Description

• Hypoglycemia is defined by the Whipple triad:
  • Low plasma glucose level (≤60 mg/dL) with hypoglycemic symptoms that are relieved when glucose is corrected
  • Occurs commonly in patients with diabetes receiving insulin secretagogues (sulfonylureas, meglitinides) or insulins; is less common in patients without diabetes
• Postprandial or reactive hypoglycemia occurs in response to a meal, drugs, herbal substances, or nutrients and may occur 2 to 3 hours postprandially or later. This is noncongenital, beta-islet dysregulation with or without hyperplasia and insulin secretion.
  • Autonomic symptoms are generally observed with a serum glucose ≤60 mg/dL, and neuroglycopenic symptoms at a serum glucose of ≤50 mg/dL, or lower in patients with hypoglycemic unawareness.
  • Hypoglycemia is also seen after GI or bariatric surgery (in association with dumping syndrome in some).
• Spontaneous (fasting) hypoglycemia may be associated with primary conditions including hypopituitarism, Addison disease, myxedema, or disorders related to critical illness, heart failure, hepatic or renal failure.
  • If hypoglycemia presents as a primary disorder, consider hyperinsulinism and extrapancreatic tumors.

Epidemiology

Incidence

• 0.5–8.6% of hospitalized patients ≥65 years without diabetes (1),(2)
• Asymptomatic in 25% of cases

Prevalence
True prevalence is unknown:

• Predominant age: older adult
• Predominant sex: female > male

Etiology and Pathophysiology

• Reactive, postprandial
  • Alimentary hyperinsulinism
  • Meals including refined or processed carbohydrates, liquid forms of fructose, sucrose, or glucose
  • Certain nutrients, including galactose, leucine
  • Glucose intolerance (prediabetes)
  • GI surgery, especially bariatric surgery (i.e., Roux-en-Y gastric bypass)
  • Idiopathic (unknown causes)
• Spontaneous
  • Fasting
  • Situations or housing with restricted food access (i.e., unhoused persons, those in hospitals, prisons)
  • Alcohol or prescription medication–associated (insulin, sulfonylureas, meglitinides, thiazolidinediones, incretin mimetics, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, DPP-IV inhibitors, angiotensin-converting enzyme inhibitors, β-blockers, salicylates, quinine, hydroxychloroquine, fluoroquinolones, doxycycline and tetracycline derivatives, linezolid, sertraline, disopyramide, pentamidine, gabapentin, tramadol) (3)
  • Nonprescription over-the-counter (OTC) agents, including performance-enhancing agents. Adulterated versions of phosphodiesterase inhibitors and performance-enhancing agents are routinely imported and may contain sulfonylureas and other hypoglycemic agents.
  • Consider medication administration errors as a source of unexplained hypoglycemia in persons without diabetes, especially those with polypharmacy (6 or more medications).
    • This includes accidental, surreptitious, or malicious use of insulin or oral hypoglycemics.
  • Natural medicines or herbs (bitter melon, caffeine, cassia cinnamon, chromium, fenugreek, ginseng, guarana, mate, stevia, vanadium)
  • Postsurgical (e.g., Roux-en-Y bariatric surgery, gastrectomy) hypoglycemia/dumping syndrome
  • Islet cell hyperplasia or tumor (insulinomas)
  • Extrapancreatic insulin-secreting tumors and other large tumors secreting insulin-like growth factor 2 (IGF-2)
  • Autoimmune hypoglycemia (Hirata disease) and insulin receptor mutations
  • Heart failure with or without SGLT-2 inhibitors (empagliflozin, dapagliflozin, canagliflozin)
  • Hepatic disease or failure; renal disease or failure
  • Renal glycosuria
  • Glucagon deficiency
  • Adrenal insufficiency
  • Catecholamine deficiency
  • Hypopituitarism
  • Hypothyroidism
  • Eating disorders
  • Exercise or physical activity (i.e., manual labor)
  • Fever
  • Pregnancy
  • Ketotic hypoglycemia of childhood
  • Severe nutrient deficiencies (i.e., selenium)
  • Congenital disorders
  • Sepsis, cachexia, anorexia

Genetics

• Monogenic and congenital hyperinsulinism (i.e., channelopathies, enzyme and transport anomalies, transcription factor or enzyme abnormalities) (4),(5)
• Inborn errors of metabolism including the glycogenoses, fructose intolerance, neoglucogenesis, and fatty acid or beta-oxidation disorders (5)

Risk Factors

Refer to “Etiology and Pathophysiology.”

General Prevention

• Follow dietary and exercise guidelines.
• Patient recognition of early symptoms and knowledge of corrective action

Pediatric Considerations

• Usually divided into two syndromes:
  • Transient neonatal hypoglycemia
  • Hypoglycemia of infancy and childhood
• Screening infants for hypoglycemia is appropriate when pregnancy was complicated by maternal diabetes.
• Cases of hypoglycemia observed in children taking propranolol for infantile hemangioma
• Associated with indomethacin when treating patent ductus arteriosus

Geriatric Considerations

• More likely to have underlying disorders or be caused by medications
• Iatrogenic hypoglycemia is common in the hospitalized elderly with renal insufficiency.

Commonly Associated Conditions

• Heart failure; severe, chronic hepatic and renal disease; alcoholism
• Addison disease; adrenocortical insufficiency
• Myxedema
• Malnutrition (patients with renal failure)
• GI and bariatric surgery
• Panhypopituitarism
• Insulinoma