Insulinoma

INSULINOMA

• Cause of Endogenous Hyperinsulinemic Hypoglycemia
  • Most common when a neoplasm of pancreatic β-cells (insulinoma) inappropriately secretes insulin.
  • Incidence: 4 cases per 1,000,000 people per year.
  • Typically benign (∼95%) and sporadic (∼95%).
  • Malignant: ∼5%.
  • Association with MEN1: ∼5% of insulinomas occur in multiple endocrine neoplasia type 1 (MEN1).

Tumor Characteristics

• Usually solitary (∼85%).
• Multiple tumors in ∼10% of cases (more common in MEN1).
• Malignant in ∼5%.

Pathophysiology

• Insulin secretion fails to decrease as plasma glucose concentrations fall.
• Primary mechanism of hypoglycemia: insulin-induced decrease in hepatic glucose output in the fasting state.

CLINICAL PRESENTATION

• Episodic Hypoglycemia with:
  1. Neuroglycopenic symptoms
     • Visual changes
     • Confusion
     • Unusual behavior
     • Possible unconsciousness or seizures if severe
  2. Sympathoadrenal symptoms
     • Tremulousness
     • Sweating
     • Palpitations
• Whipple’s Triad (classic criteria for endogenous hypoglycemia):
  1. Symptoms consistent with hypoglycemia (neuroglycopenia + sympathetic overactivity).
  2. Documented low plasma glucose (<45 mg/dL in venous plasma).
  3. Relief of symptoms when glucose is administered.

DIAGNOSIS

1. Biochemical Testing
   • Demonstrate low plasma glucose (e.g., <45 mg/dL) with inappropriately increased levels of:
     • Insulin
     • C-peptide
     • Proinsulin
   • β-hydroxybutyrate: low (<2.7 mmol/L) because of insulin’s antilipolytic effect.
   • Glucagon stimulation at end of fast: a rise in plasma glucose >25 mg/dL (within 30 min) suggests insulinoma (retained glycogen in liver due to hyperinsulinemia).
2. Fasting Tests
   • Most insulinoma patients become hypoglycemic within 48 hours of a supervised fast.
   • Some require a 72-hour fast.
3. Sulfonylurea Screening
   • Measure drugs that stimulate insulin release (e.g., sulfonylureas, repaglinide, nateglinide).
   • Exclude factitious hypoglycemia from exogenous secretagogues or insulin.
4. Differential Diagnosis
   • Pancreatic β-cell hyperplasia (nesidioblastosis).
   • Insulin autoimmune hypoglycemia.
   • Medications: exogenous insulin, oral insulin secretagogues (sulfonylureas).
   • Critical illness: hepatic/renal failure, sepsis.
   • Counterregulatory hormone deficiency: Addison disease.
   • Non-islet cell tumor hypoglycemia (large mesenchymal tumors).

LOCALIZATION STUDIES

• Tumor Size: Often very small (40% <1.0 cm).
• Imaging Approaches:
  1. Contrast-enhanced CT of the pancreas: detects ∼75% of insulinomas.
  2. Ultrasonography
     • Transabdominal
     • Endoscopic (sensitivity up to 90%).
  3. Selective Arterial Calcium Stimulation with hepatic venous sampling (for regionalizing tumor to a part of the pancreas).
  4. Intraoperative Pancreatic Ultrasound: confirmatory localization during surgery.

TREATMENT

1. Surgical Resection:
   • Best definitive therapy if complete removal is feasible.
   • Enucleation of solitary tumor if possible, sparing normal pancreas.
   • Partial pancreatectomy may be required if enucleation not feasible.
2. Special Cases:
   • Tumor in pancreatic head and cannot be enucleated: Whipple procedure (pancreaticoduodenectomy + duodenectomy + partial gastrectomy + splenectomy).
   • Malignant insulinoma:
     • Remove as much tumor as possible.
     • Metastases commonly in the liver.
3. Management of Metastatic or Unresectable Disease:
   • Ablative therapies: hepatic artery embolization, radiofrequency ablation, cryoablation, or ethanol ablation under endoscopic ultrasound guidance.
   • Medications:
     • Diazoxide (suppresses insulin release).
     • Octreotide (somatostatin analogue).
   • Chemotherapy (e.g., streptozocin-based) for advanced disease.