Hypoglycaemia refers to an abnormally low plasma glucose concentration with or without symptoms.
Hypoglycaemia is very common among patients with diabetes mellitus, usually secondary to insulin or certain hypoglycaemic agents (e.g. suphonylureas). Hypoglycaemia may also occur in patients without diabetes mellitus. In this situation, hypoglycaemia is uncommon and may occur due to a range of abnormalities, some very rare.
Hypoglycaemia is generally defined as an abnormally low blood glucose concentration (< 4.0 mmol/L).
Clinically significant hypoglycaemia is generally defined as < 3.0 mmol/L. At this level, hypoglycaemia can be associated with serious immediate and long-term consequences. A blood glucose concentration < 3.0 mmol/L rarely occurs in the absence of diabetes mellitus.
A formal diagnosis of hypoglycaemia should be based on Whipple’s triad.
In clinical practice, there may be a discrepancy between plasma glucose concentration and symptoms. A confident diagnosis of hypoglycaemia is therefore made on the basis of symptoms correlating with the episode of hypoglycaemia.
In patients with diabetes mellitus, they may have reduced hypoglycaemic awareness due to a reduced neurogenic symptom response. Therefore, Whipple’s triad is more clinically relevant to further investigate patients without diabetes mellitus.
Activation of counter-regulatory mechanisms are vital to prevent or rapidly correct low plasma glucose concentration.
During a fasting state, when blood glucose concentrations fall, there is activation of four main counterregulatory mechanisms:
The fall in insulin secretion and increase in glucagon secretion are the main counter-regulatory mechanisms. Alongside these biochemical responses, hypoglycaemia (usually at levels <3.1 mmol/L) stimulates autonomic symptoms (e.g. anxiety, hunger), which triggers the ingestion of food to restore plasma glucose concentration.
Hypoglycaemia most commonly occurs in association with treatment for diabetes mellitus.
Hypoglycaemia may occur in type 1, or less commonly, type 2 diabetes mellitus. This may be due to medication changes, concurrent illness, dietary or activity changes.
Patients with type 1 diabetes mellitus (T1DM) report an average of three episodes of severe hypoglycaemia per year. Hypoglycaemia in T1DM is commonly due to incorrect dosage of insulin and can occur during the day or night.
Patients with type 2 diabetes mellitus (T2DM) are much less likely to develop hypoglycaemia. Classically, patients treated with insulin and sulphonylureas are at increased risk of hypoglycaemia. Other diabetic medications such as metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose co-transporter 2 (SGLT2) inhibitors do not usually cause hypoglycaemia.
There are numerous causes of hypoglycaemia in the absence of diabetes mellitus. There are different ways of classifying these causes, which include:
The differentiation between unwell and well is felt to be the most practically useful and is discussed below.
Among those who appear well, hypoglycaemia may be secondary to accidental or malicious use of diabetic medications (e.g. insulin, beta cell secretagogues) or endogenous hyperinsulinaemia. The use of beta cell secretagogues will lead to endogenous hyperinsulinaemia, so it occurs in both groups.
Causes of endogenous hyperinsulinaemia:
An insulinoma refers to a tumour of the beta cells within the islets of Langerhan of the pancreas.
Insulinomas are most commonly benign tumours that cause an excess secretion of insulin. This leads to recurrent fasting hypoglycaemia due to an inappropriately high level of insulin for the blood glucose concentration. Insulinomas may occur de novo, or occur in association with multiple endocrine neoplasia, an autosomal dominant inherited condition. See our notes on MEN syndromes.
The diagnosis is usually made through a combination of prolonged fasting over 72 hours, which shows an inappropriately high level of insulin during an induced or spontaneous episode of hypoglycaemia, and imaging of the pancreas. The treatment of choice is surgical resection.
Hypoglycaemia is characterised by development of autonomic and neuroglycopaenic symptoms.
Onset of symptoms usually occur when blood glucose concentration falls below 3 mmol/L.
These are a collection of more severe symptoms that typically develop at a blood glucose concentration <2.8 mmol/L
NOTE: Patients with diabetes mellitus may lose their hypoglycaemic awareness. This may lead to reduced symptoms and presentation with severe hypoglycaemia. It can occur in patients with type 1 diabetes and long-standing type 2 diabetes mellitus. It is usually a combination of defective glucose counter-regulatory mechanisms and hypoglycaemia awareness. Collectively, this leads to recurrent hypoglycaemia.
The diagnosis of hypoglycaemia is based on capillary blood glucose or serum blood glucose measurements.
In patients with suspected hypoglycaemia, a capillary blood glucose measurement should be taken. This will confirm a blood glucose concentration < 4.0 mmol/L, which is consistent with hypoglycaemia.
Further investigations depend on the suspected diagnosis (diabetes mellitus versus no diabetes mellitus), the likely precipitant (e.g. concurrent illness) and whether it is recurrent. In patients with diabetes, simple adjustments to insulin or medications may be all that is required.
In patients without diabetes mellitus, further investigations may be warranted to determine the underlying cause.
In patients with hypoglycaemia without diabetes mellitus it is first important to document true hypoglycaemia based on Whipple’s triad. There is unlikely to be an underlying hypoglycaemic disorder if the blood glucose concentration is > 2.2 mmol/l.
Many cases of hypoglycaemia may occur transiently in an unwell patient (e.g. sepsis, alcohol consumption) and investigations should be guided by the suspected diagnosis (e.g. serum cortisol in adrenal insufficiency). Routine blood tests including full blood count, renal function and liver function are essential.
In patients who appear well and have recurrent, significant hypoglycaemia, a series of investigations can be requested
This test aims to provoke normal homeostatic responses to keep blood glucose concentration from failing. In normal individuals, a 72 hour fast should not lead to hypoglycaemia.
Each centre will have their own set test protocol for a 72 hour fast. This includes when blood tests should be taken and how to monitor individuals.
The test is stopped if:
At the end of the test, blood os taken for insulin, C-peptide, proinsulin, Beta-hydroxybutyrate, and oral hypoglycaemic agents. Glucagon may be given intravenously following venepuncture and the patient is able to eat. These blood tests are then interpreted to determine the cause. In a insulinoma, there is an inappropriately elevated level of insulin and C-peptide despite the presence of hypoglycaemia.
Hypoglycaemia may be mild with minimal symptoms or a medical emergency requiring urgent treatment.
The management of hypoglycaemia depends on whether the patients is alert or has reduced GCS.
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