Description

• Hypoglycemia is defined by the Whipple triad as 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
• Hypoglycemia is also seen after GI or bariatric surgery (in association with dumping syndrome in some).
• Postprandial or reactive hypoglycemia is insulin dependent; occurs in response to meals, drugs, herbal substances, or nutrients; and may occur 2 to 3 hours postprandially or later.
• Spontaneous (fasting) hypoglycemia may be associated with primary conditions including hypopituitarism, Addison disease, myxedema, rare metabolic diseases and inborn errors of metabolism such as glycogen storage disease, or critical illness, heart failure, hepatic or renal failure, and sepsis.

Epidemiology

Incidence
0.5–8.6% of hospitalized patients aged ≥65 years without diabetes (1),(2)

Etiology and Pathophysiology

• Reactive, postprandial, insulin dependent
  • 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)
• Spontaneous
  • Fasting
  • Restricted food access (i.e., unhoused persons, persons 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)
  • Consider medication administration errors as a source of unexplained hypoglycemia in persons without diabetes, especially those with polypharmacy.
  • Poisoning (ethanol, wild mushroom, β-adrenergic receptor antagonists) and toxidromes (salicylates, NSAIDs, oral hypoglycemics)
  • Nonprescription over-the-counter (OTC) agents, including performance-enhancing agents; adulterated versions of phosphodiesterase inhibitors and performance-enhancing agents are routinely imported and adulterated, containing sulfonylureas and other hypoglycemic agents.
  • 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), leukemia or other neoplasia related process (tumor mediated insulin-like growth factor 2 (IGF-2) and insulin receptor upregulation
  • Extrapancreatic insulin-secreting tumors and other large tumors secreting 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)
  • Pregnancy
  • Severe nutrient deficiencies (i.e., selenium)
  • Ketotic hypoglycemia of childhood
  • Congenital disorders and errors of inborn metabolism, glycogen storage disease
  • Sepsis, cachexia, anorexia

Genetics
Monogenic and congenital hyperinsulinism (i.e., channelopathies, enzyme and transport anomalies, transcription factor or enzyme abnormalities) (4)

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
• Consider errors of inborn metabolism, galactosemia, fructose intolerance, and glycogen storage disease in children and young adults.

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 and other neoplastic process