G. Toigo

ESPEN Guidelines on Parenteral Nutrition: Geriatrics

Older subjects are at increased risk of partial or complete loss of independence due to acute and/or chronic disease and often of concomitant protein caloric malnutrition. Nutritional care and support should be an indispensable part of their management. Enteral nutrition is always the first choice for nutrition support. However, when patients cannot meet their nutritional requirements adequately via the enteral route, parenteral nutrition (PN) is indicated. PN is a safe and effective therapeutic procedure and age per se is not a reason to exclude patients from this treatment. The use of PN should always be balanced against a realistic chance of improvement in the general condition of the patient. Lower glucose tolerance, electrolyte and micronutrient deficiencies and lower fluid tolerance should be assumed in older patients treated by PN. Parenteral nutrition can be administered either via peripheral or central veins. Subcutaneous administration is also a possible solution for basic hydration of moderately dehydrated subjects. In the terminal, demented or dying patient the use of PN or hydration should only be given in accordance with other palliative treatments.

Metabolic response to injury and sepsis: changes in protein metabolism

The metabolic response to trauma and sepsis involves an increased loss of body proteins. Specific sites of changes of protein and amino acid metabolism have been identified. In skeletal muscle, the rate of proteolysis is accelerated greatly. The rate of protein synthesis also may be increased but not enough to match the increase in degradation. Intramuscular glutamine concentration is decreased because of increased efflux and possibly decreased de novo synthesis. In the liver, the rate of synthesis of selected proteins (i.e., albumin, transferrin, prealbumin, retinol-binding protein, and fibronectin) is decreased, whereas acute phase protein synthesis is accelerated. Tissues characterized by rapidly replicating cells, such as enterocytes, immune cells, granulation tissue, and keratinocytes, exhibit early alterations in the case of decreased protein synthesis capacity. In these tissues, glutamine use is accelerated. Increased stress hormone (cortisol and glucagon) and cytokine secretion, as well as intracellular glutamine depletion, are potential mediators of altered protein metabolism in trauma and sepsis. However, the relative importance of these factors has not been clarified. Therapy of acute protein catabolism may include the use of biosynthetic human growth hormone, possibly in combination with insulin-like growth factor-1, and the administration of metabolites at pharmacologic doses. We recently studied the effects of carnitine and alanyl-glutamine administration in severely traumatized patients. We found that both carnitine and the glutamine dipeptide restrained whole-body nitrogen loss without affecting selected indices of protein metabolism in the skeletal muscle.

Omega-3 fatty acids and protein metabolism: enhancement of anabolic interventions for sarcopenia

Purpose of reviewThe increased age observed in most countries, with the associated higher rates of chronic illnesses and cancer, and a diffuse sedentary lifestyle, will increase the number of patients with clinically relevant anabolic resistance, sarcopenia and its complications. The need for solutions to this major health issue is, therefore, pressing. Recent findingsThe metabolic derangements and other consequences associated with sarcopenia can be slowed or even prevented by specific nutritional interventions. New evidence is available about the efficacy of omega-3 fatty acid dietary supplementation to improve protein metabolism and counteract anabolic resistance through indirect effects. Studies show that the anabolic stimuli from substrates (e.g. amino acids or proteins), hormones (e.g. insulin) and/or physical activity in skeletal muscle can be enhanced by long-term fish oil administration. SummaryThe review of data from recent studies on this topic suggests that dietary omega-3 fatty acid supplementation, in association with an anabolic stimulus, could potentially provide a safe, simple and low-cost intervention to counteract anabolic resistance and sarcopenia. This intervention may contribute to prevent cachexia and disabilities. Supplementation should be given in the earlier stages of sarcopenia (e.g. precachexia). Further research should, however, be performed to better understand the mechanisms involved and the best dosage and timing of administration.

Inverse relationship between "a body shape index" (ABSI) and fat-free mass in women and men: Insights into mechanisms of sarcopenic obesity.

BACKGROUND & AIMS Sarcopenic obesity may be defined by a high fat to fat-free mass (FM/FFM) ratio. Skeletal muscle may be negatively influenced by the pro-inflammatory milieu associated with visceral fat, while the loading effect induced by a heavier body mass index (BMI) may enhance muscle anabolism. Recently, a new anthropometric measure based on waist circumference (A Body Shape Index, ABSI) was developed. In this study we have assessed the predictive power of ABSI on the FFM index (FFMI), a surrogate marker of lean mass. METHODS Standard anthropometric parameters and ABSI as well as body composition data (fat and fat-free mass determined by bioelectrical impedance analysis) were assessed in 111 female and 89 male overweight/obese subjects, with no clinically significant co-morbidities. Groups with higher- or lower-ABSI were identified according to median values of this index. RESULTS In women and men, ABSI did not correlate with BMI, while multiple linear regression indicated that BMI (β-coefficients: 0.62 and 0.77, respectively) and ABSI (β-coefficients: -0.26 and -0.22, respectively) independently predicted FFMI (multiple R: 0.72 and 0.83, respectively, P < 0.001). Men and women with lower-ABSI exhibited significantly greater FFMI than the higher-ABSI groups for comparable values of BMI. In men, ABSI was correlated positively with C-reactive protein (CRP) (R = 0.30; P < 0.05) and negatively with the reciprocal of insulin (R = 0.28; P < 0.05), an index of insulin sensitivity. FM/FFM ratio significantly (P < 0.01) correlated with CRP (R = 0.31) in women only. CONCLUSIONS ABSI, a recently introduced marker of abdominal adiposity, may contribute to define the risk of sarcopenia in overweight/obese individuals.

Effects of growth hormone administration on skeletal muscle glutamine metabolism in severely traumatized patients: preliminary report.

We have investigated the effects of 24 h human recombinant growth hormone (hGH) administration on leg muscle glutamine exchange and protein kinetics in severely traumatized patients. Muscle amino acid exchange and protein balance were evaluated using the leg arteriovenous balance technique, whereas changes in skeletal muscle free amino acid concentrations were evaluated in biopsy specimens. hGH infusion decreased phenylalanine release from protein degradation by 56 +/- 14%, and the rate of branched chain amino acid catabolism by 51 +/- 10%. Glutamine release from leg muscle was suppressed by 58 +/- 12%. This latter effect was completely accounted for by a hGH-mediated suppression of glutamine synthesis in skeletal muscle. In conclusion, growth hormone administration in trauma patients may restrain protein and amino acid catabolism in skeletal muscle. However, the growth hormone-mediated suppression of glutamine production we have observed in this study could decrease the systemic availability of this amino acid. During growth hormone treatment, this potential side-effect could be prevented by an exogenous glutamine administration.

Slower activation of insulin action in hypertension associated with obesity.

Objective To determine whether kinetic abnormalities in the onset of insulin action contribute to the insulin resistance in obesity-associated hypertension. Design We monitored the rate of increase in glucose infusion during 6 h of hyperinsulinemic (40 mU/m2 per min) euglycemic clamps in hypertensive and normotensive obese subjects. The two groups of hypertensive (n = 9) and normotensive (n = 9) subjects were matched for age (48 ± 2 versus 45 ± 5 years), sex (five males and four females versus four males and five females) and body mass index (42 ± 3 versus 40 ± 2 kg/m2). Results In all subjects, the glucose infusion rate required to maintain euglycemia increased progressively during the clamp studies to achieve maximal, steady-state values within the fifth hour. During the first 2 h of the clamp, mean glucose infusion rate, the traditional approach to assessing insulin sensitivity, was lower in the hypertensive than in the normotensive obese patients (2.04 ± 0.13 versus 3.29 ± 0.41 mg/kg per min, respectively; P < 0.05). In contrast, the maximal steady-state glucose infusion rate, calculated as the mean value during the sixth hour of clamping, was similar in the hypertensive and in the normotensive obese patients (4.48 ± 0.43 versus 4.81 ± 0.45 mg/kg per min, respectively; NS). The time required to reach the half-maximal glucose infusion rate was greater in the hypertensive than normotensive obese patients (91 ± 12 versus 38 ± 5 min, respectively; P < 0.05). Conclusion In obesity, hypertension was associated with a slower rate of activation of the insulin effect on glucose metabolism, whereas the maximal steady-state insulin effects were not altered by elevated blood pressure. Thus, the link between obesity and hypertension may be associated with the kinetics of onset of insulin action.

Relationship between Whole-Body Protein Turnover and Serum Creatinine in Chronically Uremic Patients

To investigate the relationship between decline in renal function and alterations of protein metabolism we determined the rate of whole-body protein turnover in a group of 15 postabsorptive chronically uremic patients (9 males and 6 females) with different levels of serum creatinine concentrations (average 5.7 ± 0.4 (SE) mg·dl–1; range 3.3–9.1). Patients’ age and body mass index were 53 ± 4 years (range 26–73) and 24.7 ± 0.6 kg/m2 (range 20.3–28.7), respectively. Nutritional status (plasma albumin 3.6 ± 0.4 g·dl–1) and acid-base equilibrium (arterial pH 7.38 ± 0.01) were fairly controlled by therapy. Whole-body leucine rate of appearance (Ra), an index of whole-body protein turnover, was assessed using a stable isotope technique. L-[1-13C]leucine was continuously infused and plasma [1-13C]α-ketoisocaproic acid enrichment was determined in steady-state conditions as a marker of the intracellular leucine enrichment. The average leucine Ra was 2.03 ± 0.13 µmol·kg–1·min–1 (range 1.29–3.19). Using simple linear regression analysis, the coefficient of correlation between the individual values of serum creatinine concentration and leucine Ra was 0.59 (n = 15; p = 0.02). Leucine Ra did not significantly correlate with blood pH or plasma albumin. In conclusion, we found a positive linear relationship between the values of plasma creatinine concentration and the rate of whole-body protein degradation. This correlation suggests that the progression of renal insufficiency is associated with accelerated rates of turnover of body proteins.

Molecular regulation of protein catabolism in trauma patients

In skeletal muscle, protein degradation is accomplished by several proteolytic systems located at different parts of the cell (1,2). In the lysosomes, cathepsin B, D, E, H and L are mainly involved in the degradation of non-myofibrillar proteins such as membrane-associated proteins and endocytosed proteins. In the cytoplasm, the ubiquitin proteasome system degrades the bulk of myofibrillar protein and many other cellular proteins. Proteins to be degraded are covalently bound to multiple ubiquitin molecules by ubiquitinconjugating enzymes, and the degradation of such ubiquitinprotein complex occurs in the proteosome. Calpains m and ~t are also cytoplasmic proteases with unclear functions. Distinct proteolytic enzymes are also located in the mitochondria. Critically ill patients are characterized by accelerated degradation of both myofibrillar and non-myofibrillar muscle proteins. Recent evidence shows that in patients with severe trauma gene expression for cathepsin D, calpain m and critical components of the ubiquitin proteolytic pathway are simultaneously increased in skeletal muscle (3). However, the relative importance and the regulatory mechanisms of the different muscle proteolytic systems after trauma are not completely understood. Molecular control of proteolytic enzymes involves gene transcription, mRNA maturation, mRNA translation and subsequent protein activation (4). The aim of this study was to develop a methodology to simultaneously evaluate in human skeletal muscle gene expression of critical components of different proteolytic systems and their enzymatic activity. We used a competitive polymerase chain reaction (PCR) methodology (5) to accurately quantitate mRNA levels for cathepsin B and ubiquitin in skeletal muscle of severely traumatized patients. Ubiquitin is encoded in the human genome as a multigene family (6). Among the different ubiquitin genes we chose the UbB polyubiquitin gene which codes for three direct repeats of the ubiquitin sequence (6). Enzymatic activity of cathepsin B was also determined in the same muscle specimens.

Cathepsin B and D activity in human skeletal muscle in disease states.

The effects of nutrition and disease state on whole body protein metabolism have been widely studied in recent years, but the distribution of changes among the various body tissues is less known. It is, therefore, important to establish the contribution made by skeletal muscle to whole body protein metabolism in disease state, because skeletal muscle is quantitatively and metabolically the most important body protein “store”1 and remains a good marker of protein-energy malnutrition (PEM) when the protein pools of other tissues and organs become metabolically una vailable 1-3.

Body composition and muscular strength changes after moderate activity: association with matrix metalloproteinase polymorphisms.

Remodeling of skeletal muscles is regulated by matrix metalloproteinases (MMPs). Functional genetic polymorphism (PM), modulating the expression of some MMPs, might be associated to different body composition and muscular strength improvement after exercise. Genetic PM of MMP-1 (G+/- at -1607), MMP-3 (5A/6A at -1171) and MMP-9 (Cytosine-Adenine microsatellite=(13-27)CA) repeats, around -90), body cell mass (BCM), extracellular water (ECW) and isometric maximal extensor strength (MES) of both legs were determined in 17 old sedentary women at the beginning and at the end of a 24 week physical exercise program. A 12 and 72% increase in BCM and MES, respectively, and 11% reduction in ECW were observed at the end of the program. Carriers of G-insertion in MMP-1, PM increased their BCM (7 kg vs. -1.5, p=0.007) and lost ECW (9% of total body water vs. 0.1%, p=0.004) more than the non-carriers; homozygote for 21 or less CA repeats/allele in MMP-9 PM gained more MES (115 N, interquartile range=IQR=63-132) than carriers of longer microsatellites (63 N, IQR=40-86, p=0.028). MMP-3 did not show any association with body composition and exercise-related strength changes. Exercise in elderly women increases BCM and strength, these changes are associate to specific MMP genotypes.