EndocrinologyTier 1Disease (DEADMAN)

Acute metabolic derangements - hypoglycaemia

Description

Whipple's triad - required before investigating anyone without diabetes

1. Symptoms consistent with hypoglycaemia (ideally neuroglycopenic)

2. Low plasma glucose documented at the time of those symptoms

3. Resolution of symptoms when the glucose is corrected

A low capillary glucose in an asymptomatic person is not a hypoglycaemic disorder. Do not start a workup without the triad

Levels (diabetes)

Level	Glucose	Meaning
1 - alert	3.0-3.9 mmol/L	Treat, review regimen
2 - clinically significant	<3.0 mmol/L	Neuroglycopenia likely
3 - severe	Any level	Cognitive impairment requiring another person's help - defined by the help, not the number

Symptoms

Autonomic (adrenergic/cholinergic, ~3.6-3.9) - tremor, palpitations, sweating, hunger, anxiety, paraesthesiae
- Warning symptoms. Masked by beta blockade, and lost in hypoglycaemia unawareness
Neuroglycopenic (~<3.0) - confusion, behaviour change, slurred speech, incoordination, visual change, focal deficit, seizure, coma
- May be mistaken for stroke, intoxication or psychiatric illness

Epidemiology

Severe hypoglycaemia: ~1-3 episodes/patient/year in T1DM, ~1 in 5 patients/year in insulin-treated T2DM
Hypoglycaemia unawareness in ~25% of T1DM, rising with duration
Insulinoma incidence ~1-4 per million/year; ~90% benign, ~90% solitary, ~90% intrapancreatic, ~10% MEN1
Sulfonylurea and insulin are the two commonest causes of drug-induced hypoglycaemia presenting to hospital
Older people, CKD and alcohol markedly raise risk

Aetiopathogenesis

Normal counter-regulation - and the order it fails

Glucose	Response
~4.6	dec insulin secretion (first defence)
~3.8	inc glucagon (second) and inc adrenaline (third)
~3.6-3.9	Autonomic symptoms
~3.0	Cortisol, GH; neuroglycopenia
<2.8	Cognitive dysfunction, then seizure/coma

Hypoglycaemia-associated autonomic failure (HAAF)

In established T1DM the glucagon response is lost within ~5 years -> adrenaline becomes the only defence
Recent hypoglycaemia blunts the adrenaline response and shifts the symptom threshold downward
- -> hypoglycaemia unawareness -> more hypoglycaemia -> a self-reinforcing vicious cycle
*Reversible: 2-3 weeks of scrupulous hypoglycaemia avoidance restores awareness* - the single most useful management fact

Causes in a person WITHOUT diabetes

Ill or medicated (the common ones)

Drugs - sulfonylureas, glinides, insulin, alcohol (inhibits gluconeogenesis; classically after a binge with no food), quinine, quinolones, pentamidine, indometacin, high-dose salicylate; beta blockers mask rather than cause
Organ failure - hepatic, renal (reduced insulin clearance and gluconeogenesis), cardiac failure
Sepsis, starvation, anorexia
Hormone deficiency - cortisol (Addison's, hypopituitarism), rarely GH

Apparently well - the ones needing a workup

Insulinoma
Post-bariatric (post-gastric bypass) hypoglycaemia - late postprandial, exaggerated GLP-1/insulin response
Non-islet cell tumour hypoglycaemia - large mesenchymal tumours or HCC secreting big IGF-2
Insulin autoimmune syndrome (anti-insulin antibodies; Hirata disease; sulfhydryl drugs, methimazole)
Insulin receptor antibodies (type B insulin resistance)
Factitious / accidental - insulin or sulfonylurea; think of health workers, carers, and dispensing errors
Nesidioblastosis; congenital hyperinsulinism; inborn errors of metabolism

Diagnosis

The critical sample - take it BEFORE giving glucose

Plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, sulfonylurea/glinide screen, insulin antibodies, cortisol

	Insulin	C-peptide	Proinsulin	Beta-OHB	SU screen
Insulinoma	inc	inc	inc	dec (<2.7)	neg
Sulfonylurea	inc	inc	inc	dec	POSITIVE
Exogenous insulin	inc (often very)	*suppressed*	dec	dec	neg
Insulin autoimmune	very inc	inc	inc	dec	neg, antibodies +
NICTH (IGF-2)	dec	dec	dec	dec	neg (IGF-2:IGF-1 ratio >10)
Non-insulin-mediated (alcohol, sepsis, hypopituitarism)	dec	dec	dec	inc	neg

C-peptide is the discriminator: high = endogenous insulin, suppressed = exogenous insulin
*A high C-peptide is not automatically an insulinoma until the sulfonylurea screen is negative* - this is the commonest diagnostic error
Beta-hydroxybutyrate suppression proves insulin (or IGF) action - insulin suppresses ketogenesis

Timing separates the causes

Timing	Suggests
~1-2 h after a meal, modest C-peptide rise	Reactive/postprandial hypoglycaemia - insulin secretion overshoot in impaired glucose tolerance
1-3 h after a meal, years after gastric bypass	Post-bariatric hypoglycaemia
Fasting, >8 h after a meal or overnight	Insulinoma, NICTH, organ failure, hormone deficiency
Unrelated to meals, suppressed C-peptide	Factitious/exogenous insulin

72-hour supervised fast - the gold standard for fasting hypoglycaemia

Glucose, insulin, C-peptide, proinsulin, beta-OHB every 6 h, then hourly once glucose <3.3
End the fast when glucose <3.0 with Whipple's triad satisfied (not on a number alone)
Give 1 mg IV glucagon at the end and measure glucose at 10, 20, 30 min - a rise >1.4 mmol/L indicates preserved hepatic glycogen -> insulin-mediated hypoglycaemia
~70-75% of insulinomas declare within 24 h; ~95% by 48 h

Localising an insulinoma - only after biochemical proof

Contrast CT/MRI pancreas (often small and easily missed)
Endoscopic ultrasound - highest sensitivity for small lesions
68Ga-exendin-4 (GLP-1 receptor) PET/CT - highest sensitivity of the functional modalities; DOTATATE PET if that is unavailable
Selective arterial calcium stimulation with hepatic venous sampling if imaging is negative
Screen for MEN1 (calcium/PTH, prolactin, gastrin) in anyone young, multifocal or with a family history

Management

A. Acute treatment - conscious and able to swallow

15 g of rapid-acting carbohydrate, recheck in 15 minutes, repeat if still <4.0 (the 15-15 rule)
- 6-7 jellybeans, 150 mL soft drink (not diet), 3 teaspoons sugar, glucose tablets
- Not chocolate - fat slows absorption
Follow with long-acting carbohydrate once above 4.0, unless a meal is imminent

B. Acute treatment - unconscious, seizing, or unable to swallow

IV glucose 10-25 g (e.g. 100 mL of 20%, or 250 mL of 10% via a large vein)
- 50% glucose is sclerosant - avoid via peripheral cannula where alternatives exist
OR glucagon 1 mg IM/SC (nasal glucagon 3 mg where available)
- *Ineffective in alcohol, liver disease, starvation and sulfonylurea overdose* - no glycogen to mobilise, or it simply re-stimulates insulin
Thiamine before glucose if malnourished or alcohol-dependent
Recheck at 15 min; then hourly until stable

C. By cause - the part that decides disposition

Cause	Specific action
Sulfonylurea	Admit and observe >=24 h (longer in renal impairment); 10% glucose infusion; *octreotide 50-100 microg SC 6-12 hourly* if recurrent - it suppresses the SU-driven insulin release that glucose alone perpetuates
Long-acting insulin	Observe for the full duration of action
Alcohol	Glucose + thiamine; glucagon will not work
Adrenal insufficiency / hypopituitarism	Hydrocortisone
Insulinoma	Surgical enucleation/resection is curative; diazoxide or octreotide while awaiting surgery; everolimus for malignant disease
NICTH	Treat/debulk the tumour; glucocorticoid +/- GH
Post-bariatric	Low-GI, low-carbohydrate, small frequent meals first; acarbose; diazoxide/octreotide; GLP-1 analogue; surgery last resort
Factitious	Psychiatric involvement; do not confront without the biochemistry

D. Preventing recurrence in diabetes

Establish the cause of each episode: missed meal, exercise, alcohol, dose error, renal decline, gastroparesis, new adrenal insufficiency, weight loss
Relax the HbA1c target - a target that produces severe hypoglycaemia is the wrong target
CGM in preference to fingerstick SMBG for anyone on multiple daily injections or at high risk, and automated insulin delivery (hybrid closed loop) is the most effective single intervention in T1DM
Analogue insulins in preference to NPH and human regular insulin
2-3 weeks of strict hypoglycaemia avoidance to restore awareness; structured education (DAFNE-type)
Prescribe glucagon and train a household member; ready-to-use formulations preferred over those needing reconstitution
Review and de-escalate sulfonylureas in older people and CKD
Driving: check glucose before driving, >=5.0 to drive, carry carbohydrate; report severe hypoglycaemia per Austroads Assessing Fitness to Drive

Associations

MEN1 - insulinoma with parathyroid and pituitary disease
Adrenal insufficiency, hypopituitarism
CKD - reduced insulin clearance and gluconeogenesis; sulfonylurea accumulation
Liver failure, cardiac failure, sepsis
Bariatric surgery - post-prandial hyperinsulinaemic hypoglycaemia
Alcohol use disorder, malnutrition, anorexia nervosa
Autoimmune disease and methimazole/carbimazole, alpha-lipoic acid, hydralazine - insulin autoimmune syndrome
Beta blockers - mask warning symptoms; also impair recovery

Natural history & complications

Severe hypoglycaemia is an independent predictor of mortality, dementia and cardiovascular events - not merely a marker of tight control
Each episode lowers the threshold for the next (HAAF) - the cycle is the disease
Prolonged, profound neuroglycopenia -> permanent cognitive impairment; rarely fatal ('dead in bed' syndrome - nocturnal hypoglycaemia with arrhythmia in young T1DM)
Hypoglycaemia unawareness is reversible with avoidance; a resolved awareness restores the warning system
Insulinoma: surgical cure in >90% of benign solitary lesions; malignant insulinoma (<10%) has an indolent but progressive course
Fear of hypoglycaemia drives deliberate under-treatment and worse control - ask about it directly

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