Hypoglycaemia

Question 1

Definition in adult, classification

Answer 1

Plasma glucose <2.5 mmol/L

Whipple’s triad: low BG, symptoms of hypoglycaemia, relief of symptoms after glucose raised

Classified into:

• fasting
• reactive
• alcohol-related

Question 2

Fasting hypoglycaemia causes: Excessive Glucose Utilisation

Answer 2

Insulin administration

• most commonly encountered
• poor control of DM, injecting without food
• deliberate self harm
• suppression of endogenous insulin secretion
• Diagnosis = high serum insulin and LOW C-PEPTIDE

Insulinoma
- small adenoma of pancreatic islets which produces insulin (and C-peptide in equimolar ratio)
- Diagnosis – fasting until symptoms of hypoglycaemia –> take blood for serum insulin, C-peptide and glucose levels
==> INAPPROPRIATELY HIGH INSULIN during hypoglycaemia

Oral hypoglycaemics

• hypoglycaemia with prolonged action e.g. DPP-4 inhib (“gliptins”), pioglitazone, meglitinides, sulphonyureas (glibenclamide, glipizide) + metformin
• often need IV glucose for a few days
• Diagnosis = HX and URINE DRUG SCREEN for oral hypoglycaemics

Extra-pancreatic tumours (very rare) e.g. retroperitoneal fibrosarcoma, hepatoma

• symptoms similar to insulinoma
• rapid progression
• large amounts of glucose needed to alleviate hypoglycaemia
• “big” IGF-II from tumour = suppress GH relapse from pituitary–> decrease IGF-I and IGF binding proteins from liver –> increase free IGF-II –> inhibit hepatic glucose release and stimulate glucose uptake in muscle and fatty tissues

Question 3

Fasting hypoglycaemia causes: diminished glucose production

Answer 3

Liver disease

• reduced glycogen reserve and less gluconeogenesis e.g. cirrhosis
• Diagnosis = Hx of LIVER DISEASE and abnormal LFT
• albumin likely low, small liver on USG

Endocrine abnormalities

• adrenocortical and pituitary insufficiency most common
• SHORT SYNACTHEN TEST and PLASMA ACTH
  (adrenocortical: elevated ACTH, non-responsive synacthen test; pituitary: very low ACTH, sluggish response to synacthen)

Renal disease
- multifactorial – uraemia may inhibit liver gluconeogenesis; poor appetite and intake

Question 4

Fasting hypoglycaemia causes: autoimmune

Answer 4

Insulin receptor Ab (agonist to receptor)

Beta cell stimulating Ab (stimulate insulin production by beta-cells)

Insulin Ab (most common, similar to reactive hypoglycaemia)

Question 5

Reactive hypoglycaemia (exclude other causes before considering this)

Answer 5

Reactive to food

• can be dx from history
• physiology: rapid absorption of glucose –> EXCESSIVE INSULIN response –> rebound hypoglycaemia
• post-gastrectomy, eating rapidly absorbable carbohydrate
• Tx: change of diet to more complex carbohydrates e.g. corn starch; smaller meals post-gastrectomy

Question 6

Alcohol-related hypoglycaemia

Answer 6

Alcohol sensitivity can induce hypoglycaemia up to 36 hrs after alcohol

Reactive – re-feeding after admission to hospital
Fasting (poor intake in alcoholics)

• suppression of gluconeogenesis
• RAISED KETONES

Question 7

Hypoglycaemia in neonates

Answer 7

Full-term baby: <2.0 mmol/L

Premature infant: <1.1 mmol/L

Question 8

Causes of neonatal hypoglycaemia: excessive glucose utilisation

Answer 8

Maternal DM (common)
- macrosomia: endogenous insulin in foetus very high to handle sugar load from mother --> glucose supply lost after birth but insulin still high --> hypoglycaemia 

• persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) – developmental error of pancreas with dysregulation of beta cells leading to more insulin release

Question 9

Causes of neonatal hypoglycaemia: decreased glucose production

Answer 9

Pre-maturity 
Severe liver damage 
Sepsis
Inborn errors of metabolism
Hormonal deficiencies (CAH, GH deficiency)

= difficult to treat and usually not correctable

Question 10

Approach to Hypoglycaemia

Answer 10

1. Any symptoms
   - release of catecholamines results in sweating, tremor, anxiety
   - poor concentration, delirium, convulsion due to decreased CSF glucose (neuroglycopenia)
2. Is it genuine hypoglycaemia?
   - POCT glucometers inaccurate and imprecise in hypoglycaemic range
   - confirmation with lab method
3. Hx taking
   - diabetic relatives or work in medical field – BEWARE OF SURREPTITIOUS INSULIN OR HYPOGLYCAEMICS
   - FHx: insulinoma may be part of MEN1

Question 11

Investigations of Hypoglycaemia

Answer 11

1. Plasma glucose
   - prolonged fasting to induce hypoglycaemia –> collect blood during symptoms
   - FLUORIDE TUBE inhibits metabolism of glucose
   - laboratory method
2. Serum insulin and C-peptide
   - during hypoglycaemic episodes
   - exogenous insulin = high insulin, low C peptide
   - oral hypoglycaemics, insulinoma, insulin Ab = high insulin and C-peptide
   - liver disease, adrenal insufficiency, hypopituitarism, glycogen storage, reactive, alcohol-related = low insulin and C-peptide
3. Specific biochemical investigations
   - LRFT
   - Short synacthen test (normal cortisol >450 nmol/L), ACTH
   - Glucagon or insulin stress test for GH/Cortisol deficiency (induce reactive hypoglycaemia) – normal cortisol >450 nmol/L and GH up to 20 ng/ml
   - Extended OGTT for reactive hypoglycaemia
   - IGF-II and IGF binding proteins
   - Autoimmune Ab
   - Metabolic screening for IEM
   - Urine toxicology

Question 12

Pathophysiology of insulin autoimmune Ab

Answer 12

Similar presentation to reactive hypoglycaemia

Binds to insulin and holds it in bloodstream like reservoir (not metabolised)

• initial hyperglycaemia when binding insulin
• weakened binding can cause sudden release into bloodstream (unpredictable)
• not necessarily hypoglycaemic during fasting

C-peptide metabolised by kidney as normal

==> HIGH INSULIN:C-PEPTIDE MOLAR RATIO
(higher than exogenous insulin)