Updated: 3/18/2021

Ketone Bodies

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Overview
  •  Structure
    • two types
      • acetoacetate
      • β-hydroxybutyrate
        • β-hydroxybutyrate + NAD+ → acetoacetate + NADH
        • ↑ NADH:NAD+ ratio results in ↑ β-hydroxybutyrate:acetoacetate ratio 
    • 1 ketone body = 2 acetyl-CoA
  • Function
    • produced by the liver
      • brain can use ketones if glucose supplies fall
        • >1 week of fasting
    • can provide energy to body in prolonged energy needs
      • prolonged starvation
        • glycogen and gluconeogenic substrates are exhausted
    • can provide energy if citric acid cycle unable to function
      • diabetic ketoacidosis
        • cycle component (oxaloacetate) consumed for gluconeogenesis
      • alcoholism
        • ethanol dehydrogenase consumes NAD+ (converts to NADH)
        • ↑ NADH:NAD+ ratio in liver reduces pyruvate and oxaloacetate levels available for gluconeogenesis (both are products of reactions where NAD+ is required for as cofactor)
    • RBCs cannot use ketones as they lack mitochondria
  • Synthesis
    • occurs in hepatocyte mitochondria
      • liver cannot use ketones as energy
        • lacks β-ketoacyl-CoA transferase (thiophorase) which converts acetoacetate to acetoacetyl
    • under normal conditions acetoacetate = β-hydroxybutyrate
    • HMG CoA synthase is rate limiting enzyme
  • Clinical relevance
    • ketoacidosis
      • pathogenesis
        • ↑ ketone levels
        • caused by
          • poorly controlled type I diabetes mellitus
            • liver ketone production exceeds ketone consumption in periphery
          • possible in type II diabetes mellitus but rare
          • alcoholism
            • chronic hypoglycemia results in ↑ ketone production
      • presentation
        • β-hydroxybutyrate > acetoacetate
          • due to ↑ NADH:NAD+ ratio
        • acetone gives breath a fruity odor
        • polyuria
        • ↑ thirst
      • tests
        • ↓ plasma HCO3
        • hypokalemia
          • individuals are initially hyperkalemic (lack of insulin + acidosis) because K leaves the cells
          • overall though the total body K is depleted
            • glucosuria results in osmotic diuresis, K+ loss
            • replete K in these patients once the hyperkalemia begins to correct
        • nitroprusside urine test for ketones may not be strongly +
          • does not detect β-hydroxybutyrate
            • state favored by ↑ NADH:NAD+ ratio
          • should use a test specific for β-hydroxybutyrate

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