What are the causes of elevated beta-hydroxybutyrate (BHB) levels?

Causes of Elevated Beta-Hydroxybutyrate (BHB)

Elevated BHB is primarily caused by diabetic ketoacidosis (DKA) from insulin deficiency, alcoholic ketoacidosis (AKA), starvation/fasting states, and SGLT2 inhibitor use—with DKA being the most critical and life-threatening cause requiring immediate recognition and treatment. 1, 2

Primary Pathological Causes

Diabetic Ketoacidosis (DKA)

• Absolute or relative insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone) triggers uncontrolled lipolysis and ketone production, with BHB levels typically exceeding 1.5 mmol/L and often reaching 7-8 mmol/L or higher 1, 3
• Type 1 diabetes is the classic setting, particularly in new-onset diabetes or when established patients discontinue or receive inadequate insulin 1, 3
• Type 2 diabetes during severe illness or stress can also precipitate DKA, especially when insulin secretory capacity becomes overwhelmed 1
• Common precipitating factors include infection (most common), new-onset diabetes, insulin omission, cerebrovascular accident, myocardial infarction, pancreatitis, trauma, and certain medications (corticosteroids, thiazides, sympathomimetic agents) 4, 3

SGLT2 Inhibitor-Associated Ketoacidosis

• Euglycemic DKA occurs with SGLT2 inhibitors (including sotagliflozin), where patients develop ketoacidosis with glucose levels <250 mg/dL or even normal glucose, making diagnosis challenging if clinicians rely solely on glucose thresholds 1, 2
• Incremental increases in baseline BHB and changes from baseline are associated with higher DKA risk independent of treatment, with DKA risk increasing 18% per 0.1 mmol/L increase in baseline BHB and 8% per 0.1 mmol/L increase from baseline 5
• Median fasting BHB increases by approximately 0.04 mmol/L at 24 weeks with sotagliflozin versus placebo, though 67% of patients have minimal changes 5

Alcoholic Ketoacidosis (AKA)

• Chronic alcohol abuse with recent cessation or decreased intake combined with starvation and dehydration causes AKA, with BHB levels ranging from 1260 to 47,200 μmol/L (median 8000 μmol/L) in fatal cases 6
• Characteristic presentation includes unexpected death of chronic alcoholics with none or only traces of ethanol in blood, increased acetone, and no other identifiable cause of death on autopsy 6, 7
• BHB levels above 2500 μmol/L (approximately 2.5 mmol/L) can be lethal without medical intervention 6

Distinguishing Features by Cause

DKA vs. Other Glycogen Storage Diseases

• GSD Type I shows only modest increases in BHB during hypoglycemia, contrasting sharply with marked hyperketonemia characteristic of GSD types 0, III, VI, and IX 4
• Blood lactate increases rapidly in GSD I as glucose decreases, while BHB elevation remains modest—this pattern helps differentiate GSD I from other GSDs where ketosis is prominent 4

DKA vs. Hyperosmolar Hyperglycemic State (HHS)

• DKA presents with strongly positive serum and urine ketones due to unregulated lipolysis from severe insulin deficiency, with BHB typically >1.5 mmol/L 2
• HHS shows small or negative ketones because residual insulin is adequate to prevent lipolysis and ketogenesis but insufficient to control hyperglycemia 2
• This distinction is critical: HHS has higher mortality (15% vs. 5% for DKA) but lacks significant ketosis 2

Clinical Interpretation of BHB Levels

Normal and Pathological Ranges

• BHB <0.6 mmol/L: Normal range 1
• BHB 0.6-1.5 mmol/L: Mild to moderate ketosis requiring monitoring and possible intervention; caution needed in diabetic patients as this may indicate early ketosis 1
• BHB ≥1.5 mmol/L: Significant ketosis with high DKA risk when accompanied by hyperglycemia and acidosis; diagnostic threshold for DKA per American Diabetes Association 1
• BHB >7-8 mmol/L: Severe pathological ketoacidosis with profound acidosis 3

Postmortem Considerations

• Diabetic ketoacidosis shows highest postmortem BHB levels (median 1085 mg/L or approximately 10.4 mmol/L) and acetone (median 330 mg/L) 7
• Hypothermia deaths show similar BHB and acetone levels to AKA (median BHB 520 mg/L or approximately 5.0 mmol/L) 7
• BHB does not form or decompose postmortem, making it reliable even in decomposed bodies, unlike acetone which can form from microbial activity 6, 7

Critical Clinical Pitfalls

Measurement Issues

• Standard urine dipsticks only detect acetoacetate, missing BHB entirely and significantly underestimating total ketone burden 3
• Nitroprusside reaction methods should not be used to monitor DKA treatment as they don't quantify BHB specifically 1
• Blood ketone testing directly measuring BHB is strongly preferred for diagnosing and monitoring DKA 1, 3

Monitoring Recommendations

• Patients at risk for DKA should measure BHB when blood glucose is persistently >250 mg/dL, during illness, or when symptoms of ketosis appear 1
• Intense physical activity should be postponed when BHB ≥1.5 mmol/L in type 1 diabetes due to risk of worsening ketosis 1
• Persistent BHB elevation can occur after urine clears of ketones during DKA recovery, with unrecognized elevation causing recurrence of ketonuria; fluid therapy should continue beyond clearance of ketonuria 8

Risk Factors for Complications

• Baseline BHB levels and changes from baseline independently predict DKA risk in patients using SGLT2 inhibitors, requiring individualized patient education on DKA risk mitigation 5
• Hyperketonemia increases oxidative stress and complications in brain, kidney, liver, and microvasculature, elevating morbidity and mortality risk in diabetic patients with elevated ketones compared to those with normal levels 9