Aetiology

Hypoglycaemia is due to excessive amounts of insulin, exogenous or endogenous. Presence of a sulfonylurea, a meglitinide, or synthetic insulin indicates iatrogenic hypoglycaemia. Growth hormone deficiency and adrenal insufficiency, due to either hypopituitarism or Addison's disease, may lead to hypoglycaemia by causing a failure in the response to low glucose levels. This tends to cause significant hypoglycaemia only in the paediatric population, although there are case reports of hypoglycaemia in adults with these conditions.

Postprandial hypoglycaemia has been documented in malnourished individuals who eat unripened ackee fruit.[9] Many cases of postprandial symptoms are not confirmed to be true hypoglycaemia upon evaluation.[10] Alcohol-use disorder and malnutrition are commonly associated with a hypoglycaemic episode.[11]

Endogenous excess of insulin or substances with insulin-like action, for example, insulin-like growth factor (IGF)-II, can be the result of several rare disorders. An insulinoma typically arises from pancreatic ductal and acinar cells rather than islet cells, although the mechanism behind the unregulated/excessive excretion of insulin is not clear.[7] Similarly to an insulinoma, large mesenchymal tumours can secrete enough unregulated IGF-II to disturb glucose homeostasis. IGF-II acts directly on insulin receptors and thereby has insulin-like effects. It also induces dysregulation of glucagon and growth hormone resulting in perpetuation of hypoglycaemia. Tumours that have been reported to secrete IGF-II include sarcomas, fibromas, fibrosarcomas, and renal cell carcinoma. Large tumours in the liver may disturb gluconeogenesis and/or cause hypoglycaemia due to excess consumption of glucose to fuel high metabolic rate of the tumour cells.

Nesidioblastosis and islet hypertrophy result from genetic mutations, most often autosomal recessive although sporadic and autosomal-dominant inheritance are possible. These mutations of the adenosine triphosphate-dependent potassium channel of beta cells lead to cell membrane depolarisation and calcium ion influx. This results in insulin release despite low blood glucose concentrations.[12] Rarely, islet hypertrophy is discovered following bariatric surgery.[8][13]

Iatrogenic hypoglycaemia is an expected consequence of glucose-lowering agents, but reduction of blood glucose concentration by other drugs is also reported. Examples include fluoroquinolone antibiotics, beta-blockers, heparin, proton pump inhibitors (e.g., pantoprazole), and tramadol.[3][4][5][14]

Critical illness involving multi-organ failure can cause hypoglycaemia by reducing endogenous glucose production while increasing metabolic stress and glucose utilisation.[13]

Pathophysiology

Sympathoadrenal symptoms are the result of increased secretion of glucagon, epinephrine (adrenaline), cortisol, and growth hormone in an effort to elevate blood sugar levels:

  • Typically begin when blood glucose concentrations fall below 3.0 mmol/L (55 mg/dL)

  • Glucagon and epinephrine (adrenaline) secretion are triggered by glucose concentrations below 3.6 mmol/L (65 mg/dL)

  • Growth hormone and cortisol secretion increase when glucose concentrations fall below 3.3 mmol/L (60 mg/dL)

  • Symptoms may include sweating, anxiety, nausea, tremor, hunger, generalised tingling, and palpitations.

Neuroglycopenic symptoms result from insufficient glucose supply to the brain despite the sympathoadrenal attempts to raise blood sugar:[15]

  • Typically occur with glucose concentrations <2.8 mmol/L (<50 mg/dL)

  • Symptoms may include blurred vision, dizziness, confusion, dysarthria, and somnolence

  • At the extreme end of the spectrum, convulsion, coma, and death may occur.

Classification

Aetiologies of non-diabetic hypoglycaemia

Factitious

  • Surreptitious use of insulin

Endocrine

  • Adrenal insufficiency, most often in children

  • Growth hormone deficiency, most often in children

  • Hypopituitarism, may also occur in adults

  • Hyperthyroidism, early reactive hypoglycaemia can occur

Tumours

  • Large tumours of mesenchymal origin: may secret insulin-like compounds (e.g., IGF-II); may be metabolically active enough to cause hypoglycaemia

  • Neuroendocrine tumours, especially insulinoma

Iatrogenic

  • Insulin

  • Aspirin

  • Fluoroquinolones

  • Quinine

  • Haloperidol

  • Disopyramide

  • Sulfonylurea

  • Beta-adrenergic blockers

  • Tramadol

  • Proton pump inhibitors (e.g., pantoprazole) have been found to have a glucose-lowering effect; however, further research is required[3]

  • Heparin: there is limited evidence that heparin causes hypoglycaemia.[4][5]

Neonatal

  • Nesidioblastosis (also called “persistent hyperinsulinemia hypoglycemia of infancy”)

  • Pancreatic islet hypertrophy

  • Newborn of a diabetic mother (transient)

Toxins

  • Alcohol-use disorder, especially with starvation

  • Ackee fruit (hypoglycin)

Congenital

  • Glycogen storage disorders

Miscellaneous

  • Early pregnancy (late reactive hypoglycaemia can occur during pregnancy)

  • Hypoglycaemia of inanition (terminal cancer)

  • Acute or chronic liver disease

  • Chronic renal failure

  • Congestive heart failure

  • Autoimmune: insulin receptor abnormalities

  • Following gastric surgery: gastric bypass, vagotomy with pyloroplasty, subtotal or total gastrectomy. Early reactive hypoglycaemia can occur after gastric surgery.

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