Cachexia

Question 1

What is cachexia?

Answer 1

Cachexia is profound, unexplained weight loss and is a condition associated with cancer. It is poorly understood and hence hard to treat.

Question 2

Describe the prevalence of cachexia.

Answer 2

It is associated with the presence of certain tumour types Solid tumours, less likely in humoral cancers), with 50% of all cancer patients experiencing cachexia.

Question 3

Describe the features of cachexia.

Answer 3

Cachexia features equal breakdown of both skeletal muscle tissue; lipolysis in adipose tissue and proteolysis in skeletal muscle. It is accompanied by anorexia and a raised basal metabolic rate. Although it is accompanied by anorexia, it cannot be treated like the eating disorder of the same name.

Question 4

What are the clinical manifestations of cachexia?

Answer 4

• Malabsorption and diarrhoea.
• Nausea and vomiting.
• Decrease in motor skill.
• Anaemia.
• Weakness and tiredness.
• Impaired immune function.
• Decrease in attention span and concentration ability.

Question 5

Is it possible to reverse cachexia with nutritional supplementation or appetite stimulants?

Answer 5

It is not possible to reverse cachexia by nutritional supplementation (e.g. TPN).
It is also not possible to reverse cachexia by the use of appetite stimulants (e.g. megestrol acetate (Megace)).

Question 6

What weight gain is seen when nutritional supplementation is used to treat cachexia?

Answer 6

Any weight gain from this is often just fat.

This only leads to transient weight gain due to increased fluid load and increased adipose tissue.

Question 7

What weight gain is seen when appetite stimulants are used to treat cachexia?

Answer 7

Weight gain is seen from use of appetite stimulants, but this represents water and fat gain.

Question 8

What occurs during starvation?

Answer 8

During starvation, the brain uses ketone bodies produced by the liver, rather than glucose derived from gluconeogenesis; these aren’t good for the brain to use. Lean tissue is preserved.

Question 9

Why may resting energy expenditure be increased in some cancers?

Answer 9

This may be due to up regulation of uncoupling proteins. This leads to the body carrying out futile chemical cycles instead of energy production. The use of energy is uncoupled from food eaten, leading to a reduction in energy reserves in cells.

Question 10

In hepatomas there is a decrease in key gluconeogenic enzymes such as?

Answer 10

• Glucose 6 – phosphatase.
• Fructose 1,6-Bisphosphatase.
• Phosphoenolpyruvate carboxykinase.
• Pyruvate carboxylase.

Question 11

In hepatomas there is an increase in key glycolytic enzymes such as?

Answer 11

• Hexokinase.
• Phosphofructokinase.
• Pyruvate kinase.

Question 12

As malignancy increases, what metabolic changes also increase?

Answer 12

Aerobic glycolysis increases (lactic acid is produced from glucose even in the presence of oxygen).

Question 13

When lactic acid is produced by a tumour, where does it go and what happens?

Answer 13

The lactic acid produced by the tumour circulates to the liver and is converted back to glucose.

Question 14

Describe the process of aerobic glycolysis with emphasis on the energy (ATP) required and formed.

Answer 14

This is an energy consuming process, requiring 6 moles of ATP per mole of glucose formed. Since only 2 moles of ATP are formed in when glucose is converted to lactate, there is a net loss of 4 moles of ATP to the patient.

Question 15

What is the acute phase response in cancer/cachexia?

Answer 15

A series of physiological and metabolic changes that occurs in response to tissue injury, infection or inflammation. This causes an increase in inflammatory markers.

Question 16

Related to cachexia, what is an important cause of death in cancer?

Answer 16

Wasting of skeletal muscle.

Question 17

Death occurs when weight loss reaches around what percentage?

Answer 17

30%.

Question 18

Wasting of skeletal muscle and weight loss is responsible for up to what percentage of cancer deaths?

Answer 18

25%.

Question 19

Describe changes in protein in cachexia.

Answer 19

In cancer cachexia there is a decrease in protein synthesis, accompanied by an increase in protein degradation resulting in a loss of skeletal muscle.

Question 20

Why cant the proteins lost in cachexia be easily replaced?

Answer 20

These proteins that are lost can’t be easily replaced as there is a lack of energy needed for this process.

Question 21

What is proteolysis inducing factor?

Answer 21

This is a glycoprotein with a molecular weight of 24,000. In vitro is contributes to the proteolysis of skeletal muscle. In vivo weight loss is accompanied by the breakdown of skeletal muscle.

Question 22

When/where is proteolysis inducing factor found?

Answer 22

This factor is present in the urine of weight losing cancer patients when weight loss is above 1.5kg/month. It is not present in the urine of normal patients, or those with weight loss from other causes.

Question 23

What is zinc-alpha-2-glycoprotein (lipid mobilizing factor)?

Answer 23

This is a glycoprotein with a molecular weight of 43,000. It causes lipolysis in adipocytes in vitro. In vivo, weight loss is accompanied by the breakdown of adipose tissue.

Question 24

When are levels of zinc-alpha-2-glycoprotein elevated?

Answer 24

This factor is elevated in the urine of cachexic cancer patients relative to weight loss and decreases as the patient responds to chemotherapy.

Question 25

How does zinc-alpha-2-glycoprotein work?

Answer 25

ZAG seems to work through a β3-receptor producing increased lipolysis and also stimulates UCP-1 production in brown fat.

Question 26

As well as producing an energy source, what does catabolism of adipose tissue produce?

Answer 26

In addition to producing an energy source (tumours cannot metabolise fat to any large extent) catabolism of adipose tissue also provides unsaturated fatty acids e.g. linoleic and arachidonic acids. These may be used by the tumour to prevent cell death by apoptosis.

Question 27

What adverse effects can aggressive nutritional support lead to?

Answer 27

Aggressive nutritional support can lead to an increased risk of congestive heart failure and an increased risk of infection.
It may be possible that this can actually lead to increased tumour activity and growth.

Question 28

What are protosetrogens (methyl acetate and methoxyprogesterone)?

Answer 28

These stimulate the appetite, increasing food intake and give the patients a general sense of well-being.

Question 29

What is a possible mechanism of action for the proestrogens?

Answer 29

A possible mechanism of action for these compounds may be the down regulation of the synthesis and release of proinflammatory cytokines. Cachexic cells stimulate the immune system, leading to inflammation.

Question 30

Describe a ketogenic diet.

Answer 30

This diet features 70% medium chain triglycerides.

Question 31

Where are ketone bodies preferentially metabolised?

Answer 31

In the periphery rather than the tumour.

Question 32

In grossly cachexic patients (up to 36% weight loss), how long can a ketogenic diet be given for?

Answer 32

7 days.

Question 33

What is the median weigh gain seen with a ketogenic diet? What other effects are seen?

Answer 33

2kg. Decreased protein degradation and an increase in performance skills.

Question 34

Greece and Southern Italy show a low incidence of GI cancers, what is this believed to be due to?

Answer 34

A high dietary concentration of olive oil.

Question 35

What is HMB (beta-hydroxy-beta-methylbutyrate)?

Answer 35

This was trialled in a heterogeneous population of stage 4 cancers of the colon, lung, pancreas, and prostate, who were still receiving various chemotherapeutic agents.
Glutamine and arginine lead to enhanced net protein synthesis. HMB minimises protein breakdown.
Net weight gain including an increase in lean body mass was seen.

Question 36

Those with a high dietary concentration of n-3 polyunsaturated fatty acid (PUFA), which is found in fish oils, show a low incidence of which cancers?

Answer 36

Those with a high dietary concentration of n-3 polyunsaturated fatty acid (PUFA), which is found in fish oils, show a low incidence of breast, prostate, and gastrointestinal cancers.

Question 37

Westernised diets containing what show an increased incidence of cancer?

Answer 37

Westernised diets containing a high concentration of n-6 PUFA, found in red meat and corn oil, show a higher incidence of cancer.

Question 38

What is ghrelin?

Answer 38

This compound induces the release of growth hormone and also regulates appetite. SUN11031 synthetic ghrelin 20µg/kg/day showed an improvement in patient appetite and there was a slight increase in lean mass using DEXA. This weight gain was sustained.

Question 39

What are melanocortin-4 receptor antagonists?

Answer 39

This compound regulates appetite in the hypothalamus. Activated MC4R in mice lead to decreased food seeking. Knockout mice showed an increased intake of food. A monoclonal antibody for MC4R lead to increased food intake in rats.

Question 40

What is vitor? What does its use suggest?

Answer 40

This is an ACE inhibitor which produced muscle gain in cardiac patients. It passed phase 3 clinical trials for cachexic patients and is in phase 2 for AIDS patients.
This suggests that angiotensin 2 plays a role in cachexia.

Question 41

What is resveritol?

Answer 41

This is an extract from red grapes and appears to prevent tumour growth by inhibition of NK-κB.

Question 42

How is thalidomide believed to help in cachexia?

Answer 42

Reduces production of TNFα and blocks NFκB.