What does an elevated beta-hydroxybutyrate (BHB) level indicate?

Elevated Beta-Hydroxybutyrate: Clinical Significance and Interpretation

Elevated beta-hydroxybutyrate (BHB) primarily indicates ketosis, which can range from physiological ketosis to pathological diabetic ketoacidosis (DKA), with levels above 1.5 mmol/L strongly suggesting DKA when accompanied by hyperglycemia and acidosis.

Diabetic Ketoacidosis

• Beta-hydroxybutyrate is the predominant ketone body in diabetic ketoacidosis (DKA), which results from absolute or relative insulin deficiency leading to fat breakdown and ketone formation 1
• DKA is characterized by the triad of hyperglycemia, increased blood ketones (particularly BHB), and metabolic acidosis with increased anion gap 1
• BHB levels ≥1.5 mmol/L, when accompanied by hyperglycemia and acidosis, are diagnostic of DKA 1
• Caution is needed even with BHB levels ≥0.6 mmol/L in patients with diabetes, as this may indicate early ketosis 1

Interpretation of BHB Levels

• <0.6 mmol/L: Normal range
• 0.6-1.5 mmol/L: Mild to moderate ketosis, requires monitoring and possible intervention 1

• 1.5 mmol/L: Significant ketosis, high risk for DKA when accompanied by hyperglycemia and acidosis 1

• 5.3 mmol/L: Optimal cutoff for predicting DKA with 90.6% accuracy in pediatric patients 2

Clinical Scenarios Associated with Elevated BHB

1. Diabetes-Related Conditions

• Type 1 diabetes with insulin deficiency 1
• Type 2 diabetes during severe illness or stress 1
• Patients using SGLT2 inhibitors (can develop DKA even with normal or only mildly elevated blood glucose - "euglycemic DKA") 1, 3
• Each 0.1 mmol/L increase in baseline BHB increases DKA risk by 18%, independent of treatment 3

2. Physiological Ketosis

• Prolonged fasting or starvation 1, 4
• Ketogenic diet (therapeutic levels often >2 mmol/L) 5
• Post-exercise state, particularly after intense or prolonged exercise 1
• Pregnancy (up to 30% of pregnant women may have positive ketones in first morning urine) 1

3. Other Pathological Conditions

• Alcoholic ketoacidosis (elevated BHB without hyperglycemia) 1
• Glycogen storage disorders (elevated during fasting) 1
• Severe illness with decreased oral intake 1

Clinical Applications of BHB Measurement

• BHB is superior to urine ketone testing for diagnosing and monitoring DKA 1, 2
• Blood ketone determinations that rely on the nitroprusside reaction should not be used to monitor DKA treatment as they don't quantify BHB specifically 1
• Direct BHB measurement is recommended for:
  • Diagnosing DKA in emergency settings 2
  • Monitoring response to DKA treatment 1
  • Risk assessment in patients using SGLT2 inhibitors 1, 3
  • Evaluating ketosis in patients on ketogenic diets 5

Special Considerations

• In patients with type 1 diabetes, intense physical activity should be postponed when BHB ≥1.5 mmol/L due to risk of worsening ketosis 1
• For patients on ketogenic diets for seizure control, BHB levels >4 mmol/L correlate with better seizure control 5
• Emerging research suggests BHB may function as an epigenetic modifier and signaling molecule beyond its role in energy metabolism 6, 4
• BHB can form conjugates with amino acids (BHB-amino acids) that may have metabolic effects including appetite suppression 6

Monitoring Recommendations

• Patients at risk for DKA (type 1 diabetes, history of DKA, SGLT2 inhibitor use) should measure BHB when:
  • Blood glucose is persistently elevated (>250 mg/dL) 1
  • During illness, especially with nausea, vomiting, or abdominal pain 1
  • When symptoms of ketosis appear, even if blood glucose is not markedly elevated (especially with SGLT2 inhibitor use) 1