Hypoglycemia: Causes, Symptoms, and Diagnosis

Introduction

• Hypoglycemia is a metabolic condition characterized by a plasma glucose concentration of less than 2.5 mmol/L
• Hypoglycemia is the most common of metabolic emergencies
• Hypoglycemia may be asymptomatic if the glucose level falls gradually
• Hypoglycemia may be symptomatic if the glucose level falls rapidly, even if it doesn't reach hypoglycemic values
• Hypoglycemia is rare for patients without drug-treated diabetes mellitus
• Blood specimens for glucose analysis must contain a glycolysis inhibitor, like fluoride oxalate
• Blood cells continue to metabolize glucose in vitro
• Without an inhibitor, specimens can show falsely low glucose concentrations, causing pseudohypoglycaemia
• Very low plasma glucose concentrations can cause severe CNS dysfunction
• The brain can neither produce nor store glucose, utilizing 50% of the body's glucose at rest
• Hypoglycemia is a disease manifestation, not a diagnosis
• True hypoglycemia usually indicates a serious underlying disease

Causes of Hypoglycemia

• Drugs, especially insulin therapy and oral hypoglycemic agents with long half-lives like chlorpropamide (about 35 hrs), are the most common cause
• Hypoglycemia can be classified into:
• Hyperinsulinaemia (inappropriate)
• Hypoinsulinaemia (appropriate)
• Reactive hypoglycaemia

Hyperinsulinaemic Hypoglycemia

• High insulin concentrations are present
• Causes include:
• Pancreatic tumour (insulinoma) that increases insulin and C peptide, and decreases glucose
• Hyperplasia of pancreatic islet cells
• Insulin antibodies that increase insulin (due to assay artifact caused by the antibody), decrease C peptide and glucose, and increase serum insulin antibodies
• Often presents with postprandial hyperglycemia and fasting hypoglycemia
• OHAs (Sulphonylureas/meglitinides) can mimic an insulinoma and are differentiated by demonstrating the drug in blood or urine
• Exogenous insulin, accidental, surreptitious, malicious hypoglycemia that increases insulin, decreases C peptide and glucose
• Can result from overdose, insulin requirement changes, failure to eat after insulin, or self-administration for suicidal purposes
• Autoimmune insulin syndrome where insulin antibodies form spontaneously without exposure to exogenous insulin

Hypoinsulinaemic Hypoglycemia

• Can be caused by the following:
• Endocrine issues: Glucocorticoid deficiency/adrenal insufficiency, severe hypothyroidism, Hypopituitarism
• Organ failure: Severe liver disease, end-stage renal disease, severe congestive cardiac failure, malaria
• Non-pancreatic islet cell tumours: Insulin-like growth factor (IGF)-2-secreting tumours (e.g., liver, adrenal, breast), mesenchymal, haemangiopericytomas , leukaemias, lymphomas, myeloma, widespread metastases

Notes on Hypoglycemia

• Hormonal deficiency causes hypoglycemia in children more often than in adults
• Hepatic failure impairs gluconeogenesis or glycogen storage, rarely causing hypoglycaemia unless very severe as greater than 80% of the liver needs to be dysfunctional
• Non-pancreatic tumors overuse glucose and may inhibit glucose mobilization, secreting IGF-2, which suppresses GH/IGF-1, causing increased IGF-2:IGF-1 ratio and decreased insulin
• Renal failure can cause hypoglycaemia, since the kidney is a gluconeogenic organ
• Septicaemia can cause depleted glycogen stores, impaired gluconeogenesis, and increased peripheral glucose use

Postprandial Hypoglycemia

• Postprandial hypoglycemia occurs in the fed state
• It is caused by a multitude of factors like drugs, insulin antibodies/receptor issues, and inborn errors
• Reactive (functional) hypoglycemia is a clinical disorder with postprandial symptoms, mainly autonomic, suggesting hypoglycemia, typically occurring 1-3 hours after eating, and relieved by food intake
• Seldom presents neuroglycopenic symptoms
• Confirm hypoglycemia only if Whipple's triad is met - low blood glucose concentration with typical symptoms alleviated by glucose administration

Alcohol-Induced Hypoglycemia

• Hypoglycaemia may develop 2-10 hours after ingesting large amounts of alcohol
• It is found most often in undernourished subjects and chronic alcoholics, but occurs in young timers too
• Alcohol inhibits gluconeogenesis
• Plasma glucose concentration estimation differentiates hypoglycaemia from alcoholic stupor

Signs and Symptoms of Hypoglycemia

• Signs and symptoms related to the central and autonomic nervous systems are variable among individuals and not specific to hypoglycemia
• Classified as
• Neurogenic (adrenergic)
• Examples include trembling, sweating, nausea, vomiting, rapid pulse (tachycardia in adults)/ bradycardia (in neonates), epigastric discomfort/cramps/hunger, cold/clammy extremities from hypothermia, dry skin with loss of turgor, hypotension/hypertension, anxiety, palpitations, numbness, and tingling sensation
• Neuroglycopenic
• Examples include lightheadedness/dizziness (feeling faint), confusion/loss of concentration/disorientation, fatigue/weakness, blurred vision, loss of coordination, mental dullness, irritability, sleepiness, muscle spasms, convulsions/seizures, coma, and death

Hypoglycemia in Children

• Neonatal blood glucose concentrations tend to be lower than in adults due to lacking enough liver glycogen stores
• Hypoglycaemia (2.2mmol/L) may occur without clinical evidence
• Neonates may experience hypoglycemia
• If they are small for gestational age/premature, have respiratory distress syndrome, or maternal DM/toxemia of pregnancy, or exposed to cold, stress, and polycythemia
• Infants may experience hypoglycemia due to:
• Ketotic hypoglycemia, congenital enzyme defects, glycogen storage disease, deficiencies  of gluconeogenic enzymes, galactosemia, hereditary fructose intolerance, leucine hypersensitivity, endogenous hyperinsulinism, Reye's syndrome, idiopathic

Laboratory Investigations

• Plasma estimations for glucose, insulin, proinsulin, and C-peptide are a useful diagnostic tool
• Drug screens should be conducted
• Insulin autoantibody screens should be conducted
• Plasma Ketone concentrations should be determined, and will be either low or raised
• Urinalysis can be performed to look for presence of glucose and ketones
• Renal function tests should be conducted
• Liver Function tests should be conducted
• Hormonal assays: IGF-2, TFTs, ACTH, GH, PRL etc should be conducted
• Imaging such as magnetic resonance imaging (MRI) or computerized tomography (CT) scanning to localize tumours

Tests used if Cause is Unidentifiable and Whipple's Triad is Documented

• Overnight Fast: With spontaneous hypoglycaemia, expect manifestation of a plasma glucose concentration less than 2.5 mmol/L during an overnight (18-h) fast when assayed on three separate occasions.
• Exercise Test: Stimulates insulin-induced hypoglycaemia; look for inappropriately high plasma insulin/C-peptide in endogenous hyperinsulinaemia and suppressed plasma insulin/C-peptide in hypoinsulinaemic hypoglycaemia
• Prolonged Fast: Reserved for cases where hypoglycaemia is undocumented via the above procedures.
• Samples can be drawn every 6 hours for analysis of plasma glucose, insulin, C-peptide, proinsulin, and β-hydroxybutyrate, and the test is concluded when hypoglycaemia occurs ,otherwise, it is terminated after 72hrs with patient resampling
• Follow-up: Inject intravenously 1 mg of glucagon and measuring plasma glucose at intervals to conclude the protocol, and the patient is fed.
• Discontinue nonessential medications and administer calorie-free fluids, and some degree of activity while awake
• Absence of symptoms/signs of hypoglycemia during the fast excludes a hypoglycemic disorder diagnosis
• Symptoms/signs and biochemically documented hypoglycaemia with inappropriately high serum insulin/C-peptide for the concurrent plasma glucose suggest endogenous hyperinsulinism

Notes on Provocative Tests

• If β-hydroxybutyrate falls and glucose rises after intravenous glucagon (indicating preserved hepatic glycogen stores), hypoglycemia is mediated by insulin or IGF.
• Provocative Tests such as [glucagon, tolbutamide, or suppression tests (infusion of insulin and measurement of C-peptide)] are no longer recommended because they evoke dangerous hypoglycaemia
• In insulinoma, insulin administration fails to suppress plasma insulin/C-peptide

Mixed Meal Test

• Used to investigate post-prandial neuroglycopenia
• Capillary blood samples are taken prior to and at every half-hour for 6 hours after a mixed-meal ingestion
• Reactive hypoglycaemia diagnosis is possible if neuroglycopenic symptoms develop, and the capillary plasma glucose concentration is 3.0 mmol/L or less

Management of Hypoglycemia

• Exclude pseudohypoglycaemia
• Take detailed medical/drug histories with adequate clinical examination to include the relationship of symptoms to meals
• Less than 5 hrs after meal indicates likely reactive hypoglycemia
• Greater than 5 hrs after meal indicates likely fasting hypoglycemia
• Milder cases of hypoglycemia can be managed with oral glucose-containing preparations
• Severe hypoglycaemia should be treated with urgent intravenous administration of 10-20 mL of at least 10% (and in adults 20%) glucose solution
• Use IV 50% dextrose in double dilution push
• A patient may need a continuous glucose infusion until the cause is established and treated
• Intramuscular (IM) glucagon 1 milligram is also an option if IV access is difficult
• IM glucagon should never be given in cases of insulinoma
• Surgical resection for tumors can be performed, but if contraindicated for clinical reasons, diazoxide may maintain normoglycaemia

Conclusion

• Hypoglycaemia is a very common medical emergency that, if not promptly treated, can lead to irreversible neurological damage and eventual mortality