Hypoglycemia, Nondiabetic

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Basics

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

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Basics

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

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