Hypoglycemia

Definition

Hypoglycemia is a low plasma glucose level that can trigger activation of the sympathetic nervous system and dysfunction of the central nervous system. In people with diabetes taking glucose-lowering drugs, a value < 70 mg/dl (< 3.9 mmol/l) is regarded as hypoglycemia.

Without diabetes, hypoglycemia is rare. To diagnose a hypoglycemic disorder, Whipple's triad has to be established: symptoms of hypoglycemia, a simultaneously low plasma glucose (< 55 mg/dl or < 3.0 mmol/l) and relief of symptoms after intake of glucose.

Classification

Severity levels in diabetes:

• Level 1: glucose < 70 mg/dl (< 3.9 mmol/l) but ≥ 54 mg/dl (≥ 3.0 mmol/l)
• Level 2: glucose < 54 mg/dl (< 3.0 mmol/l)
• Level 3 (severe): hypoglycemia in which assistance from another person is needed because of altered mental or physical status

Without diabetes, a distinction is made by timing (fasting or postprandial, about 1–3 hours after a meal) and by mechanism: with or without inappropriate insulin secretion.

Aetiopathogenesis

Causes

• In diabetes: glucose-lowering drugs are by far the most common cause. Physical exertion can also trigger hypoglycemia, particularly in type 1 diabetes.
• Without diabetes, with inappropriate insulin secretion: insulinoma; post-bariatric hypoglycemia (usually postprandial, histologically nesidioblastosis); non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS); autoimmune hypoglycemia (Hirata syndrome) caused by antibodies, usually in patients with other autoimmune diseases; surreptitious intake of glucose-lowering drugs (factitious hypoglycemia).
• Without diabetes, without inappropriate insulin secretion: alcohol and certain drugs, severe liver, kidney or heart failure, sepsis, malnutrition, adrenal insufficiency and inborn errors of metabolism such as glycogen storage diseases.
• Non-islet cell tumor hypoglycemia (NICTH): a tumor produces large amounts of aberrant forms of insulin-like growth factor 2 (IGF-2), which cause the hypoglycemia; by then the tumor is usually advanced.
• Pseudohypoglycemia: falsely low values caused by glucose consumption by blood cells when sample processing is delayed (especially in leukemia or polycythemia) or by poor perfusion of the fingers.

Clinical features

• Autonomic (adrenergic) symptoms: sweating, tremor, palpitations, restlessness and anxiety, feeling of warmth, nausea, hunger, paresthesias. Under controlled conditions they begin at about 60 mg/dl (3.3 mmol/l).
• Neuroglycopenic symptoms: headache, blurred or double vision, confusion, agitation, seizures, coma; usually from about 50 mg/dl (2.8 mmol/l).
• Older people: stroke-like presentations with aphasia or hemiparesis; hypoglycemia predisposes to stroke, myocardial infarction and sudden cardiac death.
• Impaired awareness of hypoglycemia: in type 1 diabetes, long-standing type 2 diabetes or frequent hypoglycemia the warning symptoms are absent, so severe episodes occur without prodromes.
• Counter-regulatory hyperglycemia: after an episode, glucose may rise markedly because of counter-regulation.

The thresholds vary between individuals: some people have no symptoms at these values, while others have typical complaints with normal glucose.

Diagnosis

• Glucose measurement: during symptoms, laboratory glucose from a tube that stops glycolysis (e.g. a fluoride tube). Home glucose meters and glucose sensors are inaccurate in the hypoglycemic range; HbA1c is not helpful.
• Work-up without an obvious cause: the same sample taken during hypoglycemia is used for insulin secretion markers (the circulating hormone, C-peptide and proinsulin), together with beta-hydroxybutyrate, screening for oral antidiabetic agents and IAA (autoantibodies against the hormone). This distinguishes hypoglycemia with inappropriate insulin secretion, hypoglycemia without it and factitious hypoglycemia.
• Prolonged fast: the standard is a supervised fast of up to 72 hours; in almost all patients 48 hours are sufficient. Glucose is measured every 4–6 hours and every 1–2 hours once it is below 70 mg/dl (3.9 mmol/l). If glucose falls below 55 mg/dl (3.05 mmol/l), the hormone parameters are drawn. The test ends after 72 hours or when glucose is ≤ 45 mg/dl (≤ 2.5 mmol/l) with symptoms.
• Postprandial symptoms: instead of a fast, a mixed test meal is used; glucose and the secretion markers are measured every 30 minutes for up to 4 hours.

Keep learning in the app

Further reading (open access)

1. MSD Manual Professional: Hypoglycemia
2. MSD Manual Professional: Type 1 Diabetes Mellitus

Cross-references