Lec 23- Cachexia

Question 1

Cachexia

Answer 1

• unexplained weight loss
• Positive risk factor for death- cachexia and cancer- prognosis is far worse

Question 2

Cancer cachexia

Answer 2

• Profound involuntary weight loss
• Associated with the presence of certain tumour types with 50% of all cancer patients experiencing cachexia
• Associated with certain tumour types
  
  • Solid tumours can lead to cachexia whereas the blood tumours do not
• Equal breakdown of both skeletal muscle and adipose tissue- protein breakdown only done during malnourishment
  
  • Lipolysis in adipose tissue
  • Proteolysis in skeletal muscle
  • Accompanied by anorexia and a raised basal metabolic rate- faster metabolism than expected

Question 3

Comparison of body composition of cachetic cancer patients with normal control

Answer 3

*

Question 4

Weight loss in patients with advanced pancreatic cancer (n=20)

Answer 4

Question 5

Other clinical manifestations include

Answer 5

• Malabsorption and diarrhoea
• N&V
• The decrease in motor skill
• Anaemia
• Weakness and tiredness
• Impaired immune function
• The decrease in attention span and concentration ability
• Often difficult to distinguish the difference between the side effects of chemotherapy, cancer and actual cachexia

Question 6

Anorexia

Answer 6

• Although anorexia present, not responsible

1. Body composition change differs from starvation
2. Weight loss occurs first, anorexia second
3. Not possible to reverse by nutritional supplementation e.g. TPN any weight gain is fat
4. Not possible to reverse by appetite stimulants e.g. megestrol acetate (Megace). Weight gain is seen but represents water and fat
5. Presence of tumour- food aversions + obstruction
6. Loss of appetite and early satiety

Question 7

Prolonged starvation

Answer 7

• During starvation brain uses ketone bodies produced by the liver, rather than glucose derived from gluconeogenesis, lean tissue preserved
• But in cachexia loss of lean body mass
• Nutritional supplementation or pharmacological manipulation of appetite are unable to restore loss of lean body mass

Question 8

Resting energy expenditure

Answer 8

• Increase in REE with lung and pancreatic cancer patients but not gastric or colorectal cancer
  
  • Possibly due to up-regulation of uncoupling proteins- the things that are used for energy within the body are used up without getting any energy= high wastage
• Acute phase response
  
  • A series of physiological and metabolic changes that occurs in response to tissue injury, infection or inflammation
  • Pancreatic cancer- increase REE associated with APR, loss lean tissue and decrease in survival

Question 9

Carbohydrate metabolism in hepatoms

Answer 9

• Key gluconeogenic enzymes decrease
  
  • Glucose-6-phosphatase
  • Fructose-1,6- Biphosphatase
  • Phosphoenolpyruvate carboxykinase
• Key glycolytic enzymes increase
  
  • Hexokinase
  • Phosphofructokinase
  • Pyruvate kinase
• As malignancy increase aerobic glycolysis increases i.e.g produce lactic acid from glucose even in the presence of oxygen

Question 10

Lactic acid and tumours

Answer 10

• The lactic acid produced by the tumour circulates to the liver and is converted back into glucose
• This is an energy consuming process requiring 6 moles of ATP/Glucose formed. Since only 2 moles of ATP is formed in glucose => lactate there is a net loss of 4 moles of ATP to the patient
• Very inefficient process

Question 11

Carbohydrate metabolism

Answer 11

Question 12

Protein metabolism

Answer 12

• Wasting of skeletal muscle important cause of death in cancer
• Death occurs when weight loss exceeds 30% and is responsible for up to 25% of cancer deaths
• Cancer cachexia
  
  • The decrease in protein synthesis, accompanied by an increase in protein degradation resulting in loss of skeletal muscle
• Because they have a energy deficit they can’t replace the protein used for energy production

Question 13

Proteolysis inducing factor (PIF)

Answer 13

• Glycoprotein mw-24,000
• In-vitro proteolysis in skeletal muscle
• Potential marker for cachexia
• In-vivo weight loss accompanied by the breakdown of skeletal muscle
• Present in the urine of weight losing cancer patients when weight loss is above 1.5kg/month
• Not in normal patients, or those from weight loss of other causes

Question 14

Zinc-a2-glycoprotein

(Lipid mobilising factor)

Answer 14

• Glycoprotein MW- 43,000
• Causes lipolysis in adipocytes in vitro
• In-vivo weight loss accompanied by the breakdown of adipose tissue
• Elevated in the urine of cachetic cancer pateint relative to weight loss, and decreases as the patient responds to chemotherapy

Question 15

Fatty acid metabolism

Answer 15

• Adipocytes- increase in lipolysis rather than a decrease in lipogenesis
• Triglycerides => Free fatty acids + Glycerol

Answer 16

• ZAG seems to work through a b3-receptor producing increase lipolysis and also stimulates UCP-1 production in brown fat
• In addition to producing an energy source for the liver (Tumours can’t metabolise fat to any large extent) catabolism of adipose tissue also provides unsaturated fatty e.g. linoleic and arachidonic acids
• Thes may be used by the tumour to prevent cell death by apoptosis

Question 17

Agressive nutritional support

Answer 17

• Oral, parental and enteral feeding, no use in the treatment of cacheixa
• Transient weight gain, due to increased fluid load and adipose tissue- increased risk of congestive heart failure, increased risk of infection
• Benefit for strength when patient has a resectable tumour with colonic cancer patients an increase in lactate production- increased tumour activity, tumour growth

Question 18

Progestogens- steroids

Answer 18

• Methyl acetate and medroxyprogesterone
  
  • Stimulate appetite increasing food intake and give patients a general sense of well-being
  • Study of 15 randomised clinical trials increase in body weight but not lean body mass
  • A possible mechanism of action via down-regulation of the synthesis and release of pro-inflammatory cytokines
  • The inflammatory response in cachexia is strange- as the cells start to die due to energy deficit- this initiates the immune system- this progestrogens helps to combat this

Question 19

Ketogenic diet

Answer 19

• 70% medium chain triglycerides
• Ketone bodies are preferentially metabolised by peripheral tissues rather than the tumour
  
  • Brain uses these ketone bodies in different way- this diet helps in epilepsy
• Grossly cachectic patient (up to 36% weight loss) enteral feeding for 7 days
• Medium weight gain of 2kg accompanied by decrease in protein degradation and an increase in performance skills

Question 20

HMB

(b-Hydroxy-b-Methylbutyrate)

Answer 20

• Heterogenous population of stage IV cancer
  
  • Colon, lung, pancreatic and prostate still receiving various chemotherapeutic agents
  • Glutamine and arginine- enhance net protein synthesis HMB minimise protein breakdown
  • Net weight gain including an increase in lean body mass

Question 21

Type + quantity of fat in diet

Answer 21

• Greece and southern Italy low incidence of GI cancer high content of olive oil
• n-3 polyunsaturated fatty acid (PUFA), found in fish oil, high fish content of diet, low incidence of breast, prostate and GI cancers
• n-6 PUFA red meat and corn oil, westernised diet higher incidences of cance r

Question 22

Weight change after EPA enriched nutritional supplement in cachetic pancreatic cancer patients

Answer 22

• Increase in weight correlates with EPA concentration
• Increase in lean body mass
• Increase in survival and quality of life
• Low toxicity

Question 23

Ghrelin

Answer 23

• Induces the release of growth hormone
• Regulates appetite
• SUN 11031 synthetic Ghrelin 20mcg/Kg dd improved patients appetite and there was increase in lean mass using DEXA

Question 24

Melanocortin-4 receptor antagonists

Answer 24

• Regulation of appetite in the hypothalamus
• Activated MC4R in mice- decreased food seeking in mice with knockout mice increasing intake
• mAb to MC4R increased food intake in rats

Question 25

Potential treatments

Answer 25

• Vitor- ACEI which produced muscle gain in cardiac patients. Passed Phase III trials for cachectic patients and is in Phase II for Aids patients
  
  • Suggested angiotensin II plays a role in cachexia
• Resveritol- extracted from red grapes appears to prevent tumour growht by inhibition of NF-kB
• Thalidomide: reduces production of TNF-a and blocks NF-kB