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Updated: Mar 18 2021

Ketone Bodies

  • 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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