Pathophysiology of cachexia

 

The process of cachexia is a complex inflammatory state associated with  accelerated rate of catabolism (process whereby molecules are degraded to release energy), which is particularly pronounced in muscles. Many factors influence the catabolic state, this includes changes in metabolism, release of tumour factors and neuroendocrine factors.

 

Various metabolic changes occur in the body during cachexia which appear to be similar to starvation but is actually  different in many respects. This includes;

 

• no attempt to conserve energy but rather elevated energy expenditure during resting state, whereas in starvation the body reduces energy use.

 

•  Both proteins (in the form of muscles) and adipose tissues are utilised in cachexia inefficiently compared to the starvation state where ketone bodies and fatty acids are the main form of energy used and there is minimal protein breakdown unless required.

 

 

 

Changes in metabolism:

 It is postulated that the release of mediators such as lipid mobilizing (LMF) and proteolysis inducing factors (PIF) promote the cachetic state. This stimulates pathways such as the ATP ubiquitin proteasome pathway which is the major system involved in the degradation of proteins and thus increases the rate of proteolysis.

 

 

Furthermore, pro-inflammatory mediators such as cytokines (interlukin 1 ,interlukin 2 and tumour necrosis factor) are released to further potentiate the cachetic state and causes a array of events. However it is uncertain whether such factors are released by host, tumour cells or a combination of both but the presence of the tumour amplifies the host's acute phase response (APR. This leads to increased release of various pro-inflammatory mediators and pro-cachetic factors such as PIF and LMF.  Cytokines also  exert effect on the adrenal glands to stimulate the release of cortisol and catecholamines leading to further stimulation of the ubiquitin system and thus driving up the basal metabolism of the body.  

 

 

 

 

Neuroendocrine factors:

It is also speculated that the dysregulation of neuroendocrine factors such as insulin, cortisol and glucagon is caused by interlukin 6 and tumour necrosis factor (TNF) which produces effects such as insulin resistance, reduced anabolic activity and raised cortisol levels.

 

 

 

 

Central effects:

Cytokines favour sympathetic pathways as well as acting on the hypothalamus which affect the balance of the neurotransmitters involved in the control for of appetite.

Neuropeptide Y and agouti related peptide (AGRP) stimulate the appetite, whereas opiomelanocortin and amfetamine related factor (CART) gives the feeling of satiety. These neurotransmitter exist in a delicate balance in healthy individuals but in those with cachexia cytokines disrupt this harmony giving rise to anorexia.