Despite the relatively low plasma glucose levels in many cachectic patients, a factor that usually stimulates appetite, a typical characteristic of cachexia is anorexia or loss of appetite. This symptom is an extremely important characteristic of the syndrome of cachexia, as anorexia may aggravate weight loss, weakness, hormonal changes, and progressive alterations in a number of vital functions. Grosvenor and colleagues (1989) determined that anorexia occurs in approxi- mately 50% of newly diagnosed cancer patients. Even in the 1930s, it was recognized that at least 20% of all cancer deaths were due solely to malnutrition (Warren, 1932). It is not clear that any single cause is primary in the anorexia of cancer, but a number of possible factors have been described over the past two decades (Table 17.4). However, since the publication of Table 17.4, substantial evidence has developed to indicate that humoral factors, many affecting the central nervous system, may be very important in the development of anorexia in cancer patients and can be directly related to several of the factors listed in Table 17.4. In addition, recent studies in animals have demonstrated that spontaneous physical exercise may modify the cachectic state, particularly in slowing the muscle wasting, although, toward the end of the experiments, the en- ergy costs of exercise accelerated the catabolic state (Deuster et al., 1985; Daneryd et al., 1990).
Within the last decade, studies on the mechanism of anorexia have been oriented toward the effects of circulating hormones and metabolic constituents. In a rat hepatoma experimental model, Chance and associates (1991) demonstrated a correlation between increases in ammonia
concentration in the blood and the development of cancer-induced anorexia. A number of inves- tigations, some of which are considered later in this chapter, have demonstrated that specific hormones in the general class of cytokines (Chapter 19; Matthys and Billiau, 1997) may also be important in the development of anorexia. Perhaps primary among these is tumor necrosis factor α (TNF-α; see below), but other cytokines such as interleukin-1 (IL-1; Laviano et al., 1996), and even endogenous opioids that are involved in the regulation of food intake may also play a role in the mechanism of the anorexia of cancer (Yim and Lowy, 1984). Several investigations have implicated the amine hormones serotonin and dopamine as playing significant roles in the mech- anism of the anorexia of cancer. Initial studies by Chance et al. (1983) demonstrated increased concentrations of tryptophan, the precursor of serotonin, as well as the amine itself and 5-hy- droxyindoleacetic acid, one of its metabolites, in specific regions of the brain related to the con- trol of food intake and appetite in tumor-bearing rats. These studies were extended by Rossi- Fanelli and associates (Muscaritoli et al., 1996; Cangiano et al., 1996; Laviano et al., 1996). In particular, these authors demonstrated a correlation between the ratio of free tryptophan to neu- tral amino acids (valine, leucine, isoleucine, tyrosine, and phenylalanine) and the content of se-
Table 17.4 Possible Causes of Anorexia in Individuals with Cancer
1. Nonspecific manifestation of disease
2. Mechanical interference with the gastrointestinal tract
3. Alterations of taste and/or smell perception
4. Learned food aversions
5. Production of lactate
6. Production of ketones
7. Hypothetical tumor toxins
8. Direct effect on appetite center
9. Psychological factors
10. Treatment (chemotherapy, radiation therapy)
rotonin in brain. This led to a hypothesis depicted in Figure 17.1, in which tumor growth resulted in increased plasma tryptophan concentrations, which, in turn, successively competed with neutral amino acids for access to the central nervous system across the blood-brain barrier. From this, the hypothalamus metabolized tryptophan to serotonin, in turn resulting in anorexia by a direct effect of this amine hormone on centers controlling food intake. However, as pointed out by these authors, the simple concentration of serotonin in the hypothalamus is not the only factor involved, but its metabolism and release by neurons in the hypothalamus and the effect of cytokines acting directly on cells of the central nervous system are involved in the development of anorexia (Laviano et al., 1996). Later studies by Varma et al. (1999), using elaborate surgical techniques with cannulation of the hypothalamic area and ventromedial nucleus concerned with the regulation of food intake, came to similar conclusions as those noted in Figure 17.1.
While it is likely that serotonin and perhaps dopamine are involved in the mechanism of anorexia in cancer patients, it is also clear that a number of other polypeptide factors, some of which have been mentioned above, play significant roles in the anorexia of cancer. These, partic- ularly tumor necrosis factor, are discussed later in this chapter.