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

From the Guidelines

The workup for hypoglycemia should begin with confirming true hypoglycemia (blood glucose <70 mg/dL) and documenting Whipple's triad: low blood glucose, symptoms of hypoglycemia, and resolution of symptoms with glucose administration, as recommended by the most recent guidelines 1. The initial evaluation includes a comprehensive history focusing on medication use (especially insulin, sulfonylureas), alcohol consumption, liver or kidney disease, and timing of symptoms relative to meals.

• Key aspects of the history include:
  • Medication use, particularly insulin and sulfonylureas
  • Alcohol consumption
  • Liver or kidney disease
  • Timing of symptoms relative to meals Laboratory tests should include a basic metabolic panel, liver function tests, and measurement of insulin, C-peptide, and proinsulin levels during a hypoglycemic episode, as suggested by previous studies 1.
• The laboratory tests aim to:
  • Evaluate the patient's metabolic status
  • Assess liver and kidney function
  • Measure insulin and related hormone levels A 72-hour supervised fast is the gold standard test for diagnosing hypoglycemia, particularly for suspected insulinoma, as it allows for the collection of blood samples for glucose, insulin, C-peptide, and beta-hydroxybutyrate when glucose levels fall below 60 mg/dL or symptoms occur 1.
• During the fast, the following should be monitored:
  • Glucose levels
  • Insulin and C-peptide levels
  • Beta-hydroxybutyrate levels Additional testing may include sulfonylurea screening, insulin antibodies, cortisol levels, and growth hormone to evaluate for endocrine causes, as recommended by recent guidelines 1.
• These tests help to:
  • Identify potential causes of hypoglycemia
  • Evaluate the patient's endocrine function Imaging studies such as CT, MRI, or endoscopic ultrasound may be necessary if an insulinoma is suspected, as they can help to localize the tumor and guide further management 1.
• The choice of imaging study depends on:
  • The suspected location of the tumor
  • The patient's overall health status For reactive hypoglycemia, a mixed-meal test may be more appropriate than a prolonged fast, as it can help to evaluate the patient's glucose response to a meal and identify potential causes of hypoglycemia 1.
• The mixed-meal test involves:
  • Administering a standardized meal
  • Measuring glucose and hormone levels over time The workup aims to distinguish between exogenous causes (medication-induced), endogenous hyperinsulinism (insulinoma, nesidioblastosis), and non-insulin mediated causes (liver disease, adrenal insufficiency), as outlined in recent guidelines 1.
• The differential diagnosis includes:
  • Exogenous causes (e.g. medication-induced)
  • Endogenous hyperinsulinism (e.g. insulinoma)
  • Non-insulin mediated causes (e.g. liver disease)

From the Research

Workup for Hypoglycemia

• The workup for hypoglycemia involves evaluating patients in whom Whipple's triad is documented, which includes symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised 2.
• In patients with hypoglycemia without diabetes mellitus, the strategy involves pursuing clinical clues to potential hypoglycemic etiologies, such as drugs, critical illnesses, hormone deficiencies, and nonislet cell tumors 2.
• If no cause is found, the differential diagnosis narrows to accidental, surreptitious, or malicious hypoglycemia or endogenous hyperinsulinism, and measurements of plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and circulating oral hypoglycemic agents during an episode of hypoglycemia are recommended 2.
• Insulin or insulin secretagogue treatment of diabetes mellitus is the most common cause of hypoglycemia, and hypoglycemia risk factor reduction is recommended in persons with diabetes, including addressing the issue of hypoglycemia, applying the principles of intensive glycemic therapy, and considering both conventional risk factors and those indicative of compromised defenses against falling plasma glucose concentrations 2, 3.

Diagnostic Approach

• The American Diabetes Association Standards of Medical Care recommends that a management protocol for hypoglycemia should be designed and implemented by every hospital, along with a clear prevention and treatment plan 3.
• Continuous glucose monitoring (CGM) should be considered for all individuals with increased risk for hypoglycemia, impaired hypoglycemia awareness, frequent nocturnal hypoglycemia, and with a history of severe hypoglycemia 3.
• Patients with impaired awareness of hypoglycemia benefit from real-time CGM, and conversations about hypoglycemia facilitated by a healthcare professional may reduce the burden and fear of hypoglycemia among patients with diabetes and their family members 3, 4.

Treatment and Prevention

• Therapies for diabetes that increase the risk of hypoglycemia include all insulins and insulin secretagogues, such as glinides and sulfonylureas 4, 5.
• Education and regular review are essential between people with diabetes and their caregivers and healthcare professionals about symptoms, prevention, and treatment of hypoglycemia 4.
• Optimizing insulin doses and carbohydrate intake, in addition to a short warm-up before or after physical activity sessions, may help avoid hypoglycemia, and several therapeutic considerations are important to reduce hypoglycemia risk during pregnancy 3.