What does an elevated Beta-Hydroxybutyrate (BHB) level indicate in the context of a normal hypoglycemia panel, with normal proinsulin, C-peptide, and insulin levels?

Interpretation of Elevated Beta-Hydroxybutyrate with Normal Insulin Studies

An elevated beta-hydroxybutyrate (BHB) of 2.19 mmol/L with normal insulin, C-peptide, and proinsulin levels indicates appropriate ketone production in response to hypoglycemia, effectively ruling out hyperinsulinemic hypoglycemia (such as insulinoma) and suggesting either prolonged fasting, a glycogen storage disorder, or inadequate counter-regulatory response. 1, 2

What This BHB Level Tells You

The BHB of 2.19 mmol/L is physiologically appropriate for hypoglycemia and excludes insulin-mediated suppression of ketogenesis:

• In hyperinsulinemic hypoglycemia (insulinoma), BHB remains suppressed at ≤2.7 mmol/L because excess insulin blocks lipolysis and ketone production, even during profound hypoglycemia 2
• Your patient's BHB >2.7 mmol/L threshold demonstrates that insulin action is appropriately low, allowing normal ketogenic response to hypoglycemia 3, 2
• This pattern—hypoglycemia with adequate ketone production and normal insulin levels—points away from endogenous hyperinsulinism and toward disorders of glucose production or counter-regulation 2

Clinical Significance of This Pattern

The combination of hypoglycemia, elevated ketones, and normal insulin studies creates a specific differential diagnosis:

• Glycogen storage diseases (GSD types 0, III, VI, IX) characteristically produce hyperketotic hypoglycemia because impaired hepatic glucose output triggers appropriate lipolysis and ketogenesis 4
• Prolonged fasting state beyond 18-36 hours produces progressive BHB elevation (333% increase from 18-36h, 210% from 36-54h) as a normal physiologic response 3
• Inadequate counter-regulatory hormone response (cortisol, growth hormone, glucagon deficiency) can produce hypoglycemia with preserved ketogenesis 4

Critical Distinction from Diabetic Ketoacidosis

This BHB level requires careful contextualization—it has completely different meanings in diabetic versus non-diabetic patients:

• In diabetes, BHB ≥1.5 mmol/L signals significant ketosis with high DKA risk when accompanied by hyperglycemia and acidosis 1, 5
• In your hypoglycemic patient without diabetes, BHB 2.19 mmol/L represents appropriate metabolic adaptation to low glucose availability, not pathologic ketoacidosis 3, 2
• The absence of hyperglycemia and the presence of hypoglycemia fundamentally changes the interpretation—this is adaptive ketogenesis, not DKA 5

Next Diagnostic Steps

Based on this metabolic pattern, pursue these specific evaluations:

• Measure lactate and uric acid during hypoglycemia: Elevated lactate + elevated uric acid + normal carnitine strongly suggests GSD Type I, while normal lactate with hyperketosis suggests GSD III, VI, or IX 4
• Obtain plasma carnitine and acylcarnitine profile: Normal levels support GSD over fatty acid oxidation disorders, which would show hypoketotic hypoglycemia with abnormal acylcarnitine patterns 4
• Assess fasting duration and timing: BHB naturally rises during extended fasting; determine if hypoglycemia occurred after an appropriately short fast (3-4 hours suggests GSD I; longer tolerance suggests GSD III) 4
• Genetic testing for hepatic GSDs: Order gene panels for G6PC, SLC37A4, and AGL genes if clinical picture suggests glycogen storage disease 4

Common Pitfall to Avoid

Do not misinterpret this as "ruling in" insulinoma based on one study showing some insulinoma patients can have BHB >2.7 mmol/L:

• While one retrospective study found 9/39 insulinoma patients had BHB >2.7 mmol/L, all nine had undergone prior partial pancreatectomy and showed significantly lower insulin, C-peptide, and proinsulin levels than typical insulinoma patients 6
• Your patient has normal (not low) insulin studies, which combined with elevated BHB makes hyperinsulinemic hypoglycemia extremely unlikely 2
• The established diagnostic criterion remains: BHB ≤2.7 mmol/L at end of fast indicates hyperinsulinemia, while BHB >2.7 mmol/L indicates hypoinsulinemia and a negative fast for insulinoma 3, 2