What does an elevated beta‑hydroxybutyrate level indicate?

Elevated Beta-Hydroxybutyrate: Clinical Significance

An elevated beta-hydroxybutyrate (βOHB) level most commonly indicates diabetic ketoacidosis (DKA) when ≥1.5 mmol/L and accompanied by hyperglycemia and acidosis—a medical emergency requiring immediate intensive care evaluation. 1, 2

Interpretation of βOHB Levels

The American Diabetes Association provides clear thresholds for interpreting βOHB concentrations 1, 2:

• <0.6 mmol/L: Normal range in healthy individuals 2, 3
• 0.6-1.5 mmol/L: Mild to moderate ketosis requiring monitoring and possible intervention 2, 3
• ≥1.5 mmol/L: Significant ketosis with high DKA risk when accompanied by hyperglycemia and acidosis 1, 2
• ≥3.0 mmol/L: Definitive DKA diagnosis when combined with appropriate clinical and laboratory findings 3
• 7-8 mmol/L or higher: Severe pathological ketoacidosis indicating profound metabolic decompensation requiring immediate intensive care 4, 3

Primary Clinical Causes

Diabetic Ketoacidosis (Most Critical)

DKA represents the most dangerous cause of elevated βOHB and carries significant mortality risk. 1, 4 The condition results from absolute or relative insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone), triggering uncontrolled lipolysis and ketone production 1, 4.

DKA diagnostic criteria include 1, 3:

• Blood glucose ≥250 mg/dL (may be lower with SGLT2 inhibitors) 3
• Arterial pH <7.30 3
• Serum bicarbonate <15 mEq/L 3
• Elevated anion gap 3
• βOHB ≥1.5 mmol/L (preferably ≥3.0 mmol/L for definitive diagnosis) 3

Common precipitating factors include infection (most common), new-onset diabetes, insulin omission, myocardial infarction, stroke, SGLT2 inhibitors, corticosteroids, pancreatitis, and trauma 1, 3.

SGLT2 Inhibitor-Associated Ketoacidosis

Patients using SGLT2 inhibitors can develop DKA even with normal or only mildly elevated blood glucose—termed "euglycemic DKA"—making βOHB measurement essential in this population 2, 3. This represents a critical diagnostic pitfall where glucose levels may not reflect the severity of metabolic decompensation 2.

Alcoholic Ketoacidosis

This condition often presents with normal or low glucose, profound acidosis, and markedly elevated βOHB 3. Unlike DKA, treatment focuses on aggressive IV fluids with dextrose-containing solutions and thiamine administration (100 mg IV before glucose to prevent Wernicke encephalopathy), with insulin generally not required 3.

Starvation Ketosis

βOHB typically ranges 0.6-3.0 mmol/L with glucose mildly elevated or normal and bicarbonate ≥18 mEq/L (no significant acidosis) 3. Treatment involves providing carbohydrate-containing nutrition without insulin unless underlying diabetes exists 3.

Type 2 Diabetes Under Stress

Severe illness or metabolic stress can precipitate DKA in type 2 diabetes when insulin secretory capacity becomes overwhelmed 2, 4.

Critical Diagnostic Pitfalls

Standard urine dipsticks only detect acetoacetate and completely miss βOHB, which comprises 70-80% of total ketone bodies in DKA. 1, 4, 3 This leads to false-negative ketonuria despite severe ketonemia and can significantly underestimate the total ketone burden 1, 4.

Blood βOHB measurement is therefore the preferred and recommended method for both diagnosis and monitoring of DKA. 1, 2, 4 The equilibrium between acetoacetate and βOHB shifts toward βOHB formation in conditions that increase NADH concentrations (hypoxia, fasting, metabolic disorders including DKA), making methods that don't measure βOHB clinically misleading 1.

When to Measure βOHB

The American Diabetes Association recommends measuring βOHB in ketosis-prone individuals (type 1 diabetes, history of DKA, or SGLT2 inhibitor users) when 1, 2:

• Blood glucose persistently elevated >250 mg/dL 2
• Unexplained hyperglycemia 1
• Symptoms of ketosis (abdominal pain, nausea) 1
• During illness or metabolic stress 1, 2
• Before intense physical activity in type 1 diabetes 1, 2

Exercise Considerations in Diabetes

Intense physical activity should be postponed when βOHB ≥1.5 mmol/L due to risk of worsening ketosis 1, 2. Caution is needed even when βOHB levels are ≥0.6 mmol/L, as this may indicate insulin deficiency that would lead to worsening hyperglycemia with exercise 1.

Immediate Action Algorithm

When βOHB is elevated, follow this decision pathway 3:

If glucose ≥250 mg/dL with DKA symptoms (polyuria, nausea, Kussmaul respirations, altered mental status):

• Presume DKA until proven otherwise 3
• Check arterial pH and bicarbonate immediately 3
• If pH <7.30 and bicarbonate <15 mEq/L → confirms DKA requiring ICU admission 3

If glucose <250 mg/dL:

• Evaluate for alcoholic ketoacidosis, starvation ketosis, or euglycemic DKA (especially in SGLT2 inhibitor users) 3
• Check for alcohol use, recent fasting, or medication history 3

If pH ≥7.30 and bicarbonate ≥15 mEq/L:

• Favors starvation ketosis or early metabolic decompensation 3
• Provide carbohydrate-containing nutrition 3

Prognostic Significance

Elevated ketones in diabetic patients are associated with increased complications affecting the brain, kidney, liver, and microvasculature compared to diabetics with normal ketone levels 5. The mortality rate in DKA is approximately 5% in experienced centers, but rises significantly at extremes of age and in the presence of coma and hypotension 1.