STEPTRACKERBIOCHEMISTRY + ENDOCRINOLOGY | LIPID METABOLISM | HIGH-YIELD REVIEW

Ketone Bodies

When oxaloacetate runs low and acetyl-CoA piles up, the liver makes ketones for the brain and muscle — useful in starvation, dangerous in DKA.

FOCUS ON
Made in liver mitochondria: acetyl-CoA → HMG-CoA (HMG-CoA synthase, rate-limiting) → acetoacetate → β-hydroxybutyrate (NADH) or acetone (breath). Used by brain, heart, muscle, kidney via succinyl-CoA:acetoacetate CoA transferase (thiophorase) — absent in liver; RBCs can't (no mitochondria). Triggers: DKA, starvation, alcohol. Urine nitroprusside detects acetoacetate, not β-HB.
TOPIC
MECHANISM
FINDINGS
CLUE
Why ketones form
OAA diverted to gluconeogenesis (fasting) → acetyl-CoA can't enter TCA → ketogenesis
Insulin ↓, glucagon ↑, FFA flux ↑
"Fats burn in the flame of carbohydrates"
HMG-CoA synthase
rate-limiting
Acetyl-CoA + acetoacetyl-CoA → HMG-CoA (mitochondria)
HMG-CoA lyase → acetoacetate
Cholesterol uses cytosolic HMG-CoA (reductase)
Ketone use
Acetoacetate → acetoacetyl-CoA (thiophorase) → 2 acetyl-CoA → TCA
Brain (after days), heart, muscle, renal cortex
Liver lacks thiophorase · RBCs lack mitochondria
Diabetic ketoacidosis
No insulin → lipolysis, ketogenesis, gluconeogenesis unchecked
Glucose > 250, anion gap acidosis, Kussmaul breathing, fruity breath, vomiting, abdominal pain, dehydration; total K⁺ depleted despite high serum K⁺
Fluids, insulin (with K⁺), find trigger (infection, missed insulin)
Starvation ketosis
Low insulin, adaptive
Mild ketosis, normal/low glucose, mild acidosis at most
Brain gets up to ⅔ of energy from ketones
Alcoholic ketoacidosis
↑ NADH → acetoacetate shifted to β-hydroxybutyrate; poor intake
Anion gap acidosis, glucose normal/low, history of binge + vomiting
Nitroprusside test may be falsely low (mostly β-HB)
SGLT2 inhibitor euglycemic DKA
Glucose lost in urine → low insulin dosing → ketosis with near-normal glucose
DKA with glucose < 250
Empagliflozin, dapagliflozin
Ketone detection
Nitroprusside (urine/serum) detects acetoacetate (and acetone); β-HB assay is direct
Ratio β-HB : AcAc ~3:1 in DKA, higher with alcohol
Measure serum β-HB to follow DKA
Ketogenic amino acids
Leucine and lysine → acetyl-CoA/acetoacetyl-CoA only
Can't make glucose
Used in PDH deficiency diet

Mechanism — the ketone pathway

FFA → β-oxidationLiver mitochondria
→
Acetyl-CoA excess(OAA used for glucose)
→
HMG-CoA synthase
→
Acetoacetate→ β-HB (NADH) / acetone
→
Blood → brain, muscle, heartThiophorase → acetyl-CoA

Three causes of ketoacidosis

FEATURE
DKA
ALCOHOLIC
STARVATION
Glucose
High
Normal/low
Normal/low
Acidosis
Severe
Moderate
Mild
Dominant ketone
β-HB
β-HB (more)
β-HB
Insulin
Absent
Low
Low

How it's tested

COMMON CONFUSIONThe liver makes ketones but cannot use them; the brain cannot burn fatty acids but can use ketones.
THE TRAPSerum K⁺ is often high in DKA (shift out of cells), but total body K⁺ is depleted — insulin will drop it fast.
YOUR APPROACHAnion gap acidosis + ketones → check glucose (DKA vs AKA vs starvation) → drugs (SGLT2) → treat accordingly.

If you see… think…

Rate-limiting enzyme of ketogenesis → HMG-CoA synthase
Fruity breath, Kussmaul breathing, glucose 500 → DKA
Ketone causing fruity breath → acetone
Ketone missed by the nitroprusside test → β-hydroxybutyrate
Organ that makes but can't use ketones → liver (no thiophorase)
Cells unable to use ketones at all → RBCs
Binge drinker with anion gap acidosis, normal glucose → alcoholic ketoacidosis
DKA with glucose 190 on an SGLT2 inhibitor → euglycemic DKA
Brain fuel after a week of fasting → ketones
Why ketogenesis starts in fasting → OAA diverted to gluconeogenesis