ChemPath: Hypoglycaemia Flashcards
Outline the first step in the management of hypoglycaemia patients in the following states:
- Alert and orientated
- Drowsy/confused but swallow intact
- Unconscious or concerned about swallow
- Alert and orientated
- Oral carbohydrates (short acting first (juice/sweets) then long-acting (complex caarbs e.g. sandwich))
- Drowsy/confused but swallow intact
- Buccal glucose (e.g. glucogel)
- Unconscious or concerned about swallow
- IV 100 mL 20% glucose
What should be considered if a hypoglycaemic patient is deteriorating or does not appear to be responding to the first step in their management?
IM/SC 1 mg glucagon
What is the benefit of giving glucose sublingually?
Bypasses hepatic first-pass metabolism
How long is it likely to take for IM glucagon to cause an increase in blood glucose?
15-20 mins
Which group of patients may not respond to IM glucagon?
- Starving
- Anorexic
- Hepatic failure
- Glucagon mobilises glycogen stores but these patients will have poor liver glycogen stores
Describe the triad of features that is used to define hypoglycaemia.
Whipple’s triad
* Low glucose
* Symptoms - adrenergic or neuroglycopaenic
* Relief of symptoms by administration of glucose
List some symptoms of hypoglycaemia.
- Adrenergic: tremors, palpitations, sweating
- Neuroglycopaenic: confusion, seizures coma
What is a consequence of recurrent episodes of hypoglycaemia?
Hypoglycaemia unawareness (loss of adrenergic symptoms with hypoglycaemia)
Describe the order in which physiological compensatory changes in response to hypoglycaemia take place.
Low glucose
* Suppression of insulin
* Release of glucagon
* SNS activation -> release of adrenaline
* Release of cortisol
^all of these tries to increase your glucose
How does the body obtain energy in low glucose/starving states
Reduced peripheral uptake of glucose
Increase glycogenolysis and gluconeogenesis
Increase lipolysis -> FFAs enter beta oxidation to create ATP -> ketone bodies produced
What investigation may need to be performed to demonstrate hypoglycaemia in an otherwise healthy person?
Prolonged fast
What is the gold standard for measuring blood glucose?
Venous glucose
NOTE: this is collected in a grey top container that has fluoride oxalate
Describe 3 methods of measuring blood glucose
- Venous glucose (gold standard)
- Capillary blood glucose
- Continuous glucose monitoring
2 & 3 are not precise at low levels (<2.2mmol/l)
List some causes of hypoglycaemia in diabetics.
- 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)
List some diabetic medications that can causes hypoglycaemia.
- Oral hypoglycaemics: sulphonylureas, meglitinides, GLP1 analogues
- Insulin
List some non-diabetic medications that can cause hypoglycaemia.
- Beta-blockers
- Salicylates
- Alcohol
List some biochemical tests that may help differentiate between causes of hypoglycaemia.
- 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)
What would you expect the insulin and C-peptide levels to be in a hypoglycaemic patient who has anorexia nervosa but not diabetes?
- 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
List some causes of Hypoinsulinaemic hypoglycaemia.
- 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
What does hypoglycaemia with a high insulin and low C-peptide suggest?
Exogenous insulin use
Name 3 ketone bodies.
- 3-hydroxybutyrate
- Acetone
- Acetoacetate
List some physiologically explicable causes of neonatal hypoglycaemia.
- Prematurity
- IUGR
- Inadequate glycogen/fat stores
NOTE: this should improve with feeding
What is a pathological cause of neonatal hypoglycaemia?
Inborn errors of metabolism
List some causes of neonatal hypoglycaemia with high FFAs and low ketones.
- Fatty acid oxidation defects
- MCAD deficiency
- Carnitine disorders
- HMG-CoA lyase deficiency
- GSD type 1
List some causes of inappropriately high insulin levels.
- 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)
State two causes of Hyperinsulinaemic hypoglycaemia with a high C-peptide.
- Insulinoma
- Sulphonylurea abuse
What test could help differentiate between insulinoma and sulphonylureas?
Urine or serum sulphonylureas
Describe the mechanism by which beta cells release insulin in response to blood glucose.
- 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
Describe the mechanism of action of sulphonylureas.
They bind to the ATP-sensitive K+ channel making it close independently of ATP -> membrane depolarisation, calcium influx -> insulin exocytosis
State two causes of Hyperinsulinaemic hypoglycaemia with a low C-peptide.
- Factitious result
- Oral hypoglycaemic usage (not sulphonylureas)
What can cause the following: low glucose, low insulin, low C-peptide, low FFAs and low ketones?
- 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)
Describe an autoimmune cause of hypoglycaemia.
- 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)
List some genetic causes of hypoglycaemia.
- Glucokinase activating mutation
- Congenital hyperinsulinism (KCNJ11 /ABCC8, GLUD-1, HNF4A, HADH)
What is reactive hypoglycaemia?
- 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
What level of glucose is considered hypoglycaemic
Depends on context
Generally <4mmol/l
- In diabetes: <3.5mmol/l
- In paeds: <2.5mmol/l (hypoglyc common in children)
What is c-peptide & what is its half life?
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
What tumours are responsible for paraneoplastic secretion of big IGF-2?
Mesenchymal: mesothelioma, fibroblastoma
Epithelial tumours: carcinoma
