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a path 3 > CHEMPATH: Hypoglycaemia > Flashcards

CHEMPATH: Hypoglycaemia Flashcards

1
Q

Stepwise approach to hypoglycaemia

A

Summary of causes

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2
Q

What is the acute management of hypoglycaemia?

A

Based on how alert the patient is

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3
Q

What is the glucose level definition for hypoglycaemia in normal and diabetic individuals?

A
  • Hypoglycaemia = <4mmol/L
  • In diabetes = <3.5mmol/L
  • In paediatrics = <2.5mmol/L
  • NR = 4.0-5.4mmol/L (fasting)
  • NR = 4.0-7.8mmol/L (2-hour OGTT)
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4
Q

What is Wipple’s triad?

A

Wipple’s triad = a new style of definition for hypoglycaemia:

  • Symptoms can be:
    • Adrenergic
    • Neuroglycopaenic
  • Summary of triad:
    • Low glucose
    • Symptoms
    • Relief of symptoms upon treatment
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5
Q

What is the mechanism/pathophysiology of hypoglycaemia?

A

Order of physiological changes upon hypoglycaemia:

  • (1) suppression of insulin
  • (2) release of glucagon
  • (3) release of adrenaline
  • (4) release of cortisol

Counter-regulation of blood glucose (see right):

  • These methods increase glucose, and so FFA as well
  • FFAs enter beta-oxidation cycle to make ATP
  • Excess FFAs can metabolise into ketone bodies
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6
Q

What occurs first in hypoglycaemia?

  • Release of cortisol
  • Release of glucagon
  • Suppressed insulin
  • Release of adrenaline
A

Suppressed insulin - almost instantaneous

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7
Q

How do you investigate hypoglycaemia in a diabetic vs normal patient?

A
  • Diabetes = monitor blood glucose
  • Healthy person = conduct a prolonged fast to demonstrate hypoglycaemia (normal people should never become hypoglycaemic, even after a prolonged fast)
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8
Q

What is the gold standard for glucose measurement?

A
  • Venous glucose (gold standard):
    • Fluoride oxalate in grey-top, 2mL blood
    • Lab analyser with quality control but takes some time
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9
Q

What are 3 types of glucose measurement?

A

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
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10
Q
A
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11
Q

What are some causes of hypoglycaemia in non-diabetics?

A
  • Fasting or reactive
  • Paediatric or adult
  • Critically unwell
  • Organ failure
  • Hyperinsulinism
  • Post-gastric bypass
  • Drugs
  • Extreme weight loss
  • Factitious (i.e. an artefact)
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12
Q

What are the most common causes of hypoglycaemia in diabetics?

A
  • Medications (inappropriate insulin)
  • Inadequate CHO intake/missed meal
  • Impaired awareness
  • Excessive alcohol
  • Strenuous exercise
  • Co-existing autoimmune conditions
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13
Q

Which diabetic medications can cause hypoglycaemia?

A
  • Oral Hypoglycaemics:
    • Sulphonylureas
    • Meglitinides
    • GLP-1 agents
  • Insulin
    • Rapid acting with meals
    • Long acting
  • Other drugs
    • Beta-blockers
    • Salicylates
    • Alcohol (inhibits lipolysis)
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14
Q

What comorbid conditions in diabetes can also lead to hypoglycaemia?

A

Co-existing renal/liver failure alters drug clearance--> reduces the doses needed - e.g. patient on sulfonylurea, GFR decreases, sulfonylurea accumulate, more hypos

Concurrent Addison’s disease (RARE) –> hypoglycaemia (polyglandular autoimmune syndrome)

Poor awareness from autonomic neuropathy

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15
Q

Menti: C peptide is:

  • Cleavage product of insulin
  • It is equimolar to insulin
  • Half life of 2hrs
  • Interferes with insulin measurement
A

Secreted in equimolar amounts to insulin

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16
Q
A

Low C peptide - because C peptide is marker of endogneous insulin. Insulin from pancreas will be switched off in hypoglycaemia

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17
Q

To differentiate the causes of hypoglycameia a thourough history and examination should be done. What biochemical tests should also be done in hypoglycameia?

A
  • Insulin levels (exogenous insulin interferes with assays)
  • C-peptide
  • Drug screen
  • Autoantibodies
  • Cortisol/GH
  • FFAs/blood ketones
  • Lactate
  • Other specialist tests (e.g. IGFBP, IGF-2, carnitine)
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18
Q

What is the precursor of insulin? What are the breakdown products?

A

Proinsulin –> insulin and C-peptide

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19
Q

What is C-peptide? What is the use? What is the half life of C peptide?

A

C peptide = cleavage product; secreted in equimolar amounts to insulin)

C-peptide is a good marker of beta cell function

Half-life is 30 mins and renally cleared

i.e. exogenous insulin results in a low c-peptide measurement

20
Q
A

Probably has anorexia therefore poor liver glycogen stores

21
Q

Menti: case of anorexia

A

low insulin and low C peptide - hypoinsulinaemic hypoglycaemia

22
Q

What is hypoinsulinaemic hypoglycaemia? What are the causes?

A

Hypoinsulinaemic hypoglycaemia - low insulin, low C peptide

Suggests that something other than insulin is causing the hypoglycaemia. This is an 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
23
Q

What is hyperinsulinaemic hyperglycaemia?

A

High insulin + low C-peptide

suggests that there is exogenous insulin

24
Q
A

A ketone body

3 ketone bodies = 3-hydroxybutyrate, acetone, acetoacetate

25
Q

1-day old neonate, jittery, not feeding, premature (34w gestation), 1.9mmol/L lab glucose, improved on feeding but low blood glucose 4 hours postprandial, 3-hydroxybutyrate (a ketone body) measured at the hypo attack and was -ve.

A

Fatty acid oxidation defect

26
Q

What are the risk factors for neonatal hypoglycaemia?

A
  • Premature - glycogen stores double at 36w so before this, neonates are more at risk
  • Co-morbidities
  • IUGR
  • SGA
27
Q

What is the appropriate response to hypoglycaemia?

A

Hypoinsulinaemic hypoglycaemia

28
Q
A
29
Q

What is a pathological cause of hypoglycaemia in a neonate?

A

Inborn errors of metabolism

30
Q

Which 3 metabolic disorders can cause neonatal hypoglycaemia?

A
  • Fatty Acid Oxidation Disorders (FAOD) = no ketones produced
  • Glycogen Storage Disease (GSD) type 1 (gluconeogenetic disorder)
  • Medium Chain Acyl-CoA Deficiency (MCAD)
  • Carnitine Disorders
31
Q
  • Why is this response pathological in a neonate?
  • hypoglycaemia with
  • low insulin,
  • low C-peptide,
  • raised FFA,
  • low ketones
A

Low ketones are pathological as everything else ca n be explained without pathology

Whenever insulin is LOW, FFAs should be HIGH (if you have high FFAs, there should be an increase in ketone body formation. The fact that the child in this case has low ketone bodies despite having low insulin and low C-peptide suggests that there is a defect in fatty acid oxidation)

32
Q

Neonatal hypoglycaemia

A
33
Q

What are the causes of inappropriately high insulin levels?

A

Low glucose, high insulin, HIGH C-peptide

  • Drugs (sulphonylureas)
  • Islet cell tumours (e.g. insulinoma)
  • Islet cell hyperplasia
34
Q

What 3 conditions can cause islet cell hyperplasia?

A

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)

35
Q

45yo lady intermittent fitting, weight gain, increased appetite, personality changes over last month

Glucose 1.9mmol/L, insulin 35mU/L, c-peptide 1,000pmol/L [HIGH]

What do these results suggest?

A

The high C-peptide suggests that the insulin is being produced endogenously

  • This could be an insulinoma OR sulphonylurea abuse –> perform a urine or serum sulphonylurea drug screen
  • If this is NEGATIVE, then insulinoma can be diagnosed
36
Q

What must you exclude to diagnose insulinoma?

A

Drug screen for exogenous causes like sulfonylureas

Perform a urine or serum sulphonylurea drug screen

37
Q

What is the normal insulin secretion pathway?

A

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 and 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)

38
Q

How common are insulinomas? What is the usual cause?

A

1-2 per million

Usually solitary adenoma (10% malignant, 9% associated with MEN1) - treat with simple resection

39
Q

What is the most likely cause?

9yo boy fitting, glucose 1.9mmol/L, insulin 205mU/L, c-peptide <33pmol/L

A

Cause of hypoglycaemia (Insulin very HIGH, c-peptide very LOW):

  • Factitious (exogenous) insulin (most likely)
  • Oral hypoglycaemic usage (not sulphonylurea, as C-peptide would be high)
40
Q
A
41
Q

What is the cause?

60yo cachectic man unconscious, smoker, glucose 1.9mmol/L. Hypoglycaemia persists despite glucose infusion. Insulin & c-peptide undetectable, FFA undetectable, ketones -ve

A

Non-islet cell tumour hypoglycaemia:

  • Insulin is LOW so must be something else driving the hypoglycaemia
  • FFA should be high but low so 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 to IGF-1 receptors and insulin receptors = your own endogenous insulin production is switched off and FFA production is suppressed
42
Q

Why does IGF-2 release in paraneoplastic syndrome cause hypoglycaemia and low FFA?

A

Big IGF-2 binds to IGF-1 receptors and insulin receptors

So endogenous insulin production is switched off and FFA production is suppressed

43
Q

Which types of tmours can cause paraneoplastic syndromes causing hypoglycaemia ?

A

Secretion of IGF-2:

  1. Mesenchymal tumours (mesothelioma, fibroblastoma)
  2. Epithelial tumours (carcinoma)
44
Q

How can autoimmune disorders cause hypoglycaemia? (2 types)

A

Autoimmune conditions rarely cause…

  1. Antibodies against insulin R;
    • Usually presents with insulin resistance but may sometimes present with hypoglycaemia
  2. Antibodies against insulin (= autoimmune insulin syndrome)
    • Sudden dissociation of these Ab from insulin may precipitate hypoglycaemia
    • Can be caused by drugs (hydralazine, procainamide)
45
Q

List 2 genetic causes of hypoglycaemia. How will these present?

A

Present with low glucose, high insulin, high C-peptide (treated with pancreatectomy)

  1. Glucokinase activating mutation
  2. Congenital hyperinsulinism (KCNJ11 /ABCC8, GLUD-1, HNF4A, HADH)
46
Q

What are 2 causes of reactive/post-prandial hypoglycaemia?

A
  • Post gastric bypass
  • Hereditary fructose intolerance
  • Early diabetes
  • Insulin-sensitive people post-exercise or post-large meal

Difficult to define true post-prandial hypos

47
Q

In what type of diabetes do these occur?

  1. Hypoketotic hyperglycaemia
  2. Hyperketotic hyperglycaemia
A
  1. Hypoketotic hyperglycaemia - HHS/HONK (T2DM)
  2. Hyperketotic hyperglycaemia - DKA (T1DM)

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