What are the differential diagnoses for hypoglycemia (low blood sugar)?

Differential Diagnosis for Hypoglycemia

Primary Diagnostic Categories

The differential diagnosis for hypoglycemia must be systematically approached by first determining whether the patient has diabetes and is on glucose-lowering medications, as this represents the overwhelming majority of cases, followed by evaluation for rare endogenous and exogenous causes in non-diabetic patients. 1, 2

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In Patients with Diabetes (Most Common)

Medication-Related Causes

• Insulin excess: Overdosage, incorrect timing, or inappropriate insulin type relative to food intake 3, 1, 4
• Sulfonylureas: Excessive dosing or impaired clearance 5
• Meglitinides (e.g., repaglinide): Particularly when meals are skipped or with drug interactions 3
• Drug interactions: Gemfibrozil (contraindicated with repaglinide), clopidogrel, cyclosporine, and CYP3A4/CYP2C8 inhibitors increase hypoglycemia risk 3

Clinical Risk Factors in Diabetic Patients

• Impaired counterregulation: History of recurrent hypoglycemia leading to hypoglycemia-associated autonomic failure 1, 5
• Renal impairment: End-stage kidney disease or eGFR <60 mL/min increases risk 6, 3
• Hepatic impairment: Reduced drug clearance and impaired gluconeogenesis 3
• Cognitive impairment or dementia: Inability to recognize or treat hypoglycemia 6
• Alcohol or substance use disorder: Impairs gluconeogenesis and counterregulation 6
• Food insecurity or fasting: Inadequate carbohydrate intake relative to medication 6

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In Non-Diabetic Patients (Rare Causes)

Endogenous Hyperinsulinism

• Insulinoma: Functioning islet-cell tumor causing inappropriate insulin secretion 2, 7
• Post-bariatric surgery hypoglycemia: Particularly after gastric bypass, causing postprandial hyperinsulinism 2
• Genetic causes:
  • Glucokinase-activating gene mutations (postprandial hypoglycemia with marked hyperinsulinism) 2
  • Insulin receptor mutations 2
  • SLC16A1 gene mutations (exercise-induced hyperinsulinism) 2

Hormonal Deficiencies

• Cortisol insufficiency: Adrenal insufficiency or hypopituitarism 2
• Glucagon deficiency: Rare, often post-pancreas transplantation 2
• Growth hormone deficiency: Particularly in children but can present in adults 2

Inborn Errors of Metabolism (IEM)

• Fasting hypoglycemia patterns:
  • Glycogen storage disorders (types 0, I, III) 2
  • Fatty acid oxidation disorders 2
  • Gluconeogenesis disorders 2
• Postprandial hypoglycemia: Hereditary fructose intolerance 2
• Associated features: Rhabdomyolysis after fasting/exercise, hepatomegaly, cardiomyopathy, family history 2

Paraneoplastic and Tumor-Related

• Non-islet cell tumor hypoglycemia (NICTH): Large mesenchymal, epithelial, or hematopoietic tumors secreting Big-IGF2 2
  • Characterized by low insulin, low C-peptide, and low IGF-1 levels 2
• Ectopic insulin secretion: Extremely rare 2

Autoimmune Causes

• Insulin autoimmune syndrome (Hirata disease): Antibodies against insulin, often associated with Graves' disease 2
• Insulin receptor antibodies: Cause hypoglycemia through receptor activation 2

Drug-Induced (Non-Diabetes Medications)

• Alcohol: Impairs gluconeogenesis, especially with fasting 1, 2
• Quinolones, pentamidine, quinine: Various mechanisms 2
• Beta-blockers: Mask hypoglycemic symptoms and impair counterregulation 3

Critical Illness-Related

• Sepsis: Increased glucose utilization and impaired gluconeogenesis 2
• Organ failure: Hepatic or renal failure 2
• Malnutrition: Depleted glycogen stores 2

Factitious/Surreptitious

• Exogenous insulin administration: Deliberate or accidental 2
• Sulfonylurea ingestion: Intentional or unintentional 2

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Diagnostic Approach by Timing

Fasting Hypoglycemia (>8 hours without food)

• Insulinoma, glycogen storage disorders, fatty acid oxidation defects, gluconeogenesis disorders, cortisol deficiency, NICTH 2

Postprandial Hypoglycemia (2-5 hours after meals)

• Post-bariatric surgery, genetic hyperinsulinism (glucokinase mutations, insulin receptor mutations), hereditary fructose intolerance, insulin autoimmune syndrome 2

Exercise-Induced

• SLC16A1 gene mutations, inadequate carbohydrate intake in diabetic patients on insulin 2

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Key Diagnostic Pitfalls

• Do not diagnose hypoglycemia based solely on glucose level: Many asymptomatic individuals have glucose <50 mg/dL; diagnosis requires symptoms at glucose nadir that resolve with glucose administration (Whipple's triad) 7
• Hypoglycemia may be misdiagnosed as hyperglycemia: Confusion and altered mental status can mimic hyperglycemic states 4
• Imaging for occult tumors: CT or MRI of chest, abdomen, and pelvis should be performed when NICTH is suspected 8
• Measure insulin, C-peptide, and IGF-1 during hypoglycemia: Critical for distinguishing endogenous hyperinsulinism from other causes 2