Many recent advances have been made in the understanding of catabolic states. At the whole body level, a combination of anorexia and hypermetabolism contribute to the progressive depletion of body reserves. Orexigenic agents show success in improving spontaneous food intake, and recent developments in our understanding of the mechanisms of hypermetabolism raise the possibility of clinically effective strategies to reduce an inappropriately elevated metabolic rate and simultaneously raise total nutrient intake.
Anorexia and hypermetabolism
The article by Jatoi and Loprinzi (pp. 179-182) touches upon the loss of appetite that is pervasive among patients with advanced cancer. Cancer patients cite anorexia as one of their most troubling symptoms, and a very strong relationship between the perceived quality of life and the loss of enjoyment of food is established for patients with AIDS-related wasting . Clinically effective options for the reversal of anorexia remain limited, and the authors review some recent studies with agents comprising the present standard of care, such as megestrol acetate and dexamethasone, as well as novel agents such as thalidomide, adenosine triphosphate, and inhibitors of cytokine production or action.
Related work is ongoing on the clinical importance, mechanisms and treatment of hypermetabolism in a variety of disease states . Further definition is being given to the time of onset of the hypermetabolic state. Lane and Provost-Craig  investigated resting energy expenditure in early, asymptomatic HIV-infected women versus a control group matched for age, body mass index and fat-free mass. The authors observed that absolute resting energy expenditure was significantly higher by 17-23% in the HIV-positive group compared with the control group, whether data were adjusted for body composition or not. The presence of hypermetabolism may depend on the disease stage, and some authors suggested that hypometabolism may arise at advanced stages . However, the recent work of Barber et al. [4•] suggested that patients with pancreatic cancer remain hypermetabolic through to very advanced stages of disease. These observations suggest that hypermetabolism may be present during very long periods of time over the course of chronic disease, and argue for early, late, and perhaps continuous intervention to prevent the cumulative loss of body energy reserves on a very large scale.
The causes and consequences of hypometabolism are very poorly understood. Another recent study by Jatoi and coworkers  defined a relationship between hypometabolism and poor prognosis. Patients with non-small cell lung cancer (stages IA-IIIB) underwent the measurement of resting energy expenditure before the initiation of cancer treatment. Similar measurements were performed in control subjects matched for age, sex and body mass index. Patients were classified as hypermetabolic or hypometabolic on the basis of a direct comparison of measured resting energy expenditure between cancer patients and their matched controls. The hypometabolic patients had a significantly shorter mean disease-free survival compared with the hypermetabolic patients: 19 months versus 29 months, respectively. This area deserves further investigation.
There have been more recent developments in the area of dietary supplementation with fish oils in patients with cancer. A compelling aspect of recent results in this domain is that dietary fish oils appear to be able simultaneously to activate voluntary food intake and to suppress elevated basal metabolism. Fearon and coworkers [4,6] are progressing in their experience with dietary fish oil supplementation in patients with unresectable pancreatic adenocarcinoma. In earlier studies by this group , fish oil was administered orally, and this resulted in stabilization of weight in this patient group. In more recent studies by this group , fish oil has been fed as a constituent of conventional oral nutritional supplement additionally providing 620 kcal and 32 g of protein, per patient per day. All patients were losing weight at baseline at a median rate of 2.9 kg/month and after the administration of the fish oil-enriched supplement patients had a significant weight gain at both 3 (1 kg) and 7 weeks (2 kg). This reversal of weight loss could be at least partly attributed to a significant increase in total caloric intake of approximately 400 kcal/day.
The most recent contribution by this group [4•] clarified important changes in energy expenditure in these patients and a striking ability of the fish oil intervention to suppress elevated metabolic rate. At baseline, resting energy expenditure whether expressed per kilogram of body weight, lean body mass or body cell mass was significantly greater in pancreatic cancer patients compared with healthy, weight-stable controls. Fat oxidation was significantly higher by 66% in the fasting state in cancer patients than in controls. After 3 weeks of the fish oil-enriched supplement, the body weight of the cancer patients had increased, the resting energy expenditure had decreased, and fasting fat oxidation fell to healthy control values.
These results are exciting in several regards. The ability of fish oil simultaneously to reduce hypermetabolism and increase intake addresses both arms of the anorexia/hypermetabolism problem. Fish oil alone or in combination with enteral formulae, is a relatively easily administered and easily accessible intervention. The results to date imply that patients with advanced pancreatic cancer are deficient in long chain n-3 fatty acids, and that there are measurable clinical gains from supplementation. The broader significance of fish oil supplementation is at present unknown, and deserves attention for other types of cancer-associated wasting.
Signals for hypermetabolism
The identity of the specific signals responsible for the induction of hypercatabolism is a crucial point. There are many known and putative factors that could be responsible. Knowledge of the nature of these signals now allows their specific modulation, either in a laboratory setting or in a clinical setting, to determine which factors are causal in different instances of hypermetabolism. It is relatively rare for a single mediator to be held accountable for a specific instance of elevated resting energy expenditure, and relatively frequent that specific interventions exert only a partial effect. The work cited above suggests that at least in pancreatic cancer, low levels of long chain n-3 fatty acids are in some way permissive for hypermetabolism to occur. This may be related to the expression of pro-inflammatory mediators . The proinflammatory eicosanoids prostaglandin E2 and leukotriene B4 are derived from the n-6 fatty acid arachidonic acid, which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of typical Western diets. Fish oils contain both 20- and 22-carbon n-3 fatty acids, eicosapentaenoic and docosahexaenoic acid. The decreased synthesis of prostaglandin E2, leukotriene B4, and the proinflammatory cytokines, TNF-α and IL-1β, have been shown in healthy volunteers and rheumatoid arthritis patients after dietary supplementation with fish oil.
Elevated energy expenditure in cancer patients of a variety of types appears to be partly explained by increased β (1) and β (2)-adrenoceptor activity and there are a couple of recent studies addressing this mechanism. Hyltander et al.  used various blockers of β-adrenoceptor activity to implicate this mechanism in abnormal resting energy expenditure of cancer patients with progressive weight loss caused by solid malignant tumours. The oral administration of a β 1 receptor blocker (atenolol) and a non-specific β 1, β 2-adrenoceptor blocker (propranolol) blockade was employed in a randomized study design. Atenolol treatment reduced resting energy expenditure by 77 kcal/day and propranolol by 48 kcal/day compared with pretreatment values, and this decrease was significantly greater for atenolol. Whole-body oxygen uptake and carbon dioxide production were decreased similarly by both atenolol and propranolol treatment. Atenolol decreased fat oxidation and increased carbohydrate oxidation, whereas propranolol decreased carbohydrate oxidation without affecting fat oxidation.
These results support the earlier observations of Gambardella et al. [10•] in a group of elderly malnourished cancer patients showing elevated resting energy expenditure. The patients received an infusion of Intralipid with and without propranolol for 6 days. The intent of these treatments was to enhance daily caloric intake by Intralipid administration, and simultaneously to reduce hypermetabolism by propanolol administration. The administration of propranolol plus Intralipid infusion produced a strong decline in resting energy expenditure. Such studies with specific inhibitors provide evidence for a causal role of β adrenergic stimulation in cancer-associated hypermetabolism, and show the effectiveness of β adrenergic blockade plus vigorous nutritional support.
Recent work by Simons et al.  suggested that in human lung cancer weight loss and elevated resting energy expenditure are associated with multiple systemic changes in anabolic and catabolic mediators. Male lung cancer patients were stratified by weight loss less than or greater than 10%, and then evaluated for indices of systemic inflammation, acute-phase response, gonadal steroids and insulin-like growth factor I (IGF-I). Patients with a greater degree of weight loss showed higher levels of soluble tumour necrosis factor receptors, lower levels of albumin, testosterone and IGF-I. In the patient group as a whole, the percentage weight loss was significantly correlated with the 55 000 Mr soluble TNF-receptor (r = 0.59), albumin (r = −0.63) and IGF-I (r = −0.50) levels. Specific intervention studies will be required to determine whether cytokine blockade, gonadal steroid supplementation, or IGF-I administration will alter the progression of hypermetabolism and weight loss. As in the past, the tremendous challenge in this domain will be properly to identify the specific mechanisms at play in individual patients, so that therapy can be applied appropriately to correct the disturbances in anabolic and catabolic signal pathways, and nutritional support can be provided.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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2 Pi-Sunyer FX. Overnutrition and undernutrition as modifiers of metabolic processes in disease states [Review]. Am J Clin Nutr 2000; 72(2 Suppl.):533S-537S.
3 Lane BJ, Provost-Craig MA. Resting energy expenditure in asymptomatic HIV-infected females. J Womens Health Gender-Based Med 2000; 9:321-327.
4• Barber MD, McMillan DC, Preston T, et al
. Metabolic response to feeding in weight-losing pancreatic cancer patients and its modulation by a fish-oil-enriched nutritional supplement. Clin Sci 2000; 98:389-399. This study shows the power of a combination of vigorous nutritional support with the simultaneous suppression of the metabolic rate, to enhance the net deposition of body weight and of lean body mass.
5 Jatoi A, Daly BD, Hughes V, et al
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6 Barber MD, Ross JA, Voss AC, et al
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7 Ross JA, Moses AG, Fearon KC. The anti-catabolic effects of n-3 fatty acids. Current Opinion in Clinical Nutrition & Metabolic Care 1999; 2(3):219-226.
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9 Hyltander A, Daneryd P, Sandstrom R, et al
. β Adrenoceptor activity and resting energy metabolism in weight losing cancer patients. Eur J Cancer 2000; 36:330-334.
10• Gambardella A, Tortoriello R, Pesce L, et al
. Intralipid infusion combined with propranolol administration has favorable metabolic effects in elderly malnourished cancer patients showing elevated resting metabolic rate. Metab: Clin Exp 1999; 48:291-297. Another example of combined therapy with nutritional support and the simultaneous suppression of metabolic rate, to enhance the net deposition of body weight and of lean body mass.
11 Simons JP, Schols AM, Buurman WA, Wouters EF. Weight loss and low body cell mass in males with lung cancer: relationship with systemic inflammation, acute-phase response, resting energy expenditure, and catabolic and anabolic hormones. Clin Sci 1999; 97:215-223.