ChemPath: Hypoglycaemia

Question 1

Outline the first step in the management of hypoglycaemia patients in the following states:

1. Alert and orientated
2. Drowsy/confused but swallow intact
3. Unconscious or concerned about swallow

Answer 1

1. Alert and orientated
   
   • Oral carbohydrates (short acting first (juice/sweets) then long-acting (complex caarbs e.g. sandwich))
2. Drowsy/confused but swallow intact
   
   • Buccal glucose (e.g. glucogel)
3. Unconscious or concerned about swallow
   
   • IV 100 mL 20% glucose

Question 2

What should be considered if a hypoglycaemic patient is deteriorating or does not appear to be responding to the first step in their management?

Answer 2

IM/SC 1 mg glucagon

Question 3

What is the benefit of giving glucose sublingually?

Answer 3

Bypasses hepatic first-pass metabolism

Question 4

How long is it likely to take for IM glucagon to cause an increase in blood glucose?

Answer 4

15-20 mins

Question 5

Which group of patients may not respond to IM glucagon?

Answer 5

• Starving
• Anorexic
• Hepatic failure
• Glucagon mobilises glycogen stores but these patients will have poor liver glycogen stores

Question 6

Describe the triad of features that is used to define hypoglycaemia.

Answer 6

Whipple’s triad
* Low glucose
* Symptoms - adrenergic or neuroglycopaenic
* Relief of symptoms by administration of glucose

Question 7

List some symptoms of hypoglycaemia.

Answer 7

• Adrenergic: tremors, palpitations, sweating
• Neuroglycopaenic: confusion, seizures coma

Question 8

What is a consequence of recurrent episodes of hypoglycaemia?

Answer 8

Hypoglycaemia unawareness (loss of adrenergic symptoms with hypoglycaemia)

Question 9

Describe the order in which physiological compensatory changes in response to hypoglycaemia take place.

Answer 9

Low glucose
* Suppression of insulin
* Release of glucagon
* SNS activation -> release of adrenaline
* Release of cortisol

^all of these tries to increase your glucose

Question 10

How does the body obtain energy in low glucose/starving states

Answer 10

Reduced peripheral uptake of glucose
Increase glycogenolysis and gluconeogenesis
Increase lipolysis -> FFAs enter beta oxidation to create ATP -> ketone bodies produced

Question 11

What investigation may need to be performed to demonstrate hypoglycaemia in an otherwise healthy person?

Answer 11

Prolonged fast

Question 12

What is the gold standard for measuring blood glucose?

Answer 12

Venous glucose

NOTE: this is collected in a grey top container that has fluoride oxalate

Question 13

Describe 3 methods of measuring blood glucose

Answer 13

1. Venous glucose (gold standard)
2. Capillary blood glucose
3. Continuous glucose monitoring

2 & 3 are not precise at low levels (<2.2mmol/l)

Question 14

List some causes of hypoglycaemia in diabetics.

Answer 14

• Medications (inappropriate insulin, sulphonylureas)
• Inadequate carbohydrate intake (missed meal)
• Impaired awareness
• Excessive alcohol
• Strenous exercise
• Co-existing conditions - end stage renal / liver cirrhosis (this alters drug clearance), Addison’s (compromises gluc counter-regulation)

Question 15

List some diabetic medications that can causes hypoglycaemia.

Answer 15

• Oral hypoglycaemics: sulphonylureas, meglitinides, GLP1 analogues
• Insulin

Question 16

List some non-diabetic medications that can cause hypoglycaemia.

Answer 16

• Beta-blockers
• Salicylates
• Alcohol

Question 17

List some biochemical tests that may help differentiate between causes of hypoglycaemia.

Answer 17

• Insulin levels (NOTE: exogenous insulin can interfere with assays)
• C-peptide (marker of endogenous insulin production)
• Drug screen (excluding sukphonylureasa needed for dx of insulinoma)
• Autoantibodies
• Cortisol/GH
• Free fatty acids/ketone bodies
• Lactate
• IGF-2

NOTE: it is important to perform these tests at the time of the hypo (but try not to delay treatment)

Question 18

What would you expect the insulin and C-peptide levels to be in a hypoglycaemic patient who has anorexia nervosa but not diabetes?

Answer 18

• Low insulin and low C-peptide
• The patient is hypoglycaemic because of poor liver glycogen stores (not an issue with insulin) so their insulin response will be normal

Question 19

List some causes of Hypoinsulinaemic hypoglycaemia.

Answer 19

• Fasting/starvation
• Strenous exercise
• Critical illness
• Endocrine deficiencies (adrenal failure, hypopituitarism)
• Liver failure
• Anorexia nervosa
• Drugs: Beta blockers, sulphonylureas

NOTE: this is a normal response to hypoglycaemia

Question 20

What does hypoglycaemia with a high insulin and low C-peptide suggest?

Answer 20

Exogenous insulin use

Question 21

Name 3 ketone bodies.

Answer 21

• 3-hydroxybutyrate
• Acetone
• Acetoacetate

Question 22

List some physiologically explicable causes of neonatal hypoglycaemia.

Answer 22

• Prematurity
• IUGR
• Inadequate glycogen/fat stores

NOTE: this should improve with feeding

Question 23

What is a pathological cause of neonatal hypoglycaemia?

Answer 23

Inborn errors of metabolism

Question 24

List some causes of neonatal hypoglycaemia with high FFAs and low ketones.

Answer 24

• Fatty acid oxidation defects
• MCAD deficiency
• Carnitine disorders
• HMG-CoA lyase deficiency
• GSD type 1

Question 25

List some causes of inappropriately high insulin levels.

Answer 25

* Islet cell tumours (eg. insulinoma) * Drugs (e.g sulphonylureas) * Post-prandial/reactive (post gastic bypass dumping) * Autoimmune insulin syndrome In neonates specifically: * Islet cell hyperplasia * Infant with diabetic mother * Beckwith-Wiedemann syndrome (overgrowth disorder) * Nesidioblastosis (excessive function of beta cells with abnormal microscopic appearance) * Congenital hyperinsulin (KCNJ11/ABCC8) (all will have high c-peptide)

Question 26

State two causes of Hyperinsulinaemic hypoglycaemia with a high C-peptide.

Answer 26

* Insulinoma * Sulphonylurea abuse

Question 27

What test could help differentiate between insulinoma and sulphonylureas?

Answer 27

Urine or serum sulphonylureas

Question 28

Describe the mechanism by which beta cells release insulin in response to blood glucose.

Answer 28

* Glucose crosses the membrane of beta cells and enters glycolysis via glucokinase * Glycolysis produces ATP * The rise in ATP leads to the closure of ATP-sensitive K+ channels * This leads to membrane depolarisation, calcium influx and insulin exocytosis

Question 29

Describe the mechanism of action of sulphonylureas.

Answer 29

They bind to the ATP-sensitive K+ channel making it close independently of ATP -> membrane depolarisation, calcium influx -> insulin exocytosis

Question 30

State two causes of Hyperinsulinaemic hypoglycaemia with a low C-peptide.

Answer 30

* Factitious result * Oral hypoglycaemic usage (not sulphonylureas)

Question 31

What can cause the following: low glucose, low insulin, low C-peptide, low FFAs and low ketones?

Answer 31

* This suggests that something is pretending to be insulin * This is non-islet cell hypoglycaemia caused by secretion of big IGF-2 * Big IGF-2 binds to IGF-1 receptors and insulin receptors * It behaves like insulin, so it causes hypoglycaemia and suppresses insulin and FFA/ketone production * It is a paraneoplastic syndrome usually caused by mesenchymal tumours (e.g. mesothelioma, fibroblastoma) and epithelial tumours (carcinoma)

Question 32

Describe an autoimmune cause of hypoglycaemia.

Answer 32

* Autoimmune insulin syndrome - antibodies are directed towards insulin so sudden dissociation of the antibodies can precipitate hypoglycaemia (could be caused by drugs e.g. hydralazine, procainamide)

Question 33

List some genetic causes of hypoglycaemia.

Answer 33

* Glucokinase activating mutation * Congenital hyperinsulinism (KCNJ11 /ABCC8, GLUD-1, HNF4A, HADH)

Question 34

What is reactive hypoglycaemia?

Answer 34

* Hypoglycaemia following food intake (post-prandial) * Can occur after gastric bypass (dumping in SI causing big increase of insulin) * May be suggestive of early diabetes * May occur in insulin-sensitive individuals after exercise or large meals * May be due to hereditary fructose intolerance

Question 35

What level of glucose is considered hypoglycaemic

Answer 35

Depends on context Generally <4mmol/l - In diabetes: <3.5mmol/l - In paeds: <2.5mmol/l (hypoglyc common in children)

Question 36

What is c-peptide & what is its half life?

Answer 36

Cleavage product of proinsulin, secreted in equimolar amounts to insulin Hence is a marker of endogenous insulin and good beta cell function Half life = 30 mins

Question 37

What tumours are responsible for paraneoplastic secretion of big IGF-2?

Answer 37

Mesenchymal: mesothelioma, fibroblastoma Epithelial tumours: carcinoma