Why do Betahydroxybutyrate (BHB) levels increase in pediatric patients experiencing hypoglycemic seizures?

Why Beta-Hydroxybutyrate Increases in Children with Hypoglycemic Seizures

Beta-hydroxybutyrate (BHB) increases during hypoglycemic seizures as a physiological protective mechanism—the body produces ketones as an alternative fuel source when glucose is critically low, attempting to prevent irreversible neurological damage by providing the brain with emergency energy substrate. 1

The Physiological Mechanism

Ketone production, particularly BHB, is the body's adaptive response to metabolic stress and serves as a critical marker of hypoglycemia. When blood glucose drops to dangerous levels, the body shifts to fat metabolism, producing ketones that can cross the blood-brain barrier and serve as alternative fuel for neurons that would otherwise be starved of glucose. 1

• BHB is the primary ketone body generated during states of glucose deprivation and represents the brain's most important alternative energy source when glucose availability is compromised. 2
• This ketogenic response is a protective physiological phenomenon specifically designed to avoid irreversible neurological damage from hypoglycemia. 1

The Critical Exception: Hyperinsulinemic States

However, a critical diagnostic pitfall exists: in hyperinsulinemic hypoglycemia, BHB levels remain abnormally LOW despite severe hypoglycemia, because excess insulin suppresses both lipolysis and ketogenesis. 2, 3

• In hyperinsulinism (HI), the most common cause of both transient and permanent hypoglycemic disorders in children, dysregulated insulin secretion results in persistent hypoglycemia with inappropriately suppressed ketone production. 2
• This hypoketotic hypoglycemia is particularly dangerous because it deprives the brain of both glucose AND its alternative fuel source, dramatically increasing the risk of seizures, developmental delay, and permanent brain damage. 2, 3
• The combination of low glucose with low BHB (hypoketotic hypoglycemia) should immediately raise suspicion for hyperinsulinism or fatty acid oxidation defects. 4

Diagnostic Interpretation During Hypoglycemic Seizures

The American Academy of Pediatrics recommends drawing critical diagnostic samples including BHB before treating hypoglycemia (if the child is stable enough) to differentiate between metabolic causes. 4, 5

Expected BHB Patterns by Etiology:

• Ketotic hypoglycemia (normal response): BHB elevated (typically >1.5-2.0 mmol/L), indicating appropriate metabolic adaptation to low glucose—seen in prolonged fasting, glycogen storage diseases, or cortisol/growth hormone deficiency. 4
• Hypoketotic hypoglycemia (pathologic): BHB inappropriately low (<1.0 mmol/L) despite hypoglycemia—strongly suggests hyperinsulinism or fatty acid oxidation defects requiring urgent specialized evaluation. 4, 2

Clinical Application and Monitoring

Point-of-care BHB testing is accurate and comparable to serum BHB levels in children, making it a valuable bedside diagnostic tool. 1

• In healthy children after overnight fasting, serum BHB averages 0.25 ± 0.23 mmol/L, with strong correlation between POC and serum measurements (r = 0.803). 1
• The American College of Medical Genetics recommends that fatty acid oxidation defects should be suspected when hypoglycemia occurs with hypoketotic features. 4

Critical Diagnostic Samples to Obtain:

Before treating hypoglycemia in a stable child, draw blood for: glucose, insulin, cortisol, growth hormone, lactate, free fatty acids, beta-hydroxybutyrate, acetoacetate, liver function tests, ammonia, and urine for ketones and organic acids. 4, 5

Key Clinical Pitfalls to Avoid

• Never assume elevated BHB is always present with hypoglycemic seizures—hyperinsulinemic states paradoxically suppress ketone production despite critical hypoglycemia, creating a metabolic emergency. 2, 3
• Never delay glucose administration to obtain diagnostic samples if the child is symptomatic or glucose <50 mg/dL—brain injury prevention takes absolute priority over diagnostic testing. 5
• The combination of hypoglycemia with LOW ketones is more concerning than hypoglycemia with appropriately elevated ketones, as it suggests an underlying endocrine or metabolic disorder requiring specialized management. 4, 2