What investigations are recommended for recurrent hypoglycaemia?

Investigation for Recurrent Hypoglycaemia

Immediate Documentation and Assessment at Every Clinical Encounter

Assess hypoglycemia history at every clinical encounter, documenting frequency, severity, timing, precipitants, symptoms (or lack thereof), and treatment approach to identify patterns revealing underlying causes. 1, 2

• Record whether events are fasting (>8 hours without food) or postprandial (within 4 hours of eating), as this distinction guides subsequent testing 3, 4
• Correlate all home glucose readings from meters and CGM systems with symptoms and treatment, since patients frequently treat symptoms without checking glucose, treat normal values as hypoglycemic, or tolerate hypoglycemia without treatment 1, 2
• Classify every event using standardized definitions: Level 1 (glucose <70 mg/dL but ≥54 mg/dL), Level 2 (glucose <54 mg/dL), or Level 3 (severe event requiring assistance) 1
• Prior Level 2 or 3 hypoglycemic events within the past 3-6 months are the strongest predictors of recurrence and mandate immediate investigation 1, 2

Screening for Impaired Hypoglycemia Awareness

Screen for impaired hypoglycemia awareness at least yearly using validated questionnaires, as this dramatically increases risk for severe hypoglycemia and requires immediate treatment modification. 1

• Use the single-question Pedersen-Bjergaard or Gold tools for rapid screening, or the longer Clarke or HypoA-Q questionnaires for comprehensive evaluation 1
• Ask specifically: "Do you ever experience low blood glucose without feeling symptoms?" and "At what glucose level do you typically begin feeling symptoms?" 2
• Impaired awareness occurs when patients do not experience typical counterregulatory hormone release or associated symptoms at low glucose levels, often presenting with confusion as the first sign 1

Systematic Risk Factor Evaluation

Medication-Related Investigation

• Review all glucose-lowering medications, particularly insulin regimens (multiple daily injections, pumps, automated delivery systems) and sulfonylureas 2
• Check for drug interactions if patient uses sulfonylureas, as fluoroquinolones, clarithromycin, sulfamethoxazole-trimethoprim, metronidazole, and fluconazole dramatically increase sulfonylurea effect and cause severe hypoglycemia 2, 5
• Assess additive effects of multiple glucose-lowering agents (e.g., basal insulin + rapid-acting insulin + GLP-1 agonist) 2
• Screen plasma and urine for sulfonylureas and exogenous insulin to detect factitious hypoglycemia in patients with mental health issues 3

Organ Function Assessment

• Check renal function immediately, as end-stage kidney disease dramatically increases hypoglycemia risk through altered insulin clearance 2, 5
• Evaluate hepatic function, as liver disease impairs gluconeogenesis and glycogenolysis 4, 6
• Assess for critical illness, which can cause hypoglycemia through multiple mechanisms 4, 6

Endocrine and Metabolic Evaluation

• Screen for hormonal deficiencies including cortisol (primary adrenal insufficiency) and growth hormone/ACTH (hypopituitarism), as these impair counterregulatory responses 3, 4, 6
• Evaluate for cognitive impairment or dementia, which has a bidirectional association with hypoglycemia 2

Social Determinants Assessment

• Screen for food insecurity, as this is strongly associated with increased hypoglycemia-related emergency visits and hospitalizations 2
• Assess low-income status or residence in socioeconomically deprived areas, which independently increase hypoglycemia risk 2

Supervised Diagnostic Testing When Organic Cause Suspected

For Fasting Hypoglycemia

Perform a supervised 72-hour fast with measurement of plasma glucose, insulin, C-peptide, pro-insulin, and beta-hydroxybutyrate levels when Whipple's triad is present (symptoms/signs of hypoglycemia, low plasma glucose, resolution after glucose correction). 3, 4

• This test forms the first step in diagnostic evaluation for suspected insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome, or insulin autoimmune syndrome 3
• Obtain plasma/urine sulfonylurea screen during the fast to exclude factitious hypoglycemia 3

For Postprandial Hypoglycemia

Perform a mixed meal test rather than oral glucose tolerance test for patients with predominantly postprandial symptoms, as the OGTT has poor reproducibility with 37% of patients changing diagnostic classification on repeat testing. 3, 7, 8

• The mixed meal test better recreates the physiologic situation under which symptoms occur 3, 4
• Oral glucose tolerance testing is unreliable for diagnosing reactive hypoglycemia, with glucose nadirs showing significant variability between consecutive tests 7, 8
• Accurate diagnosis requires symptoms developing concurrently with documented low blood sugar and absent at other times, not just a low glucose nadir 8

Common Pitfalls to Avoid

• Never rely on patient self-diagnosis of hypoglycemia without documented glucose correlation, as placebo tests provoke symptoms patients consider indicative of hypoglycemia even when normoglycemic 8
• Do not pursue extensive workup without first confirming Whipple's triad, as hypoglycemia is uncommon in people not on glucose-lowering medications 4
• Avoid using OGTT for postprandial hypoglycemia diagnosis given its poor reproducibility and overlap between hypoglycemic and control subjects 7, 8