Hypoglycemia Workup
The workup for hypoglycemia begins with documenting Whipple's triad during a symptomatic episode: low blood glucose (<70 mg/dL), neuroglycopenic symptoms, and resolution of symptoms when glucose normalizes—without this confirmation, further investigation is unnecessary. 1
Initial Assessment and Documentation
Confirm True Hypoglycemia
- Obtain laboratory-measured blood glucose during symptoms, not just point-of-care testing, as many patients are asymptomatic and normoglycaemic at review 1
- Verify all three components of Whipple's triad are present before proceeding with extensive workup 1
- In ambulatory patients, blood glucose levels obtained during normal diet intake are more reliable than glucose tolerance testing 2
Critical Blood Samples During Hypoglycemic Episode
When blood glucose is <70 mg/dL with symptoms, immediately obtain blood for:
- Laboratory glucose measurement (confirmatory) 1
- Insulin level 1, 3
- C-peptide 1, 3
- Proinsulin 1
- Beta-hydroxybutyrate 1
These samples will classify hypoglycemia into three categories that direct further investigation: non-ketotic hyperinsulinaemia, non-ketotic hypoinsulinaemia, or ketotic hypoinsulinaemia 1
History and Risk Factor Assessment
Medication and Substance History
- Document all medications, self-medications, and access to hypoglycemic drugs including insulin, sulfonylureas, and other diabetes medications 1, 4
- Assess alcohol use, as it is a common cause of hypoglycemia 3, 5
- Review drug interactions that may potentiate hypoglycemia 6, 7
Timing of Hypoglycemic Episodes
- Fasting hypoglycemia suggests glycogen storage disorders (types 0, I, III), fatty acid oxidation disorders, gluconeogenesis disorders, insulinoma, or cortisol insufficiency 3
- Postprandial hypoglycemia suggests inherited fructose intolerance, post-bariatric surgery dumping syndrome, glucokinase-activating gene mutations, or insulin receptor mutations 3
- Exercise-induced hypoglycemia suggests SLC16A1 gene mutations 3
High-Risk Populations Requiring Evaluation
- Patients with renal impairment (increased hypoglycemia risk due to reduced insulin clearance and impaired renal gluconeogenesis) 7, 3
- Patients with hepatic impairment (impaired gluconeogenesis and insulin clearance) 7, 3
- Elderly patients with reduced ability to recognize symptoms 6
- Young children with type 1 diabetes who cannot effectively communicate symptoms 6
- Patients with cognitive impairment (bidirectional association with hypoglycemia) 6
Social and Economic Risk Factors
- Food insecurity (associated with increased hypoglycemia-related emergency visits) 6
- Low household income, socioeconomic deprivation, underinsured, or homeless status 6
- Cultural practices such as religious fasting 6
Diagnostic Workup Algorithm
For Diabetic Patients
If the patient is on insulin or insulin secretagogues:
- Review insulin regimen, dosing, timing, and injection sites 7
- Check for lipodystrophy or localized cutaneous amyloidosis at injection sites (causes erratic absorption) 7
- Assess for medication errors, missed meals, or changes in physical activity 6, 7
- Evaluate for hypoglycemia unawareness (requires 2-3 weeks of scrupulous hypoglycemia avoidance) 5
- Consider continuous glucose monitoring for patients with impaired hypoglycemia awareness, frequent nocturnal hypoglycemia, or history of severe hypoglycemia 4
Common pitfall: Insulin pump malfunction can rapidly cause hyperglycemia, but overcorrection leads to hypoglycemia—always verify pump function 7
For Non-Diabetic Patients (Spontaneous Hypoglycemia)
If severely ill or hospitalized:
- Recognize that hypoglycemia may occur in critical illness—prevention is key, and further investigation is unnecessary unless another cause is suspected 1
- Check for excessive insulin/oral hypoglycemic agent administration, drug effects, or chronic renal failure as most common causes 2
If ambulatory and otherwise healthy:
Provoke hypoglycemia under controlled conditions (fasting or postprandial as directed by symptom timing) 1
Analyze hypoglycemic blood samples to classify the type:
- Non-ketotic hyperinsulinaemia (elevated insulin, C-peptide): suggests insulinoma, sulfonylurea use, insulin autoimmune syndrome (Hirata syndrome), or insulin receptor antibodies 3
- Non-ketotic hypoinsulinaemia (low insulin, low C-peptide): suggests non-islet cell tumor hypoglycemia (NICTH) with Big-IGF2 secretion—check IGF-1 (will be low) 3
- Ketotic hypoinsulinaemia: suggests cortisol deficiency, hypopituitarism, or inborn errors of metabolism 3
Evaluate for endocrine causes if initial workup is unrevealing:
Screen for paraneoplastic and autoimmune causes:
Management During Workup
Immediate Treatment Protocol
- Administer 15-20 grams of oral glucose (pure glucose tablets preferred) when blood glucose is <70 mg/dL 8
- Recheck glucose after 15 minutes and repeat treatment if still <70 mg/dL 8
- For severe hypoglycemia with altered mental status, administer glucagon (if available) or 10-20 grams IV 50% dextrose 8
Prevention During Investigation
- Prescribe glucagon for all patients at risk of severe hypoglycemia 8
- Educate patients to carry glucose tablets at all times 8
- Adjust insulin doses by 25-50% in patients with renal impairment 9
- Avoid overly tight glycemic control during workup (keep glucose >70 mg/dL) 9
Critical pitfall: Many episodes are misdiagnosed because symptoms are nonspecific and blood glucose is not measured during symptoms—clinical acumen requires laboratory confirmation during symptomatic episodes 1, 5