Ketones

🧪 Ketones (ketone bodies) are small, water-soluble molecules produced mainly by the liver during periods of low carbohydrate availability or relative insulin deficiency. They act as an important alternative fuel when glucose use is limited, particularly for the brain, myocardium, and skeletal muscle. The three physiologically relevant ketone bodies are acetoacetate, β-hydroxybutyrate, and acetone.

🧠 What are ketones?

Ketones are a normal metabolic adaptation to fasting and reduced carbohydrate supply. They allow the body to continue generating energy when glycogen stores are depleted or when insulin levels are too low to permit normal glucose utilisation. Of the three ketone bodies, β-hydroxybutyrate is the main circulating ketone measured in blood and is the most clinically useful marker when assessing for diabetic ketoacidosis (DKA). :contentReference[oaicite:1]{index=1}

⚙️ How ketones are produced (ketogenesis)

Ketogenesis occurs in the mitochondria of hepatocytes. When insulin levels fall and counter-regulatory hormones such as glucagon, catecholamines, and cortisol rise, adipose tissue lipolysis increases. This releases free fatty acids, which are transported to the liver and undergo β-oxidation to generate acetyl-CoA. When acetyl-CoA production exceeds the capacity of the TCA cycle — often because oxaloacetate is being diverted toward gluconeogenesis — excess acetyl-CoA is shunted into ketone body synthesis.

• ⬇️ Low insulin or relative insulin deficiency increases lipolysis
• 🧈 Free fatty acids are released from adipose tissue and transported to the liver
• 🔥 β-oxidation generates large amounts of acetyl-CoA
• 🧪 Excess acetyl-CoA is converted into acetoacetate and β-hydroxybutyrate
• 💨 A small proportion of acetoacetate breaks down into acetone, which contributes to the characteristic fruity breath smell in ketosis

🔬 Why β-hydroxybutyrate matters clinically

Although people often refer to “ketones” generically, the dominant circulating ketone in significant ketosis is usually β-hydroxybutyrate. Standard urine dipsticks detect mainly acetoacetate, so they can lag behind the true metabolic state and may not reflect real-time severity as accurately as a capillary blood ketone measurement. This is why UK guidance prefers blood ketone testing when assessing possible DKA. :contentReference[oaicite:2]{index=2}

🫀 Physiological role of ketones

Ketones are a normal adaptive response to fasting, starvation, prolonged exercise, and carbohydrate restriction. After roughly 24–72 hours of fasting, the brain increasingly uses ketones as fuel, reducing its reliance on glucose and helping to limit muscle breakdown for gluconeogenesis. Ketones cross the blood–brain barrier via monocarboxylate transporters, which is why they become such an important emergency fuel during prolonged fasting.

• 🍽️ Provide energy during fasting, starvation, and prolonged exercise
• 🛡️ Help spare glucose and reduce muscle catabolism
• 🧠 Become an increasingly important fuel for the brain during prolonged fasting
• ❤️ Are also efficiently used by the heart and skeletal muscle

⚠️ Physiological ketosis vs pathological ketoacidosis

This distinction is crucial. Physiological ketosis occurs in fasting, low-carbohydrate intake, or prolonged exercise and is usually mild, with preserved acid–base balance. Ketoacidosis occurs when ketone production becomes excessive and overwhelms buffering capacity, causing a high anion gap metabolic acidosis. In diabetes, this usually reflects absolute or severe relative insulin deficiency, especially in type 1 diabetes, but it can also occur in type 2 diabetes under major stress or with SGLT2 inhibitor use. :contentReference[oaicite:3]{index=3}

🧪 Interpreting ketone levels in UK practice

Ketone results must always be interpreted alongside the patient’s glucose, venous pH, bicarbonate, clinical hydration status, and overall physiology. A mildly elevated ketone level in a fasting person is very different from the same ketone level in an unwell person with hyperglycaemia, vomiting, tachypnoea, and dehydration. Blood ketones are preferred because they reflect active ketogenesis more accurately than urine ketones. :contentReference[oaicite:4]{index=4}

✅ Normal ketone levels

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

These values are considered normal and are commonly seen in the fed state. Even during short fasting or minor intercurrent illness, ketones may remain below this threshold and are not usually associated with significant acidosis. :contentReference[oaicite:5]{index=5}

🟡 Mildly raised ketones

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

This range suggests increased fat metabolism and may occur with fasting, vomiting, reduced oral intake, intercurrent illness, or early insulin deficiency. In a person with diabetes, this should prompt closer review, hydration, and consideration of whether insulin delivery is inadequate. NHS advice describes this range as slightly high, with repeat testing advised. :contentReference[oaicite:6]{index=6}

🟠 Ketones suggesting increased risk of DKA

• Blood ketones: 1.6–3.0 mmol/L
• Urine ketones: often ++

This level suggests a clinically important degree of ketogenesis and should raise concern in anyone with diabetes, particularly if accompanied by rising glucose, nausea, abdominal pain, or dehydration. NHS patient guidance advises urgent contact with the diabetes team in this range because it may represent evolving DKA. :contentReference[oaicite:7]{index=7}

🔴 High ketones — strongly suggestive of DKA

• Blood ketones: ≥ 3.0 mmol/L
• Urine ketones: typically ++ to +++ or more

In UK guidance, blood ketones ≥3.0 mmol/L are a key biochemical threshold for suspected DKA, especially when accompanied by hyperglycaemia and metabolic acidosis. In adults, DKA is commonly diagnosed when all three are present: glucose ≥11 mmol/L, ketones ≥3.0 mmol/L, and venous pH ≤7.3 and/or bicarbonate ≤15 mmol/L. However, lower ketone levels do not completely exclude DKA if the clinical picture is concerning. :contentReference[oaicite:8]{index=8}

🫁 Why ketones cause acidosis

Acetoacetate and β-hydroxybutyrate are organic acids. When they accumulate rapidly, bicarbonate is consumed buffering the acid load, producing a metabolic acidosis. The patient then develops compensatory hyperventilation to lower CO₂, which is why tachypnoea or deep “air-hunger” breathing can be such an important bedside clue in DKA. This is also why ketone values must never be interpreted in isolation from the blood gas. :contentReference[oaicite:9]{index=9}

🩺 Clinical interpretation tip

Ketones alone do not diagnose DKA. A patient with blood ketones of 1.0 mmol/L after vomiting and poor oral intake may simply have starvation ketosis, whereas a patient with blood ketones ≥3.0 mmol/L, hyperglycaemia, dehydration, abdominal pain, and tachypnoea may have life-threatening DKA. The real question is not “are ketones present?” but rather “is there clinically significant ketonaemia with acidosis and insulin deficiency?”

🚨 Important caveat — euglycaemic DKA

DKA can occasionally occur with a normal or only modestly raised glucose, particularly with SGLT2 inhibitors, pregnancy, prolonged starvation, or partial treatment before presentation. NICE CKS specifically notes that ketones should be checked even if glucose is near normal when DKA is suspected. This is a very important clinical trap. :contentReference[oaicite:10]{index=10}

🧒 Paediatric note

UK paediatric guidance uses a very similar biochemical definition: ketones >3.0 mmol/L with pH <7.3 or bicarbonate <15 mmol/L, alongside hyperglycaemia. The principles of interpretation are therefore similar in children, although management pathways differ and paediatric protocols should be followed. :contentReference[oaicite:11]{index=11}

🎓 Exam pearls

• β-hydroxybutyrate is the main blood ketone measured in clinical practice
• Blood ketones are preferred over urine ketones for suspected DKA
• <0.6 mmol/L is normal
• 0.6–1.5 mmol/L = mildly raised / early warning zone
• 1.6–3.0 mmol/L = increased risk of DKA
• ≥3.0 mmol/L = strong concern for DKA, especially with acidosis
• Ketones alone do not diagnose DKA — always check pH and bicarbonate
• Think about euglycaemic DKA if the patient looks acidotic but glucose is not massively elevated