What is the diagnosis for a baby presenting with hypoglycemia, low beta hydroxybutyrate (BHB) levels, and normal fasting insulin levels?

Diagnosis: Congenital Hyperinsulinemia (Option B)

The combination of hypoglycemia (55 mg/dL), inappropriately low beta-hydroxybutyrate (0.6 mmol/L), and normal fasting insulin strongly suggests congenital hyperinsulinemia, as this represents hypoketotic hypoglycemia—the hallmark biochemical signature of endogenous hyperinsulinism where insulin suppresses both ketogenesis and lipolysis despite hypoglycemia. 1

Diagnostic Reasoning

Why This is Hyperinsulinemia

• The critical diagnostic feature is hypoketotic hypoglycemia: beta-hydroxybutyrate of 0.6 mmol/L is inappropriately suppressed for a glucose of 55 mg/dL, when it should be elevated above 1.5-2.0 mmol/L during hypoglycemia. 1, 2

• Normal insulin levels do NOT exclude hyperinsulinemia: In the context of hypoglycemia, any detectable insulin is inappropriate—insulin should be undetectable when glucose is <55 mg/dL. A "normal" insulin level during hypoglycemia is actually pathologically elevated. 1, 2

• Insulin suppresses ketone production: Even modest insulin excess prevents the lipolysis and fatty acid oxidation needed to generate ketones, creating the characteristic hypoketotic pattern seen in this infant. 3

• Congenital hyperinsulinemia typically presents in infancy with hypoglycemia that appears when feeding intervals increase, exactly matching this clinical scenario. 4

Why NOT Glycogen Storage Disease

• GSD would show elevated or normal ketones: In GSD Type I, beta-hydroxybutyrate levels are "mildly or moderately increased relative to the corresponding free fatty acid levels," not suppressed. 4

• GSD Type I has additional discriminating features: Elevated lactate and elevated uric acid are essential discriminators, with "elevated lactate plus elevated uric acid and normal carnitine strongly suggesting GSD I." 5, 6

• GSD Type III shows hyperketotic hypoglycemia: Unlike GSD I, Type III produces "normal lactate + normal uric acid + hyperketosis," the opposite of this patient's presentation. 6

• The timing is wrong: GSD I causes severe hypoglycemia 3-4 hours after feeding, while GSD III causes less severe hypoglycemia at longer intervals. 5, 6

Why NOT Adrenal Insufficiency

• Adrenal insufficiency would not suppress ketones: Cortisol deficiency impairs gluconeogenesis but does not prevent ketogenesis—ketones would be appropriately elevated during hypoglycemia, not suppressed. 1

• Adrenal insufficiency presents with additional features like hyponatremia, hyperkalemia, and hyperpigmentation that are not mentioned in this case. 1

• The normal insulin level argues against adrenal insufficiency as the primary diagnosis, though it could theoretically coexist. 1

Critical Biochemical Pattern Recognition

The diagnostic algorithm for hypoketotic hypoglycemia in infancy:

• Step 1: Confirm hypoglycemia with simultaneous ketone measurement—this patient has glucose 55 mg/dL with beta-hydroxybutyrate 0.6 mmol/L (inappropriately low). 1, 2

• Step 2: Measure insulin, C-peptide, and proinsulin during hypoglycemia—any detectable insulin during hypoglycemia is pathologic. 1

• Step 3: The combination of low glucose + low ketones + detectable insulin = endogenous hyperinsulinism until proven otherwise. 1, 3

• Step 4: Rule out exogenous insulin by measuring C-peptide (elevated in endogenous hyperinsulinism, suppressed with exogenous insulin) and screen for oral hypoglycemic agents. 1

Common Diagnostic Pitfalls

• Never assume "normal" insulin excludes hyperinsulinemia: The reference range for insulin is established in euglycemic individuals. During hypoglycemia, insulin should be undetectable (<3 μU/mL). Any measurable insulin during glucose <55 mg/dL is inappropriate. 1, 2

• Do not rely on beta-hydroxybutyrate alone: While low ketones strongly suggest hyperinsulinism, some patients with hyperinsulinemia can have beta-hydroxybutyrate >2.7 mmol/L, particularly after partial pancreatectomy, though this is uncommon in newly diagnosed cases. 7

• Distinguish from ketotic hypoglycemia: Idiopathic ketotic hypoglycemia, the most common cause of childhood hypoglycemia, shows beta-hydroxybutyrate ≥1.0 mmol/L with glucose <70 mg/dL—the opposite pattern. 8

• Consider that GSD can be missed: Some cases labeled as "idiopathic ketotic hypoglycemia" may represent undiagnosed GSD IXa or other metabolic disorders, but these would show elevated ketones, not suppressed ketones. 8

Immediate Management Implications

• This diagnosis is urgent: Congenital hyperinsulinemia causes severe, recurrent hypoglycemia that can lead to permanent brain damage if untreated. 4, 3

• Frequent feeding is essential: These infants require continuous glucose supply through frequent feeds or continuous tube feeding to prevent hypoglycemia. 4

• Ketone supplementation may be neuroprotective: Oral beta-hydroxybutyrate supplementation (880-1000 mg/kg/day) can provide alternative brain fuel during hypoglycemic episodes while definitive treatment is arranged. 3

• Definitive diagnosis requires genetic testing: Molecular testing for genes causing congenital hyperinsulinism (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A, UCP2) should be pursued. 5