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Hypoglycaemia in the Absence of Diabetes in Adults

Essentials

  • Blood glucose should be measured without delay if there has been a rapid change in cognitive functions or in the level of consciousness.
  • Definition of clinical hypoglycaemia (Whipple triad)
    • plasma glucose< 3 mmol/l and
    • symptoms or findings consistent with hypoglycaemia that are
    • corrected as the glucose level rises.
  • The cause of hypoglycaemia should be established in patients with the Whipple triad.
    • The most common cause of hypoglycaemia is either medication or chronic disease.
    • A tendency to postprandial hypoglycaemia may develop as a late complication of gastric bypass surgery.
    • In previously healthy patients, hypoglycaemia may be due to endogenous hyperinsulinism, related to insulinoma or dysfunction of pancreatic beta cells or an autoimmune mechanism.
  • Clinical hypoglycaemia in the absence of diabetes or antidiabetic medication is very rare.
  • Symptoms consistent with hypoglycaemia in the absence of low (< 3 mmol/l) plasma glucose detected with a reliable method do not warrant further investigations because mild hypoglycaemia may cause symptoms even in healthy people.

Symptoms

  • Plasma glucose levels must remain in the physiological range to ensure brain energy supply. In healthy people, blood glucose varies very little due to the intrinsic regulation system.
  • The symptoms of hypoglycaemia are divided into autonomic and neuroglycopenic symptoms (table T1).
  • Autonomic symptoms are due to beginning secretion of hormones as plasma glucose levels fall below 3.8 mmol/l (adrenaline, cortisol, glucagon and growth hormone). These hormones increase gluconeogenesis and glycogenolysis in the liver and prevent muscle glucose uptake, preventing severe neuroglycopenic symptoms.
  • Neuroglycopenic symptoms are due to glucose deficiency in the brain and usually appear as plasma glucose levels fall below 3 mmol/l.

Symptoms of hypoglycaemia

Autonomic symptomsNeuroglycopenic symptoms
TremorHeadache
SweatingFatigue, vertigo
PalpitationsAbnormal behaviour, aggressiveness
RestlessnessVisual disturbances
IrritabilityImpaired judgement, memory problems
HungerConfusion
PallorConvulsions, loss of consciousness

Causes

  • In patients with other diseases and hospital patients, in particular, hypoglycaemia is usually associated with the disease or medication.
  • Hypoglycaemia associated with a disease is usually due to increased or more rapid use of glucose, a disturbance of gluconeogenesis or depletion of liver glycogen stores.
    • Hepatic or renal insufficiency
    • Severe bacterial infection
    • Malnutrition (due to anorexia nervosa or other cause)
    • Failure of the adrenal cortex: primary and secondary glucocorticoid deficiency
    • Malignant tumours: myeloma and Hodgkin's disease may be associated with hypoglycaemia due to insulin antibody formation. Sarcoma, mesothelioma and tumours metastasizing to the liver or the adrenal glands may be associated with hypoglycaemia developing through reduced glucose production in the liver or increased glucose utilization.
  • Hypoglycaemia associated with medication is usually due to increased insulin effect or decreased glucose production in the liver. Chronic diseases - hepatic or renal insufficiency, in particular - make patients susceptible to drug-induced hypoglycaemia.
  • Alcohol
    • Hypoglycaemia associated with alcohol consumption is due to glycogen deficiency in the liver and disturbed gluconeogenesis.
    • Hypoglycaemia is often associated with regular alcohol consumption over several days, a poor nutritional status and acute illness.
  • A tendency to postprandial hypoglycaemia may develop as a rare late complication of gastric bypass surgery (see article on Bariatric surgery Bariatric Surgery (Obesity Surgery)).
    • Symptomatic hypoglycaemia 1-3 hours after the intake of fast carbohydrates, beginning no sooner than one year after surgery
    • In mild cases, this can be controlled by dietary treatment prescribed by a therapeutic dietitian and by avoiding fast-acting carbohydrates. In more severe cases, investigations and treatment in specialized care are indicated.
  • In previously healthy people, causes related to endogenous hyperinsulinism predominate.
    • Insulinoma: fasting hypoglycaemia (see article on rare endogenous tumours Rare Endocrine Tumours)
    • Pancreatic beta-cell hyperplasia: postprandial hypoglycaemia
    • Autoimmune hypoglycaemia: antibodies against either insulin or the insulin receptor
    • Rare exercise-induced hyperinsulinism (EIHI) associated with strenuous exercise
  • Hereditary metabolic disorders
    • Hereditary metabolic disorders are suggested by hypoglycaemia associated with short stature, hypogonadism, enlarged liver, metabolic acidosis, muscle symptoms or hyperammonaemia. Investigations should be carried out in specialized care, as necessary.

Workup

Primary care

  • Patient history
    • Medication
    • Alcohol consumption
    • Chronic disorders (hepatic and renal insufficiency, malignant diseases, diabetes)
    • Gastric or intestinal surgery
    • Nutritional status
  • Investigation of symptoms
    • Symptoms (neuroglycopenic symptoms, in particular)
    • Weight change
    • Frequent need to eat
    • Factors provoking the symptoms
  • Clinical exam
    • Weight, height and BMI, in particular
    • Pigmentation
    • Signs of chronic disease
  • Laboratory tests
    • Plasma glucose, insulin and C-peptide measured preferably in association with symptoms or after fasting
    • Basic blood count with platelet count, creatinine, ALT, ESR, HbA1c, cortisol at 8 a.m., TSH

Specialized care

  • 72-h fasting test: plasma glucose, insulin, C-peptide every 4 hours
    • The test must be interrupted sooner if the plasma glucose level decreases below 3 mmol/l in a patient with a clear Whipple triad, or below 2.5 mmol/l in a patient without a clear Whipple triad.
    • Symptoms of hypoglycaemia with simultanous plasma glucose < 3 mmol/l or plasma glucose < 2.5 mmol/l in an asymptomatic patient both suggest endogenous hyperinsulinaemia. Plasma insulin > 3 mU/l, C-peptide > 0.2 nmol/l and beta-hydroxybutyrate < 2.7 mmol/l taken simultaneously confirm the diagnosis.
    • After the test, the patient can be given 1 mg glucagon i.v. An increase in blood glucose exceeding 1.4 mmol/l in 30 minutes suggests endogenous hyperinsulinaemic hypoglycaemia.
  • Oral mixed-meal tolerance test
    • Can be performed in patients with mostly postprandial symptoms of hypoglycaemia.
    • The test involves measuring plasma glucose, C-peptide and insulin 0, 15, 30, 60, 90, 120, 180 and 240 min after a Nutridrink® or similar test meal (200 ml).
    • The meal contains about 300 kcal of energy, about 40 g carbohydrates, about 11-12 g protein, 10-11 g fat, 0 g fibre and < 0.5 g lactose.
    • The test should be interpreted similarly to the fasting test.
    • Find out about local implementation of such a test and its instructions.
  • If hyperinsulinaemic hypoglycaemia is detected, insulin antibodies and insulin receptor antibodies should also be tested to exclude an autoimmune mechanism.
  • Only if biochemical tests suggest endogenous hyperinsulinaemic hypoglycaemia should investigations to determine the location of an insulinoma be done.
    • Determining the location of an insulinoma is challenging because insulin-secreting tumours in the pancreas, which should preferably be treated by enucleation, are small and their detection often requires two or more imaging modalities.
    • CT and MRI of the pancreas are often done, as well as an endoscopic ultrasound examination by a gastroenterologist.
    • If no insulinoma can be detected or the results of two imaging tests are contradictory, the patient should be referred for 68Gallium or L-Dopa-PET scanning.

Treatment

  • For mild hypoglycaemia, a rapidly absorbed oral carbohydrate can be given.
    • 4 glucose tablets (10 g)
    • 3-5 lumps of sugar
    • Fruit juice
  • For severe hypoglycaemia or in an unconscious patient
    • G10% infusion i.v. (a 100-ml bolus will increase the plasma glucose level momentarily by about 2-3 mmol/l)
    • 1 ampoule of glucagon i.m. if venous access cannot be established immediately (slow effect)
    • 200 mg thiamine i.v. if the patient is severely undernourished (alcohol dependent, for example); given before intravenous glucose
  • In addition to treating the acute hypoglycaemia, the cause of the hypoglycaemia should be treated so as to avoid future severe hypoglycaemias. Investigations into the cause of severe hypoglycaemia and its treatment should be carried out in specialized care.

    References

    • Cryer PE, Axelrod L, Grossman AB et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009;94(3):709-28. [PubMed]