Weight-losing Cancer Patients Research Articles

Protein and amino acid metabolism in cancer cachexia: investigative techniques and therapeutic interventions.

Cancer cachexia is a complex syndrome characterized primarily by diminished nutrient intake and progressive tissue depletion that is manifest clinically as anorexia and host weight loss. The gradual loss of host protein stores is central to this process. This review outlines the techniques that have been used to evaluate human amino acid metabolism, their application in patients with cancer cachexia, and possible therapeutic interventions designed to overcome alterations in host protein and amino acid metabolism associated with malignant cachexia. The techniques of nitrogen balance and 3-methylhistidine excretion provide indirect estimates of overall nitrogen metabolism and skeletal muscle myofibrillar protein breakdown. Measurement of circulating amino acid concentrations, particularly when combined with assessment of arterial-venous differences and regional amino acid balance allows for investigation of interorgan amino acid metabolism. One of the most significant advances in in vivo amino acid metabolic research has been the development of labeled amino acid tracer studies to evaluate whole body and regional amino acid kinetics. The use of stable and unstable amino acid isotopes in these techniques is reviewed in detail. Virtually all of these techniques have now been employed in the evaluation of human cancer cachexia. The results of studies evaluating amino acid concentrations, regional amino acid balance, and 3-methylhistidine excretion are summarized. The use of regional and whole body kinetic studies in cancer cachexia are reviewed extensively. Most investigators have observed increased rates of whole body protein turnover, synthesis, and catabolism in both weight-stable and weight-losing cancer patients. Some studies have suggested a relationship between the extent of disease and the degree of aberration in amino acid kinetic parameters. Investigators have attempted to reverse some of these alterations by provision of substrate (nutritional support) or administration of specific pharmacologic or anabolic agents such as hydrazine sulfate, insulin, growth hormone, and beta-2 agonists. The role of total parenteral nutrition (TPN) in cancer and its effects on protein and amino acid kinetics and tumor growth are addressed. The possible benefits of specific amino acid nutritional formulations with increased branched chain amino acids, arginine, and glutamine are reviewed. Although many of these approaches appear promising, significant impact on clinically definable parameters remains to be demonstrated. A better understanding of the underlying protein catabolic mechanisms of cancer cachexia will likely lead to more effective therapies to reverse the protein calorie malnutrition associated with cancer cachexia.

The effect of insulin on glucose and protein metabolism in the forearm of cancer patients

This study was designed to study the effect of systemic hyperinsulinaemia (INS) on glucose and protein metabolism in cancer patients. Sixteen cancer patients (8 >10% weight loss (WL); 8 < 10% weight loss (NWL)) were compared with 12 healthy controls. Glucose uptake (GU) and phenylalanine (PHE) exchange kinetics were measured across the forearm in the postabsorptive state (PA) and in response to INS (71 ± 5 μU ml −1). At steady state in response to INS, the negative PA PHE net balance became significantly positive, and GU significantly increased, for cancer and control groups, with no significant differences between the two groups. Subset analysis of NWL cancer vs. WL cancer found no difference between WL and NWL for the change in PHE balance from PA and INS, however GU increased significantly only for the NWL group between PA and INS. These data indicate that cancer patients are not resistant to the anabolic effect of INS on protein metabolism, regardless of weight loss, but are resistant to the effect of INS on glucose metabolism when further along in the disease process as evident by more significant weight loss. This differential response to the effect of INS can be exploited in an attempt to promote protein accrual in weight-losing cancer patients.

Palmitate turnover and its response to glucose infusion in weight-losing cancer patients

Palmitate turnover in weight-stable control subjects (n = 4) and weight-losing patients with progressive malignant disease (n = 4) has been determined. Measurements were made after an overnight fast and during glucose infusion (3.5 mg/kg/min). Turnover rates were calculated from plateau isotopic enrichment of palmitate in plasma during a continuous infusion of 1–13C palmitate. Palmitate turnover was higher in the cancer group before (180%) and during glucose loading (170%) compared with the control group. Palmitate turnover was reduced during glucose administration by approximately 34% in both groups. Plasma concentration of insulin was decreased and of cortisol was increased in the cancer group compared with the control group before and during glucose infusion. We conclude that cancer patients with weight loss have increased rates of fatty acid turnover indicative of enhanced mobilisation of body fat stores. Altered plasma concentrations of insulin and cortisol may mediate this effect. Nonetheless, even at more advanced stages of cachexia cancer patients have normal control mechanisms for inhibiting fatty acid turnover following administration of carbohydrate.

Diet-induced thermogenesis in patients with gastrointestinal cancer cachexia.

1. Indirect calorimetry has been used to measure resting energy expenditure (REE) and the thermogenic response to a test meal (diet-induced thermogenesis) in groups of weight-stable and weight-losing patients with gastrointestinal adenocarcinoma. Average daily intakes of energy and protein were computed from dietary assessment for the week before hospitalization. Results were compared with a control group of patients with benign gastrointestinal disease. 2. Weight-losing cancer patients had a significantly reduced mean total energy and protein intake. 3. There was no significant difference in REE between the groups when results were normalized in terms of metabolic body size (kJ/kg 0.75) and lean body mass (kJ/kg). 4. Diet-induced thermogenesis was reduced in weight-losing cancer patients. 5. It is suggested that the reduction of diet-induced thermogenesis in weight-losing cancer patients is another element of starvation adaptation, subsequent to their weight loss, and that altered thermogenesis does not contribute to the weight loss seen in cancer cachexia.

Monocytic production and plasma bioactivities of interleukin-1 and tumour necrosis factor in human cancer.

Plasma concentrations and in-vitro production of interleukin-1 and tumour necrosis factor were evaluated in 23 weight-losing patients with cancer, six bacterially infected patients without cancer and six healthy controls. Bioactivity of interleukin-1 was found in the plasma from five of six bacterially infected patients but only from one of 23 cancer patients. Tumour necrosis factor activity was not detected in the plasma of any patient. In four of 23 patients with cancer, in-vitro stimulation of peripheral blood monocytes by either endotoxin or heat-killed Staphylococcus albus resulted in no significant production of interleukin-1. Such a defect was not seen in any of the bacterially infected or control patients. Tumour necrosis factor production by endotoxin-stimulated blood monocytes was unaffected by the presence of cancer or bacterial infections and was normal in the four individuals with defective interleukin-1 production. We can therefore conclude that interleukin-1 bioactivity is not generally found in the plasma of weight-losing cancer patients. Furthermore, in a fraction of such cancer patients, monocytic production of interleukin-1 is markedly down-regulated. However, this defect appears to be specific for interleukin-1 since in-vitro tumour necrosis factor production is normal.

Fatty Acid and Glycerol Kinetics in Septic Patients and in Patients with Gastrointestinal Cancer

The rates of glycerol and free fatty acid (FFA) kinetics in normal volunteers (VOL), non-weight-losing (NWL) gastrointestinal cancer patients, weight-losing (WL) gastrointestinal cancer patients, and in severely septic patients, using constant infusions of d-glycerol and 1-13C palmitic acid; were determined. Rates of FFA oxidation have also been quantitated. Measurements were made in the basal state, during glucose infusion (4 mg/kg/min), and during total parenteral nutrition (TPN). Rates of glycerol and FFA appearance (Ra) in volunteers and NWL cancer patients were similar, and in both groups there was a significant suppression after glucose infusion. The basal Ra values for glycerol and FFA were 2.4 +/- 0.2 and 6.5 +/- 0.8 mumol/kg/min, respectively, in the volunteers, and in the NWL cancer patients the corresponding values were 2.7 +/- 0.4 and 7.1 +/- 1.1 mumol/kg/min (not significantly different). Compared with the volunteers, the rates of glycerol and FFA turnover were significantly elevated in both septic patients and WL cancer patients. The values for glycerol and FFA Ra were 6.3 +/- 1.1 and 13.1 +/- 3.0 mumol/kg/min, respectively, in the septic patients. The corresponding values were 4.1 +/- 0.4 and 11.7 +/- 1.6 mumol/kg/min in the WL cancer patients. In contrast to the response seen in the volunteers and NWL cancer patients, glucose infusion did not suppress lipolysis in either the septic or WL cancer patients. In all groups studied, glucose infusion resulted in an increase in FFA recycling. Despite the fact that the WL cancer patients had an increased FFA availability, they were significantly less able to oxidize either endogenous FFA or infused lipid when compared with NWL cancer patients (the basal % of FFA uptake oxidized in WL cancer patients was 10 +/- 2% vs. 18 +/- 3% in NWL cancer patients). In contrast, the septic patients had an enhanced capacity to oxidize either endogenous FFA or infused lipid (the basal % of FFA uptake oxidized was 40 +/- 8%, and during TPN this increased in 65 +/- 10%). From these studies the following was concluded: in terms of lipid kinetics, NWL cancer patients are not significantly different from volunteers; WL cancer patients and septic patients have elevated rates of lipolysis, and in contrast to what was seen in NWL cancer patients and in volunteers, glucose infusion in WL cancer patients and in septic patients does not result in a significant inhibition of lipolysis; and WL cancer patients have an impaired capacity to oxidize either endogenous FFA or infused lipid.(ABSTRACT TRUNCATED AT 400 WORDS)

The oxidation of body fuel stores in cancer patients.

In an attempt to define the mechanism of weight loss in cancer patients, fat and carbohydrate oxidation rates were calculated in 93 patients. Seventy patients with colorectal or gastric cancer were compared with a control group of 23 patients with nonmalignant illness. Twenty-seven patients with cancer and 13 control patients had lost more than 10% of their pre-illness body weight. Fat and carbohydrate oxidation rates were derived from measurements of oxygen consumption, carbon dioxide production, and urinary nitrogen excretion. Patients with cancer had significantly higher fat oxidation rates (p less than 0.01) and significantly lower carbohydrate oxidation rates (p less than 0.05) when compared with controls. Weight-losing cancer patients had significantly higher fat oxidation rates when compared with weight-stable cancer patients (p less than 0.02), weight-stable controls (p less than 0.01), and weight-losing controls (p less than 0.02). Cancer patients with liver metastases (N = 14) had significantly higher fat oxidation rates (p less than 0.01) and significantly lower carbohydrate oxidation rates (p less than 0.01) compared with cancer patients who had localized disease. There were no significant differences among the groups with respect to resting energy expenditure when expressed as kilocalorie per kilogram lean body mass per day. The presence of cancer appears to be associated with abnormal fat and carbohydrate metabolism. The increased rate of fat oxidation seen in patients with cancer, especially those with weight loss or liver metastases, may be a significant factor in the development of cancer cachexia.

Cancer cachexia and the rate of whole body lipolysis in man

While malnutrition attending cancer cachexia may be associated with variable losses of body fat, lipid metabolism has been only minimally studied. To clarify potential aberrations of lipid metabolism in weight losing cancer patients, the whole body rate of lipolysis was determined in 9 cancer patients in the postabsorptive state and compared to that in 5 normal subjects. A primed-three stage infusion of glycerol was used to measure plasma glycerol clearance and turnover. A positive correlation between glycerol turnover and plasma concentration was demonstrated in both cancer patients (r = 0.72) and in normal subjects (r = 0.81). Glycerol turnover rate in cancer patients (2.05 ± 0.14 umol · kg −1 · min −1) was not different from that in normals (2.31 ± 0.50); while glycerol clearance in cancer patients (1.72 ± 0.13 L/min) was significantly lower ( P < 0.025) by 32% than that in normals. This study demonstrates that the whole body lipolytic rate in cancer patients is not different from healthy normals. As a consequence, the loss of body fat in patients with cancer cachexia may be due to a reduced rate of lipogenesis rather than augmented lipolysis as is observed in nonmaligant malnutrition, starvation, or injury.

Utilisation of fat, carbohydrate and protein stores in weight stable and weight losing cancer patients : H.J.G. Burns, [formula omitted], J.W.L. Davies & A. Shenkin (University Departments of Surgery and Biochemistry, Roya Infirmary, Glasgow, Scotland)

Utilisation of fat, carbohydrate and protein stores in weight stable and weight losing cancer patients : H.J.G. Burns, [formula omitted], J.W.L. Davies & A. Shenkin (University Departments of Surgery and Biochemistry, Roya Infirmary, Glasgow, Scotland)

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 < 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.

Resting energy expenditure in malnourished patients with and without cancer

Resting energy expenditure was measured in a heterogenous group of weight-losing cancer patients (n = 28) in comparison with noncancer patients with (n = 26) and without (n = 17) weight Joss. Energy expenditure was measured in a ventilated hood after an overnight fast. The results are presented in relationship to the nutritional state of the patients. Cancer patients had elevated energy expenditure compared to noncancer patients when compared on several different bases. The slopes of the regressions between the degree of malnutrition and energy expenditure differed between cancer and noncancer patients. Depleted cancer patients had similar resting energy expenditure as predicted for healthy well-nourished individuals, but significantly higher compared with hospitalized malnourished noncancer patients. However, the differences in resting energy expenditure seemed to be less pronounced swhen very severely depleted cancer and noncancer patients were compared. The results indicate that a small but statistically significantly elevated energy expenditure occurs in a considerable number of cancer patients. It may, therefore, add to weight loss due to anorexia, but anorexia is considered to be quantitatively the more important factor of the two.

Metabolic Response of Whole Body and Peripheral Tissues to Enteral Nutrition in Weight-Losing Cancer and Noncancer Patients

This study evaluated whether or not the efficiency of utilizing energy substrates and nitrogen differs among cancer and control patients during enteral feeding. Oxygen uptake and glucose, lipid, and amino acid metabolism across the leg were measured in cancer patients who had lost approximately 18% of their body weight and were compared with that of patients without cancer with similar body-weight loss. Metabolic balances across the leg were evaluated relative to food intake, energy expenditure, energy balance, nitrogen balance, and urinary excretion of urea, creatinine, adrenaline, and noradrenaline. All measurements were performed twice in each patient: first in the fasted state and second during nutrition after 14 days of a controlled enteral infusion of a formula diet of 35 kcal/kg . day. Quantitative measurements of metabolism across the leg before and after 14 days of enteral nutrition were compared with changes in nutritional status. Whole body utilization of energy and of nitrogen were not significantly different among cancer patients and controls, whereas the simultaneously measured net balances of glycerol and free fatty acids across the leg of cancer patients were statistically significantly more negative during the constant infusion of the formula diet. The results in this study emphasize that malnourished cancer patients are quite comparable with patients with benign malnutrition in terms of whole body and peripheral metabolism both before and in the response to enteral feeding.

Serum amino acids in weight-losing patients with cancer and tuberculosis

A study of arterial and arterio-venous amino acid concentration differences across the forearm was performed in 19 weight-losing cancer (CWL) patients (9 with lung cancer and 10 with other types of cancer), 8 weight-losing patients with active pulmonary tuberculosis (TWL) and 10 normal controls. Arterial concentrations of many of the amino acids measured were found to be lower in CWL than in TWL patients. In addition, the data suggested a venous excess of amino acids in the CWL patients compared with TWL patients and controls. The increased release of alanine from forearm muscles in the CWL group, together with the low arterial glycogenic amino acid levels, supports the concept of enhanced gluconeogenesis in CWL patients. Low arterial amino acid levels and possible increased release of amino acids from forearm muscle in CWL patients implies enhanced proteolysis with increased central clearance or tumour sequestration of these amino acids, though decreased proteogenesis cannot be excluded in accounting for the venous excesses in this group. Hypocitrullinemia in lung cancer patients was marked, and possible mechanisms to account for this are discussed.

O.73 Whole-body tyrosine flux and energy expenditure in weight-losing cancer and non-cancer patients

O.73 Whole-body tyrosine flux and energy expenditure in weight-losing cancer and non-cancer patients

Lack of evidence for increased breakdown of skeletal muscles in weight losing cancer patients: [formula omitted] Department of Surgery I and Anaesthesiology II, Sahlgren's Hospital, University of Gothenburg, Gothenburg, Sweden and Department of Medicine, University College, London, Great Britain

Lack of evidence for increased breakdown of skeletal muscles in weight losing cancer patients: [formula omitted] Department of Surgery I and Anaesthesiology II, Sahlgren's Hospital, University of Gothenburg, Gothenburg, Sweden and Department of Medicine, University College, London, Great Britain

A comparative study of peripheral metabolism after an overnight fast in weight losing cancer patients as compared with weight losing non-cancer patients: [formula omitted] Department of Surgery I and Anaesthesiology II, Sahlgren's Hospital, University of Gothenburg, Gothenburg, Sweden

A comparative study of peripheral metabolism after an overnight fast in weight losing cancer patients as compared with weight losing non-cancer patients: [formula omitted] Department of Surgery I and Anaesthesiology II, Sahlgren's Hospital, University of Gothenburg, Gothenburg, Sweden