The appearance of wasting represents the net visible result of metabolic and functional alterations such as anorexia, malabsorption and inflammation, including cytokine as well as hormone cascades. In rare cases, uncoupling of energy metabolism may also lead to wasting. Undernutrition has repeatedly been reported to be associated with increased morbidity, in both surgical and nonsurgical patients. Of particular importance in this respect are the well recognized observations that a variety of rather harmless viral infections (such as measles) in well nourished individuals are associated with increased mortality in areas where malnutrition is endemic, frequently due to the socio-economic status. From a global health care perspective, such consequences are probably more important than the more limited aspects and consequences of malnutrition in patients subjected to medical treatment as elective and acute surgery.
However, a lot of information and knowledge about nutrition related physiology and the effects of nutrients on cellular as well as organ related metabolism have been collected in studies on such rather limited aspects over the past decades by nutrition orientated researchers. Thus, an overwhelming body of information exists which confirms that undernourished individuals are increasingly susceptible to both internal and external stress factors, such as infection, cardiovascular overload and possibly mental dysfunctions. These observations have stimulated researchers to perform further studies aimed at understanding the pathophysiology and mechanisms behind increased vulnerability in patients who suffer from wasting. It is possible that well-defined models of programmed undernutrituion will gain more attention in this respect as reviewed by Cannizzo and Kral in this issue (pp 363-368).
Several hypotheses have been evaluated in clinical studies conceptually based on the reasonably well-established information that integrated metabolic host-responses represent the maximum adaptations for conserving particularly lean tissue at the expense of body fat during disease progression. Lean body mass is usually regarded as a more limited compartment than body fat. It is therefore believed that lean tissues are preferentially spared during wasting. However, Professor Grimble came across little evidence in the literature during his search of the information to substantiate this concept (pp 369-374). Classical work published by Cahill et al. on starvation emphasises the importance of included conservation of lean body mass . It may be that more recent studies on wasting conditions, with new techniques, will not reveal that pronounced adaptation to spare lean tissues as described in classic work found in metabolic handbooks . There is, however, no doubt that adaptation to undernutrition is associated with a less than normal overall metabolic turnover, including global protein metabolism and energy expenditure, which also includes lean body compartments. This is not to say that single or isolated protein components, or parts of some tissue compartments, cannot be degraded at increased rates during stress combined with undernutrition as exemplified by HIV-infected patients described in this volume (Schwenk pp 375-380).
Several examples of elevated energy expenditure in undernourished patients, irrespective of the origin of the underlying wasting condition, are presented. This phenomenon is most evident when resting energy expenditure is normalized to lean body mass. It is usually thought that such findings in these patients, when compared to a control group, represent either activated metabolism or an inappropriate adaptation to starvation. However, although semantically correct, the phenomenon may simply reflect that peripheral tissues (including lean body mass) are wasted at the expense of visceral tissues which are relatively more preserved for survival reasons. Thus, increased energy expenditure in such patients may simply reflect altered body composition, due to the fact that peripheral tissues have a lower oxygen uptake and protein turnover than visceral organs in general.
Though the acute phase reactions in malnourished patients contribute to this alteration, it does not necessarily exclude the fact that a major part of elevated energy expenditure (as referred to in cancer and HIV-infected patients) primarily reflects the loss of low consuming peripheral tissue. It would in theory be possible to estimate the partition of increased energy expenditure from inflammation by measurements of energy expenditure before and after introduction of anti-inflammatory treatment. Seen together, several reports in cited publications point to the possibility that anorexia is perhaps the most important factor behind long-term wasting in most clinical conditions; acute sepsis may be one of the few exceptions to this conclusion. Based on this suggestion, it is remarkable that so little is actually known about appetite regulation in acute and progressive undernutrition.
In the literature, there is sometimes a tendency to regard metabolic alterations associated with disease as abnormal, and to some extent inappropriate. On the contrary, life has probably developed to represent a suitable integrated homeostatic system, with the possibility of large variations and fluctuations in metabolism to provide renewal of damaged tissues and cell proliferation at an optimal level to support survival and guarantee reproduction. Looking upon life as a network of integrated functions among cells and organs with large margins to withstand stress, it is difficult not to regard metabolic and physiologic alterations as a continuum of appropriate changes, being only quantitatively different in response to various conditions of stress, with or without infection, and tissue damage. If so, the always present risk for limited food and substrate availability to a living organism is probably one of the most common and natural threats to life, although technical development in modern societies has successively attenuated this risk by offering effective production and provision of food.
Thus, there may not exist any truly qualitative differences in metabolic response to noxious stimuli among individuals, but rather quantitative differences. In support of this speculation may be a regular finding of depressed food intake in most conditions with associated stress, although some reports are cited in the present reviews suggesting that wasting conditions in patients (usually cancer) have been observed to occur without the presence of anorexia. Such observations are probably more the result of technical difficulties in measuring precisely quantitative and qualitative differences in nutrient intake in unrestrained outpatients. It remains, however, totally unexplained as to why food intake should decline during conditions with stress, when there is actually an increased demand for nutrients during disease. A more appropriate response should be to upregulate appetite at a particular degree of undernutrition to prevent the risk of death related to drainage of body stores and nutrients.
Obviously, we lack relevant information related to the appetite/undernutrition paradox. It is likely that metabolic signals for mobilization of substrates and carbon-skeleton for intermediary metabolism have developed in life and mankind to have priority under all circumstances with stress. Phyllogenetically, these signal systems have most likely developed in the context of an extracellular milieu, characterized by severe shortage or lack of nutrients. In the light of this situation, it would be inappropriate for neurones in the control of food intake to fire for increased intake, simply because of the fact that substrates were not available in the extracellular compartment. Therefore, over millions of years, stress reactions have developed simultaneously with a programmed downregulation in appetite. This combination of events, low appetite and increased stress hormone levels, would also allow the catabolic cascade to act optimally within the underfed patients. This theory may explain why undernourished individuals under stress do not seem to do well when exposed to a surplus of exogenously delivered nutrients by artificial nutrition. This may simply disturb a finely tuned system with the purpose of directing certain substrates from stores to specific organs and cells. Also, the acute phase reaction tends to decrease the availability of certain substrates and trace elements, particularly from the plasma compartment. This may be a means to prevent intruding microbes from rapid proliferation due to the lack of certain co-factors, for example iron. Normal food intake in such conditions would disturb or prevent this counterregulation.
Based on the above speculations, it seems reasonable and wise not to try to change or influence metabolic adaptations in malnourished individuals too rapidly. In the context of nutrition, this means that early intervention or prevention should be safer and more effective than treatment of manifest undernutrition with pronounced adaptation. When necessary, nutritional intervention to severely undernourished individuals should be slow and successively increased. In the reviews presented in this section, and in several other recent publications, it also appears that organ and body functions are not directly correlated to compositional changes in tissues. Future research on wasting should therefore consider function rather than traditional composition measures in clinical evaluations. However, composition measures in relation to appetite should be of interest in future studies, when feasible technology for reproducible and direct measurements of body components are available at reasonable costs. It is at present unclear to what extent anorexia and well defined body compositional changes are correlated during the development of wasting. It would also be of particular interest to demonstrate whether a primary decline in food intake explains secondary alterations of body composition in ageing, or whether altered composition in body compartments leads to adaptation in appetite.