Blood Ketones (Beta-Hydroxybutyrate)

Ketones are produced in the liver from fatty acids when insulin is low and counter regulatory hormones are high. The main circulating ketone is beta hydroxybutyrate (BHB), which makes up about 70 to 80% of ketone bodies in ketosis. Acetoacetate makes up most of the remainder, and acetone is a minor volatile product. In a state of marked ketosis, the BHB to acetoacetate ratio rises, up to 10 to 1 in diabetic ketoacidosis and higher in alcoholic ketoacidosis.

Blood BHB is measured at the bedside with a meter (a dehydrogenase enzyme method) or in the laboratory, and reported in mmol/L. It quantifies ketosis directly, unlike the nitroprusside urine strip, which detects acetoacetate and acetone only.

Diabetic ketoacidosis occurs in 1 to 5% of people with type 1 diabetes each year, remains a leading cause of death in young people with diabetes, and has an inpatient mortality of about 1 to 5%. Euglycaemic ketoacidosis has become more frequent with sodium-glucose cotransporter 2 inhibitors.

Indications. Hyperglycaemia in type 1 diabetes, nausea and vomiting or abdominal pain in a person with diabetes, illness or insulin pump failure, suspected diabetic ketoacidosis, monitoring during treatment, high anion gap acidosis of unknown cause, alcohol dependence with vomiting, patients on sodium-glucose cotransporter 2 inhibitors who are acutely unwell, hypoglycaemia in children, and ketogenic diet monitoring.

Specimen. Capillary blood on a meter strip, venous blood in serum or fluoride oxalate, or a blood gas analyser with a BHB electrode. Point-of-care meters are accurate to about 3 mmol/L and less accurate over 6 mmol/L. Analyse promptly.

Reference range. Under 0.6 mmol/L.

Interpretation bands for BHB.

• Under 0.6 mmol/L: normal.
• 0.6 to 1.5 mmol/L: ketosis from fasting, low carbohydrate intake, exercise, vomiting, pregnancy, or early insulin deficiency.
• 1.5 to 3.0 mmol/L: high risk of ketoacidosis, and clinical review is needed.
• Over 3.0 mmol/L: ketoacidosis is likely, especially with hyperglycaemia and acidosis.
• Over 6.0 mmol/L: severe ketoacidosis, and the meter becomes unreliable.

Diabetic ketoacidosis. Defined by three features: hyperglycaemia (glucose over 11 mmol/L or known diabetes), ketonaemia (BHB 3.0 mmol/L or more, or 2+ ketonuria), and acidosis (pH under 7.30 or bicarbonate under 15 mmol/L). Severity by pH: mild 7.25 to 7.30, moderate 7.00 to 7.24, severe under 7.00. A high anion gap is the usual marker. Euglycaemic ketoacidosis is the same but with a glucose under 11 mmol/L.

Monitoring during treatment. Aim to reduce BHB by at least 0.5 mmol/L each hour and glucose by 3 mmol/L each hour. Resolution is BHB under 0.6 mmol/L and pH over 7.30. Venous bicarbonate and pH are used, and anion gap normalisation confirms resolution. Failure of BHB to fall suggests inadequate insulin dose, an infusion problem or ongoing precipitant.

Causes of ketosis and ketoacidosis.

• Insulin deficiency: type 1 diabetes, new onset, omitted insulin, pump failure, infection, myocardial infarction, stroke, pancreatitis, and drugs (corticosteroids, antipsychotics, immune checkpoint inhibitors).
• Sodium-glucose cotransporter 2 inhibitors: ketoacidosis with normal or only mildly raised glucose, triggered by illness, surgery, fasting, alcohol and low carbohydrate intake.
• Alcoholic ketoacidosis: heavy drinking, vomiting and poor intake, low or normal glucose, high BHB and a high anion gap acidosis.
• Starvation and very low carbohydrate diets: BHB up to 3 to 5 mmol/L with normal pH.
• Pregnancy: ketosis develops quickly with vomiting or fasting, even at low glucose.
• Children: ketotic hypoglycaemia (idiopathic, usually in children 2 to 6 years), inborn errors of metabolism, and gastroenteritis.
• Other: salicylate poisoning, prolonged vomiting, isopropanol, and neonates with organic acidaemias.

Hyperosmolar hyperglycaemic state. Marked hyperglycaemia (over 30 mmol/L), osmolality over 320 mOsm/kg, and little or no ketosis (BHB under 3 mmol/L).

Urine ketones. The nitroprusside reaction detects acetoacetate (and acetone weakly) but not BHB. Urine strips are semi-quantitative. In early treatment, BHB converts to acetoacetate and urine ketones can appear to worsen as ketoacidosis improves.

Critical values and findings needing immediate action.

• BHB 3.0 mmol/L or more in a person with diabetes or hyperglycaemia, or any BHB over 1.5 mmol/L with vomiting.
• pH under 7.30, bicarbonate under 15 mmol/L or a high anion gap with ketones.
• Ketones with drowsiness, Kussmaul breathing, dehydration, or abdominal pain.
• Ketonaemia with normal glucose in a patient on a sodium-glucose cotransporter 2 inhibitor.
• Potassium under 3.3 mmol/L, or over 6.0 mmol/L at presentation, before insulin is given.

Interferences and pitfalls.

• Urine nitroprusside strips underestimate ketosis in alcoholic ketoacidosis and in states where BHB predominates. They also give false positives with drugs that contain sulfhydryl groups (captopril, mesna) and false negatives with old or degraded strips.
• Meters are less accurate over 6 mmol/L and in extreme haematocrit, and high concentrations of ascorbic acid or paracetamol may interfere with some meters.
• Poor perfusion and cold hands lower capillary accuracy.
• Ketosis without acidosis is not diabetic ketoacidosis, and fasting or a low carbohydrate diet can give BHB of 1 to 3 mmol/L.
• Glucose may be normal in ketoacidosis from sodium-glucose cotransporter 2 inhibitors, in pregnancy and in alcoholic ketoacidosis.
• Lactate, salicylates and toxic alcohols should be excluded when the anion gap is higher than the ketones explain.

Special groups.

• Children: diabetic ketoacidosis presents with vomiting and abdominal pain, and cerebral oedema is a risk during treatment.
• Pregnancy: ketoacidosis occurs at lower glucose and threatens the foetus.
• Older adults: infection, myocardial infarction and stroke are common precipitants.
• Insulin pump users: ketoacidosis develops within 3 to 5 hours of failure, since there is no depot.
• Regions: new onset type 1 diabetes often presents late with ketoacidosis in settings with limited access to care.

Follow up tests. Venous blood gas, glucose, urea and electrolytes, anion gap, phosphate and magnesium, osmolality, full blood count, C-reactive protein, blood and urine cultures, ECG, troponin, lipase, HbA1c, pregnancy test, and toxicology screen when the cause is not clear.