Causes of Persistent Hypoglycemia
The most common causes of persistent hypoglycemia include medication effects (particularly insulin and insulin secretagogues), advanced chronic kidney disease, hepatic failure, malnutrition, endocrine disorders, and tumors. 1
Medication-Related Causes
- Insulin therapy: Excessive dosing, timing errors, or inappropriate insulin regimens 2
- Insulin secretagogues: Sulfonylureas causing prolonged insulin secretion 3
- Other medications: Beta-blockers, alcohol, and drug interactions in polypharmacy 1
Endocrine and Metabolic Causes
- Advanced chronic kidney disease: Decreased insulin clearance and impaired renal gluconeogenesis 4
- Hepatic failure: Reduced glycogen storage and impaired gluconeogenesis 1
- Adrenal insufficiency: Cortisol deficiency impairs counterregulatory responses 5
- Hypopituitarism: Multiple hormone deficiencies affecting glucose regulation 5
- Insulinoma: Autonomous insulin-secreting pancreatic tumor 6
- Non-islet cell tumors: Production of IGF-2 by mesenchymal tumors 5
Autoimmune Causes
- Insulin autoimmune syndrome (Hirata syndrome): Antibodies against insulin, especially in Graves' disease 5
- Insulin receptor antibodies: Antibodies binding to insulin receptors 5
Post-Surgical and Anatomical Causes
- Post-bariatric surgery hypoglycemia: Altered gut hormone secretion 6
- Post-gastrectomy hypoglycemia: Rapid gastric emptying 7
Nutritional and Systemic Causes
- Malnutrition: Inadequate substrate for gluconeogenesis 1
- Sepsis: Increased glucose utilization and impaired counterregulatory responses 1
- Critical illness: Multiple factors including organ failure and inflammatory mediators 1
- Food insecurity: Irregular or inadequate food intake 1
Genetic and Inborn Errors of Metabolism
- Glycogen storage disorders: Types 0, I, or III affecting glucose release from liver 5
- Fatty acid oxidation disorders: Impaired alternative energy production during fasting 5
- Gluconeogenesis disorders: Impaired glucose production 5
- Congenital hyperinsulinism: Genetic mutations causing inappropriate insulin secretion 5
Risk Factors for Persistent Hypoglycemia
- Advanced age: Impaired counterregulatory responses in those ≥75 years 1
- Impaired awareness of hypoglycemia: Common in long-standing diabetes 4
- History of severe hypoglycemia: Increases risk for subsequent episodes 4
- Cognitive impairment: May lead to unrecognized symptoms or medication errors 1
- Low albumin levels: Marker for malnutrition and predictor of hypoglycemia 1
Special Considerations in Diabetes
For patients with diabetes, hypoglycemia often results from the interplay between insulin excess and compromised glucose counterregulation 3:
- Defective glucose counterregulation: Failure of glucagon and epinephrine responses 3
- Hypoglycemia unawareness: Reduced sympathoadrenal responses to falling glucose 3
- Hypoglycemia-associated autonomic failure: Recurrent hypoglycemia leading to blunted counterregulatory responses 3
Diagnostic Approach
Diagnosis requires establishing Whipple's triad:
- Symptoms consistent with hypoglycemia
- Low plasma glucose (<70 mg/dL)
- Resolution of symptoms with glucose administration 1
When evaluating persistent hypoglycemia, timing is important:
- Fasting hypoglycemia: Suggests insulinoma, medications, hormonal deficiencies, or inborn errors of metabolism
- Postprandial hypoglycemia: Suggests reactive causes, post-bariatric surgery, or inherited fructose intolerance 5
Understanding these diverse causes is essential for appropriate management of persistent hypoglycemia and preventing its recurrence and potentially serious consequences.