Nutritional Care in Cachexia – Flashcards

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Cachexia
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a wasting syndrome that is an energy imbalance in both muscle and tissue. It is *not overcome with nutritional support.* There is altered metabolism, insulin resistance, hypothalamic aberrations, and increased inflammatory pattern, and there appears to be a genetic predisposition.
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What are the clinical manifestations of cachexia?
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- Non-voluntary weight loss (> 5% in 6 mos) - Anorexia/early satiety - Hypermetabolism (catabolism>anabolism) - Loss of body mass (skeletal muscle and adipose tissue) - Anemia and weakness - Decreased quality of life
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This is a result of insufficient appetite/diet, and is easily corrected by an improved diet, appetite enhancing drugs, vitamin support, and increased exercise.
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nutritional deficiency
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This is a result of muscle wasting, anorexia, apoptosis, and GI difficulties of aging, and can be improved by medications, appetite support, and exercise
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Sarcopenia of aging
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This is induced by energy conservation, ↓REE, insulin sensitivity, ↑ketones, ↓proteolysis, weight loss from fat, and refeeding reverses the entire condition.
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Starvation
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This is induced by hypermetabolism, ↑REE, insulin resistance, ↑gluconeogenesis, ↑proteolysis and lipolysis, preferential depletion of skeletal muscle, cardiac muscle loss, preserved visceral protein, severe anorexia, and ↑feeding does not reverse it.
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Cachexia
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This is a wasting syndrome involving loss of muscle and fat directly caused by tumor products and host response to tumor.
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Cancer Cachexia
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When does death occur from cancer cachexia?
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30% weight loss
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What is cancer cachexia characterized by?
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↑ inflammatory response
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What is cancer cachexia initiated by?
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- The hypothalamus senses tumor products in the circulation - Muscle and adipose tissue respond to both tumor and aberrant hypothalamic signals
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What is cancer cachexia exacerbated by?
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Therapy-induced side effects, altered taste perception, and psychological factors
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When neurons secrete these hormones, they support satiety, Cocaine-amphetamine-regulated transcript (CART), Pro-opiomelanocortin (POMC), In ARC nucleus, Serotonin POMC.
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anorexigenic hormones
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When neurons secrete these hormones, they encourage food intake, Agouti-related protein (AgRP), Neuropeptide Y (NPY), and can increase gherkin production.
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orexigenic hormones
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This function has balance between protein synthesis and protein catabolism, uses the Ubiquitin-proteosome system for proteolysis, and can induce cell apoptosis and autophagy.
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Normal protein catabolism
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This function has influence of insulin, liver control, hormone-sensitive lipase role, and thermogenesis.
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Normal Lipolysis
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In the Ubiquitin-Proteosome System (UPS), this step depends upon 3 ATP-dependent enzymatic steps.
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conjugation
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What are the 3 steps of conjugation in the UPS?
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E1 = ubiquitin *activating* E2 = ubiquitin *conjugating* E3 = ubiquitin *ligating*
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In the UPS, this step is effected by 26S proteasome cylindrical complex.
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Degradation
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What are the pro-inflammatory cytokines that are mediators of cancer cachexia?
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IL-1 (α,β), IL-6, TNF-α, IFN-γ
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What do the pro-inflammatory cytokines use to ↑E3 ligases, which ↑UPS activity ?
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NFκB
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What are the prostaglandins involved in cancer cachexia, and what are their effects?
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PGE-2 and HETE. they ↑ inflammation
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What are the effects of ROSs in cancer cachexia?
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↑ apoptosis & proteolysis
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This tumor product ↑lipolysis.
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LMF
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This tumor product ↑apoptosis.
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TWEAK
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Which tumor products lead to skeletal muscle wasting?
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cytokines
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This tumor product ↑ mRNA of ubiquitin-carrier protein & proteosome subunits which ↑ proteolysis.
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PIF
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This tumor product ↑HSL activation which ↑ lipid mobilization.
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ZAG
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What inhibits glucose transport into cells, and what induces this?
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GLUT4. induced by cytokines
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What increases serotonin levels, resulting in increased anorexia?
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IL-1
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What are the effects of cachexia on the gut?
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- Chemo or Radio --> breakdown of mucin and epithelial barrier - BacT entry ↑ inflammation - Stomach ↑ gherkin but has hypothalamic resistance
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What are the effects of cachexia on the liver?
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- ↑ Acute phase proteins: C-reactive protein, serum amyloid A, α1-antitrypsin - ↑ SM proteolysis which leads to insulin resistance.
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What are the effects of cachexia on the heart?
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- HM Proteolysis by UPS and autophagy - Cardiac remodeling & atrophy
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What are the effects of cachexia on the adipose tissue?
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- decreased uptake of VLDL & TAG - decreased lipoprotein lipase lipid storage
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What is UPS modulated by?
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Pro-inflammatory cytokines and malignant proteins like PIF.
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When this is degraded by UPS, this allows T-cell expression of pro-inflammatory cytokines and their receptors.
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E3 ubiquitin ligase
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What is UPS 11S particle expression induced by?
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IFN-γ
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What are the clinical interventions for cachexia?
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- medications - nutriceuticals - hyper caloric feeding - combination approaches - increased physical activity
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Which medications improve appetite and increase weight?
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progestins
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This medication is a good immunomodulator and decreases TNF-α and IL-6.
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Thalidomide
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This is good at increasing anabolic metabolism
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testosterone
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These Cox inhibitors are helpful with cachexia.
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indomethacin and celebrex
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this medication decreases the activity of the UPS
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Eicosapentaenoic acid (EPA)
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This medication decreases insulin resistance.
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ACE inhibitors
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These medications block cardiac apoptosis and support cardiac proliferation.
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Statins
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This is used to tx n/v following cancer therapy.
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Dronabinol
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This medication mimics ghrelin
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Anamorelin
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This β adrenergic blocker is a pro-anabolic, anti-metabolic transforming agent.
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Espindolol
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This nutriceutical promotes aerobic metabolism, FA transport in mitosis, and ↓ pro-inflammatory cytokines, proteolysis, fatigue.
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L-Carnitine
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This nutriceutical ↓ proteolysis and ↑ SM mass. Together w/ arginine & glutamine, it counteracts PIF.
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β-hydroxy-β-methylbutyrate (HMB)
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This neutriceutical ↓ proteolysis by down-regulating the UPS pathway and ↓ cytokine production.
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EPA (eicosopentaenoic acid)
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This neutriceutical inhibits PIF and ↓ proteolysis, and inhibit COX and cytokine production. Found in green tea.
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Polyphenols
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Combined Therapy for Cachexia #1
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Treatment: Diet high polyphenol content; antioxidants; 2 cans enteral formula enriched with omega-3's; medroxyprogesterone acetate COX-2 inhibitor celecoxib. Outcomes: 22 of 39 were "responders" or "high responders." ↑: bw, lean body mass, appetite ↓ pro-inflammatory cytokines marked improvement in quality of life
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Combined Therapy for Cachexia #2
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25 cancer patients given over 4 months: Diet high in polyphenols, EPA, α-lipoic acid + carbocysteine, vits A, E, C Anti-inflammatories: medroxyprogesterone, COX-2 inhibitor Results: ↑ body weight 51.3-58.1 kg. ↑ Lean BM, appetite, grip strength, and quality of life. ↓ pro-inflammatory cytokines
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Combined Therapy for Cachexia #3
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60 patients w/advanced-stage tumors, non-voluntary weight loss Treatment (4 months): L-Carnitine, Polyphenols, Carbocysteine, Lipoic Acid, Vitamins E/C/A Celecoxib, Megestrol Acetate Results: ↑ LBM (41 - 45 kg), appetite (5.9-7.3) ↑ Physical Performance (1831-3131 steps/d) ↓ pro-inflammatory cytokines ↓ REE
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Results of Hypercaloric Feeding
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- Helpful once cytokines addressed - Enteral better than parenteral - All inclusive commercial formula available - Extra feedings between chemo bouts - Vita-Mix blender used to prepare
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Summary
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Treat chronic inflammatory state first for aggressive nutrition therapy to work. Multimodal approach best Ongoing MENAC trial -Multimodal Exercise/Nutrition/Anti-inflammatory treatment for Cachexia Phase III trial currently enrolling. Assess for cachexia early to prevent substantial weight loss before treatment.
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