What causes hypoglycemia (low blood sugar) in non-diabetic individuals?

Causes of Hypoglycemia in Non-Diabetic Individuals

The primary causes of hypoglycemia in non-diabetic individuals include medications, endocrine disorders, critical illness, organ failure, tumors, autoimmune conditions, and post-bariatric surgery complications.

Definition of Hypoglycemia

Hypoglycemia is defined as a blood glucose level below 70 mg/dL (<3.9 mmol/L), with severity classified as:

• Level 1: Glucose <70 mg/dL but ≥54 mg/dL
• Level 2: Glucose <54 mg/dL
• Level 3: Severe event with altered mental/physical status requiring assistance 1

Major Causes of Hypoglycemia in Non-Diabetics

1. Medication-Related Causes

• Non-diabetes medications:
  • NSAIDs
  • Antibacterials (especially quinolones)
  • Antimalarials
  • Antiarrhythmics
  • Antidepressants
  • Beta-blockers
  • Warfarin (can increase hypoglycemia risk) 2, 3
• Alcohol consumption: Inhibits gluconeogenesis and can cause severe hypoglycemia, especially when combined with malnutrition 4, 5

2. Endocrine Disorders

• Insulinoma: Pancreatic beta-cell tumor causing inappropriate insulin secretion 4
• Hormonal deficiencies:
  • Adrenal insufficiency (cortisol deficiency)
  • Hypopituitarism
  • Glucagon deficiency 4, 6

3. Critical Illness and Organ Failure

• Hepatic failure: Reduced glycogen storage and impaired gluconeogenesis 1
• Renal failure: Decreased renal gluconeogenesis, impaired insulin clearance 1
• Sepsis: Increased glucose utilization and impaired counterregulatory responses 1
• Cardiac insufficiency: Reduced tissue perfusion affecting glucose metabolism 5

4. Tumor-Related Causes

• Non-islet cell tumor hypoglycemia (NICTH): Large mesenchymal tumors secreting IGF-II 4, 6
• Ectopic insulin secretion: Rare paraneoplastic syndrome 4

5. Autoimmune Conditions

• Insulin autoimmune syndrome (Hirata syndrome): Antibodies against insulin, especially in patients with Graves' disease 4
• Insulin receptor antibodies: Autoantibodies binding to insulin receptors 4, 6

6. Post-Surgical Causes

• Post-bariatric surgery hypoglycemia: Altered gut hormone secretion after gastric bypass 4, 6
• Post-gastrectomy hypoglycemia: Rapid gastric emptying causing reactive hypoglycemia 5

7. Genetic Disorders

• Monogenic congenital hyperinsulinism: Mutations in genes regulating insulin secretion
• Inborn errors of metabolism (IEM):
  • Glycogen storage disorders (types 0, I, III)
  • Fatty acid oxidation disorders
  • Gluconeogenesis disorders
  • Inherited fructose intolerance 4

8. Nutritional and Other Causes

• Food insecurity: Irregular or inadequate food intake 1
• Fasting: Religious or cultural fasting 1
• Malnutrition: Inadequate substrate for gluconeogenesis 1
• Factitious hypoglycemia: Surreptitious insulin or oral hypoglycemic agent use 4, 6

Risk Factors for Severe Hypoglycemia

• Age ≥75 years: Higher risk due to impaired counterregulatory responses 1
• Female sex: Independent risk factor for hypoglycemia 1
• End-stage kidney disease: Impaired insulin clearance and gluconeogenesis 1
• Cognitive impairment/dementia: May not recognize or report symptoms 1
• Low albumin levels: Marker for malnutrition and predictor of hypoglycemia 1
• Polypharmacy: Increased risk of drug interactions 1

Clinical Presentation

Symptoms of hypoglycemia include:

• Shakiness, irritability, confusion
• Tachycardia, sweating, hunger
• Neuroglycopenic symptoms at glucose <54 mg/dL
• Altered mental status in severe cases 1

Diagnostic Approach

Diagnosis requires establishing Whipple's triad:

1. Symptoms consistent with hypoglycemia
2. Low plasma glucose (<70 mg/dL)
3. Resolution of symptoms with glucose administration 6

For accurate diagnosis:

• Evaluate during spontaneous hypoglycemic episodes when possible
• For fasting hypoglycemia, conduct a supervised 72-hour fast
• For postprandial symptoms, perform a mixed meal test 6

Management of Acute Hypoglycemia

For immediate treatment of hypoglycemia:

• Administer 15-20g of fast-acting carbohydrates
• Recheck glucose after 15 minutes; repeat treatment if hypoglycemia persists
• For severe hypoglycemia (Level 3), glucagon administration may be necessary 1, 2

Prevention Strategies

• Identify and address risk factors: Especially in elderly or those with renal/hepatic disease
• Medication review: Adjust or discontinue medications that may cause hypoglycemia
• Regular meals: Ensure adequate and regular nutritional intake
• Monitor glucose: Consider monitoring in high-risk individuals
• Education: Teach recognition and management of hypoglycemic symptoms

Remember that hypoglycemia in non-diabetic individuals often indicates a serious underlying condition and warrants thorough investigation to identify and address the root cause.