CHEMPATH: Hypoglycaemia Flashcards
Stepwise approach to hypoglycaemia
Summary of causes
What is the acute management of hypoglycaemia?
Based on how alert the patient is
What is the glucose level definition for hypoglycaemia in normal and diabetic individuals?
- Hypoglycaemia = <4mmol/L
- In diabetes = <3.5mmol/L
- In paediatrics = <2.5mmol/L
- NR = 4.0-5.4mmol/L (fasting)
- NR = 4.0-7.8mmol/L (2-hour OGTT)
What is Wipple’s triad?
Wipple’s triad = a new style of definition for hypoglycaemia:
- Symptoms can be:
- Adrenergic
- Neuroglycopaenic
- Summary of triad:
- Low glucose
- Symptoms
- Relief of symptoms upon treatment
What is the mechanism/pathophysiology of hypoglycaemia?
Order of physiological changes upon hypoglycaemia:
- (1) suppression of insulin
- (2) release of glucagon
- (3) release of adrenaline
- (4) release of cortisol
Counter-regulation of blood glucose (see right):
- These methods increase glucose, and so FFA as well
- FFAs enter beta-oxidation cycle to make ATP
- Excess FFAs can metabolise into ketone bodies
What occurs first in hypoglycaemia?
- Release of cortisol
- Release of glucagon
- Suppressed insulin
- Release of adrenaline
Suppressed insulin - almost instantaneous
How do you investigate hypoglycaemia in a diabetic vs normal patient?
- Diabetes = monitor blood glucose
- Healthy person = conduct a prolonged fast to demonstrate hypoglycaemia (normal people should never become hypoglycaemic, even after a prolonged fast)
What is the gold standard for glucose measurement?
- Venous glucose (gold standard):
- Fluoride oxalate in grey-top, 2mL blood
- Lab analyser with quality control but takes some time
What are 3 types of glucose measurement?
Venous glucose (gold standard):
- Fluoride oxalate in grey-top, 2mL blood
- Lab analyser with quality control but takes some time
Capillary glucose:
- Point of care analyser with instant results
- Poor precision at low glucose levels, not quality controlled
Continuous glucose monitoring:
- Small device attached to abdomen wall that monitors continually
- Not accurate below 2.2mmol/L
What are some causes of hypoglycaemia in non-diabetics?
- Fasting or reactive
- Paediatric or adult
- Critically unwell
- Organ failure
- Hyperinsulinism
- Post-gastric bypass
- Drugs
- Extreme weight loss
- Factitious (i.e. an artefact)
What are the most common causes of hypoglycaemia in diabetics?
- Medications (inappropriate insulin)
- Inadequate CHO intake/missed meal
- Impaired awareness
- Excessive alcohol
- Strenuous exercise
- Co-existing autoimmune conditions
Which diabetic medications can cause hypoglycaemia?
- Oral Hypoglycaemics:
- Sulphonylureas
- Meglitinides
- GLP-1 agents
-
Insulin
- Rapid acting with meals
- Long acting
- Other drugs
- Beta-blockers
- Salicylates
- Alcohol (inhibits lipolysis)
What comorbid conditions in diabetes can also lead to hypoglycaemia?
Co-existing renal/liver failure alters drug clearance--> reduces the doses needed - e.g. patient on sulfonylurea, GFR decreases, sulfonylurea accumulate, more hypos
Concurrent Addison’s disease (RARE) –> hypoglycaemia (polyglandular autoimmune syndrome)
Poor awareness from autonomic neuropathy
Menti: C peptide is:
- Cleavage product of insulin
- It is equimolar to insulin
- Half life of 2hrs
- Interferes with insulin measurement
Secreted in equimolar amounts to insulin
Low C peptide - because C peptide is marker of endogneous insulin. Insulin from pancreas will be switched off in hypoglycaemia
To differentiate the causes of hypoglycameia a thourough history and examination should be done. What biochemical tests should also be done in hypoglycameia?
- Insulin levels (exogenous insulin interferes with assays)
- C-peptide
- Drug screen
- Autoantibodies
- Cortisol/GH
- FFAs/blood ketones
- Lactate
- Other specialist tests (e.g. IGFBP, IGF-2, carnitine)
What is the precursor of insulin? What are the breakdown products?
Proinsulin –> insulin and C-peptide
What is C-peptide? What is the use? What is the half life of C peptide?
C peptide = cleavage product; secreted in equimolar amounts to insulin)
C-peptide is a good marker of beta cell function
Half-life is 30 mins and renally cleared
i.e. exogenous insulin results in a low c-peptide measurement
Probably has anorexia therefore poor liver glycogen stores
Menti: case of anorexia
low insulin and low C peptide - hypoinsulinaemic hypoglycaemia
What is hypoinsulinaemic hypoglycaemia? What are the causes?
Hypoinsulinaemic hypoglycaemia - low insulin, low C peptide
Suggests that something other than insulin is causing the hypoglycaemia. This is an appropriate response to hypoglycaemia which can be caused by:
- Fasting/starvation
- Strenuous exercise
- Critical illness
- Endocrine deficiencies (i.e. hypopituitarism, adrenal failure)
- Liver failure
- Anorexia nervosa
What is hyperinsulinaemic hyperglycaemia?
High insulin + low C-peptide
suggests that there is exogenous insulin
A ketone body
3 ketone bodies = 3-hydroxybutyrate, acetone, acetoacetate
1-day old neonate, jittery, not feeding, premature (34w gestation), 1.9mmol/L lab glucose, improved on feeding but low blood glucose 4 hours postprandial, 3-hydroxybutyrate (a ketone body) measured at the hypo attack and was -ve.
Fatty acid oxidation defect
What are the risk factors for neonatal hypoglycaemia?
- Premature - glycogen stores double at 36w so before this, neonates are more at risk
- Co-morbidities
- IUGR
- SGA
What is the appropriate response to hypoglycaemia?
Hypoinsulinaemic hypoglycaemia
What is a pathological cause of hypoglycaemia in a neonate?
Inborn errors of metabolism
Which 3 metabolic disorders can cause neonatal hypoglycaemia?
- Fatty Acid Oxidation Disorders (FAOD) = no ketones produced
- Glycogen Storage Disease (GSD) type 1 (gluconeogenetic disorder)
- Medium Chain Acyl-CoA Deficiency (MCAD)
- Carnitine Disorders
- Why is this response pathological in a neonate?
- hypoglycaemia with
- low insulin,
- low C-peptide,
- raised FFA,
- low ketones
Low ketones are pathological as everything else ca n be explained without pathology
Whenever insulin is LOW, FFAs should be HIGH (if you have high FFAs, there should be an increase in ketone body formation. The fact that the child in this case has low ketone bodies despite having low insulin and low C-peptide suggests that there is a defect in fatty acid oxidation)
Neonatal hypoglycaemia
What are the causes of inappropriately high insulin levels?
Low glucose, high insulin, HIGH C-peptide
- Drugs (sulphonylureas)
- Islet cell tumours (e.g. insulinoma)
- Islet cell hyperplasia
What 3 conditions can cause islet cell hyperplasia?
Infant of a diabetic mother
Beckwith-Wiedemann syndrome (specific body parts overgrowth disorder usually presents at birth)
Nesidioblastosis (hyperinsulinaemic hypoglycaemia caused by excessive function of beta cells with an abnormal microscopic appearance)
45yo lady intermittent fitting, weight gain, increased appetite, personality changes over last month
Glucose 1.9mmol/L, insulin 35mU/L, c-peptide 1,000pmol/L [HIGH]
What do these results suggest?
The high C-peptide suggests that the insulin is being produced endogenously
- This could be an insulinoma OR sulphonylurea abuse –> perform a urine or serum sulphonylurea drug screen
- If this is NEGATIVE, then insulinoma can be diagnosed
What must you exclude to diagnose insulinoma?
Drug screen for exogenous causes like sulfonylureas
Perform a urine or serum sulphonylurea drug screen
What is the normal insulin secretion pathway?
Glucose crosses membrane and enters glycolysis via glucokinase
Glycolysis produces ATP –> rise in ATP leads to closure of the ATP-sensitive K+ channel (a lot of genetic mutations that affect this channel) –> membrane depolarisation, calcium influx and insulin exocytosis
Sulphonylureas bind to the ATP-sensitive K+ channel and makes it close, independently of ATP –> insulin release even when there is no ATP around (this is why sulphonylureas can cause hypoglycaemia)
How common are insulinomas? What is the usual cause?
1-2 per million
Usually solitary adenoma (10% malignant, 9% associated with MEN1) - treat with simple resection
What is the most likely cause?
9yo boy fitting, glucose 1.9mmol/L, insulin 205mU/L, c-peptide <33pmol/L
Cause of hypoglycaemia (Insulin very HIGH, c-peptide very LOW):
- Factitious (exogenous) insulin (most likely)
- Oral hypoglycaemic usage (not sulphonylurea, as C-peptide would be high)
What is the cause?
60yo cachectic man unconscious, smoker, glucose 1.9mmol/L. Hypoglycaemia persists despite glucose infusion. Insulin & c-peptide undetectable, FFA undetectable, ketones -ve
Non-islet cell tumour hypoglycaemia:
- Insulin is LOW so must be something else driving the hypoglycaemia
- FFA should be high but low so there is something pretending to be insulin (i.e. a paraneoplastic syndrome from secretion of big IGF-2)
- Produced by mesenchymal tumours (mesothelioma, fibroblastoma) and epithelial tumours (carcinoma)
- Big IGF-2 binds to IGF-1 receptors and insulin receptors = your own endogenous insulin production is switched off and FFA production is suppressed
Why does IGF-2 release in paraneoplastic syndrome cause hypoglycaemia and low FFA?
Big IGF-2 binds to IGF-1 receptors and insulin receptors
So endogenous insulin production is switched off and FFA production is suppressed
Which types of tmours can cause paraneoplastic syndromes causing hypoglycaemia ?
Secretion of IGF-2:
- Mesenchymal tumours (mesothelioma, fibroblastoma)
- Epithelial tumours (carcinoma)
How can autoimmune disorders cause hypoglycaemia? (2 types)
Autoimmune conditions rarely cause…
-
Antibodies against insulin R;
- Usually presents with insulin resistance but may sometimes present with hypoglycaemia
-
Antibodies against insulin (= autoimmune insulin syndrome)
- Sudden dissociation of these Ab from insulin may precipitate hypoglycaemia
- Can be caused by drugs (hydralazine, procainamide)
List 2 genetic causes of hypoglycaemia. How will these present?
Present with low glucose, high insulin, high C-peptide (treated with pancreatectomy)
- Glucokinase activating mutation
- Congenital hyperinsulinism (KCNJ11 /ABCC8, GLUD-1, HNF4A, HADH)
What are 2 causes of reactive/post-prandial hypoglycaemia?
- Post gastric bypass
- Hereditary fructose intolerance
- Early diabetes
- Insulin-sensitive people post-exercise or post-large meal
Difficult to define true post-prandial hypos
In what type of diabetes do these occur?
- Hypoketotic hyperglycaemia
- Hyperketotic hyperglycaemia
- Hypoketotic hyperglycaemia - HHS/HONK (T2DM)
- Hyperketotic hyperglycaemia - DKA (T1DM)
