What is the workup for persistent hypoglycemia in a cancer patient?

Workup for Persistent Hypoglycemia in Cancer Patients

In a cancer patient with persistent hypoglycemia, immediately perform a supervised fast with simultaneous measurement of insulin, C-peptide, and glucose levels, followed by a glucagon stimulation test to distinguish between insulinoma and non-islet cell tumor hypoglycemia (NICTH), as this determines both prognosis and treatment strategy. 1, 2

Initial Diagnostic Evaluation

Laboratory Testing During Hypoglycemia

The cornerstone of diagnosis requires obtaining specific labs when blood glucose is <45 mg/dL 1:

• Insulin level: Should be >3 mcIU/mL (usually >6 mcIU/mL) in insulinoma; will be <1 uIU/mL in NICTH 1, 3
• C-peptide: Elevated in insulinoma; low (<0.16 ng/mL) in NICTH 1, 4, 3
• Insulin-to-glucose ratio: ≥0.3 indicates inappropriate insulin secretion from insulinoma 1
• Urinary sulfonylurea: Must be checked to rule out factitious hypoglycemia 1

Extended Fasting Test

If the diagnosis remains uncertain, perform a 48-72 hour observed inpatient fast 1. This test is critical because it captures the biochemical profile during spontaneous hypoglycemia and differentiates endogenous hyperinsulinism from other causes.

Glucagon Stimulation Test

Administer 1 mg glucagon intravenously and measure serial glucose levels 2:

• Rise in glucose >30 mg/dL: Indicates adequate hepatic glycogen stores, suggesting insulinoma or insulin-like tumor product (IGF-II mediated NICTH) 2
• No glucose rise: Indicates depleted hepatic glycogen or liver failure, suggesting NICTH with hepatic involvement 2

This test serves dual purposes: diagnostic clarification and prediction of response to glucagon therapy 2.

Tumor-Specific Workup

For Suspected Insulinoma

Endoscopic ultrasound (EUS) is the primary localization study, detecting approximately 82% of pancreatic neuroendocrine tumors 1. Additional imaging includes:

• Multiphasic CT or MRI to rule out metastatic disease 1
• Chromogranin A levels (though less specific) 1
• Avoid Octreoscan unless octreotide therapy is planned, as insulinomas are less consistently octreotide-avid, and octreotide can paradoxically worsen hypoglycemia in octreoscan-negative tumors 1

For persistent or recurrent insulinoma when other tests are equivocal, consider selective arterial calcium stimulation with hepatic venous sampling (Imamura-Doppman procedure) 1.

For Suspected NICTH

When insulin and C-peptide are suppressed, measure 4, 3:

• IGF-II levels: Typically elevated (>290 ng/mL) 3
• IGF-I levels: Usually low (<51 ng/mL) 3
• IGF-II/IGF-I ratio: Elevated ratio confirms NICTH 4
• "Big" IGF-II: Gold standard but not widely available 3
• Beta-hydroxybutyrate: Low in NICTH 4

Imaging for Tumor Localization

Perform comprehensive imaging to identify the primary tumor and assess metastatic burden 1:

• Multiphasic contrast-enhanced CT or MRI of chest, abdomen, and pelvis 1
• Focus on hepatocellular carcinoma, mesenchymal tumors, and sarcomas as most common causes 2, 5, 6

Critical Pitfalls to Avoid

Do not measure gastrin or other hormone levels while patient is on proton pump inhibitors, as these falsely elevate gastrin and chromogranin A 1. Discontinue PPIs for at least 1 week before testing 1.

Never administer octreotide to patients with suspected insulinoma without confirming octreoscan positivity, as it can profoundly worsen hypoglycemia in the absence of somatostatin receptors 1.

Recognize that approximately 50% of NICTH patients present with hypokalemia (potassium <2.8 mEq/L), which should prompt consideration of this diagnosis 3.

Additional Considerations

In patients with known liver metastases and hypoglycemia, the glucagon stimulation test rapidly distinguishes between insulin-mediated hypoglycemia (insulinoma or IGF-II producing tumors with preserved hepatic function) versus hepatic failure-related hypoglycemia 2. This distinction is crucial because treatment strategies differ fundamentally: the former may respond to continuous glucagon infusion (0.06-0.3 mg/hour), while the latter requires cytoreduction or supportive care 2, 6.

Maintain high clinical suspicion for NICTH in patients with hepatocellular carcinoma, even those with pre-existing chronic hypoglycemia from cirrhosis, as NICTH can be the initial presentation and is often underdiagnosed 4.