T2 L11 Hypoglycaemia Flashcards
What is the definition of hypoglycaemia?
A blood glucose of below 4mM (72mg//dL)
Normal levels are around 6.1mM
Above 7mM is indicative of diabetes
What blood glucose level does a loss of consciousness occur at?
2.5mmol/L
What are the symptoms of hypoglycaemia?
Equivalent to cerebral anoxia Moodiness Faintness Numbness in arms & hands Blurred vision Dizziness Lethargy - may progress to a coma which can lead to death or permanent cerebral damage if not treaed
What are the causes of hypoglycaemia?
Fasting
Exercise
Hypernatraemia -such as diabetes insipidus
Hypovolaemia from vomiting, dehydration etc.
Ingestion of alcohols
Pathologies such as adrenal insufficiency
When does alcohol induced hypoglycaemia occur?
Several hours after alcohol ingestion
Occurs on depletion of glycogen stores when blood glucose is reliant on hepatic gluconeogenesis
What may decrease gluconeogenesis?
Liver damage
Reduced muscle mass
Why does the consumption of alcohol place additional stress on gluconeogenesis?
Alcohol is primarily metabolised in the liver by an unregulated process
What is the initial step for the metabolism of alcohol?
Ethanol –> acetaldehyde
Uses alcohol dehydrogenase
NAD+ is used as a co-enzyme & converted to NADH
Acetaldehyde is transported into the mitochondria
What is the 2nd step for the metabolism of alcohol?
Acetaldehyde –> acetate acid
Uses acetaldehyde dehydrogenase
NAD+ is used & converted t NADH
What are the biochemical consequences of alcohol consumption?
High levels of NADH inhibit fatty acid oxidation.
Triglycerides accumulate in the liver leading to fatty liver
Acetate produced can be converted to acetyl CoA. Further processing of acetyl CoA in the TCA cycle is prevented as the high levels of NADH inhibit isocitrate dehydrogenase & alpha-ketoglutarate dehydrogenase
Acetaldehyde is the immediate end product of alcohol metabolism & is highly toxic.
What are the consequences of an accumulation of acetyl CoA?
Production of ketone bodies which are released into the blood. Exacerbates the already acidic conditions caused by high lactate levels
Processing of acetate in the liver becomes inefficient leading to a build up of acetylaldehyde
What are the steps for the biochemical consequences of alcohol consumption?
1) Ethanol enters hepatocytes from portal circulation & is converted to acetaldehyde by ADH
2) Acetaldehyde enters mitochondria & is converted to acetate by ALDH. Both of these reduce NAD+ to NADH & generate oxidative stress by increasing ROS
3) Large amounts of NADH formed stimulate synthesis of fatty acids & triacylglycerols & prevents oxidation of lactate to pyruvate. This inhibits gluconeogenesis & generates lactic acidosis.
4) Acetate converted to acetyl CoA or exported from the liver.
5) Acetyl CoA produces ketone bodies & supports TG synthesis by conversion to fatty acyl CoA.
Why does hepatomegaly occur?
Alcohol decreases activity of proteasome
Leads to accumulation of protein –> enlargement of liver
Decreased proteasome activity –> oxidative stress
What are the causes of thiamine deficiency?
Malnourishment
Ethanol interferes with GI absorption
Hepatic dysfunction - hinders storage & activation to thiamine pyrophosphate
What is thiamine?
Co-factor for many enzymes
Half life of 10-20 days
Coenzyme in central energy yielding pathways