In a 42-year-old man with endogenous hyperinsulinemic hypoglycemia (insulin 222 µU/mL, C‑peptide 16 ng/mL) and bilateral multiple renal cysts on contrast CT, what is the next step in diagnosis and management?

Endogenous Hyperinsulinemic Hypoglycemia with Bilateral Renal Cysts

This patient requires immediate evaluation for insulinoma with pancreatic imaging (CT/MRI with contrast or endoscopic ultrasound) followed by surgical consultation, as the markedly elevated insulin (222 µU/mL) and C-peptide (16 ng/mL) during hypoglycemia confirm endogenous hyperinsulinism, most commonly caused by insulinoma. 1, 2

Diagnostic Confirmation

The biochemical profile definitively establishes endogenous hyperinsulinemic hypoglycemia:

• Insulin level of 222 µU/mL with concomitant C-peptide of 16 ng/mL during hypoglycemia confirms inappropriate endogenous insulin secretion, meeting diagnostic criteria for insulinoma (insulin >3 µU/mL and C-peptide ≥0.6 ng/mL). 1, 2

• The simultaneous elevation of both insulin and C-peptide excludes factitious hypoglycemia from exogenous insulin administration, which would suppress C-peptide. 1, 3

• These values far exceed diagnostic thresholds and indicate a high likelihood of insulinoma (present in 55% of endogenous hyperinsulinism cases). 4, 5

Immediate Next Steps: Tumor Localization

First-Line Imaging

Proceed directly to pancreatic imaging without delay:

• Endoscopic ultrasound (EUS) is the preferred initial localization method, achieving 82-93% sensitivity for detecting pancreatic neuroendocrine tumors and allowing simultaneous tissue sampling via fine needle aspiration. 1, 2

• Multiphasic CT or MRI of the pancreas should be performed to assess for metastatic disease and provide complementary anatomic detail (CT sensitivity 57-94%, MRI sensitivity 74-94%). 2

• The bilateral renal cysts are likely incidental findings unrelated to the hyperinsulinism, though they should be documented. 6

Advanced Imaging if Initial Studies Are Negative

• 68Ga-DOTATOC/DOTATATE PET/CT demonstrates the highest sensitivity (87-96%) and should be considered if conventional imaging fails to localize a tumor. 2

• Selective arterial calcium stimulation with hepatic venous sampling (Imamura-Doppman procedure) achieves up to 90% success rate for localizing occult insulinomas and should be reserved for cases where non-invasive imaging is inconclusive. 1, 2

• Avoid somatostatin receptor scintigraphy (SSRS) as it has only 50-60% sensitivity for insulinomas, significantly lower than for other pancreatic neuroendocrine tumors. 2

Preoperative Stabilization

While awaiting imaging and surgical evaluation, stabilize blood glucose levels:

• Implement frequent small meals with complex carbohydrates and protein to prevent fasting hypoglycemia. 3

• Diazoxide is first-line medical therapy for managing hypoglycemia due to hyperinsulinism, though it requires close monitoring of blood glucose and clinical response for 2-3 weeks. 2, 7

• Everolimus can be considered as an alternative for preoperative stabilization. 2

• Avoid somatostatin analogs (octreotide, lanreotide) entirely or use with extreme caution, as they suppress counterregulatory hormones (glucagon, growth hormone) and can precipitously worsen hypoglycemia, potentially causing fatal complications. 1, 2

Surgical Planning

Surgical resection is the definitive treatment:

• 90% of insulinomas are benign, single, and curable with surgical excision, making surgery the optimal treatment for locoregional disease. 2, 8

• Intraoperative ultrasound is mandatory and improves sensitivity to 92-97% for identifying small lesions during surgery. 2

• Surgical approach depends on tumor location: enucleation for exophytic/peripheral tumors, distal pancreatectomy with splenic preservation for body/tail lesions, or pancreatoduodenectomy for deep tumors in the pancreatic head. 2

Critical Pitfalls to Avoid

• Do not delay imaging based on the renal cysts—these are unrelated to the hyperinsulinism and should not distract from urgent insulinoma workup. 6

• Do not measure chromogranin A if the patient is on proton pump inhibitors, as these medications cause spuriously elevated levels; patients must be off PPIs for at least 1 week before testing. 2

• Do not assume the renal cysts indicate chronic kidney disease without checking renal function; however, if advanced CKD is present (GFR <20 mL/min/1.73 m²), decreased insulin clearance by the kidney could contribute to hypoglycemia risk. 6

• Do not use somatostatin analogs for preoperative glucose control in insulinoma patients, as this can worsen hypoglycemia by suppressing counterregulatory hormones more than insulin secretion. 1, 2