Chemical Pathology 16 - Hypoglycaemia

Question 1

How should hypoglycaemia be managed if the patient is alert and oriented?

Answer 1

Oral carbs

Rapid - juice/sweets

Long - sandwich

Continuous monitoring and treat cause

Question 2

How should hypoglycaemia be managed if the patient is drowsy, but not unconscious?

Answer 2

Buccal glucose (bypasses 1st pass metabolism) -Hypostop/glucogel
Continuous monitoring and treat cause

Question 3

How should hypoglycaemia be managed if the patient is unconscious or has a reduced swallow reflex?

Answer 3

IV glucose 20%

IM glucagon (mobilises glycogen stores so takes 15-20mins to raise levels)

• must be adequate glycogen stores to mobilise and beware of rebound hypoglycaemia from insulin release → f/u with slower acting carbs

Continuous monitoring and treat cause

Question 4

Define hypoglycaemia

Answer 4

Hypoglycaemia = <4mmol/L (really 3.5 ish)

In diabetes = <3.5mmol/L NR = 4.0-5.4mmol/L (fasting)

In paediatrics = <2.5mmol/L NR = 4.0-7.8mmol/L (2-hour OGTT)

Question 5

What is Wipple’s triad

Answer 5

Low glucose

Symptoms (adrenergic or neuroglycopaenic)

Relief of symptoms upon treatment

Question 6

What are the possible symptoms of hypoglycaemia?

Answer 6

Adrenergic symptoms - tremors and sweating
Neuroglycopaenic symptoms - somnolence and confusion
None - in some type 1 diabetic

Question 7

What is the body’s physiological response to hypoglycaemia, and which of these responses if the first?

Answer 7

1. suppression of insulin
2. release of glucagon
3. release of adrenaline
4. release of cortisol

Question 8

Recall the effects of glucagon

Answer 8

Directly:

1. ↓ peripheral glucose uptake
2. ↑ glycogenolysis
3. ↑ gluconeogenesis in the liver and kidneys
4. ↑ lipolysis

This then leads to:
1. ↑ glucose
2. ↑ free fatty acids
Fatty acids undergo beta oxidation –> ketones

Question 9

What is the best measure of glucose?

Answer 9

Venous glucose (way better than capillary - poor precision at low levels)

Fluoride oxalate grey-top, 2mL blood

Question 10

Recall 6 differentials for the cause of hypoglycaemia in a NON-diabetic patient

Answer 10

1. Critically unwell pt
2. Organ failure
3. Hyperinsulinism
4. Drugs
5. Extreme weight loss
6. Factitious

Question 11

Recall 5 differentials for the cause of hypoglycaemia in diabetic patients

Answer 11

1. Medications - these iatrogenically reduce glucose
2. Inadequate CHO intake (T1D especially)
3. Impaired awareness (eg EtOH)
4. Exercise
5. In presence of autoimune conditions eg Addissons

Question 12

What class of drug is gliclazide?

Answer 12

Sulphonylurea

Question 13

Which 2 classes of oral diabetic drug are most likely to cause a hypo?

Answer 13

Sulphonylureas (eg gliclazide)
GLP-1 agents

Meglitinides

Question 14

Recall 3 non-diabetes drugs that can cause a hypo

Answer 14

Beta blockers (impair adrenergic response so have impaired awareness of symptoms)
Salicylates - impair regulation of glucose
Alcohol

Question 15

What are the 4 first basic biochemical tests that should be done in hypoglycaemia investigation?

Answer 15

1. Glucose
2. Insulin
3. C peptide
4. Drug screen

Question 16

Recall 5 advanced biochemical tests that can be used in investigating a hypoglycaemia

Answer 16

Ketones and FFAs
IGF studies
Ammonia
Lactate
Inborn error of metabolism screen

Question 17

Recall 3 possible causes of hyperinsulinaemic hypoglycaemia

Answer 17

inappropriate response to hypoglycaemia - excess endogenous insulin production

high insulin and high C peptide

1. Insulinoma (islet cel tumour)
2. Drugs (eg insulin/ sulphonylurea)
3. Islet cell hyperplasia

Question 18

Recall some causes of hypoinsulinaemic hypoglycaemia

Answer 18

appropriate response to hypoglycaemia - cause is something other than insulin

Fasting/starvation

Strenuous exercise

Critical illness

Endocrine deficiencies (i.e. hypopituitarism, adrenal failure)

Liver failure

Anorexia nervosa

Question 19

Recall 3 causes of islet cell hyperplasia in the neonate

Answer 19

1. Infant of a diabetic mother
2. Beckworth Wiedmann syndrome
3. Nesidioblastosis

Question 20

How can non-islet cell tumours cause hypoglycaemia?

Answer 20

This is a RARE case - most likely to occur in mesothelioma/ carcinoma of the lung
These tumours secrete ‘big IGF-2’ (paraneoplastic syndrome) which binds to both IGF-1 and insulin receptors
In this case, insulin and C peptide will both be low

Question 21

What is C peptide a marker of?

Answer 21

cleavage product of pro-insulin

secreted in equimolar amounts to insulin

good marker of beta cell function i.e. exogenous insulin results in a low c-peptide measurement

better than insulin as exogenous insulin interferes with assays

Question 22

How does anorexia lead to hypoglycaemia?

Answer 22

poor liver glycogen stores due to long term starvation

Question 23

How would insulin and C peptide be in anorexia?

Answer 23

pt would have switched off her insulin production

Question 24

In a neonate with hypoglycaemia but no ketones, what is the likely diagnosis?

Answer 24

Inborn error of fatty acid metabolism

normal response to hypoglycaemia → HIGH ketones

FFA oxidation defect (less ketones are produced)

Question 25

what is 3-hydroxybutarate?

Answer 25

ketone body - marker of ketones

Question 26

How would insulin and C peptide be in metabolic disorder of FFAs?

Answer 26

low insulin, low C-peptide, (raised FFA), low ketones = metabolic disorder

Question 27

How would you differentiate hypoglycaemia caused vy insulinoma or factitious sulphonylurea

Answer 27

urine or serum sulphonylurea drug screen NEGATIVE → insulinoma

Question 28

What are the differentials for low glucose, high insulin, high C-peptide?

Answer 28

endogenous insulin production → insulinoma or factitious sulphonylurea

Question 29

what is the mechanism of action of insulin?

Answer 29

Glucose crosses membrane -\> glycolysis via glucokinase Glycolysis → ATP → closure of ATP-sensitive K+ channel (a lot of genetic mutations that affect this channel) → membrane depolarisation, calcium influx and insulin exocytosis Sulphonylureas bind ATP-sensitive K+ channel and makes it close, independently of ATP → insulin release even when no ATP around (this is why sulphonylureas can cause hypoglycaemia)

Question 30

how to treat insulinoma?

Answer 30

simple resection

Question 31

cause of hypoglycaemia if insulin high and c peptide low

Answer 31

Factitious (exogenous) insulin (most likely) Oral hypoglycaemic usage (not sulphonylurea, as C-peptide would be high)

Question 32

Hypoglycaemia due to excess injected insulin would result in

Answer 32

a low C-peptide ## Footnote ↑ exogenous insulin → ↓ pancreas insulin production → ↓ C-peptide but there would still be ↑ insulin (as cannot differentiate between exogenous and endogenous insulin)

Question 33

what is the cause of hypoglycaemia if ↓insulin/Cpeptide/FFA/ketones

Answer 33

Non-islet cell tumour hypoglycaemia: ↓ insulin → something else driving hypoglycaemia 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) Produced by mesenchymal tumours (mesothelioma, fibroblastoma) and epithelial tumours (carcinoma) Big IGF-2 binds IGF-1 R and insulin R → endogenous insulin production is switched off and FFA production is suppressed

Question 34

What are some genetic causes of hypoglycaemia?

Answer 34

Glucokinase activating mutation Congenital hyperinsulinism:

Question 35

What is Reactive/Post-prandial Hypoglycaemia

Answer 35

hypoglycaemia following food intake Can occur after gastric bypass Hereditary fructose intolerance Early diabetes In insulin-sensitive people post-exercise or large meals