What is the appropriate workup for hypoglycemia (low blood sugar)?

Workup of Hypoglycemia

The workup of hypoglycemia begins with immediate blood glucose measurement to confirm the diagnosis (threshold <70 mg/dL or 3.9 mmol/L), followed by systematic investigation of the underlying cause through medication review, assessment of timing relative to meals and insulin administration, and evaluation for risk factors including insulin deficiency, prior severe hypoglycemia episodes, and hypoglycemia unawareness. 1, 2

Immediate Diagnostic Confirmation

• Measure blood glucose immediately when hypoglycemia is suspected based on symptoms (shakiness, confusion, tachycardia, diaphoresis, altered mental status) 1, 2
• If glucose testing is unavailable, initiate treatment immediately and confirm the diagnosis retrospectively 2
• Document all symptoms and their resolution with treatment to establish the clinical pattern 2

Classification of Hypoglycemia Severity

The workup should categorize the episode by severity to guide further investigation:

• Level 1 (Alert value): Glucose 54-70 mg/dL (3.0-3.9 mmol/L) 1, 2
• Level 2 (Clinically significant): Glucose <54 mg/dL (<3.0 mmol/L) - threshold for neuroglycopenic symptoms 1, 2
• Level 3 (Severe): Cognitive impairment requiring external assistance, regardless of specific glucose level 1, 2

Systematic Investigation of Etiology

Medication-Related Causes (Most Common in Diabetes)

• Review all antidiabetic medications: insulin doses, timing, and type; oral hypoglycemic agents 1, 2, 3
• Assess for absolute or relative insulin excess from incorrect dosing or timing 3
• Evaluate medication interactions with alcohol and other drugs that may potentiate hypoglycemia 3
• Check for medications with increased hypoglycemia risk based on renal function 4

Temporal Pattern Analysis

• Fasting hypoglycemia suggests: glycogen storage disorders (types 0, I, III), fatty acid oxidation defects, gluconeogenesis disorders, or insulinoma 5
• Postprandial hypoglycemia suggests: inherited fructose intolerance, glucokinase-activating mutations, insulin receptor mutations, post-bariatric surgery, or reactive hypoglycemia 5
• Exercise-induced hypoglycemia suggests: SLC16A1 gene mutations or inadequate carbohydrate intake relative to activity 3, 5

Assessment of Glucose Counterregulation

Evaluate for clinical surrogates of compromised counterregulation:

• History of severe hypoglycemia or hypoglycemia unawareness - indicates defective glucagon and epinephrine responses 3
• Degree of endogenous insulin deficiency (C-peptide levels if indicated) 3, 5
• Recent antecedent hypoglycemia episodes creating a vicious cycle of impaired counterregulation 3
• Lower HbA1c levels or aggressive glycemic targets suggesting iatrogenic risk 3

Evaluation for Non-Diabetic Causes

When hypoglycemia occurs in patients without diabetes or cannot be explained by medications:

Endocrine Evaluation

• Cortisol insufficiency and hypopituitarism 5
• Glucagon deficiency 5

Tumor-Related Causes

• Insulinoma: Check insulin, C-peptide, and proinsulin levels during hypoglycemic episode 5
• Non-Islet Cell Tumor Hypoglycemia (NICTH): Measure Big-IGF2, with expected low insulin, C-peptide, and IGF-1 levels 5
• Ectopic insulin secretion (rare) 5

Autoimmune Causes

• Insulin autoantibodies (Hirata syndrome), especially with Graves' disease history 5
• Insulin receptor antibodies 5

Genetic/Metabolic Causes

• Consider when systemic involvement present: rhabdomyolysis after fasting/exercise, cardiomyopathy, hepatomegaly, or family history of hypoglycemia 5
• Inborn errors of metabolism may present in adulthood 5

Other Causes

• Critical illness 5
• Alcohol consumption 3, 5
• Post-gastric or bariatric surgery 5
• Pancreas transplantation 5
• Surreptitious insulin or sulfonylurea use 5

Risk Stratification

Identify high-risk patients requiring intensified monitoring:

• Those with hypoglycemia unawareness (one or more Level 3 episodes) 1
• Patients with defective glucose counterregulation 3
• History of recurrent hypoglycemia creating autonomic failure 3
• Consider continuous glucose monitoring for high-risk individuals 4, 2

Common Pitfalls to Avoid

• Do not confuse hypoglycemia with hyperglycemia - symptoms can overlap, making glucose measurement essential 6
• Recognize that neurogenic and neuroglycopenic symptoms are nonspecific and insensitive - many episodes go unrecognized 3
• Do not overlook medication review when blood glucose <70 mg/dL is documented 2
• Remember that in insulin-deficient diabetes, exogenous insulin levels do not decrease as glucose falls, eliminating the first line of defense 3