Investigation of hypoglycaemia Flashcards
What are signs and symptoms of Hypoglycaemia?
Activation of autonomic nervous system
- Adrenergic responses e.g. palpitations, tremor, anxiety
- Cholinergic responses e.g. sweating, hunger
Neuroglycopenia
- Confusion, coma, seizures
What is the definition of hypoglycaemia?
- Glucose concentration low enough to cause symptoms/ signs of impaired brain function
- Whipple’s triad in adults: signs/ symptoms, documented low glucose, administration of glucose relieves symptoms
Why is hypoglycaemia hard to define in infants?
In infants/ young children, it is difficult to reliably recognise/ communicate symptoms. Not possible to identify a single plasma glucose concentration below which brain injury occurs
- Altered by presence of alternative fuels such as ketones
- Extent of injury influenced by duration and degree of hypoglycaemia
- Analytical variation in glucose concentration
What is the figure used to define hypoglycaemia?
Hypoglycaemia often defined as plasma glucose <2.6 mmol/L
What is the effect of insulin on metabolism?
- Increase glucose uptake
- Decrease lipolysis
- Deceased ketogenesis
- Decrease gluconeogenesis
- Decreased glycogenolysis
Counter-regulatory hormones such as glucagon, adrenaline, cortisol, growth hormone acts in reverse to the effects below
How does Hypoglycaemia occur in Neonates?
- In the first hours after birth: hepatic glycogen breakdown. Capable of gluconeogenesis 4-6 hours of age
- Transient low blood glucose common in first 12 hours of life
- Greater risk of hypoglycaemia as larger relative brain size and comparatively small muscle mass
- Full biochemical screening unrequired unless not responding to feed
What are indications for neonatal glucose monitoring?
- Preterm (<37 weeks gestation): Less adipose tissues, less glycogen stores as it occurs in the 3rd trimester
- Low birth weight (<2.5kg)
- Large for dates (>4.5kg): Large insulin but not a large supply of glucose anymore
- Maternal diabetes mellitus
- Infection or other illness
- Poor condition at birth
- Maternal use of β blockers (e.g. Labetolol)
What is the Pathogenesis of hypoglycaemia in Paediatrics?
- Increased glucose utilisation
- Impaired glycogen metabolism
- Impaired ketogenesis and ketone body utilisation
- Reduced gluconeogenesis
- Interference with glucose homeostasis secondary to a disturbance of intermediary metabolism
- Other causes and associations
- Drug-related
- Idiopathic ketotic hypoglycaemia
What are causes of increased glucose utilisation?
- Hyperinsulinaemic hypoglycaemia
- Stress e.g. hypoxia, respiratory distress, hypothermia
What are causes of Hyperinsulinaemia Hypoglycaemia?
- Congenital hyperinsulinism (CHI): mutations in ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF4A
- Secondary Causes (usually transient): Maternal Diabetes Mellitus, Intrauterine Growth Retardation, Perinatal Asphyxia, Rhesus Isoimmunisation.
- Other syndromes: Beckwith-Wiedemann, Soto
- Insulinoma
How is insulin secreted?
- ATP sensitive potassium channel made up by Kir 6.2 and SUR-1. These channels are involved in the channelopathies
- Potassium sensitive channel is usually open and calcium channel is usually closed
- Glucose enters the cell through the GLUT2 and is phosphorylated by the glucokinase. Increase in ATP/ADP ratio which causes the potassium sensitive channel to close.
- Leads to depolarisation of the membrane and influx of calcium ions through voltage gated channels. The rise in intracellular calcium causes secretion of insulin.
How does Diazoxide work?
If the channels are dysfunctional, the potassium channel remains closed and therefore the Diazoxide binds the SUR-1 to keep the channel open and stop depolarisation.
What are examples of impaired glycogen metabolism?
Impaired Glycogen Synthesis
- Glycogen synthase deficiency (GSD 0): Uncommon cause of fasting ketotic hypoglycaemia
Impaired Glycogenolysis
- Hepatic glycogen storage disorders: I, III, VI, IX
What are causes of impaired ketogenesis and ketone body utilisation?
- Disorders of carnitine transport
- Fatty acid oxidation defects
- Mitochondrial respiratory chain disorders
What are are some causes of reduced gluconeogensis?
Defects of gluconeogenesis (enzyme deficiency)
- Fructose 1,6 bisphosphatase deficiency
- Phosphoenolpyruvate carboxykinase deficiency
- Pyruvate carboxylase deficiency
Endocrine (failure of counter-regulatory response)
- Cortisol deficiency (hypopituitarism/ adrenal insufficiency)
- Growth hormone deficiency (isolated/ panhypopituitarism
What are causes of defects of intermediary metabolism?
Organic acid disorders
- Methylmalonic acidaemia
- Propionic acidaemia
Amino acid disorders
- Maple syrup urine disease
- Tyrosinaemia
Carbohydrate disorders
- Galactosaemia
- Hereditary fructose intolerance
What are other causes of hypoglycaemia?
- Liver and multi-organ failure
- Gastroenteritis
- Sepsis
- Neonatal complications: prematurity, small for gestational age, congenital heart disease
What are drug related causes of hypoglycaemia?
Sulphonylureas
- Bind receptors on KATP channels to stimulate insulin secretion
Exogenous insulin
- Suppressed C-peptide
- Consider cross-reactivity of insulin assay
What are some issues with cross-reactivity of insulin assays?
- Some recombinant analogues not detected
- Less specific method preferable if suspected
What some factors to consider when assessing clinical history of Hypoglycaemia?
- Timing of hypoglycaemia in relation to feeds/ meals
- Drugs including steroids
- Glucose requirement: >8mg/kg/min is suggestive of hyperinsulinism
What are some physical signs for the differentials considered in hypoglycaemia?
- Macrosomia = Hyperinsulinism
- Hepatomegaly = Glycogen Storage Disease
- Micropenis = Hypopituitarism
- Hyperpigmentation = Adrenal insufficiency
- Short stature = Growth hormone deficiency
- Decreased subcutaneous fat = Inadequate stores
Why are POCT methods less accurate?
- Limitations: severe dehydration/ peripheral vascular disease
- Training issues
- Neonates: falsely increased in anaemia and decreased if haematocrit high.
How is should a hypoglycaemia screen be conducted?
- Collect at the time of hypoglycaemia prior to treatment with dextrose
- Hypo-packs issued to wards. Instructions and correct bottle
How should sample timing be used in investigation of Hypoglycaemia?
- Ammonia, amino acids and acylcarnitine which is preferably collected during hypoglycaemia but timing not essential
- Glucose, insulin, c-peptide, β-hydroxybutyrate, free fatty acids MUST be collected at the time of the hypoglycaemic episode
- Growth hormone not included in hypo pack. Poor specificity for growth hormone deficiency
