Causes of Elevated Beta-Hydroxybutyrate
Elevated beta-hydroxybutyrate (BHB) is most commonly caused by diabetic ketoacidosis (DKA) in patients with diabetes, but also occurs in alcoholic ketoacidosis, starvation/fasting states, ketogenic diets, and SGLT2 inhibitor use.
Pathological Causes (Most Clinically Significant)
Diabetic Ketoacidosis (DKA)
- BHB levels ≥1.5 mmol/L accompanied by hyperglycemia and acidosis are diagnostic of DKA, representing the most critical cause requiring immediate intervention 1
- Type 1 diabetes with absolute insulin deficiency is the classic setting, particularly in new-onset diabetes, insulin omission, or during infection 2
- Type 2 diabetes during severe illness or stress can precipitate DKA when insulin secretory capacity becomes overwhelmed 2
- BHB levels in DKA typically reach 7-8 mmol/L or higher, reflecting profound metabolic derangement 2
Alcoholic Ketoacidosis (AKA)
- AKA produces high BHB levels (median 500 mg/L or approximately 4.8 mmol/L) with acetone levels around 110 mg/L 3
- This occurs in chronic alcohol users during periods of poor nutritional intake and relative starvation 3
SGLT2 Inhibitor-Associated Ketoacidosis
- Patients using SGLT2 inhibitors (like sotagliflozin) can develop "euglycemic DKA" with elevated BHB even when blood glucose is normal or only mildly elevated 1
- Each 0.1 mmol/L increase in baseline BHB increases DKA risk by 18%, and each 0.1 mmol/L increase from baseline raises risk by 8% 4
- Baseline BHB levels and changes in BHB are independent predictors of DKA risk regardless of treatment 4
Physiological/Metabolic Causes
Starvation and Fasting States
- Prolonged fasting or starvation triggers lipolysis and ketone production as the body shifts to fat metabolism for energy 5
- Overnight fasting typically produces BHB levels around 0.20 mmol/L, which remain in the normal range (<0.6 mmol/L) 6
Ketogenic Diet
- Intentional carbohydrate restriction induces nutritional ketosis with BHB elevation 5
- This represents a controlled metabolic state distinct from pathological ketoacidosis 5
Hypothermia
- Hypothermia as a cause of death is associated with BHB levels around 520 mg/L (approximately 5.0 mmol/L), similar to alcoholic ketoacidosis 3
Clinical Interpretation Framework
BHB Level Thresholds
- <0.6 mmol/L: Normal range 1
- 0.6-1.5 mmol/L: Mild to moderate ketosis requiring monitoring 1
- ≥1.5 mmol/L: Significant ketosis with high DKA risk when accompanied by hyperglycemia and acidosis 1, 2
- >7-8 mmol/L: Severe pathological ketoacidosis requiring immediate medical attention 2
Critical Diagnostic Pitfall
- Standard urine dipsticks only detect acetoacetate and completely miss BHB, significantly underestimating total ketone burden 2
- Blood ketone testing directly measuring BHB is strongly preferred for diagnosing and monitoring DKA 2
- The nitroprusside reaction should not be used to monitor DKA treatment as it doesn't quantify BHB specifically 1
When to Measure BHB
High-Risk Scenarios Requiring Testing
- Blood glucose persistently elevated >250 mg/dL in diabetic patients 1
- During any illness in patients with type 1 diabetes 1
- When symptoms of ketosis appear (nausea, vomiting, abdominal pain, fruity breath) 1
- Before intense physical activity in type 1 diabetes patients (postpone exercise if BHB ≥1.5 mmol/L) 1
- In any patient on SGLT2 inhibitors presenting with metabolic symptoms, regardless of glucose level 1