or adults, although a bias trend (P = 0.11) was detected in the child subgroup. CONCLUSION: With additional refinements, the air displacement plethysmography system has the potential of providing an accurate and practical method of quantifying body fat in children as it now does in adults.

Cytokine production and nutritional status in hemodialysis patients.

Malnutrition is an important predictor of mortality in patients on chronic hemodialysis, however the pathogenesis of wasting in this population remains unclear. Experimental data suggest that the dialysis procedure per se leads to enhanced catabolism, as well as direct loss of plasma amino acids and proteins into the dialysate. In the present study, the primary hypothesis examined is that hemodialysis-induced cytokine production is associated with reductions in lean body mass and other plasma markers of nutrition. We used the production of interleukin-1 receptor antagonist (IL-1Ra) by peripheral blood mononuclear cells (PBMC) as an indicator of cytokine production. PBMC were obtained pre-dialysis on the first and second sessions of the week in a cohort of 16 patients on chronic hemodialysis using reprocessed cellulose dialyzers who fulfilled rigorous entry criteria designed to eliminate known etiologies of increased cytokine production, e.g. chronic infections. PBMCs were either immediately frozen (cell content) or incubated for 24 hours at 37 degrees C in the presence or absence of endotoxin 10 ng/ml and total IL-1Ra was measured by radioimmunoassay. Nutritional staus was assessed using body mass index (BMI), total body potassium (TBK), anthropometry-derived arm muscle area (AMA), and measurements of plasma albumin, transferrin, total cholesterol, and triglycerides. Over the subsequent 3 months, patients were monitored carefully for pyrogen reactions, hemodynamic stability and intra-interdialytic symptoms. There was a direct correlation of cell content of IL-1Ra with several indices of nutritional status including BMI (r = 0.90, p = 0.0001), AMA (r = 0. 77, p = 0.0008), serum total cholesterol (r = 0.57, p = 0.03) and serum triglycerides (r = 0. 73, p = 0.002). Endotoxin-stimulated IL-1Ra production correlated directly with AMA (r = 0.59, p = 0.02), TBK (r = 0.71, p = 0.01) and serum triglycerides (r = 0.51, p = 0.05). These studies suggest a direct correlation between nutrition and cytokine production, and that malnutrition could depress cytokine production and potentially contribute to reduced immune responsiveness in patients on chronic hemodialysis.

Nutritional alterations and the effect of fish oil supplementation in dogs with heart failure.

Alterations in body composition and nutritional status are common in humans with heart failure and are related, in part, to increases in cytokine concentrations. Cytokines have not been studied previously in dogs with naturally occurring cardiac disease nor has fish oil administration been used in this population to decrease cytokine production. The purposes of this study were to characterize nutritional and cytokine alterations in dogs with heart failure and to test the ability of fish oil to reduce cytokines and improve clinical outcome. Body composition, insulinlike growth factor-1, fatty acids, and cytokines were measured in 28 dogs with heart failure and in 5 healthy controls. Dogs with heart failure then were randomized to receive either fish oil or placebo for 8 weeks. All parameters were measured again at the end of the study period. At baseline, 54% of dogs with heart failure were cachectic and the severity of cachexia correlated with circulating tumor necrosis factor-alpha concentrations (P = .05). Cytokine concentrations at baseline, however, were not significantly increased in dogs with heart failure compared to controls. Baseline plasma arachidonic acid (P = .02), eicosapentaenoic acid (P = .03), and docosahexaenoic acid (P = .004) concentrations were lower in dogs with heart failure than in controls. Fish oil supplementation decreased interleukin-1 beta (IL-1) concentrations (P = .02) and improved cachexia (P = .01) compared to the placebo group. The mean caloric intake of the heart failure dogs as a group was below the maintenance energy requirement (P < .001), but no difference was found in food intake between the fish oil and placebo groups. Insulinlike growth factor-1 concentrations (P = .01) and reductions in circulating IL-1 concentrations over the study period (P = .02) correlated with survival. These data demonstrate that canine heart failure is associated with cachexia, alterations in fatty acids, and reduced caloric intake. Fish oil supplementation decreased IL-1 concentrations and improved cachexia. In addition, reductions in IL-1 predicted survival, suggesting that anticytokine strategies may benefit patients with heart failure.

Assessment of body fat and lean in the elderly by measuring body carbon and oxygen: validation against hydrodensitometry.

Based on the observation that the carbon-to-oxygen ratio (C/O) in tissue is a measure of fat content, we developed a model which correlates C/O to percent body fat. Carbon and oxygen mass and their ratio are measured in vivo by fast neutron inelastic scattering, using a miniature D-T neutron generator, at a radiation exposure of less than 0.06 mSv. We tested the validity of this model against hydrodensitometry with 19 healthy adult volunteers. The method was found to be accurate and insensitive to assumptions about the composition of lean tissue and, therefore, appropriate for studying the elderly and patients with catabolic conditions.

Use of fast neutrons for measuring muscle.

Elemental Partition Analysis (EPA) is a new approach to body composition. A major element of the body is measured and then, by means of other measurements, is partitioned to the contributing body compartments. We developed a model for measuring total body muscle by applying the EPA method to total body phosphorus (TBP). We measure TBP (head excluded) by in vivo fast neutron activation analysis using the reaction 31P(n, alpha)28 Al. The main contributors to TBP are the bone and skeletal muscle. Adipose tissue and the liver contribute less than 3%. We use dual-energy X-ray absorptiometry (DXA) to evaluate the contribution of bone to TBP. Corrections are applied for the small contributions of the liver and adiopose tissue to TBP to derive muscle phosphorous. The technique requires high precision measurements for both TBP (+/- 2%) and DXA (+/- 1%). The total body radiation exposure for measuring human subjects is 0.60 mSv. We observed that nitrogen can also be measured by fast neutron activation analysis through the (n,2n) reaction, simultaneously with TBP.

What makes a BIA equation unique? Validity of eight-electrode multifrequency BIA to estimate body composition in a healthy adult population.

BACKGROUND/OBJECTIVES: The validity of bioelectrical impedance analysis (BIA) for body composition analysis is limited by assumptions relating to body shape. Improvement in BIA technology could overcome these limitations and reduce the population specificity of the BIA algorithm. SUBJECTS/METHODS: BIA equations for the prediction of fat-free mass (FFM), total body water (TBW) and extracellular water (ECW) were generated from data obtained on 124 Caucasians (body mass index 18.5-35 kg/m(2)) using a four-compartment model and dilution techniques as references. The algorithms were validated in an independent multiethnic population (n=130). The validity of BIA results was compared (i) between ethnic groups and (ii) with results from the four-compartment model and two-compartment methods (air-displacement plethysmography, dual-energy X-ray absorptiometry and deuterium dilution). RESULTS: Indices were developed from segmental R and Xc values to represent the relative contribution of trunk and limbs to total body conductivity. The coefficient of determination for all prediction equations was high (R(2): 0.94 for ECW, 0.98 for FFM and 0.98 for TBW) and root mean square error was low (1.9 kg for FFM, 0.8 l for ECW and 1.3 kg for TBW). The bias between BIA results and different reference methods was not statistically different between Afro-American, Hispanic, Asian or Caucasian populations and showed a similar difference (-0.2-0.2 kg FFM) when compared with the bias between different two-compartment reference methods (-0.2-0.3 kg FFM). CONCLUSIONS: An eight-electrode, segmental multifrequency BIA is a valid tool to estimate body composition in healthy euvolemic adults compared with the validity and precision of other two-compartment reference methods. Population specificity is of minor importance when compared with discrepancies between different reference methods.

Water homeostasis, frailty and cognitive function in the nursing home.

OBJECTIVE: - To develop and test a practical clinical method to assess frailty in nursing homes; - To investigate the relationship between cognitive status of the elderly and the balance between water compartments of their body composition. DESIGN AND SUBJECTS: Cross-sectional study, conducted at two nursing homes in Boston-MA. METHODS: Body mass and height (Ht) were evaluated to calculate BMI (body mass index, in Kg/m²). The cognitive decline was evaluated based on the scores obtained from the Mini-Mental State Examination (MMSE); The extracellular to total body water ratio (ECW/TBW) was calculated after the analysis of TBW from deuterium and tritium dilution and ECW from bromide dilution. Single-frequency BIA analysis data were investigated for resistance (R) and reactance (Xc), plotted in an R/Ht Xc/Ht graph (vectorial analysis-BIVA). The BIVA results of nursing home residents were compared against the data obtained from the NHANES III study. TBW and ECW values were compared with a group of free-living elderly volunteers. RESULTS: The ECW/TBW was significantly higher in nursing home residents than in the free-living individuals. BIVA analysis showed significantly higher Xc/Ht values in the reference subjects. The MMSE did not present a significant correlation with ECW/TBW for either gender. CONCLUSION: We proposed the ECW/TBW ratio and BIVA as surrogate methods for the clinical assessment of frailty. We tested successfully both approaches with nursing home patients and free-living volunteers and compared them to a national data base. The advent of new, portable instruments will enable field tests to further validate our proposed "Frailty Factor" in future studies. We found no correlation between frailty and cognitive decline in the nursing home.