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About the book: Golwalla's Medicine for Students (25th Edition) by Aspi F. Golwalla and Sharukh A. Golwalla, edited by Milind Y. Nadkar, is a long-standing reference for Indian medical students and family physicians. It covers internal medicine comprehensively and is published by Jaypee Brothers Medical Publishers, New Delhi.

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Explain about ketone bodies

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Ketone Bodies

What Are Ketone Bodies?

Ketone bodies are three water-soluble compounds produced in the liver mitochondria from acetyl-CoA derived primarily from fatty acid oxidation. The three ketone bodies are:

Compound	Notes
Acetoacetate	Primary ketone body; a functional energy substrate
3-Hydroxybutyrate (β-hydroxybutyrate)	Most abundant in blood (~75%); also an energy substrate
Acetone	Formed by spontaneous decarboxylation of acetoacetate; volatile, excreted via lungs, not metabolically useful

Note: Despite the name, acetoacetate and 3-hydroxybutyrate are organic acids, not true ketones in the chemical sense.

Lippincott's Illustrated Reviews: Biochemistry, 8th ed, p. 555
Basic Medical Biochemistry: A Clinical Approach, 6th ed, p. 1097

Why Are Ketone Bodies Made?

The liver produces ketone bodies when acetyl-CoA accumulates faster than it can enter the TCA cycle. This happens when:

Fasting/starvation - fatty acids flood the liver; OAA is diverted to gluconeogenesis, so acetyl-CoA cannot condense with OAA to enter the TCA cycle
Uncontrolled diabetes mellitus - lack of insulin causes unopposed lipolysis and massive fatty acid delivery to the liver
High-fat, low-carbohydrate diet - reduced glucose metabolism limits OAA availability

The decreased NAD+/NADH ratio (from active fatty acid oxidation) further shifts OAA toward malate, reducing acetyl-CoA entry into the TCA cycle and forcing ketogenesis. - Ganong's Review of Medical Physiology, 26th ed, p. 37

Synthesis of Ketone Bodies (Ketogenesis) - Liver Only

Ketogenesis occurs exclusively in liver mitochondria. Here is the step-by-step pathway:

Step 1: Two acetyl-CoA molecules condense (via thiolase, reverse of β-oxidation thiolase reaction) to form acetoacetyl-CoA

Step 2: Acetoacetyl-CoA + acetyl-CoA → HMG-CoA (3-hydroxy-3-methylglutaryl-CoA)

Enzyme: HMG-CoA synthase (mitochondrial)
This is the rate-limiting step of ketogenesis
HMG-CoA synthase is found in significant quantity only in the liver

Step 3: HMG-CoA is cleaved by HMG-CoA lyase → acetoacetate + acetyl-CoA

Step 4 (from acetoacetate):

Reduced by β-hydroxybutyrate dehydrogenase (using NADH) → 3-hydroxybutyrate
OR spontaneously decarboxylated → acetone + CO₂

Ketone body synthesis pathway - Lippincott

Figure: Ketogenesis pathway from 2 Acetyl-CoA to acetoacetate, 3-hydroxybutyrate, and acetone (Lippincott's Biochemistry, 8th ed)

The ratio of 3-hydroxybutyrate : acetoacetate is normally ~3:1 and is determined by the NADH/NAD+ ratio in the mitochondrial matrix. During heavy fatty acid oxidation, the high NADH level favors 3-hydroxybutyrate formation.

Why Can't the Liver Use Its Own Ketone Bodies?

The liver produces ketone bodies but cannot use them for energy because it lacks the enzyme thiophorase (succinyl-CoA:acetoacetate CoA transferase), which is required for the first step of ketolysis. - Lippincott's Biochemistry, 8th ed, p. 558

Utilization of Ketone Bodies (Ketolysis) - Peripheral Tissues

Extrahepatic tissues (skeletal muscle, cardiac muscle, renal cortex, intestinal mucosa, and even the brain during prolonged starvation) utilize ketone bodies as follows:

Step 1: 3-Hydroxybutyrate → acetoacetate (by 3-hydroxybutyrate dehydrogenase, producing NADH)

Step 2: Acetoacetate + succinyl-CoA → acetoacetyl-CoA + succinate (by thiophorase)

This "activates" acetoacetate by borrowing CoA from succinyl-CoA (TCA cycle intermediate)

Step 3: Acetoacetyl-CoA → 2 acetyl-CoA (by thiolase)

Step 4: Acetyl-CoA enters the TCA cycle → ATP generation

Formation and metabolism of ketone bodies - Ganong's

Figure: Formation and peripheral utilization of ketone bodies (Ganong's Review, 26th ed)

Cannot use ketone bodies: Red blood cells (no mitochondria) and the liver (no thiophorase).

Physiological Importance

State	Blood ketone level	Role
Well-fed	~1 mg/dL	Negligible
Overnight fast	~1-3 mg/dL	Minor energy supplement
Prolonged fasting (>3 days)	Up to 6-8 mg/dL	Major fuel for brain and muscle, sparing glucose and protein
Diabetic ketoacidosis	Up to 90 mg/dL	Pathological

Key advantages of ketone bodies as fuel:

Water-soluble, so they travel freely in plasma without needing lipoproteins or albumin
Cross the blood-brain barrier and supply energy to the brain when glucose is scarce
Spare glucose (anti-gluconeogenic), protecting muscle protein from being broken down
Lippincott's Biochemistry, 8th ed, p. 555

Pathology: Ketoacidosis

When ketone body production exceeds tissue utilization, they accumulate:

Ketonemia - elevated ketones in blood
Ketonuria - ketones spilled into urine
Ketoacidosis - acetoacetate and 3-hydroxybutyrate are moderately strong acids (pKa ~4); they release H+ in blood, lowering pH and causing metabolic acidosis

Three main causes:

Diabetic ketoacidosis (DKA) - uncontrolled Type 1 DM; blood ketones can reach 90 mg/dL; accompanied by dehydration from glucose/ketone loss in urine
Starvation ketoacidosis - prolonged fasting
Alcoholic ketoacidosis - excessive ethanol consumption

Key clinical sign: Fruity/acetone breath from exhaled acetone.

Treatment concept: Small amounts of IV glucose abolish ketosis because glucose restores OAA availability, allowing acetyl-CoA to re-enter the TCA cycle. This is why carbohydrate is called "antiketogenic." - Ganong's Review of Medical Physiology, 26th ed, p. 38

Summary Diagram of Ketone Body Metabolism

Adipose tissue
      ↓ (fasting/low insulin)
  Fatty acids → liver
      ↓ β-oxidation
  Acetyl-CoA
      ↓ (OAA low → can't enter TCA cycle)
  Acetoacetyl-CoA → HMG-CoA → Acetoacetate
                                    ↙         ↘
                    3-Hydroxybutyrate      Acetone (breath)
                           ↓ (in peripheral tissues)
                      Acetyl-CoA → TCA cycle → ATP

Sources:

Lippincott's Illustrated Reviews: Biochemistry, 8th ed, Chapter 16 (pp. 555-559)
Basic Medical Biochemistry: A Clinical Approach, 6th ed, Chapter 30 (pp. 1097-1102)
Ganong's Review of Medical Physiology, 26th ed, pp. 37-38

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