Elisabeth Edén

Whole-body tyrosine flux in relation to energy expenditure in weight-losing cancer patients

Whole-body tyrosine flux was measured in seven weight-losing cancer patients and compared with that of seven noncancer patients with malnutrition. L[U-14C] tyrosine was infused intravenously (IV) after an overnight fast under resting conditions and flux rates, oxidation, and incorporation into proteins of tyrosine were calculated from plateau values of specific activity of tyrosine in plasma and of labeled expired carbon dioxide. Rates of protein synthesis were calculated from the flux rate of tyrosine after subtracting the proportion oxidized. Simultaneous measurements of whole-body carbon dioxide production and oxygen uptake were also performed in each subject. Cancer patients had elevated whole-body tyrosine flux, protein synthesis, and energy expenditure when expressed in relation to body weight and whole-body potassium while the differences in tyrosine kinetics became of borderline significance when expressed in relation to energy expenditure. Tyrosine incorporation into whole-body proteins corresponded to a synthesis rate of 2.70 +/- 0.17 protein/kg/d in cancer patients and 2.18 +/- 0.17 in control patients (P less than 0.025). The results show that elevated protein synthesis in weight-losing cancer patients may explain not more than one third of the elevated energy expenditure. Therefore, other systems that utilize energy must increase in activity.

Effect on whole-body protein synthesis after institution of intravenous nutrition in cancer and non-cancer patients who lose weight

Cancer and non-cancer patients received total parenteral nutrition (TPN) corresponding to either 120% or 200% non-protein energy resting energy expenditure. Whole-body tyrosine flux and leg exchange of various metabolites were measured in the fasted and fed state. Feeding with the moderate TPN rate did not stimulate whole-body protein synthesis in either group, but the high rate did. Both TPN rates switched an efflux of branched-chain aminoacids from the leg to an uptake in both groups, but this did not apply to tyrosine or phenylalanine. Only the high TPN rate stimulated glucose uptake across the leg in both groups. The leg exchanges of lactate, glycerol and free fatty acids were not significantly influenced by moderate or high TPN rates in either group, although changes in arterial concentrations indicated significant exchanges in compartments other than leg tissues. Thus standard TPN is insufficient to stimulate overall protein synthesis in both malnourished cancer and non-cancer patients, which may explain why previous studies have demonstrated insignificant functional effects with nutritional support to cancer patients.

Thermic effect and substrate oxidation in response to intravenous nutrition in cancer patients who lose weight.

This study examined oxidative metabolism and thermogenesis in the acute response to controlled intravenous nutrition in seven cancer patients who lost weight. Six weight-losing and malnourished patients without cancer served as controls. Indirect calorimetry was used and measurements of arterial concentrations of various substrates, metabolic end products, and insulin were performed. Resting energy expenditure (REE) was measured after an overnight fast. The resting energy need was calculated for each patient according to REE. The nutrition program consisted of glucose and lipids (Intralipid KabiVitrum AB, Stockholm, Sweden) each as 50% of nonprotein calories and amino acids (6.9 mg N/kcal). These substrates were infused simultaneously at rates equivalent to one, two, and three times REE, over periods of 6.5 hours on 3 consecutive days after a 12-hour fast. Arterial substrate levels and energy expenditure were measured between 6 and 6.5 hours after the start of the infusion. The cancer patients had well-recognized metabolic changes in the fasted state, such as elevated plasma levels of glycerol, triglycerides, free fatty acids, and lactate, and higher energy expenditure than predicted. The cancer patients responded to strictly defined substrate challenge in a similar way as the malnourished patients without cancer. Whole body oxidative capacity and the proportion of infused glucose and lipids that were oxidized at different levels of infusion rates were not decreased in cancer patients compared with control patients. Similar arterial substrate concentrations among the groups during infusions argues for a maintained plasma clearance of the substrate in the cancer patients. This study supports the suggestion that cachectic cancer patients can generate and conserve energy normally in response to intravenous nutrition. This refers to cancer patients with a history of weight loss up to 15% of their normal body weight. Therefore, weight loss due to altered tumor-host metabolism in cancer patients is of quantitative importance in the fasted state rather than in the fed state.

The inefficiency of total parenteral nutrition to stimulate protein synthesis in moderately malnourished patients

The acute whole-body and peripheral tissue protein response to total parenteral nutrition (TPN) was evaluated before surgery in moderately malnourished patients with stable disease. A primed constant infusion of (U-14C) tyrosine was used in combination with simultaneous measurements of the leg exchange of amino acids, glucose, glycerol, and free fatty acids (FFA). Energy expenditure was measured by indirect calorim-etry. Sixteen patients with stable disease and in need of nutritional support were randomized to receive TPN at rates either corresponding to resting requirements (nonprotein calories at 120% of REE with 0.2 g of N/kg/d) or at increased rates (200% of REE with 0.33 g of N/kg/d). Energy expenditure was not affected by the low rate of TPN, but increased with the high rate, with a thermic effect corresponding to 16% of basal levels. Tyrosine flux and incorporation rate into whole-body proteins (protein synthesis) were not altered by the low TPN rate, but increased with the high rate. Estimates of protein breakdown decreased, and tyrosine oxidation increased significantly with both rates of TPN. Protein synthesis was stimulated at the high dose rate only. However, a positive whole-body tyrosine balance (net protein synthesis) measured by the 14C tyrosine technique was associated with a continued negative tyrosine balance across the skeletal muscle compartment in the leg. The results demonstrate that TPN given at rates corresponding to resting needs of 0.2 g of N/kg/day is insufficient to promote protein synthesis in the majority of body proteins. Skeletal muscles may remain in negative protein balance even at high TPN loads. Our results reflect the difficulties of expanding lean body mass through intravenous nutrition in moderately malnourished patients—even those with stable disease.

Ultrastructural changes and enzyme activities for energy production in hearts concomitant with tumor-associated malnutrition

Morphometric data on left ventricular papillary muscle structures have been determined in tumor-induced malnutrition and related to the maximum activities of key enzymes for energy production in the whole myocardium. Adult, nongrowing mice with a syngeneic sarcoma were used to represent a condition of cancer associated host tissue wasting. Hearts from mice 11 days after tumor implantation showed atrophy and a significantly reduced amount of myofibrillar, soluble, and collagen proteins than hearts from control animals. The cross-sectional area of myocardial cells was 33% smaller in tumor-bearing mice (p less than 0.025), but the total number of capillaries and the residual interstitial volume were similar in the two groups. The total number of subcellular structures per cell, such as mitochondria, myofibrils, and myosin filaments per myofiber, were significantly lower in the tumor-bearing animals (p less than 0.025). Conversely, the proportion of myofibrils was higher (p less than 0.05) in tumor-bearing animals while the proportion of mitochondria was lower. Maximum activities (Vmax) of selected regulatory key enzymes for energy production (glycogenolytic, glycolytic, and mitochondrial) were not significantly altered in hearts from tumor-bearing mice. The results support the conclusion that myocardial functional capacity is better preserved than overall structural components would imply in tumor-host associated malnutrition, which is probably secondary to deprived food intake. Teleologically, this may be a means by which functional deterioration of the heart is minimized during the induction of malnutrition.