What laboratory tests should be obtained for a patient with documented hypoglycemia and compatible symptoms?

Laboratory Tests for Documented Hypoglycemia

When a patient presents with documented hypoglycemia and compatible symptoms, obtain a comprehensive hypoglycemic blood panel that includes glucose, insulin, C-peptide, pro-insulin, beta-hydroxybutyrate, and a sulfonylurea/oral hypoglycemic agent screen to determine the underlying mechanism. 1, 2, 3

Immediate Confirmatory Testing

• Confirm the hypoglycemia with laboratory plasma glucose measurement rather than relying solely on point-of-care testing, as capillary glucose meters can be inaccurate in critically ill patients 4
• Document that Whipple's triad is fulfilled: symptoms/signs of hypoglycemia, low plasma glucose concentration, and resolution of symptoms after glucose correction 2, 3
• For critically ill patients with invasive monitoring, draw blood samples from arterial lines and analyze using blood gas analyzers or central laboratory methods rather than glucose meters 4

Essential Hypoglycemic Blood Panel

When hypoglycemia is documented, the following tests should be obtained simultaneously during the hypoglycemic episode (ideally when glucose <55 mg/dL):

• Plasma glucose (laboratory measurement, not fingerstick) 1, 5, 3
• Serum insulin level to assess for endogenous hyperinsulinism or exogenous insulin administration 6, 2, 3
• C-peptide level to distinguish endogenous insulin secretion (elevated C-peptide) from exogenous insulin administration (suppressed C-peptide) 1, 2, 3
• Pro-insulin level as insulinomas characteristically produce excess pro-insulin 2, 3
• Beta-hydroxybutyrate which should be suppressed (<2.7 mmol/L) in insulin-mediated hypoglycemia but elevated in non-insulin-mediated causes 2
• Plasma or urine sulfonylurea/oral hypoglycemic agent screen to detect factitious hypoglycemia from oral agents 2, 3
• Insulin antibodies to evaluate for insulin autoimmune syndrome (Hirata syndrome), particularly in patients with autoimmune conditions like Graves' disease 6, 7

Additional Diagnostic Tests Based on Clinical Context

For Suspected Hormonal Deficiency

• Cortisol level and ACTH to rule out adrenal insufficiency or hypopituitarism, which are important causes of hypoglycemia 6, 7
• Growth hormone level if hypopituitarism is suspected 6

For Suspected Non-Islet Cell Tumor Hypoglycemia (NICTH)

• IGF-1 and IGF-2 levels as large mesenchymal, epithelial, or hematopoietic tumors can secrete "Big-IGF2" causing hypoglycemia with suppressed insulin, C-peptide, and IGF-1 8, 6, 7
• CT or MRI of chest, abdomen, and pelvis to identify occult tumors when NICTH is suspected 8, 9

For Metabolic or Organ Dysfunction

• Complete metabolic panel including creatinine and eGFR as acute kidney injury dramatically increases hypoglycemia risk due to decreased insulin clearance 8, 9
• Liver function tests since hepatic failure impairs gluconeogenesis and can cause hypoglycemia 7, 5
• Lactate and ammonia if inborn errors of metabolism are suspected, particularly in patients with systemic involvement (rhabdomyolysis, hepatomegaly, cardiomyopathy) 6

Timing-Specific Diagnostic Approaches

Fasting Hypoglycemia

• If hypoglycemia occurs in the fasting state, consider a supervised 72-hour fast test with serial measurements of glucose, insulin, C-peptide, pro-insulin, and beta-hydroxybutyrate to provoke and characterize the hypoglycemic episode 2, 3
• Fasting hypoglycemia suggests insulinoma, non-islet cell tumors, hormonal deficiencies, or glycogen storage disorders 6, 5

Postprandial (Reactive) Hypoglycemia

• For predominantly postprandial symptoms, perform a mixed meal test rather than a prolonged fast 2
• Postprandial hypoglycemia may indicate post-bariatric surgery hypoglycemia, glucokinase-activating mutations, insulin receptor mutations, or inherited fructose intolerance 6, 2

Critical Pitfalls to Avoid

• Do not rely on capillary glucose meters alone in critically ill patients, as they can be inaccurate; use arterial samples analyzed by blood gas analyzers or central laboratory 4
• Do not dismiss borderline-low fasting glucose values (<100 mg/dL) in hospitalized patients, as they predict subsequent hypoglycemia on the following day 1
• Do not delay obtaining the hypoglycemic blood panel—samples must be drawn during the hypoglycemic episode, not after glucose correction, as insulin and C-peptide levels will normalize 2, 3
• Do not overlook factitious hypoglycemia from surreptitious insulin or sulfonylurea use, particularly in patients with mental health issues or healthcare workers with access to medications 6, 2
• Minimize glycolysis in samples by using tubes with citrate buffer or placing samples immediately in ice-water slurry and centrifuging within 15-30 minutes 1

Interpretation Algorithm

High insulin + High C-peptide → Endogenous hyperinsulinism (insulinoma, nesidioblastosis, sulfonylurea use, insulin autoimmune syndrome) 2, 3

High insulin + Low C-peptide → Exogenous insulin administration (factitious hypoglycemia) 2, 3

Low insulin + Low C-peptide + Low IGF-1 → Non-islet cell tumor hypoglycemia (Big-IGF2 secretion) 6, 7

Low insulin + Low C-peptide + Normal IGF-1 → Hormonal deficiency, liver failure, renal failure, or alcohol-induced hypoglycemia 6, 7, 5