Metabolic response to starvation vs injury, sepsis Flashcards
simple starvation vs injury, sepsis
Simple starvation - metabolic adaptation, lean tissue conserved
Catabolic weight loss - no adaptation, lean tissue breakdown continues despite nutrient intake
Features of simple starvation
- Decreased BMR
- Low glucose levels
- Increase gluconeogenesis initially, decrease after 5-7 days
- Protein catabolism low
- High fat catabolism
- Increased ketone use
- Ketosis present
- Ketosuria present
Features of starvation superimposed on to injury or stress
- Decreased or normal BMR initially
- High glucose levels
- Increased gluconeogenesis
- High protein catabolism
- Low/none fat catabolism
- Decreased ketone use
- Ketosis absent
- Ketosuria absent
Starvation - anorexia nervosa
- Nutritional deficiency, severe
- Severe restriction of nutritional intake - despite extremely low body weight
- Glucose - low
- Starvation ketosis
- Physiological response for alternative energy supply
Case - starvation - 17 y female, depressed, stopped eating, lost weight and was weak
- Glucose maintained > 2.2 mmol/L at expense of protein to provide energy for RBCs which do not have mitochondria and require glucose for energy
- Brain requires some glucose for energy, but adapts to using ketones as can cross blood-brain barrier
- In liver FFA for energy and conversion to ketones
- Low glucose causes decline in insulin and increase in glucagon release resulting in degradation: glycogen, fat stores, protein
- To maintain glucose supply to cells without mitochondria: RBCs brain requires some glucose
- Brain adapts further to ketones for energy
- Muscles adapt to ketones and spare further protein breakdown
- Low insulin does not allow glucose uptake, ketones used
- High glucagon activate hormone sensitive lipase, breakdown of TG to FFA (Fat tissue)
What do low glucose levels result in
- Low glucose causes decline in insulin and increase in glucagon release
- Resulting in degradation: glycogen, fat stores, protein
What might serum analysis show in starvation
- Increased urea, ketones
- High urea indicates protein(muscle) breakdown and or AKI
- Ketones indicate use of an alternative energy supply from TG-FFA breakdown
Starvation case - treatment and prognosis
Rx: psychotherapy, antidepressants, diet 1800 cal
Survival time depends on fat stores
After depletion of fat stores
Only source energy is protein
Protein degradation accelerates
Death from loss of heart, liver or kidney function
Normal glucose metabolism
- Postprandial increase blood glucose
- Stimulates insulin release
- Insulin mediates glucose uptake into skeletal muscle, fat tissue
- Suppresses hepatic gluconeogenesis
Most common cause of ketoacidosis
Diabetes
Why does ketoacidosis occur in diabetes
The absence of insulin also leads to the release of free fatty acids from adipose tissue (lipolysis), which are converted through a process called beta oxidation, again in the liver, into ketone bodies (acetoacetate and β-hydroxybutyrate).
β-Hydroxybutyrate can serve as an energy source in the absence of insulin-mediated glucose delivery, and is a protective mechanism in case of starvation.
The ketone bodies, however, have a low pKa and therefore turn the blood acidic (metabolic acidosis)
Ketoacidosis
Glucose high, but cannot be utilised
Ketones alternative energy supply
Fasting ketosis
Alcoholic ketoacidosis
Alcoholic ketoacidosis; characterized by
hyperketonemia and metabolic acidosis without significant hyperglycemia
Especially if malnourished
Ethanol metabolised to acetic acid(ketone)
Noradrenaline & cortisol amplify fasting lipolysis (Trigs-FFA-ketones)
What is ketoacidosis stimulated by
- Liver production of ketones
- Stimulated by low insulin and high glucagon
- Secondary to low glucose - fasting, low carbohydrate diet, diabetes
- Lipase activated
- Fat stores - triglycerides - long chain fatty acids and glycerol
- Fatty acids transporter to liver
Fate of fatty acids in ketoacidosis
Ketones synthesis occurs in the Liver Fatty acids enter mitochondria Fatty acids oxidised to acetyl-CoA Either enter Krebs cycle generate ATP Generate ketones (Acetone, Acetoacetate, beta-hydroxybutyrate) FFA, cholesterol
What is depleted in the live in prolonged starvation
- Oxaloacetate is depleted in liver due to gluconeogenesis
- This impedes entry of acetyl-CoA into krebs cycle
- Acetyl-CoA in liver mitrochondria is then converted to ketone bodies, acetone, acetoacetate and beta-hydroxybutyrate
How is acetone produced
beta-hydroxybutyric acid –NAD+ -> NADH + H+ –> acetoacetic acid –> acetone
Fasting ketosis levels
Liver generation of ketones is the physiological response to fasting
Mild ketosis ~1mmol/L after 12h fast
Fasting for 20 days: 8 - 10mmol/L
β-hydroxy butyrate is major ketone
Synthesis matches utilization : in brain, muscle, kidney etc
s-bicarbonate falls by 7 - 8mmmol/L
Fasting ketosis stabilisation mechanisms
Stabilization:3 mechanisms:
Stimulation insulin release, despite low glucose
Increased sensitivity of adipose tissue to insulin inhibitory effect on fatty acid release
Direct inhibition of lipolysis by ketones
No adverse effects with fasting ketosis
Features of ketones
Water-soluble
Fat-derived fuel
Used when glucose low
Brain especially dependent when serum glucose levels low
Neurologic manifestations hypoglycemia plasma glucose
Nutritional support in critical illness
- Catabolism exceeds anabolism
- Carbs are preferred energy
- Fat mobilisation is impaired
- Protein administration to decrease breakdown of muscle protein
Hypermetabolic response to injury: trauma, surgical, critically ill
Increased blood pressure & heart rate Peripheral insulin resistance Increased protein and lipid catabolism Increased resting energy expenditure Increased body temperature Total body protein loss Muscle wasting Acute-phase protein response
Why are glucose levels raised in critical illness
Stress mediators oppose anabolic actions of insulin
Enhanced Adipose tissue lipolysis, Skeletal muscle proteolysis, Gluconeogenic substrates (glycerol, alanine, lactate) increased glucose production Suppressive effect of insulin on hepatic glucose release is attenuated
Other reasons why glucose levels raised in critical illness
High catecholamines, cortisol
Increased gluconeogenesis Catecholamines:
Enhance glycogen breakdown
Impair glucose disposal via alterations of the insulin-signaling pathway; & GLUT4 translocation in muscle & adipose tissue, resulting in peripheral insulin resistance
What is lean-muscle protein breakdown due to in illness
lean-muscle protein breakdown due to:
Pro-inflammatory cytokines: tumor necrosis factor (TNF)
Reduces ability to use lipids as energy
Skeletal muscle is major source of substrate for glucose production
What protects muscle reserves in starvation
In starvation, lipolysis & ketosis provide energy, protect muscle reserves
What causes insulin resistance in illness
Skeletal muscle is responsible for 75% of whole-body insulin-stimulated glucose uptake
Decreases in muscle contribute to this persistent insulin resistance
Effects of catecholamines after injury
Catecholamines initiate adipose tissue browning afterinjury, may facilitate hypermetabolic response & cachexia
Effects of loss of lean body mass
Increase in infection Delays wound healing Muscle weakness Prolongs mechanical ventilatory utilization Inhibits cough reflexes Delays mobilization Contributing to mortality
Starvation - endocrine complications
Hypothalamic-pituitary abnormalities-multiple
Suppression hypothalamic-pituitary-ovarian axis
Hypogonadotropic hypogonadism
Low GnRH, LH, FSH, estradiol
Amenorrhea, infertility
Due to energy deficit, low fat mass, leptin low
Bone loss - severe
Endocrine complications - adrenal
Increased hypothalamic-pituitary-adrenal activity
Stress of chronic starvation
High cortisol (glucocortcoid ):
Breakdown of protein (muscle, collagen) to glucose & urea
Loss of collagen: Osteopenia
Loss of muscle: Weakness
Endocrine complications - thyroid
Sick euthyroid pattern: TSH low-normal, FT4 low-normal, FT3 low Due to chronic undernutrition Decreased metabolic rate Decreased conversion FT4 to FT3 (low) TSH & FT4 levels: low normal or low Reduced metabolic rate
