What are the types of ketone bodies in human physiology, including endogenous and exogenous forms?

Types of Ketone Bodies

There are three types of ketone bodies in human physiology: β-hydroxybutyrate (β-OHB), acetoacetate (AcAc), and acetone. 1

The Three Ketone Bodies

1. Acetoacetate (AcAc)

• This is the first ketone body produced during hepatic ketogenesis from Acetyl-CoA through a series of enzymatic reactions 1
• Formed when HMG-CoA lyase catalyzes the conversion of HMG-CoA to acetoacetate plus acetyl-CoA 1
• Typically present in approximately equimolar amounts with β-hydroxybutyrate under normal conditions 1

2. β-Hydroxybutyrate (β-OHB or 3-Hydroxybutyrate)

• Produced when acetoacetate is reduced by NADH-dependent β-hydroxybutyrate dehydrogenase 1
• This is the most abundant and clinically important ketone body, serving as the primary energy substrate during ketosis 2, 3
• The equilibrium between AcAc and β-OHB shifts toward β-OHB formation in conditions that increase hepatic mitochondrial NADH concentrations, such as hypoxia, fasting, metabolic disorders (including DKA), and alcoholic ketoacidosis 1
• The β-OHB:AcAc ratio normally is 1:1 but can rise to as high as 10:1 in acute diabetic ketoacidosis 4

3. Acetone

• The third and least abundant ketone body, derived from spontaneous decarboxylation of acetoacetate 1
• This is a volatile ketone that is typically present in only small quantities 1
• Usually present in minimal amounts compared to the other two ketone bodies 4

Endogenous vs. Exogenous Forms

Endogenous Ketone Production

• Ketone bodies are produced mainly in the liver (ketogenesis) from fatty acids during carbohydrate restriction 1
• Production occurs during fasting, prolonged exercise, pregnancy, neonatal period, and when consuming a high-fat/ketogenic diet 5
• In physiological ketosis, levels typically range from 0.3 to 4 mmol/L 1, 6

Exogenous Ketones

• Recent evidence indicates that exogenous ketones can be administered therapeutically, particularly for treating the failing heart 7
• Some individuals following ketogenic diets may supplement with exogenous ketone bodies 2

Critical Clinical Distinction: Physiological vs. Pathological Ketosis

Physiological ketosis (as described by Hans Krebs in 1966):

• Normal pH 1, 6
• Low but physiological insulin levels 1, 6
• Normal blood glucose 1, 6
• Ketone body levels: 0.3-4 mmol/L 1, 6

Pathological ketosis (e.g., decompensated diabetes):

• Low systemic pH 1, 6
• No insulin 1, 6
• Hyperglycemia 1, 6
• Very high ketone body levels: >7-8 mmol/L 1, 6

Important Measurement Caveat

Assay methods that do not include measurement of β-hydroxybutyrate may provide misleading clinical information by underestimating total ketone body concentration, particularly since the β-OHB:AcAc ratio can shift dramatically in various metabolic states 1. The frequently employed nitroprusside test only detects acetoacetate in blood and urine, missing the most abundant ketone body (β-OHB) 4.