Physiological Effects of Malignancy

Cancer cachexia is a syndrome suffered by many, but not all, patients with cancer. It is most prevalent in patients with tumors of the lung, head and neck, or gastrointestinal tract. Features of cachexia include weight loss, muscle wasting, lethargy, anorexia, early satiety, anemia of a nonspecific type, and altered host metabolism.

Weight loss is the most obvious feature of cachexia. In patients with cancer, an unintentional weight loss of 10% is deemed to be a significant change. Cachexia may be masked in people who were previously overweight or who have oedema. These people may be especially at risk of suffering from the consequences of cachexia, such as poor wound healing and increased risk of infection because their nutritional problems may not be addressed as promptly as those of patients who are obviously underweight. The causes of cancer cachexia are multifactorial (Figure 1).

Physiological Causes of Cancer Cachexia

Weight-losing patients with cancer may have a reduced energy intake, increased energy expenditure, or a combination of both. It has been estimated that 50-60% of cancer patients in hospital have abnormal resting energy expenditures, although this may be restricted to certain diagnoses, such as pancreatic, lung, and gastrointestinal cancers. Cachexia differs from uncomplicated starvation in that the usual adaptation to a reduced food intake, such as a reduction in energy expenditure and conservation of body protein stores, does not appear to take

Causes of cancer cachexia

Physiological alterations in metabolism

• Carbohydrate

Reduced absorption or digestion of nutrients due to

• Treatment

Reduced food intake due to

• Presence of disease

• Side effects of treatment

• Social and psychological factors

Figure 1 Causes of cancer cachexia.

place. In the starving state, metabolic rate is decreased, weight loss occurs mostly from fat stores, and nitrogen losses are reduced; however, the reverse occurs in many patients with cancer.

Carbohydrate Metabolism

Some patients with cancer have been demonstrated to have a high rate of glucose turnover in both the fasting and the fed states and one cause may be increased Cori cycle activity. In the Cori cycle, glucose is metabolized anaerobically by the tumor, producing lactate (Figure 2). The tumor cannot utilize lactate and so it is returned to the liver where it is converted back into glucose. This utilizes energy, and the process is thus an energy-wasting cycle: 0nly 2 mol of ATP is produced by anaerobic glycolysis, and gluconeogenesis requires 6 mol of ATP. Had the lactate been metabolized aerobically via the Krebs cycle, 30 mol of ATP would have been synthesized. It has been estimated that Cori cycle activity may account for increased energy requirements of 1260 kJ (300kcal) per day. Lactate has been shown to cause nausea, so it is possible that another side effect of the Cori cycle is reduced food intake.

Insulin resistance has been established as a common hormonal alteration, and raised levels of growth hormone seen in some patients with cancer may contribute to insulin resistance. Glucose intolerance is associated with sepsis, bed rest, starvation, and malnutrition, all of which may occur in cancer patients, making it difficult to establish how much the tumor contributes to glucose intolerance.

Protein Metabolism

Muscle wasting or loss is common in patients with cancer. It has been estimated that protein-energy malnutrition may be present in 50-80% of patients with cancer. Data from human studies indicate increased whole-body protein turnover, synthesis, and catabolism, increased hepatic protein synthesis, and reduced rates of albumin and skeletal muscle protein synthesis. It has been estimated that whole-body protein turnover in cancer patients is 32%

Lactate

Lactate

Glucose

Figure 2 The Cori cycle.

Glucose

Figure 1 Causes of cancer cachexia.

Figure 2 The Cori cycle.

higher than in noncancer patients and 35% higher than in starved normal subjects.

Glucose required by the tumor may be supplied from dietary glucose or by the conversion of amino acids into glucose. Weight-losing patients with cancer may have reduced plasma levels of amino acids alanine, glycine, and glutamine, possibly because these compounds are used for gluconeogenesis, and this may be a cause of increased protein catabolism.

Fat Metabolism

Loss of fat or adipose tissue is common in patients with cancer and is one of the most obvious signs of cachexia. Adipose tissue consists of triglycerides, which can be metabolized to yield free fatty acids and glycerol. In patients without cancer, glycerol concentrations are decreased postprandially because the body does not need to break down adipose tissue; however, patients with cancer have been shown to have raised glycerol concentrations in the fed state, which suggests they are in a hypermeta-bolic condition.

Alterations in carbohydrate and protein metabolism are greater than those for fat, and it is likely that loss of body fat is mostly due to raised energy expenditure as a consequence of glucose intolerance and cycling.

Differences between Malnourished Patients with and without Cancer

During starvation, the metabolism of people without cancer adapts in order to conserve body tissue. Patients with cancer, however, do not exhibit these mechanisms and therefore lose weight (Table 1).

The Role of Cytokines in Patients with Cancer

Cytokines are a range of polypeptides produced by cells of the immune system in response to an inflammatory action. Cytokines, including tumor necrosis factor, interleukins-1 and -6, and interferon-gamma, have been shown to induce some of the features of cancer cachexia when administered to humans. The tumors of patients with cancer may induce an

Table 1 Metabolic differences between cancer patients and noncancer patients during starvation

Noncancer patients

Reduced glucose tolerance Reduced total body protein turnover, including reduced hepatic protein synthesis Slow weight loss, preferentially of stored fat

Cancer patients

Increased glucose turnover Total body protein turnover maintained or increased

Rapid weight loss of fat and protein inflammatory reaction resulting in raised levels of cytokines, or it may be that the cytokines produce proinflammatory cytokines. There may be amplification of the effect of cytokines by interaction between two or more.

There is much interest in the possible modulation of cytokine activity by fish oils that contain eicosa-pentenoic acid. Fish oil supplements rich in n-3 fatty acids may reduce production of cytokines and have been shown to inhibit fat and protein breakdown in animal models of cancer cachexia. Small studies of humans have demonstrated a reduction of proin-flammatory cytokines in pancreatic cancer patients when given a supplement equivalent to 2 g of eico-sapentaenoic acid (EPA) per day. However, in a clinical trial EPA-supplemented high-energy drinks and standard high-energy drinks slowed weight loss to the same extent.

Mechanisms of Cancer-Related Anorexia

Anorexia is the term given to loss of appetite, and it is thought that varying levels of neurotransmitters within the hypothalamus influence appetite. The neurotransmitter serotonin reduces appetite and neuropeptide Y stimulates appetite. Levels of neuro-transmitters in the brain may be altered by plasma nutrients, hormones, and nerve impulses arriving from the gastrointestinal tract.

Although not all mechanisms controlling appetite are known, several theories have been suggested to account for anorexia in cancer patients. The amino acid tryptophan is usually bound to albumin. In cancer patients, because albumin synthesis may be reduced, there may be more free tryptophan circulating in the plasma. Tryptophan is a precursor of serotonin, which is known to inhibit appetite. This model has been used to examine appetite in animal models of cachexia but there is still debate as to whether this is the main cause of the anorexia of cachexia. Cytokines are also known to cause anorexia and, as discussed previously, cancer patients have raised levels of cytokines.

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