What are the normal and abnormal serum beta‑hydroxybutyrate levels, their clinical significance, and how should elevated levels be evaluated and managed?

Beta-Hydroxybutyrate: Normal and Abnormal Levels, Clinical Significance, and Management

Normal Reference Values

Normal serum beta-hydroxybutyrate (BHB) levels are below 0.5 mmol/L in healthy individuals. 1 In fasting states, levels may be detectable but remain below detection limits under normal circumstances. 2

• Urine ketones can be positive in up to 30% of normal fasting individuals and pregnant women, making blood BHB measurement more reliable than urine testing. 2
• Normal ketosis during fasting, prolonged exercise, or high-fat diet consumption is physiologic and expected. 3
• During neonatal period, infancy, and pregnancy, ketosis develops readily due to particularly active lipid energy metabolism. 3

Pathologic Thresholds and Clinical Significance

Diabetic Ketoacidosis (DKA)

Blood BHB ≥3.8 mmol/L in adults and ≥3.0 mmol/L in children, when combined with hyperglycemia and acidosis, establishes the diagnosis of DKA. 2, 4

• DKA requires three simultaneous components: hyperglycemia (≥250 mg/dL), metabolic acidosis (pH ≤7.3, bicarbonate ≤15-18 mEq/L), and significant ketonemia. 2, 1
• Pathological ketosis in DKA typically exceeds 7-8 mmol/L with severe acidosis. 1
• BHB is the predominant and strongest acid in DKA, making it superior to other ketone measurements. 2, 1

Exercise and Type 1 Diabetes

Intense physical activity should be postponed when BHB >1.5 mmol/L, with caution needed when BHB ≥0.6 mmol/L. 5

• These thresholds prevent worsening hyperglycemia and ketosis risk during exercise in patients with type 1 diabetes. 5
• Marked hyperglycemia (≥350 mg/dL) combined with elevated BHB indicates insulin deficiency requiring correction before exercise. 5

Differential Diagnosis Based on BHB Patterns

Elevated BHB (Hyperketonemia)

The presence of marked hyperketonemia distinguishes glycogen storage disease (GSD) types 0, III, VI, and IX from GSD type I, which shows only modest BHB elevation despite severe hypoglycemia. 5

• In GSD III, BHB concentration is elevated at the time of hypoglycemia, contrasting with hypoketosis in fatty acid oxidation disorders and hyperinsulinism. 5
• Pathologic causes of ketosis include diabetes, ketotic hypoglycemia of childhood, corticosteroid or growth hormone deficiency, alcohol or salicylate intoxication, and several inborn errors of metabolism. 3

Inappropriately Low BHB (Hypoketotic Hypoglycemia)

The absence of ketosis in a patient with hypoglycemia is abnormal and suggests either hyperinsulinism or an inborn error of fat energy metabolism. 3

• This pattern indicates that lipid energy metabolism has not been appropriately activated despite hypoglycemia. 3
• GSD type I characteristically shows blood BHB levels that increase only modestly despite severe hypoglycemia (glucose <40-50 mg/dL). 5

Diagnostic Evaluation Algorithm

When to Measure BHB

Individuals with type 1 diabetes, history of DKA, or those treated with SGLT2 inhibitors should measure ketones with unexplained hyperglycemia or symptoms of ketosis (abdominal pain, nausea). 6, 2

• SGLT2 inhibitors increase DKA risk and can cause euglycemic DKA with lower glucose levels than typical DKA, requiring higher suspicion even with borderline values. 6, 2

Laboratory Workup for Hypoglycemia with Hepatomegaly

When evaluating hypoglycemia with hepatomegaly, the following tests should be obtained: 5

Primary evaluation:

• Blood glucose (ideally at time of hypoglycemia)
• Blood lactate
• Uric acid
• Hepatic profile including liver function studies
• Serum lipid profile
• Plasma CK
• Plasma total and free carnitine
• Plasma acylcarnitine profile
• Plasma amino acids
• Urinalysis and urine organic acids

Secondary evaluation when diagnosis unclear:

• Insulin
• Growth hormone
• Cortisol
• Free fatty acids
• Beta-hydroxybutyrate and acetoacetate 5
• Review newborn screening results

Critical Testing Considerations

Blood BHB measurement is the preferred and superior method for both diagnosing and monitoring DKA—never use nitroprusside-based tests for monitoring treatment. 6, 2, 1

• Standard urine dipsticks and nitroprusside methods only measure acetoacetate and acetone, completely missing BHB, which is the predominant ketone body. 2, 1
• During DKA treatment, BHB falls while acetoacetate may paradoxically increase, making nitroprusside methods misleading and unreliable for monitoring therapy. 2, 1
• Urine ketones have high sensitivity but poor specificity for DKA diagnosis. 2

Specimen Collection and Handling

Blood samples for BHB can be collected into heparin, EDTA, fluoride, citrate, or oxalate tubes. 6

• Whole blood specimens are stable at 4°C for up to 24 hours. 6
• Serum/plasma specimens are stable for up to 1 week at room temperature, 2 weeks at 4°C, and at least several weeks at -20°C. 6
• Ascorbic acid and acetoacetate may interfere with some BHB assay methods. 6

Management of Elevated BHB

DKA Management

When DKA is diagnosed (BHB ≥3.8 mmol/L in adults with hyperglycemia and acidosis), initiate IV regular insulin at 0.15 units/kg bolus followed by 0.1 unit/kg/h continuous infusion after excluding hypokalemia. 2

• Expect plasma glucose to decrease at 50-75 mg/dL/h; if glucose doesn't fall by 50 mg/dL in the first hour, check hydration and double insulin infusion hourly. 2
• Ketonemia takes longer to clear than hyperglycemia, requiring direct BHB measurement to monitor resolution. 2
• DKA is resolved when glucose <200 mg/dL, serum bicarbonate ≥18 mEq/L, and venous pH ≥7.3. 2

Outpatient Management for Ketosis-Prone Patients

Implement oral hydration, take additional short- or rapid-acting insulin with oral carbohydrates, and monitor blood glucose and BHB frequently. 2

• Seek medical advice if symptoms worsen or ketone concentrations increase. 2
• Present to emergency room if adequate oral hydration cannot be maintained due to vomiting or mental status changes. 2

Common Pitfalls to Avoid

Never start insulin therapy if potassium is low, as it can precipitate life-threatening hypokalemia and cardiac complications. 2

• Check serum potassium before initiating insulin therapy in all DKA cases. 2
• Do not rely on urine ketones or nitroprusside-based blood ketone tests for monitoring DKA treatment—they will mislead you as acetoacetate rises while the patient improves. 2, 1
• Do not confuse beta-hydroxybutyrate (BHB) with beta-hydroxy-beta-methylbutyrate (HMB), a leucine metabolite used as a dietary supplement, or with gamma-hydroxybutyrate (GHB), a controlled substance. 6

Special Clinical Applications

BHB serum levels can confirm adequate ketosis following myocardial suppression preparation for cardiac [18F]FDG PET/CT imaging when evaluating cardiac sarcoidosis and infective endocarditis. 6

• Protocols typically include prolonged fasting (≥12 hours) preceded by high fat-low/no carbohydrate diet for 24-48 hours. 6