ChemPath - Hypoglycaemia Flashcards
What is the definition of hypoglycaemia
Glucose < 4mmol/L
Paediatrics = <2.5mmol/L
Diabetes = <3.5mmol/L
What are the main physiological changes that occur in hypoglycaemia
(1) suppression of insulin
(2) release of glucagon
(3) release of adrenaline
(4) release of cortisol
Describe what happens physiologically in hypoglycaemia
- Low glucose → insulin ↓ + glucagon ↑
- Reduction in peripheral uptake of glucose
- Glycogenolysis → ↑ FFAs → enter the beta-oxidation cycle to make ATP (excess become ketones)
- Gluconeogenesis
- Lipolysis - hypothalamus senses hypoglycaemia → catecholamine release + ACTH → cortisol + GH release
What is Wipple’s triad
- Low glucose
- Symptoms (adrenergic or neuroglycopaenic)
- Relief of symptoms upon treatment
What are the symptoms of hypoglycaemia
Asymptomatic
Adrenergic:
- Tremors
- Palpitations
- Sweating
- Hunger
Neuroglycopaenic
- Somnolence
- Confusion
- Incoordination
- Seizures, coma
What can be used to measure glucose if suspecting hypoglycaemia and what are the limitations
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 is the management for hypoglycaemia in adults
Alert & orientated: oral carbohydrates (Rapid = juice, sweets | long = sandwich)
Drowsy/confused with swallow: buccal glucose (hypostop/glucogel)
Unconscious or swallow compromised: IV 20% glucose
Deteriorating → IM/SC 1mg glucagon (15-20mins)
What are the caveats to management of hypoglycaemia
Requires continuous monitoring
Glucagon takes 15-20 mins to mobilise glycogen stores
Glucagon not suitable for liver failure (no glycogen)
Glucagon → rebound hypoglycaemia
Recurrent hypos → hypoglycaemia unawareness
What are the causes of hypoglycaemia in non-diabetics
Fasting or reactive
Critically unwell
Organ failure i.e. renal failure
Hyperinsulinism
Post-gastric bypass
Drugs
Extreme weight loss
Factitious (i.e. an artefact)
What are the causes of hypoglycaemia in diabetics
Medications (inappropriate insulin)
Inadequate CHO intake/missed meal
Impaired awareness (autonomic neuropathy)
Excessive alcohol
Strenuous exercise
Co-existing autoimmune conditions e.g. Addison’s
Renal/liver failure alters drug clearance
Which medications are hypoglycaemic
Sulphonylureas (causes endogenous insulin production)
Meglitinides
GLP-1 agents in conjunction with insulin
INsulin
Beta-blockers
Salicylates
Alcohol (inhibits lipolysis)
What investigations should be done to determine the cause of hypoglycaemia
Insulin levels (4-6min half life, hepatic clearance)
C-peptide
Drug screen
Autoantibodies
Cortisol/GH
FFAs/blood ketones
Lactate
IGF-2
Carnitine
Ammonia
Describe C-peptide
cleavage product; secreted in equimolar amounts to insulin
good marker of beta cell function (endogenous)
Half-life is 30 mins and renally cleared
What are the causes of a low insulin and low C-peptide
Hypoinsulinaemic hypoglycaemia
Suggests that something else is causing the hypoglycaemia.
The insulin level is 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 causes high insulin and high c peptide
Hyperinsulinaemic hypoglycaemia
Endogenous insulin production
- Drugs (sulphonylureas - will make the pancreas produce more insulin)
- Islet cell tumours (e.g. insulinoma)
- Islet cell hyperplasia
What are the causes of 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)
What are the causes of high insulin and low c peptide
exogenous insulin
What are the causes of neonatal hypoglycaemia
Explainable:
- Premature, co-morbidities, IUGR, small-for-gestational-age
- Inadequate glycogen and fat stores
- Should improve with feeding
Pathological:
- Inborn errors of metabolism
What suggests a pathological cause of neonatal hypoglycaemia and what are the causes
low insulin, low C-peptide, raised FFA, low ketones
Fatty Acid Oxidation Disorders (FAOD) = no ketones produced
Glycogen Storage Disease (GSD) type 1 (gluconeogenetic disorder)
Medium Chain Acyl-CoA Deficiency (MCAD)
Carnitine Disorders
Describe the normal insulin secretion pathway and what is the role of sulphonylureas in it
- 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
- 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)
Describe insulinomas
LOW glucose, HIGH insulin, HIGH c-peptide
Usually a small solitary adenoma (10% malignant, 8% associated to MEN1)
Treatment is simple resection
Describe non-islet cell tumour hypoglycaemia
Glucose, insulin, C-peptide, FFA, and ketones are all low
FFA should be high but are also low here so most likely, there is something pretending to be insulin (i.e. a paraneoplastic syndrome from secretion of big IGF-2)
Big IGF-2 binds to IGF-1 receptors and insulin receptors → your own endogenous insulin production is switched off and FFA production is suppressed
Produced by mesenchymal tumours (mesothelioma, fibroblastoma) and epithelial tumours (carcinoma)
What are the autoimmune causes of hypoglycaemia
Autoimmune conditions: Abs against insulin receptors (rarely causes hypoglycaemia)
Autoimmune insulin syndrome: Abs against insulin → sudden dissociation (hydralazine, procainamide) → hypoglycaemia
What are the genetic causes of hypoglycaemia
LOW glucose, HIGH insulin, HIGH c-peptide (treat with pancreatectomy)
Glucokinase activating mutation
Congenital hyperinsulinism:
- KCNJ11 /ABCC8
- GLUD-1
- HNF4A
- HADH
What are the causes of reactive/post-prandial hypoglycaemia
Can occur after gastric bypass
Hereditary fructose intolerance
Early diabetes
In insulin-sensitive people post-exercise or large meals
