Introduction

Hypoglycaemia occurs when glucose concentration falls below the normal fasting glucose level. Generally, this is defined as blood glucose levels below 3.3 mmol/L.

Episodes of hypoglycaemia are more common in patients with diabetes due to the variable response of blood glucose levels to their medications. However, hypoglycaemia may present for other reasons.

Epidemiology

  • Incidence: 250.00 cases per 100,000 person-years
  • Peak incidence: 30-40 years
  • Sex ratio: 1:1
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Aetiology

Hypoglycaemia is most often associated with diabetes and is frequently a multi-factorial presentation.

Diabetes:
  • One study found that at least one episode of hypoglycaemia occurred in 90% of type I and 60% of type II diabetics who injected insulin over a 4 week period.
  • Excess levels of insulin causes hypoglycaemia. Most commonly this is from exogenous, injectable insulin used in the management of type I or type II diabetes mellitus. Levels of insulin may be higher than necessary if the patient has taken too much insulin, or has used the same amount of insulin whilst not eating enough or skipping a meal or snack.
  • Sulfonylureas (e.g. gliclazide) act by increasing the secretion of insulin from β-cells. Hypoglycaemia is a common adverse effect, especially when starting this medication or increasing dose.
  • Hypoglycaemia is more likely to occur in diabetics who have a viral illness, have drunk alcohol, exercised more than usual or have just started or changed dosage of a new medication.

Non-diabetic causes:
  • Iatrogenic: indomethacin, pentamidine, quinine, sulfonamide, IGF-1 and lithium.
  • Alcohol consumption is the most common non-iatrogenic cause of hypoglycaemia. This is due to its inhibitory effect on gluconeogenesis and glycogenolysis.

Rarer causes:
  • Hypopituitarism and Addison's disease: both of these rare conditions cause a reduced physiological response to hypoglycaemia as there is reduced secretion of growth hormone from the pituitary in hypopituitarism, and adrenaline and cortisol from the adrenals in Addison's disease.
  • Another rare cause of hypoglycaemia is an insulinoma, a neuroendocrine tumour of the pancreas which causes unregulated secretion of insulin.

Pathophysiology

Normal physiological response to hypoglycaemia
  • As blood glucose is taken up by cells, levels within the blood drop. This stimulates increased production of glucagon from the α-cells of the pancreas and reduced production of insulin from the β-cells of the pancreas. These changes act to increase liver gluconeogenesis and glycogenolysis.
  • Reduced blood glucose also stimulates sympathoadrenal outflow, leading to the secretion adrenaline from the adrenal medulla.
  • Reduced blood glucose also stimulates the secretion of growth hormone from the pituitary. ACTH is also secreted from the pituitary which stimulates cortisol secretion from the adrenal cortex.
  • All of these mechanisms act to increase blood glucose rapidly to normal levels. At this point, a negative feedback mechanism acts to normalise the secretion of the aforementioned hormones.

Abnormal physiological response to hypoglycaemia
  • The pathophysiology of hypoglycaemia depends on its cause. However, in every case, it will be due to an interruption of one of the above mechanisms of glucose homeostasis.
  • More information on the pathophysiology of each cause can be found below.

Clinical features

Blood glucose levels and the severity of symptoms are not always correlated, especially in patients with diabetes.

Blood glucose concentrations <3.3 mmol/L cause autonomic symptoms due to the release of glucagon and adrenaline (average frequency in brackets):


Blood glucose concentrations below <2.8 mmol/L cause neuroglycopenic symptoms due to inadequate glucose supply to the brain:

  • Weakness (50%)
  • Vision changes (42%)
  • Confusion (33%)
  • Dizziness (26%)

Severe and uncommon features of hypoglycaemia include:

  • Convulsion
  • Coma

Investigations

Whipple's triad aids the diagnosis of hypoglycaemia. It consists of symptoms or signs of hypoglycaemia, low blood glucose, and the resolution of symptoms with the correction of blood glucose.

Further tests to diagnose the cause of hypoglycaemia include:

  • Serum insulin: elevated in insulinoma.
  • Serum C-peptide: elevated in insulinoma or sulfonylurea use.
  • Serum cortisol: reduced in adrenal insufficiency or hypopituitarism.
  • 48 to 72-hour fast with serial blood glucose, serum proinsulin, C-peptide and insulin levels: the gold standard investigation for insulinoma.
  • TSH, U&E, LFTs: abnormalities help identify secondary causes of hypoglycaemia such as hypothyroidism, chronic liver disease or kidney disease.

Differential diagnosis

Conditions which may present with similar symptoms to hypoglycaemia:
  • Stroke or transient ischaemic attack (TIA): may present with sensory and/or motor deficits, visual disturbances, autonomic dysfunction, reduced consciousness and confusion. However, symptoms of stroke/TIA will be of sudden onset whereas symptoms of hypoglycaemia will develop more gradually. Serum blood glucose may be deranged in stroke/TIA. If stroke is suspected, patients should undergo non-contrast head CT which will be abnormal. However, CT may be unremarkable in TIA. The resolution of symptoms with the correction of blood glucose would suggest a diagnosis hypoglycaemia over TIA.
  • Myocardial infarction: may present with weakness, nausea and vomiting, especially in diabetics where chest pain is more likely to be absent. Serial troponin and ECG should be performed which will be abnormal.
  • Sepsis: altered mental status may be the only presenting feature of sepsis, especially in elderly patients or patients with neurological disorders such as dementia. Temperature will be high or low and there may be a specific source of infection as well as signs of shock (low blood pressure and poor capillary refill time).
  • Epilepsy: focal seizures may present with sensory and/or motor deficits, aphasia and impaired consciousness. However, blood glucose is likely to be normal and symptoms will begin and resolve suddenly.

Pseudohypoglycaemia (idiopathic postprandial syndrome)
  • A rare condition that presents with symptoms of hypoglycaemia after ingesting a meal, with a normal blood glucose level.

Management

The following guidelines are based on the BNF hypoglycaemia treatment summary.

Management of hypoglycaemia in the community (for example, diabetes mellitus patients who inject insulin):
  • Initially, oral glucose 10-20g should be given in liquid form or sugar lumps. This may be done in the community.
  • Alternatively, a propriety quick-acting carbohydrate may be given: GlucoGel or Dextrogel.
  • A 'HypoKit' may be prescribed which contains a syringe and vial of glucagon for IM or SC injection at home

Management of hypoglycaemia in hospital setting
  • If the patient is alert, a quick-acting carbohydrate may be given (as above).
  • If the patient is unconscious or unable to swallow, subcutaneous or intramuscular injection glucagon may be given.
  • Alternatively, intravenous 20% glucose solution may be given through a large vein

Further management
  • Diazoxide may be used in some patients with chronic hypoglycaemia from excess endogenous insulin secretion
  • Depending on the cause of hypoglycaemia, patients may require medical management (renal or liver failure, sepsis, endocrinopathy) or surgical management (insulinoma, IGF-II secreting tumour).

Complications

Short term

  • Neuroglycopenic complications include coma and seizures. These can lead to permanent neurological sequelae and should be managed in an intensive care setting.

Long term

  • Recurrent episodes of hypoglycaemia lead to 'hypoglycaemic unawareness' where patients do not develop autonomic symptoms of low blood glucose. This is more frequent in type II diabetes and increases the chance of neuroglycopenic complications of hypoglycaemia.