Cachexia

Patients with advanced cancer, human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) and a number of other chronic diseases are frequently undernourished. Physically they show all the signs of marasmus, but there is considerably more loss of body protein than occurs in starvation. The condition is called cachexia, from the Greek Ka%e^io for 'in a poor condition'). A number of factors contribute to the problem:

  • The patients are extremely sick, and because of this their wish to eat may be impaired.
  • Many of the drugs used in chemotherapy can cause nausea, loss of appetite and alteration of the senses of taste and smell (section 1.3.3.1), so that foods that were appetizing are now either unappetizing or even aversive.
  • Chemotherapy and radiotherapy inhibit cell division; this leads to reduced cell proliferation in the intestinal mucosa, and hence malabsorption (section 8.3.1.2).
  • There is a considerable increase in basal metabolic rate, to the extent that patients are described as being hypermetabolic. Even a mild fever causes an increase in basal metabolic rate of about 13% per degree Celsius increase in body temperature.
  • The secretion of cytokines, including tumour necrosis factor (also known as cachectin), in response to infection and cancer increases the rate of breakdown of tissue protein. This is a major difference from marasmus, in which protein synthesis is reduced but catabolism in unaffected.

A number of factors account for the increase in metabolic rate in cachexia:

  • Many tumours metabolize glucose anaerobically to release lactate. This is then used for gluconeogenesis in the liver — as discussed in section 5.4.1.2, there is a net cost of six ATP for each mole of glucose cycled between lactate and glucose in this way, and hence there has to be an increased rate of metabolism on the liver. Figure 8.4 shows the increase in glucose cycling in patients with advanced cancer.
  • There is increased stimulation of uncoupling proteins (section 3.3.1.4), leading to thermogenesis and hence increased oxidation of metabolic fuels.
  • There is futile cycling of lipids. Hormone sensitive lipase in adipose tissue (section 10.5.1) is activated by a small proteoglycan produced by tumours that cause cachexia (but not by those that do not). This results in liberation of fatty acids from adipose tissue, and re-esterification to triacylglycerols (which are exported in VLDL; section 5.6.2.2) in the liver. As discussed in section 5.6.1.2, esterification of fatty acids to triacylglycerol is an energy-expensive process.

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  • glucose oxidation
  • Cori cycle
  • glucose oxidation
  • Cori cycle

stable weight weight loss hypermetabolic

Figure 8.4 Glucose cycling in patients with cancer cachexia. From data reported by Holroyde CP et al.

stable weight weight loss hypermetabolic

Figure 8.4 Glucose cycling in patients with cancer cachexia. From data reported by Holroyde CP et al.

(1975) Cancer Research 35: 3710-3714.

Both decreased synthesis and accelerated catabolism contribute to the loss of tissue protein.

  • There is a considerable depletion of individual amino acids, resulting in an incomplete mixture of amino acids available for protein synthesis (section 9.1.2.2):
  • many tumours have a high requirement for glutamine and leucine;
  • there is increased utilization of alanine and other amino acids as a result of the stimulation of gluconeogenesis by tumour necrosis factor;
  • interferon-y induces indoleamine dioxygenase and depletes tissue pools of tryptophan.
  • Tumour necrosis factor causes increased protein catabolism. It increases both expression of ubiquitin and the activity of the ubiquitin-dependent proteolysis system (section 9.1.1.1).
  • The proteoglycan produced by tumours that cause cachexia also stimulates protein catabolism — in this case the mechanism is unknown.
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