Ketone Bodies - Biochemistry - Medbullets Step 1

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