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BASICS

  • Defined by Whipple triad: low plasma glucose (≤60 mg/dL), hypoglycemic symptoms, symptom relief on glucose correction.
  • Common in diabetics with insulin secretagogues but less frequent in non-diabetics.
  • Postprandial/reactive hypoglycemia occurs 2-3 hours after meals, associated with insulin response.
  • Spontaneous (fasting) hypoglycemia linked to endocrine, metabolic, or neoplastic causes.

EPIDEMIOLOGY

  • Incidence 0.5-8.6% in hospitalized patients ≥65 years without diabetes.

ETIOLOGY AND PATHOPHYSIOLOGY

  • Reactive hypoglycemia:
  • Alimentary hyperinsulinism triggered by high carbohydrate meals, certain nutrients.
  • Glucose intolerance or prediabetes.
  • GI surgeries (e.g., Roux-en-Y gastric bypass).
  • Spontaneous (fasting) hypoglycemia:
  • Restricted food access.
  • Medication-induced (insulin, sulfonylureas, thiazolidinediones, SGLT2 inhibitors, DPP-IV inhibitors, ACE inhibitors, β-blockers, others).
  • Poisoning/toxidromes (ethanol, β-blockers, salicylates).
  • OTC/adulterated supplements containing hypoglycemic agents.
  • Natural herbs (bitter melon, ginseng, fenugreek, cinnamon, others).
  • Post-surgical syndromes.
  • Insulinomas, islet cell hyperplasia.
  • Extrapancreatic insulin-like growth factor secretion tumors.
  • Autoimmune hypoglycemia.
  • Organ failure (hepatic, renal).
  • Endocrine deficiencies (adrenal, pituitary, thyroid).
  • Ketotic hypoglycemia in childhood.
  • Congenital metabolic disorders.
  • Sepsis, cachexia, malnutrition.
  • Genetic forms: monogenic hyperinsulinism and congenital enzyme defects.

RISK FACTORS

  • Prolonged fasting or oral intake inability.
  • Alcohol, medications, pregnancy.
  • Critical illness or surgery.
  • Endocrine tumors or disorders.
  • Family history of metabolic diseases.
  • Excess caffeine intake.

GENERAL PREVENTION

  • Dietary and exercise recommendations.
  • Patient awareness of early symptoms and corrective action.

PEDIATRIC CONSIDERATIONS

  • Neonatal and childhood hypoglycemia syndromes.
  • Screen infants with maternal diabetes history.
  • Consider inborn errors of metabolism in children/young adults.

GERIATRIC CONSIDERATIONS

  • Higher prevalence of underlying disorders or medication-induced hypoglycemia.
  • Common iatrogenic causes in hospitalized elderly with renal insufficiency.

COMMONLY ASSOCIATED CONDITIONS

  • Heart failure, chronic liver and renal disease.
  • Addison disease, hypopituitarism.
  • Malnutrition.
  • GI and bariatric surgeries.
  • Insulinoma and other tumors.

DIAGNOSIS

History

  • Adrenergic symptoms: anxiety, tremulousness, diaphoresis, palpitations.
  • May be masked by β-blockers or rate-blocking CCBs.
  • CNS symptoms at glucose ≤50 mg/dL: confusion, visual changes, personality changes.
  • GI symptoms: hunger, nausea.
  • Surgical history including bariatric procedures.

Physical Exam

  • CNS symptoms: seizures, coma.
  • Adrenergic signs: tremor, sweating, palpitations.
  • Hypotension may be present.

Differential Diagnosis

  • CNS disorders.
  • Psychogenic/pseudohypoglycemia.

Diagnostic Tests

  • Document low plasma glucose ≤45 mg/dL with symptoms relieved by feeding.
  • Confirm fasting glucose ≤60 mg/dL on two occasions.
  • 72-hour fasting test: ≤45 mg/dL in females, ≤55 mg/dL in males to confirm hypoglycemia.
  • Imaging (US, CT, MRI, PET) to identify insulinoma or tumors.
  • C-peptide, insulin, ACTH, cortisol levels.
  • β-hydroxybutyrate <2.7 mg/dL with high insulin and low glucose suggests endogenous hyperinsulinism.
  • Consider drug and toxicology screens.

TREATMENT

General Measures

  • Oral carbohydrates for alert patients (e.g., sugar water, juice, milk, fruit).
  • Glucagon IM or SC if unable to swallow.
  • Avoid causative medications and alcohol.
  • For post-surgical patients, consider agents delaying gastric emptying (propantheline, fiber).
  • Nonhypoglycemic or pseudohypoglycemia may require counseling and dietary adjustments.

Medication

  • Treat underlying disorder once diagnosed.
  • Glucagon 1 mg IV/IM/SC or intranasal 3 mg; repeat dose if needed.
  • IV dextrose 25-50 g if no response to glucagon.

ISSUES FOR REFERRAL

  • Suspected metabolic/genetic disorders.
  • Intractable or refractory hypoglycemia.

SURGERY/OTHER PROCEDURES

  • Surgical removal for insulinoma or insulin-secreting tumors.
  • Diazoxide for inoperable tumors.

ADMISSION CONSIDERATIONS

  • Persistent hypoglycemia unresponsive to oral glucose.

ONGOING CARE

  • Monitor for prolonged hypoglycemia post sulfonylurea use.
  • Dietary: high-protein, high-fiber, complex carbs; frequent small meals; avoid fasting and liquid calories.

PATIENT EDUCATION

  • Early symptom recognition and corrective action.
  • Adjust exercise or activity per glucose levels.
  • Keep glucose source accessible at all times.

PROGNOSIS

  • Generally favorable with appropriate treatment.

COMPLICATIONS

  • Surgical risks for insulinoma removal.
  • Organic brain syndrome with prolonged hypoglycemia.

REFERENCES

  1. Ben Salem C, Fathallah N, Hmouda H, et al. Drug-induced hypoglycaemia: an update. Drug Saf. 2011;34(1):21-45.
  2. Kittah NE, Vella A. Management of endocrine disease: pathogenesis and management of hypoglycemia. Eur J Endocrinol. 2017;177(1):R37-R47.
  3. Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: clinical practice guideline. J Clin Endocrinol Metab. 2009;94(3):709-728.

Clinical Pearls

  • Hypoglycemia symptoms align with low blood glucose and improve with glucose administration.
  • Avoid agents and foods triggering hypoglycemia.
  • Treat underlying causes for lasting resolution.