Hypoglycaemia

What is hypoglycaemia?

The diagnosis of hypoglycaemia rests on three criteria (Whipple's triad):²

• Plasma hypoglycaemia.

• Symptoms attributable to a low blood sugar level.

• Resolution of symptoms with correction of the hypoglycaemia.

There are many causes of hypoglycaemia but it is most commonly the result of an excess of either insulin or oral hypoglycaemic medications combined with reduced sugar intake or increased activity. Hypoglycaemia adversely affects quality of life in patients with diabetes.³

With its potential to disrupt cerebral function, hypoglycaemia can have a major effect on peoples' lives. Studies have also suggested that hypoglycaemia is associated with an increased risk of cardiovascular events and mortality.⁴ Severe hypoglycaemia is estimated to be associated with an increased future mortality risk of 50-60%.⁵

Hypoglycaemia epidemiology

Hypoglycaemia is uncommon in people without diabetes² .

Hypoglycaemia causes^{2 6}

• Alcohol is the most common non-iatrogenic (non-physician) cause of hypoglycaemia in adults.

• People with diabetes treated with insulin or sulfonylureas:
  

  • Recurrent hypoglycaemia often responds to changes in diet or treatment but referral for structured education may be required (eg, to a Diabetes Specialist Nurse or a local education programme).

  • People with diabetes may develop impaired awareness of hypoglycaemia.⁷

  • Daytime non-severe hypoglycaemic episodes may have a significant adverse effect on day-to-day functioning.⁸

  • People with diabetes with poor glycaemic control may experience hypoglycaemic symptoms with normal glucose concentrations ('false hypoglycaemia').

• Ketotic hypoglycaemia (see under 'Hypoglycaemia symptoms', below).

• Other drugs and toxins including pentamidine, quinine, paracetamol and toadstools.

• Rare causes (if insulin and C-peptide levels are elevated, an endogenous insulin source is the cause):
  

  • Pancreatic endocrine tumours - eg, insulinoma.

  • Extrapancreatic IGF-II-secreting neoplasms - eg, adrenal tumours.

  • Autoimmune hypoglycaemia (endogenous antibodies reacting with insulin or the insulin receptors).

  • Reactive hypoglycaemia: may be caused by upper gastrointestinal surgery or congenital enzyme deficiencies such as hereditary fructose intolerance, galactosaemia or leucine sensitivity of childhood.

  • Hormone deficiencies - eg, hypoadrenalism, hypopituitarism.

  • Starvation.

  • Factitious hypoglycaemia or self-induced hypoglycaemia.

Insulinomas

• Insulinomas usually cause semiautonomous release of insulin, resulting in fasting hypoglycaemia.

• In response to meals these tumours usually respond subnormally, so that postprandial glucose levels are normal or even mildly elevated, although postprandial hypoglycaemia can occur.

• Insulinomas may be too small to be seen on CT scans and further investigation with endoscopic ultrasound should be considered, if no other cause for the hypoglycaemia is apparent.

• Glucagon should be used with caution in insulinoma.

Hypoglycaemia symptoms⁶

There is poor correlation between blood glucose and symptoms, especially in patients with diabetes. Patients can often recognise the symptoms themselves and this state responds to sugar in water or a few lumps of sugar. Children may not have such prominent changes but may appear unduly lethargic.

Hypoglycaemia

Presents as:

• Shaking and trembling.

• Sweating, pins and needles in the lips and tongue.

• Hunger, palpitations.

• Headache (occasionally), double vision, difficulty in concentrating.

• Slurring of speech, confusion, change of behaviour, truculence.

• Stupor, coma.

Hypoglycaemia unawareness⁹

• This is seen in people with diabetes treated with insulin who may show reduction in spontaneous movements and speech, somnolence, poor thinking and work performance, changes in personality and amnesia.

• It may also present with transient hemiplegia, hypothermia or hyperthermia, convulsions, diplopia and strabismus. If untreated, it can progress to stupor, coma and, exceptionally, death.

• Chronic - a rare presentation with insidious changes in personality, defects in memory, paranoia and apparent dementia. Can also appear as neuropathy mistaken for motor neurone disease.

Ketotic hypoglycaemia¹⁰

• Most often affects young children aged between 18 months and 5 years.

• Ketotic hypoglycaemia in young children usually resolves over time and only rarely persists over the age of 9 years.

• Ketotic hypoglycaemia presents with symptoms of hypoglycaemia (eg sweating, irritable, confused) and also nausea and vomiting.

• Severe hypoglycaemia may cause fainting, seizures and loss of consciousness.

• The underlying problem is the inability to tolerate prolonged periods without food.

• Therefore, management includes regular meals/snacks and a snack before bed (and sometimes also during the night).

Assessment^{2 11 12}

Consider possible underlying causes and take a thorough medical and drug history.

Investigations

• True hypoglycaemia should be confirmed by documentation of Whipple's triad: symptoms or signs of hypoglycaemia, a low plasma glucose concentration, and resolution of symptoms or signs after plasma glucose returns to normal.¹³

• Assessment of glucose control for people with diabetes, including HbA1c.

• Other initial investigations include LFTs and TFTs.

Further investigations¹³

• Insulin radioimmunoassay if an islet cell tumour is suspected (elevated insulin levels). Inappropriately high insulin concentrations are seen in hyperinsulinaemic hypoglycaemia.

• A 72-hour fast is the gold standard for the diagnosis of insulinoma. The fast only rarely needs to be extended beyond 16 hours.

• Plasma concentrations of C-peptide are above the reference range in endogenous hyperinsulinaemia but low in exogenous hyperinsulinaemia. Exogenous insulin-induced hypoglycaemia can be detected by an insulin to C-peptide ratio greater than 1.0.

• Proinsulin should be measured because some insulinomas secrete much, or sometimes all, of their insulin in the unaltered proinsulin form and such tumours will go undetected if only insulin is measured. Proinsulin is usually less than 20% of total immunoreactive insulin. In patients with islet cell tumours, proinsulin may contribute as much as 70% of insulin immunoreactivity.

• A low level of glucose in a patient with confirmed endogenous hyperinsulinaemia should raise suspicion of sulfonylurea-induced hypoglycaemia.

• Blood and urine assays for sulfonylureas will detect factitious hypoglycaemia caused by these drugs.

• Further investigations for possible underlying endocrine cause - eg, pituitary function tests, adrenal function tests. See the separate Adrenal Insufficiency and Addison's Disease article.

Hypoglycaemia treatment and management

Emergency management

See the separate Emergency Management of Hypoglycaemia article.

Treatment of any underlying cause

This may involve management of alcohol abuse, review and changes to prescribed medications or removal of an insulin-secreting tumour.

Reactive hypoglycaemia

• Advise a diet with restriction of refined carbohydrates; the patient should avoid simple sugars.

• They should increase the frequency of their meals and reduce the size of meals (may need to have six small meals and two to three snacks each day).

• It may be beneficial to increase protein and fibre in the meal.

Chronic hypoglycaemia

Diazoxide, administered by mouth, is useful in the management of chronic intractable hypoglycaemia caused by excess endogenous insulin secretion, either from an islet cell tumour or islet cell hyperplasia.¹⁴

• Diazoxide has no place in the management of acute hypoglycaemia.

• Sodium and water retention induced by diazoxide may be reduced by concurrent use of a diuretic.

• Chlorothiazide 3-5 mg/kg twice-daily has the added benefit of potentiating the glycaemic effect of diazoxide.

• If diazoxide and chlorothiazide fail to suppress excessive glucose requirements then octreotide or nifedipine may be added. There is limited experience for this indication.

• Octreotide may suppress growth hormone secretion but there is little evidence that this has any long-term adverse effect on growth.