HYPOGLYCAEMIA:

Objectives:
At the end of this session each participant will be able to:
1. Define hypoglycaemia.
2. Describe epidemiology of hypoglycaemia.
3. Mention causes of hypoglycaemia.
4. Describe pathophysiology of hypoglycaemia.
5. Mention clinical features of hypoglycaemia.
6. Diagnose hypoglycaemia.
7. Name differential diagnoses of hypoglycaemia.
8. Mention complications of hypoglycaemia.
9. Investigate patients with hypoglycaemia.
10. Treat patients with hypoglycaemia.
11. Describe prognosis of patients with hypoglycaemia.
12. Mention preventive measures for hypoglycaemia.

J.J. Kambona (M.B.Ch.B; M.Med)

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Definition:
Hypoglycaemia is a clinical situation characterized by a reduction in plasma glucose
concentration to a level that may induce symptoms or signs such as altered mental status
and/or sympathetic nervous system stimulation.
The glucose level at which an individual becomes symptomatic is highly variable, although
a plasma glucose level less than 50 mg/dL (less than 2.8 mmol/L) is generally considered
the threshold.

Epidemiology:
 Age:
o Symptoms of hypoglycaemia are fewer in elderly persons and they frequently appear
at a lower threshold of plasma glucose than in younger persons.
o Insulin-producing tumours:
The average age of a patient diagnosed with an insulinoma is the early 40s but cases
have been reported in patients ranging from birth to age 80 years.
 Gender:
Reactive hypoglycaemia is reported most frequently by women aged 25-35 years. Other
causes of hypoglycaemia are not associated with a gender preference.
 Incidence:
The true prevalence of hypoglycaemia with blood sugar levels below 50 mg/dL generally
occurs in 5-10% of people presenting with symptoms suggestive of hypoglycaemia.
The incidence of hypoglycaemia in a population of people with diabetes is very different
from that in a population of people without diabetes.

Causes:
1. Drugs:
 Insulin.  Quinine.
 Lithium.  Isoniazid.
 Methanol.  Salicylates.
 Didanosine.  Haloperidol.
 Pentamidine.  Trimethoprim.
 Chlorpromazine.  Cytotoxic agents.
 Thiazide diuretics.  Tricyclic antidepressants.
 Oral hypoglycaemics drugs.
 Sulphonamides ("sulphur drugs").
 Angiotensin converting enzyme inhibitors.
 Ethanol (including propranolol plus ethanol).
 Organophosphates and carbamate insecticides.
 Disodium ethylenediaminetetraacetic acid (EDTA).
2. Endogenous insulin secretion:
A. Insulin-producing tumours of pancreas:
Epidemiology:
 Incidence and prevalence:
o Islet cell adenoma or carcinoma (insulinoma) is an uncommon and usually
curable cause of fasting hypoglycaemia most often diagnosed in adults.
o Carcinomas account for only 10% of insulin-secreting islet cell tumours.
 Age:

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 o Insulinomas are uncommon in persons younger than 20 years and are rare in
those younger than 5 years.
o Ten percent of patients with insulinoma are older than 70 years.
o The median age at diagnosis is about 50 years, except in patients with MEN
syndrome, in which the median age is in the mid 20s.
 Gender: Approximately 60% of patients with insulinoma are female.
Cause:
 It may occur as an isolated abnormality or as a component of the multiple
endocrine neoplasia type-1 (MEN-1) syndromes.
 Hypoglycaemia in patients with islet cell adenomas results from uncontrolled
insulin secretion, which may be clinically determined during fasting and
exercise.
B. Non-insulin-secreting tumours:
 Hypoglycaemia may also be caused by large non-insulin-secreting tumours,
most commonly retroperitoneal or mediastinal malignant mesenchymal
tumours.
 Pathophysiology:
The tumours secrete abnormal insulin-like growth factor-II (large IGF-II), which
does not bind to its plasma binding proteins. This increase in free IGF-II exerts
hypoglycaemia through the IGF-I or the insulin receptors.
 Treatment and prognosis:
The hypoglycaemia is corrected when the tumour is completely or partially
removed and usually recurs when the tumour re-grows.
3. Reactive hypoglycaemia:
A. Idiopathic reactive hypoglycaemia: (dumping syndrome)
Idiopathic reactive hypoglycaemia is an alimentary hypoglycaemia occurring in
patients who have had previous upper gastrointestinal surgical procedures such as:
 Vagotomy.  Gastrectomy.
 Pyloroplasty.  Gastrojejunostomy.
They allow rapid glucose entry and absorption in the intestine, provoking excessive
insulin response to a meal. This may occur within 1-3 hours after a meal.
Very rarely it may occur in patients who have not had GI operations.
B. Congenital enzyme deficiencies reactive hypoglycaemia:
 Galactosaemia.
 Hereditary fructose intolerance.
 Leucine sensitivity of childhood.
In hereditary fructose intolerance and galactosaemia, an inherited deficiency of a
hepatic enzyme causes acute inhibition of hepatic glucose output when fructose or
galactose is ingested respectively.
Leucine provokes an exaggerated insulin secretory response to a meal and reactive
hypoglycaemia in patients with leucine sensitivity of childhood.
4. Fasting hypoglycaemia:
Causes of fasting hypoglycaemia usually diagnosed in infancy or childhood include:

A. Nesidioblastosis:

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 Incidence:
It is a rare cause of fasting hypoglycaemia in infants and an extremely rare cause in
adult.
Cause:
 This condition is characterized by a diffuse budding of insulin-secreting cells
from pancreatic duct epithelium and pancreatic microadenomas of such cells.
 Several cases of nesidioblastosis were reported recently after gastric bypass
surgery.
B. Inherited liver enzyme deficiencies that restrict hepatic glucose release:
 Phosphorylase.  Pyruvate carboxylase.
 Glycogen synthetase.  Glucose-6-phosphatase.
 Fructose 1, 6-diphosphatase.
 Phosphoenolpyruvate carboxykinase.
C. Inherited defects in fatty acid oxidation, including that resulting from systemic
carnitine deficiency and inherited defects in ketogenesis (3-hydroxy-3-
methylglutaryl-CoA lyase deficiency):
 They cause fasting hypoglycaemia by restricting the extent to which non-neural
tissues can derive their energy from plasma free fatty acids (FFA) and ketones
during fasting or exercise.
 This results in an abnormally high rate of glucose uptake by non-neural tissues
under these conditions.
5. Factitious hypoglycaemia:
Secret sulfonylurea use/abuse for an intention of causing self-induced hypoglycaemia
can be seen in healthcare workers or in relatives who care for diabetic family members
at home.
6. Others:
 Artefact.  Starvation.
 Pregnancy.  Hypopituitarism.
 Renal glycosuria.  Chronic renal failure.
 Adrenal insufficiency.  Liver cirrhosis/failure.
 Critical illnesses:
o Sepsis with multiorgan failure.
o Cardiac, hepatic and renal diseases.
 Hormonal deficiencies:
o Glucagons (rare).
o Epinephrine (very rare).
o Growth hormone (in children).
o Hypoadrenalism (hypocortisolism).
 Ketotic hypoglycaemia of childhood.
 Exercise in patients with diabetes treated with diabetes medications.
 Autoimmune hypoglycaemia: Insulin antibodies and insulin receptor antibodies.

Pathophysiology:
Hypoglycaemic symptoms are related to sympathetic activation and brain dysfunction
secondary to decreased levels of glucose.

A. Adrenergic symptoms:

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 They are produced in response to the stimulation of the sympathoadrenal nervous
system:
 Hunger.  Sweating.
 Anxiety.  Palpitations.
 Tremulousness.  Pounding heart.
B. Neuroglycopenic symptoms:
Reduction in cerebral glucose availability can manifest with:
 Tiredness.  Dizziness.
 Weakness.  Irritability.
 Confusion.  Hallucinations.
 Blurred vision.  Coma and death.
 Difficulty concentration.  Inappropriate behaviour.
 Focal impairments e.g. hemiplegia.
C. Asymptomatic:
It is important to note that a patient with repeated hypoglycaemia can have almost no
symptoms (hypoglycaemic unawareness). The threshold at which a patient feels the
hypoglycaemic symptoms decreases with repeated episodes of hypoglycaemia.
The adrenergic symptoms often precede the neuroglycopenic symptoms and, thus, provide
early warning symptoms for the patient. The primary stimulus for the release of
catecholamines is the absolute level of plasma glucose; the rate of decrease of glucose is less
important. Previous blood sugar levels can influence an individual's response to a particular
level of blood sugar.

Clinical features:
History:
 Main complaints:
o Neurogenic (adrenergic) symptoms:
 Worries.  Hunger.
 Sweating.  Shakiness.
 Palpitation.
 Pounding heart.
o Neuroglycopenic symptoms:
 Tiredness.  Blurred vision.
 Dizziness.  Coma and death.
 Weakness.  Inappropriate behaviour.
 Confusion.  Difficulty with concentration.
o Reactive hypoglycaemia seldom causes glucose levels to drop low enough to induce
severe neuroglycopenic symptoms; therefore, a history of true loss of consciousness
is highly suggestive of aetiology other than reactive hypoglycaemia.
 Review of other systems:
o GIT:
 Dyspepsia.  Abdominal cramping.
 Weight loss.  Nausea and vomiting.
o Musculoskeletal: Fatigue.

 Dietary history:

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 o Skipping a meal.
o Nutritional disorders e.g. Protein calorie malnutrition.
o The timing of onset of symptoms relative to the time of meal ingestion:
 Fasting hypoglycaemia typically occurs in the morning before eating or during
the day, particularly in the afternoon if meals are missed or delayed.
 Idiopathic reactive hypoglycaemia occurs within 1-3 hours after a meal.
 Past medical history:
o Drug history. o Diabetes mellitus.
o Hepatic cirrhosis/failure. o History of toxic ingestion.
o Renal insufficiency/failure.
o Patients with a family history of type-2 diabetes or insulin-resistance syndrome (i.e.
hypertension, hyperlipidaemia and obesity) may be at higher risk for developing
reactive hypoglycaemia.
 Past surgical history of recent surgery.
 Social history: Alcohol intake.
Gestational hypoglycaemia:
 Patients with hypoglycaemia are at greater risk of pre-eclampsia/eclampsia.
 Hypoglycaemia occurs more frequently in women younger than 25 years and those who
had a pre-existing medical condition.
 Hypoglycaemia is less frequent in women whose pre-pregnancy body mass index (BMI)
was ≥ 30 kg/m2.
Physical examination findings:
 General examination:
o Sweating.
o Parotid tenderness (due to endocrine causes).
o Jaundice (usually cholestatic due to hepatic disease).
o The patient's skin may be diaphoretic and warm or show signs of dehydration with
decrease in turgor.
 Cardiovascular disturbances:
o Dysrhythmias.
o Hypertension or hypotension.
o Tachycardia (bradycardia in neonates).
 Central nervous system:
o Coma. o Fatigue.
o Tremors. o Anxious.
o Diplopia. o Confusion.
o Convulsions. o Stroke syndrome.
o Loss of co-ordination.
o Combative or agitated disposition.
o Pupils normal to fixed and dilated.
 Respiratory disturbances:
o Dyspnoeia.
o Tachypnoeia. o Acute pulmonary oedema.

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Diagnosis:
To diagnose hypoglycaemia, the Whipple’s triad is characteristically present. This triad
includes the documentation of:
 Low blood sugar.
 Presence of symptoms.
 Reversal of these symptoms when the blood sugar level is restored to normal.

Differential diagnoses:
 Drugs:
o Substance abuse:
 Cocaine.  Salicylates.
 Alcohol.  Pentamidine.
 Beta-blockers.
o Hypoglycaemic agents:
 Insulin.
 Oral hypoglycaemic agents.
o Potassium administration during periodic attacks of paralysis.
o Ingestion of ethanol-containing mouthwash or cologne (children).
 Psychogenic.
 Cardiovascular:
o Cardiogenic shock. o Cardiac dysrhythmias.
 Gastric surgery.
 Hepatic disease:
o Cirrhosis. o Fructose intolerance.
o Hepatic failure. o Galactose intolerance.
o Glycogen storage diseases.
 Nutritional disorders:
o Renal disease. o Low-calorie ketogenic diet.
o Diarrhoea (childhood). o Protein calorie malnutrition.
o Prolonged starvation before anaesthesia.
o L-leucine-sensitive hypoglycaemic defect in children.
 Endocrine disorders:
o Carcinomas. o Adrenal crisis.
o Addison disease. o Pheochromocytoma.
o Glucagon deficiency.
o Extrahepatic tumour e.g. insulinoma.
o Hypopituitarism (Panhypopituitarism).
o Autoimmune disorders e.g. Graves’ disease.
 Pseudohypoglycaemia.
 Central nervous system:
o Transient ischaemic attacks. o Jamaican vomiting sickness.
o Central nervous system disorders.
 Excessive muscular activity.

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Complications:
 Death:
Untreated fasting hypoglycaemia can lead to severe neuroglycopenia and possibly
death.
 Coma.  Cardiac dysrhythmia.
 The risk of permanent neurological deficits increases with prolonged hypoglycaemia;
such deficits can include:
o Ataxia. o Memory impairment.
o Hemiparesis. o Diminished language skills.

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 o Decreased abstract thinking capabilities.

Investigations:
 Random blood glucose level and amount of insulin:
o Test glucose and insulin levels simultaneously to document low glucose levels occurring in
conjunction with inappropriate insulin levels.
o Keep in mind that whole blood glucose values may be falsely low in polycythaemia rubra
Vera because of the unequal distribution of glucose between erythrocytes and plasma,
excessive glycolysis by erythrocytes or both.
o Low blood glucose values in leukaemia are due to excessive glycolysis by leukocytes and in
haemolytic crisis from excessive glycolysis by nucleated erythrocytes.
In such cases, prompt measurement of glucose in plasma to which an antiglycolytic agent
has been added should provide accurate results.
 Oral glucose tolerance test:
o Administer an oral glucose tolerance test if reactive hypoglycaemia is suspected. An oral
glucose tolerance test provides little benefit for the evaluation of fasting hypoglycaemia.
o Perform the test for 5 hours while simultaneously testing glucose and insulin levels.
o To be meaningful, low blood sugar (< 50 mg/dL [< 2.8 mmol/L]) during the test should be
accompanied by typical symptoms.
o Response to a mixed meal may be more representative.
 72-hour fasting plasma glucose:
Supervised fasting plasma glucose is the most reliable diagnostic test for the evaluation of
fasting hypoglycaemia.
o Continue the fast for as long as 72 hours or until symptoms develop in the presence of
hypoglycaemia (blood sugar < 45 mg/dL (< 2.5 mmol/L) for women; < 55 mg/dL (3.1
mmol/L) for men).
o Obtain simultaneous insulin levels and beta-hydroxybutyrate serum level every 6 hours,
when glucose is low and when symptoms develop.
o Glucose and/or glucagon must be administered after blood sample withdrawal to abort
hypoglycaemic symptoms.
o The diagnosis of insulinoma is likely if the patient, at the conclusion of the fast, has:
 Neuroglycopenic symptoms.
 A fall in plasma glucose to less than 45 mg/dL (< 2.5 mmol/L).
 Inappropriately elevated beta-cell polypeptides (insulin, proinsulin and C-peptide
levels).
 A beta-hydroxybutyrate level of less than 2.7 mmol/L.
o For overnight fasting plasma glucose levels, symptoms of hypoglycaemia may develop when
the blood sugar is below 60 mg/dL (3.3 mmol/L).
 C-peptide levels:
Obtain C-peptide levels any time an elevated insulin level is obtained.
o Endogenous hyperinsulinaemia from insulinoma and the use of oral Sulphonylureas is
associated with elevated C-peptide concentrations with concurrent hypoglycaemia.
o Exogenous hyperinsulinaemia from injected insulin results in low concentrations of C-
peptide, both because of the effect of the associated hypoglycaemia and because of the
direct suppressive effect of insulin on the pancreatic beta cell.
 Selective percutaneous transhepatic venous sampling:
It is often is helpful for localizing an insulinoma to the head, body or tail of the pancreas.
 Radiological studies:
o Magnetic resonance imaging:
For the evaluation of insulinomas, computed tomography scanning and ultrasonography
often are not helpful, because most of these tumours are small. Magnetic resonance
imaging may yield better results.
o Computed tomography scanning:
Retroperitoneal tumours that are producing insulin-like growth factor (IGF) are usually
imaged easily using a computed tomography scan.
o Selective arteriography:
It is also often helpful in localizing insulin-secreting lesions. Octreotide scanning localizes
insulinomas in approximately 50% of cases.

Treatment:
The mainstay of therapy for hypoglycaemia is glucose. Other medications may be administered
based on the underlying cause or the accompanying symptoms (not discussed here).
A. Stop the medication causing hypoglycaemia.
B. Fasting hypoglycaemia:
 Dietary therapy:
Frequent meals/snacks are preferred, especially at night, with complex carbohydrates.
 Glucose:
If dietary therapy is inadequate, medical care for patients with fasting hypoglycaemia may
include:
o Give 50 ml of 50% dextrose IV bolus (1 ml/kg), followed by IV infusion of 5%. Or
o Give 5 ml/kg of the 10% dextrose, followed by IV infusion of 5%. Or
o Give 2.5 ml/kg for the 25% dextrose, followed by IV infusion of 5%.
o Where dextrose is not available, sugar water should be prepared by mixing 20 g of sugar
(4-level tea spoons) with 200 ml of clean water. About 50 ml of this solution is given
orally or by nasogastric tube in unconscious patient.
 Intravenous Octreotide is effective for suppressing endogenous insulin secretion.
 Physical activity:
Because exercise burns carbohydrates and increases sensitivity to insulin, patients with
fasting hypoglycaemia should avoid significant activity.
 Surgical resection of the tumour:
Definitive treatment for fasting hypoglycaemia caused by a tumour is surgical resection.
The success rate is good for benign islet-cell adenomas and the success rate for malignant
islet-cell tumours can be as high as 50%.

C. Reactive hypoglycaemia:
 Physical activity:
Patients with reactive hypoglycaemia often find that their symptoms improve after
embarking on a routine exercise program.
 Restriction to refined carbohydrates:
Patients should
o Avoid simple sugars.
o Reduce the size of their meals.
o Increase the frequency of their meals.
 Patients may require 6 small meals and 2-3 snacks per day. Increased protein and fibre in
the meal may be beneficial.
 Use of alpha-glucosidase inhibitors: (Acarbose and miglitol)
These medications cause reversible inhibition of pancreatic alpha-amylase and membrane-
bound intestinal alpha-glucoside hydrolase enzymes.
This enzyme inhibition results in delayed glucose absorption and a lowering of post-
prandial hyperglycaemia and thus may prevent reactive hypoglycaemia.

Prognosis:
 The prognosis of hypoglycaemia depends on the:
o Cause:
If the cause of fasting hypoglycaemia is identified and treated early, the prognosis is
excellent. If the problem is not curable, such as an inoperable malignant tumour, the long-
term prognosis is poor. However, note that these tumours may progress rather slowly.
o Its severity. o Its duration.
Severe and prolonged hypoglycaemia can be life threatening and may be associated with
increased mortality in patients with diabetes.
 Reactive hypoglycaemia:
Symptoms often spontaneously improve over time and the long-term prognosis is very good.
Reactive hypoglycaemia is often treated successfully with dietary changes and is associated with
minimal morbidity. Mortality is not observed.
Untreated reactive hypoglycaemia may cause significant discomfort to the patient but long-
term sequelae are not likely.
 Drug-associated hypoglycaemia:
It is not associated with increased mortality risk among patients admitted to general wards.
This suggests that hypoglycaemia may be a marker of disease burden and not a direct cause of
death.

Prevention:
 Diabetic patients with episodes of hypoglycaemia need education in:
o Nutrition.
o Checking glucose levels at home.
o Early signs and symptoms of hypoglycaemia. Recognition of early symptoms is paramount
for self-treatment.
 If the patient has fasting hypoglycaemia and the cause is treatable, long-term follow-up usually
is not needed.
 If the cause cannot be treated definitively e.g. inoperable pancreatic insulinoma, diazoxide can
be used to elevate blood glucose levels and chemotherapy that specifically targets the beta cell
i.e. using cytotoxic agents such as streptozotocin, should be considered.
 If the patient has reactive hypoglycaemia, periodic outpatient monitoring is warranted to assess
the continued presence of symptoms.
Guidelines for drivers with diabetes:
 Travel with a blood glucometer.
 Always test blood glucose before driving.
 Test blood glucose during medium and long voyages.
 Keep carbohydrates – glucose tablets or a sugary drink in the vehicle.
 Do not drive for more than 2 hours without making a stop to check blood glucose. Eat a snack.
 If a driver feels hypoglycaemia coming on, stop as soon as it is safe to do so, check and act
accordingly.
 When blood glucose before driving is at about or below 5.5 mmol/l, eat snacks before starting
the journey.
 Occupations which may be limited for people with insulin treated diabetes:
o Police. o Prison service.
o Train driver. o Deep sea diving.
o Armed forces. o Air traffic control.
o Emergency services e.g. fire fighters.
o Airline pilot or airline cabin crew (certain airlines).
o Jobs requiring a Large Goods Vehicle (LGV), Passenger Carrying Vehicle (PCV) licence or a
minibus licence.

References:
1. Hamdy O. Hypoglycaemia. www.emedicine.medscape.com last updated: December 9, 2011.
2. Hamdy O. Hypoglycaemia. www.emedicine.medscape.com last updated: September 08, 2015.
3. Nabais J.M.V. Diabetes at the wheel-The need for safety and fairness under the law; Diabetes
voice, June 2010. 55 (1): 43-46.
4. http://www.nhsgrampian.org/guidelines/diabetes/topics/B32Occupations.html Downloaded
on: October 13, 2015.
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