Makindo Medical Notes

Ketones

Ketones (or ketone bodies) are small, water-soluble molecules produced by the liver during periods of low carbohydrate availability. They act as an alternative energy substrate and useful alternative fuel when glucose supply is reduced, particularly for the brain, myocardium, and skeletal muscle. The three physiologically relevant ketone bodies are acetoacetate, β-hydroxybutyrate, and acetone.

How ketones are produced (ketogenesis)

Ketogenesis occurs in hepatic mitochondria when insulin levels are low and counter-regulatory hormones (glucagon, cortisol, catecholamines) are high. Increased lipolysis releases free fatty acids, which undergo β-oxidation to acetyl-CoA. When acetyl-CoA exceeds the capacity of the TCA cycle (often due to oxaloacetate depletion), it is diverted into ketone body synthesis.

• Low insulin → increased lipolysis in adipose tissue
• Free fatty acids transported to the liver
• β-oxidation generates excess acetyl-CoA
• Acetyl-CoA converted into ketone bodies

Physiological role of ketones

Ketones are a normal and adaptive response to fasting, prolonged exercise, and carbohydrate restriction. After 24–72 hours of fasting, the brain increasingly relies on ketones, reducing its dependence on glucose and limiting muscle protein breakdown for gluconeogenesis. Importantly, ketones cross the blood–brain barrier via monocarboxylate transporters.

• Provide energy during fasting and starvation
• Spare glucose and reduce muscle catabolism
• Efficient fuel for brain and heart

Normal and raised ketone levels – interpreting risk of DKA 🧪

Ketone levels must always be interpreted alongside glucose, pH, bicarbonate, and the clinical picture. In UK practice, blood ketones (β-hydroxybutyrate) are preferred because they reflect real-time ketogenesis and correlate with severity of metabolic decompensation.

Normal ketone levels

• Blood ketones: < 0.6 mmol/L
• Urine ketones: Negative or trace

These levels are considered physiological and are commonly seen in the fed state. Even in short fasting or overnight illness, values usually remain below this threshold and are not associated with acidosis.

Raised ketones – early warning zone

• Blood ketones: 0.6–1.5 mmol/L
• Urine ketones: + or ++

This range suggests increased fat metabolism and may be seen with fasting, intercurrent illness, vomiting, or reduced carbohydrate intake. In people with diabetes, this should prompt increased monitoring, hydration, and review of insulin, as it may represent evolving insulin deficiency.

High ketones – suggestive of DKA

• Blood ketones: ≥ 3.0 mmol/L (diagnostic threshold for DKA in UK guidelines)
• Urine ketones: ++ to +++

Blood ketones at or above 3.0 mmol/L strongly suggest diabetic ketoacidosis when accompanied by hyperglycaemia and metabolic acidosis (pH < 7.3 and/or bicarbonate < 15 mmol/L). At this level, ketone production has overwhelmed buffering capacity, leading to acidemia and systemic illness.

Clinical interpretation tip 💡

Ketones alone do not diagnose DKA. A patient with mild ketonaemia and normal pH is very different from a patient with ketones ≥ 3.0 mmol/L, rising glucose, dehydration, and tachypnoea. Always integrate ketone levels with acid–base status and overall physiology before escalating treatment.