Metabolic Regulation in Simple Malnutrition vs Malnutrition in Metabolic Stress 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 Stephanie Chevalier Starvation • The physiological condition created in the body as a co...

Metabolic Regulation in Simple Malnutrition vs Malnutrition in Metabolic Stress Starvation Cancer Surgery Clinical Metabolic Cellular Acknowledgements: Undernutrition/Starvation – Dr John Hoffer Cachexia – Dr Stephanie Chevalier Starvation • The physiological condition created in the body as a consequence of chronic insufficient food intake – Starvation can be physiological (adaptive to promote survival) or pathological (adaptation is some sort of stress intervened to compromise adaptation: infection, cancer, drugs, surgery… compromised) – Protein energy malnutrition…undernutrition means Hoffer, L J. “Clinical nutrition: 1. Protein-energy malnutrition in the inpatient.” CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne vol. 165,10 (2001): 1345-9 complicated area to investigate Ethics in Nutrition Research • Do no harm putting healthy humans on diet to see malnutrition —> can’t do that clinical: do no harm and if malnutrition —> need to treat, can’t just observe them can look before and after treatment of malnutrition must offer standard care as control group • Must treat rather than observe • Offer best standard of care as control • Double-blinded randomized placebo- controlled clinical trials • Drug trials yes, malnutrition NO • Malnutrition is complex energy deficiency along with protein • Rarely single nutrient deficiency usually and other macronutrient • Biomarkers of mild deficiency • Subclinical infections not diagnosed but there zinc deficiency causes side effects and symptoms similar to protein deficiency can’t assess zinc status really well —> plasma zinc level does not mean anything men were fed a low protein and energy low diet during 6 months and studied how they were adapted to diet + recovery They felt terrible psychologically and physically —> problems recovering from it People survive starvation and regain normal health. How is survival possible in the face of continuing starvation? The Biology of Human Starvation Ancel Keys et al (1950) • • • • Conscientious objectors 1500 kcal per day 50 g protein per day For 6 months 50% of the energy they would normally eat low protein diet about protein RDA about 0.7 grams/ kg/day Muscle and fat mass at first: 69.5 kg —> 20% body fat Same men after 6 months: 53.6 kg, lost fat mass and muscle mass —> less than 10% body fat, loss 25% of his bodyweight After 6 months of starvation… Total weight change: 23% (15.9 kg) Change in lean tissue mass: -24% (9.7 kg) Change in fat mass: -71% (6.9 kg) Change in ECF mass: +4% Rate of weight change: zero —> adaptation Rate of fat loss: zero Rate of lean tissue loss: zero Successful adaptation: stable body composition Reduced energy expenditure in starvation • Reduced resting energy expenditure - Reduced mass of metabolically active tissue (slow, weeks) - reduced energy expenditure per unit active tissue (fast, days) hematocrit - reduced heart rate, muscle tone lower less intentional activity, less engagement felt empathetic, slowed, reduced movement —> everything to reduce energy expenditure • Reduced non-resting energy expenditure - reduced work of moving - reduction of voluntary movements Reduced protein requirement in starvation • Diminished lean tissue mass • More efficient retention of dietary protein • Lean tissue mass stabilizes despite continued low protein intake Cellular Regulation Protein Synthesis Regulation Energy State of the Cell Absence of Essential AA’s in the cell Low energy state of the cell Gcn2 (general control nonderepressible 2), a protein kinase …inhibits general translation by phosphorylation of eIF-2α …..binds to uncharged tRNA ...general inhibition of translation. …downregulates genes regulating fattyacid and triglyceride synthesis through SREBP-1c …delays entry into S phase of cell cycle AMPK (5' AMP-activated protein kinase) Senses energy charge of the cell, with high AMP ATP levels are low …inhibits mTORC1 …decreases protein synthesis …downregulates genes regulating fattyacid and triglyceride synthesis through SREBP-1c decrease anabolism, cellular turnover —> slowing up metabolism contributing for successful adaptation at cellular level Reducing energy and protein requirement to survive under long term undernutrition No reserver —> only have the strict minimum to survive Successful adaptation • Accomplished through – Reduced energy “requirement” for homeostasis – Reduced protein “requirement” for homeostasis • Benefit – Survival • Cost – – – – – Lean tissue loss Fatigue, inactivity Immunodeficiency Reduced tolerance to stress metabolic stress, infection, etc. Irritability didn’t want to do anything Clinical Features of PEM Hoffer, L J. “Clinical nutrition: 1. Protein-energy malnutrition in the inpatient.” CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne vol. 165,10 (2001): 1345-9 Pathophysiology of PEM adapt to spend less protein levels, albumin normal are vulnerable to other stressors After 6 months: 0 nitrogen balance, so low protein intake and low excretion —> maintaining homeostasis low energy intake and expenditure Hoffer, L J. “Clinical nutrition: lower plasma 1. Protein-energy malnutrition in the albumin concentration inpatient.” CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne vol. 165,10 (2001): 1345-9 Dutch Famine 1944-45 •Hongerwinter ("Hunger winter") •Famine in German-occupied part of the Netherlands near the end of World War II •Sudden and Extreme: a German blockade cut off food and fuel shipments from farm areas. •4.5 million people were affected and survived because of soup kitchens, estimated 22,000 died •Pregnant women particularly affected. Dutch Famine Birth Cohort Study epigenetic changes •Intrauterine growth restricted (IUGR) •Infants have been followed for decades –Chronic disease risks –Their own infants were IUGR –Barker Hypothesis…Epigenetics increase small for their gestational age and DNA methylation Epigenetic changes… Infants born in the Great Depression of the 1930’s https://www.nature.com/articles/d41586-022-03789-z Infants born after the Ice Storm in Montreal in 1998 Hunger Winter 1944-45 in the Netherlands Winter in Ukraine 2022-23 ? The First 1000 Days from conception to approximatively second birthday really important Babies have high metabolism —> high requirements The 10 Building Blocks for Nutrition During the First 1,000 Days 2023: every 11 seconds a child dies of malnutrition https://thousanddays.org/wp-content/uploads/StandaloneCharts2019Update-10BuildingBlocks.pdf Edematous Undernutrition with Edema accumulation of fluid that are leaked from capillaries also see that in patient with heart failure ascites : feature of edametous undernutrition —> undernutrition of energy protein with failed adaptation probably have subclinical infections body meets potentially invading pathogens requires vitamin A for good immune response Infections Diarrhea Pneumonia and other respiratory tract infections Urinary tract infections Measles Tuberculosis Parasitic infections Lack of antibodies Hb synthesis decreased Anemia exacerbated by parasitic infections Dysentery – GI infection Fever Fluid imbalances Heart failure, possible death bc of fluid and electrolyte imbalance Medical Nutrition Therapy for Rehabilitation sodium Restore fluid and outside cell, potassium electrolyte imbalances inside cell 2.Nutrition intervention and slow must be cautious, slowly increasing protein and calories 3.Treat infections 4. Programs should involve term prevention increase food security, etc. the local people longer 1. Unsuccessful Adaptation • Add a micronutrient deficiency • Add a stress/surgery – Trauma – Cancer – Inflammation/infection /accommodation All the others: hyper metabolic infection to perinial cavity hypometabolic Long, C L et al. “Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance.” JPEN. Journal of parenteral and enteral nutrition vol. 3,6 (1979): 452-6. doi:10.1177/014860717900300609 major increase in urinary nitrogen: nitrogen comes from amino acids from protein breakdown losing lean mass and potentially compromising functions Losing muscle —> a lot of reasons Urinary nitrogen negative nitrogen balance Long, C L et al. “Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance.” JPEN. Journal of parenteral and enteral nutrition vol. 3,6 (1979): 452-6. doi:10.1177/014860717900300609 Importance to intervene before too intense —> treatment is not just to eat more Sarcopenia The 6 causes of muscle atrophy 1. Cachexia – cancer, systemic inflammation cortisol, epinephrine 2. Hormone excess or deficiency like decrease in insulin, insulin growth factor 3. Old age – sarcopenia 4. Protein-energy malnutrition – starvation 5. Inactivity – disuse atrophy bed rest, space flight, 0 gravity 6. Neuromuscular disease