What causes hyperinsulinism in a child with normal glucose and Hemoglobin A1c (HbA1c) levels?

Hyperinsulinism in Children with Normal Glucose and HbA1c

In a child with hyperinsulinism but normal glucose and HbA1c levels, the most likely causes are congenital hyperinsulinism (CHI) with adequate compensatory mechanisms maintaining normoglycemia, transient hyperinsulinism related to perinatal stress factors, or early-stage disease where the pancreatic beta-cells are hypersecretng insulin but the child's counter-regulatory systems are still maintaining euglycemia. 1, 2

Primary Diagnostic Considerations

Congenital Hyperinsulinism (CHI)

• CHI represents dysregulated insulin secretion that can initially maintain normal glucose levels through compensatory hyperinsulinemia before progressing to overt hypoglycemia. 1, 3
• Genetic mutations in 14 different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, PPM2, CACNA1D, FOXA2) can cause unregulated insulin secretion despite low or normal blood glucose levels. 4
• The child may be in a compensated state where beta-cell hypersecretion is balanced by adequate glucose intake and counter-regulatory mechanisms, preventing hypoglycemia but maintaining elevated insulin levels. 1, 3

Transient Hyperinsulinism (THI)

• Perinatal stress factors including birth asphyxia, maternal toxemia, prematurity, or intrauterine growth retardation can cause prolonged neonatal hyperinsulinism that resolves spontaneously within weeks to months. 1, 5
• 83% of THI cases are diagnosed on day of life 1, but children without routine screening may present later with normal glucose levels maintained through frequent feeding. 5
• Any perinatal stress might pose a risk for developing THI, and the pathomechanism involves temporary beta-cell dysfunction that eventually resolves. 5

Insulin Resistance States with Compensatory Hyperinsulinemia

• Obesity in children causes profound insulin resistance, with obese children demonstrating 40% lower insulin-stimulated glucose metabolism compared to non-obese children, resulting in compensatory hyperinsulinemia to maintain normal glucose levels. 6
• During puberty, physiological insulin resistance increases (30% lower insulin-mediated glucose disposal in Tanner stages II-IV), causing compensatory hyperinsulinemia with normal glucose tolerance in children with intact beta-cell function. 6
• Visceral adiposity in obese adolescents directly correlates with basal and glucose-stimulated hyperinsulinemia while maintaining euglycemia through compensatory mechanisms. 6

Critical Diagnostic Workup

Laboratory Testing Required

• Measure plasma insulin, beta-hydroxybutyrate, fatty acids, and ammonia during a supervised fasting test to demonstrate inappropriate insulin secretion despite normal or low glucose levels. 1, 2
• The diagnostic hallmark of hyperinsulinism is non-ketotic hypoglycemia (or inappropriately low ketones for the glucose level), suppressed fatty acids, and detectable insulin when glucose is low or normal. 1, 3
• Plasma acylcarnitine profile and urine organic acids help identify specific genetic forms like HADH deficiency or glutamate dehydrogenase hyperactivity. 1
• Acute insulin response (AIR) tests are useful for phenotypic characterization of the hyperinsulinism subtype. 1

Genetic Testing

• Rapid molecular genetic testing for the 14 known CHI genes should be performed, as results can guide treatment decisions and identify surgically-curable focal lesions. 2, 4
• Genetic testing is commercially available and essential for distinguishing focal from diffuse disease, which dramatically impacts surgical management. 1, 2

Imaging Studies

• 18F-DOPA PET-CT scanning can localize focal lesions in children with congenital hyperinsulinism, identifying surgically-curable disease in a large proportion of cases. 2, 4
• This advanced imaging is only available in certain specialized centers but has revolutionized the ability to distinguish focal from diffuse disease. 2

Conditions That Mimic Hyperinsulinism

Important Differential Diagnoses

• Neonatal panhypopituitarism can present with hypoglycemia and must be excluded through hormonal evaluation. 1
• Drug-induced hypoglycemia (maternal medications, inadvertent insulin administration) should be considered in the history. 1
• Beckwith-Wiedemann Syndrome is associated with hyperinsulinism and has characteristic physical findings including macroglossia and hemihypertrophy. 1
• Congenital disorders of glycosylation can mimic hyperinsulinism biochemically. 1
• Anti-insulin and insulin-receptor stimulating antibodies are rare causes of hyperinsulinemic hypoglycemia. 1

Management Approach

Immediate Goals

• The primary goal is preventing brain damage from hypoglycemia by maintaining plasma glucose levels above 70 mg/dL (3.9 mmol/L) through pharmacologic or surgical therapy. 1, 2
• Frequent feeding schedules (every 2-3 hours) may be maintaining normoglycemia in early or mild cases, masking the underlying hyperinsulinism. 2

Pharmacologic Treatment

• Diazoxide is the only FDA-approved medication for hyperinsulinism due to islet cell adenoma, carcinoma, extrapancreatic malignancy, leucine sensitivity, islet cell hyperplasia, nesidioblastosis, or adenomatosis in infants and children. 7
• Diazoxide is effective in 42-81% of children with transient hyperinsulinism and should be initiated when hypoglycemia is documented. 5
• Continuous glucagon infusion is used in 42% of severe cases when diazoxide fails or before surgical intervention. 5

Surgical Considerations

• Laparoscopic pancreatectomy can cure focal hyperinsulinism when lesions are identified by 18F-DOPA PET-CT and confirmed by rapid genetic testing showing paternally-inherited ABCC8 or KCNJ11 mutations. 2, 4
• Diffuse disease may require near-total pancreatectomy (95-98% resection) but carries risk of diabetes mellitus. 3

Common Pitfalls to Avoid

• Delaying diagnosis because glucose and HbA1c are currently normal can result in irreversible brain damage when hypoglycemia eventually occurs. 1, 2
• Failing to perform supervised fasting tests in children with suspected hyperinsulinism misses the diagnostic window when insulin levels are inappropriately elevated. 1
• Not screening for hypoglycemia in children with perinatal stress factors (83% of THI diagnosed on day 1 when screened, but those without screening present with dangerously low glucose levels). 5
• Discontinuing diazoxide without proper fasting studies demonstrating ability for ketogenesis can lead to recurrent severe hypoglycemia. 5
• Assuming normal glucose excludes hyperinsulinism—the child may be in a compensated state with frequent feeding preventing hypoglycemic episodes. 1, 3