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
What are glycogen storage diseases?
Inherited diseases where the stores of glycogen are affected by defects in enzymes of synthesis or degradation of glycogen.
All result in production of an abnormal amount or type of glycogen
Family of inborn errors of metabolism
What is type I glycogen storage disease?
G-6-Pase
Von Gierke’s disease
Most common type
Mainly affects the liver & kidneys caused by a deficiency in glucose-6-phosphatase
Body attempts to compensate for hypoglycaemia by releasing glucagon & adrenaline leading to mobilisation of fat stores & release of fatty acids
Conversion of fatty acids to TAGs & VLDL in the liver –> accumulation of fat in the liver & hyperlipidaemia –> hepatomas
What do high levels of G-6-P lead to?
Abnormal levels of glycogen accumulation in liver & kidneys
Increased glycolysis –> lactic acidosis
Increased fatty acid, triacylglycerides & VLDL synthesis & excretion
What are the signs & symptoms of type I glycogen storage disease?
Enlarged livers and/or kidneys Stunted growth Severe tendencies to hypoglycaemia Hyperlactaemia Hyperlipidaemia Hyperuricaemia Neutropenia - may have recurrent bacterial infections Symptoms appear when intervals between feeds increase such as when an infant sleeps through the night
What is the treatment for type I glycogen storage disease?
Young infants are fed glucose through NG tubes
Older. children are fed glucose drinks at 2-3 hours intervals throughout the day & night to prevent the fall in blood glucose & cerebral damage
Uncooked corn-starch may be used to prolong the periods between feeds.
What is type II glycogen storage disease?
Lysosomal storage disease. Cytosolic glycogen metabolism is unaffected
Pompe’s disease
Deficiency of alpha-1,4- glucosidase activity in the lysosomes. Causes death by cardiorespiratory failure
What is type III glycogen storage disease?
Debranching enzyme Cori's disease Amylo-1,6-glucosidase is deficient Unable to break down glycogen --> hypoglycaemia Symptoms often disappear at puberty
What is type IV glycogen storage disease?
Branching enzyme Andersen's disease One of the most severe Liver glycogen is in normal amounts but has long unbranched chains that have low solubility Sufferers rarely live beyond 4 years
What is type V glycogen storage disease?
Glycogen phosphorylase
McArdel’s syndrome
Affects muscle glycogen phosphorylase
Muscle can’t break down glycogen causing it to accumulate
Sufferers have a low tolerance to exercise & fatigue easily with painful muscle cramps
Have a normal life span
