PRIMARY PANCREATIC β-CELL HYPERPLASIA

• Definition
  • A rare cause of hypoglycemia due to an overgrowth (hyperplasia) of the pancreatic β-cells.
  • Can present as either focal or diffuse hyperplasia.
  • Nesidioblastosis: neoformation of islets of Langerhans from pancreatic duct epithelium; often accompanies β-cell hyperplasia.

CONGENITAL HYPERINSULINISM

• Epidemiology
  • Occurs in ∼1 in 50,000 live births.
  • Inherited in an autosomal dominant or autosomal recessive pattern.
• Pathophysiology
  1. Common Cause: Loss-of-function mutations in the K-ATP channel genes on β-cells
     • Key genes:
       • Sulfonylurea receptor type 1 subunit (SUR1, coded by ABCC8)
       • Potassium channel subunit (Kir6.2, coded by KCNJ11)
     • Channel closure → persistent membrane depolarization → insulin oversecretion despite hypoglycemia.
  2. Other Mutations: Activating variants in genes encoding glutamate dehydrogenase or glucokinase.
  3. Focal vs. Diffuse
     • Focal adenomatous islet hyperplasia: involves biallelic inactivation (loss of maternal allele + paternal abnormal allele) → hyperplasia localized to one area.
     • Diffuse hyperplasia: entire pancreas involved.

• Clinical Presentation
  • Severe, intractable hypoglycemia in neonates/infants.
  • Neonatal signs:
    • Altered consciousness
    • Tremors
    • Hypotonia
    • Seizures
    • Apnea
    • Cyanotic spells
  • Macrosomia common.
  • Milder or partial defects can present later in childhood.
• Differential Diagnosis of Hypoglycemia in Infancy/Childhood
  • Hyperinsulinism: congenital hyperinsulinism, nesidioblastosis, infant of a diabetic mother, maternal sulfonylureas.
  • Drug-related: exogenous insulin, sulfonylureas.
  • Severe illness: e.g., sepsis, renal/hepatic failure.
  • Counterregulatory hormone deficiency: e.g., hypopituitarism, Addison disease.
  • Metabolic enzyme defects: glycogen storage diseases, fatty acid oxidation defects, organic acidemias.
• Treatment
  1. Medical: Diazoxide (inhibits insulin release), octreotide (somatostatin analogue).
  2. Surgical:
     • Focal lesion: resect focal hyperplastic area → potential cure.
     • Diffuse disease: more extensive pancreatectomy may be required.

NONINSULINOMA PANCREATOGENOUS HYPOGLYCEMIA SYNDROME (NIPHS)

• Definition
  • A form of islet β-cell hyperplasia that typically causes postprandial (rather than fasting) hypoglycemia.
  • Also called “nesidioblastosis” in adults.
• Clinical Presentation
  • Postprandial hyperinsulinemic hypoglycemia and related adrenergic/neuroglycopenic symptoms.
  • Surgical partial pancreatectomy often cures the condition.
• Post–Gastric Bypass Hypoglycemia
  • Similar pathologic changes (β-cell hyperplasia, nesidioblastosis) seen after Roux-en-Y gastric bypass.
  • Onset: 6 months to 8 years postoperatively.
  • Mechanisms may involve reduced ghrelin or other incompletely understood factors.

EVALUATION AND DIAGNOSIS

• Timing of Hypoglycemia
  • β-cell hyperplasia typically → postprandial hypoglycemia (insulinoma usually → fasting hypoglycemia).
  • Lab abnormalities (low glucose, inappropriately high insulin/C-peptide/proinsulin) resemble those in insulinoma.
• Imaging
  • Often not helpful in localizing diffuse hyperplasia (unlike insulinoma, which is typically a discrete tumor).
• Selective Arterial Calcium Stimulation with Hepatic Venous Sampling
  1. Inject Ca²⁺ gluconate into branches of arterial supply to the pancreas (gastroduodenal, splenic, superior mesenteric).
  2. Measure insulin in timed hepatic venous samples.
  3. Abnormal: ≥2–3× increase in hepatic vein insulin from baseline.
  4. Helps regionalize dysfunctional β-cells → partial pancreatectomy guided by the arterial distribution with abnormal insulin response.