Metabolic Regulation in Simple Malnutrition - PDF

Metabolic Regulation in Simple Malnutrition vs Malnutrition in Metabolic Stress       Starvation Cancer Surgery Clinical Metabolic Cellular Acknowledgements: Undernutrition/Starvation – Dr John Hoffer Cachexia – Dr Chevalier Benefits of assessing nutrition Early identification of patients...

Metabolic Regulation in Simple Malnutrition vs Malnutrition in Metabolic Stress       Starvation Cancer Surgery Clinical Metabolic Cellular Acknowledgements: Undernutrition/Starvation – Dr John Hoffer Cachexia – Dr Chevalier Benefits of assessing nutrition Early identification of patients at risk, or experiencing malnutrition allows for early intervention  Helps design appropriate nutrition support  Improves patient wellbeing, survival, immune to know weight of patients: bed function and reduced morbidity need weights them blood test, etc. to design nutritional therapy to  Improves response to treatment BMI  Cost effective every dollar invested in nutrition support, Canadian Malnutrition Task Force for saves 99$ in healthcare system  https://nutritioncareincanada.ca/ Critical Care Nutrition https://www.criticalcarenutrition.com/ Impact of cancer on nutritional status Cancer Presence of tumor and metabolism Host response to tumour and factors compromise Nutritional status Anti-cancer treatment Consequences of compromised status Primary malnutrition Reduced intake Altered metabolism Malnutrition Weight loss ↓Quality of life ↓Response to treatment ↓Survival Consensus definition of cachexia important to know the definition and that key is loss of muscle b disturbance in protein metabolism    From the Greek: “kakos” = bad and “hexis” = condition A complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature is weight loss… Prevalence 50-80% in cancers Evans et al., Clinical Nutrition (2008) 27:793-799 Chronic illness and cachexia promoting catabolism or lack of appetite reduced muscle strength including respiratory and cardiac muscle Evans et al., Clinical Nutrition (2008) 27:793-799 Consequences  Muscle wasting predicts poor cancer-associated outcomes:       ↑ fatigue ↑ treatment-induced toxicity ↓ host response to tumor ↓ performance status ↓ survival Sarcopenic obesity: obesity with depleted muscle mass   ≈15% of patients with lung or gastro-intestinal tumors Worse outcomes than obese or sarcopenic patients Pathophysiology of cachexia Dual contribution of metabolic change and reduced food intake to cachexia Systemic inflammation Catabolic factors Anorexia (1° and 2°) Negative energy and protein balance Adapted from Fearon et al., Nat Rev Clin Oncol 10:90-99, 2013 Stages of cachexia Fearon, Kenneth et al. “Definition and classification of cancer cachexia: an international consensus.” The Lancet. Oncology vol. 12,5 (2011): 489-95. doi:10.1016/S1470-2045(10)70218-7 Clinical diagnosis of cancer cachexia Fearon, Kenneth et al. “Definition and classification of cancer cachexia: an international consensus.” The Lancet. Oncology vol. 12,5 (2011): 489-95. doi:10.1016/S1470-2045(10)70218-7 Anorexia  Associated with >50% cases of cachexia  ↓ in food intake may result from:  GI problems           Obstruction of the GI tract Malabsorption Constipation Early satiety – GI motility Pain Depression/anxiety Radio- and chemo-therapy Inflammation Defective central regulation of appetite and food intake (hypothalamus) Medications Nausea and chemosensory abnormalities   Direct consequences of antineoplastic therapies Nausea:    Side effect of drugs Abdominal disease, intracranial metastases, derangements, GI stasis Distortion of taste and smell:   Hypersensitivity to odors & flavors, persistent bad tastes, phantom smells, food aversions May also result from chronic nutritional deficiencies Treatment  Goals       ↑LBM Predispose to a better response to antineoplastic therapy ↑ Immunocompetence decreased food intake Symptom management causing (ex: managing GI mobility) ↑ Perception of well-being Multi-modal approach Pathophysiology – Inflammation/acute phase response  Acute phase response   Coordinated adaptations of the body to limit and clear tissue damage caused by hydrolases released from inflammatory, injured or malignant cells accommodation (not adaptation) Hepatic synthesis of acute-phase proteins: their plasma concentrations ↑ (positive) or decrease ↓ (negative) by > 25% positive acute-phase protein increases protein concentration to fight infections, etc. Damaged LDL can sneak through lining of arteries and continue cycle of atherosclerosis —> escape from capillaries Acute phase proteins Positive Negative if concentration goes down, acute phase (subclinical infection) —> not a  Complement system  Albumin response biomarker of pure malnutrition  Coagulation and  Transferrin fibrinolytic system  Transthyretin binds thyroid hormone  Antiproteases  Thyroxin-binding globulin C-reative protein studies  Participants in (increases severely during  IGF-1 anabolic hormone infection) inflammatory responses  Factor XII  Others: C-reactive protein, fibronectin, Albumin: most abundant one in plasma, concentration goes down during infection/inflammation —> synthesis rate of ferritin, ceruloplasmin, albumin can increase a lot during infection —> needs its function = transporting nutrients, drugs, toxins —> increased haptoglobin removal of albumin —> could be catabolized more —> key increased in order to clear RBC and iron released from RBC (free iron is toxic) and during infection, particular response to increase ferritin, etc. to bind iron so that bacterias can’t have it that albumin is a small protein and as such, its loss through capillaries is increased Electrolytes and water can follow albumin through capillaries —> edema The acute-phase response is modulated by cytokines  Cytokines are produced by the tumor and/or the host:   Secreted from immunocompetent cells: lymphocytes, macrophages They act locally (paracrine and autocrine) and systemically (endocrine) Proinflammatory cytokines  High serum levels of these cytokines have been found in some, but not all types of cancer:     Tumor-necrosis factor alpha (TNF-α) Interleukins 1 and 6 (IL-1, IL-6) Interferon gamma (IFN-γ) Leukemia inhibitory factor (LIF) Other effects of cytokines       ↓ Appetite and food intake, resulting from both central and peripheral elements ↓ GI functions: ↓ gastric emptying, intestinal mobility ↓ Blood flow Inhibit lipoprotein lipase (LPL) Inhibit growth hormone and IGF-1 signaling Induce insulin resistance (IL-6) Cachexia is often accompanied by hypermetabolism but reduced total energy expenditure increased basal metabolic rate, but severely decreased activity energy expenditure : eat less, so thermic effect of eating will be less Contrasts with simple starvation where everything would be decreased —> hypo metabolic Pathophysiology – Metabolic alterations ↓ Concentration of or responsiveness to anabolic factors      Insulin IGF-1 Growth hormone Thyroid hormone Testosterone ↑Concentration of catabolic factors promote protein breakdown and insulin resistance     Glucagon Cortisol Pro-inflammatory cytokines Tumor-derived factors Metabolic alterations - Lipids  Mobilization of lipids and ↑ turnover of fatty acids    ↑ Lipolysis, FFA, VLDL ↓ LPL activity Hypertriglyceridemia Metabolic alterations Glucose     Glucose is a fuel for tumors Tumors produce lactate Cori cycle (uses ATP) ↑ Gluconeogenesis  ↑ proteolysis (muscle) Insulin resistance Metabolic alterations - Protein      Negative N balance ↑ Basal protein turnover ↑ or ↔ muscle proteolysis: provides AA for GNG, acute-phase protein synthesis and tumour growth ↓ or ↔ in muscle protein synthesis ↑ Hepatic protein synthesis (APPs) class stopped here Nutritional alterations in starvation and cachexia Kotler, D P. “Cachexia.” Annals of internal medicine vol. 133,8 (2000): 622-34. doi:10.7326/0003-4819-1338-200010170-00015 Catabolic Response to Surgery Inflammatory Response T2D Neuro-Endocrine Response Insulin Resistance, Hyperglycemia Loss of Body Protein Immunosuppression Delayed wound healing Muscle Wasting Delayed convalescence NORMAL FASTING GLYCOGENOLYSIS [GLUCOSE] GLUCONEOGENESIS lactate pyruvate amino acids glycerol GLYCOLYSIS PROTEOLYSIS LIPOLYSIS SURGICAL STRESS GLYCOGENOLYSIS [GLUCOSE] GLUCONEOGENESIS COUNTERREGULATORY HORMONES lactate pyruvate amino acids glycerol CYTOKINES GLYCOLYSIS PROTEOLYSIS LIPOLYSIS SURGICAL STRESS Nutrition Support GLYCOGENOLYSIS [GLUCOSE] GLUCONEOGENESIS COUNTERREGULATORY HORMONES lactate pyruvate amino acids glycerol CYTOKINES GLYCOLYSIS PROTEOLYSIS LIPOLYSIS SURGICAL STRESS Nutrition Support Glucose GLYCOGENOLYSIS Epidural [GLUCOSE] GLUCONEOGENESIS COUNTERREGULATORY HORMONES lactate pyruvate amino acids glycerol CYTOKINES GLYCOLYSIS PROTEOLYSIS LIPOLYSIS SURGICAL STRESS Nutrition Support Glucose GLYCOGENOLYSIS Epidural [GLUCOSE] GLUCONEOGENESIS COUNTERREGULATORY HORMONES lactate pyruvate amino acids glycerol CYTOKINES GLYCOLYSIS PROTEOLYSIS PROTEIN SYNTHESIS LIPOLYSIS Nutrition Support Amino Acids