T2 L10: Hypoglycaemia

• What is hypoglycaemia?

  blood glucose level below 4mM

  rapid fall in blood glucose:

  activation of sympathetic nervous system -> release of adrenaline & glucagon -> sweating, tachycardia, agitation
• What are the symptoms of hypoglycaemia?

  equivalent to cerebral anoxia

  moodiness, faintness, numbness in arms and hands, blurred vision, confusion, memory loss, dizziness, lethargy that may progress to coma
• What are the effects of hypoglycaemia on the brain and how do they arise?

  occurs at blood glucose levels 2.5mM (45 mg/dL)

  loss of cognitive function, seizures, coma
• Why is rapid restoration of blood glucose (by IV / injection of glucagon) essential in hypoglycaemia?

  prolonged or repeated hypoglycaemia may result in premanent brain damage
• What are the causes of hypoglycaemia?

  mild hypoglycaemia in healthy individuals may be due to fasting or exercise

  other causes:

  • hypernatraemia (high sodium levels, eg diabetes insipidus)
  • hypovolaemia (low blood volume, due to vomiting, dehydration etc)
  • pathologies such as adrenal insufficiency
• How does alcohol-induced hypoglycaemia occur?

  occurs on depletion of glycogen stores when blood glucose is reliant on hepatic gluconeogenesis

  • short term (24 hours): alcohol in liver metabolised primarily by unregulated process, so places additional stress on gluconeogenesis
  • long term (years): reduced gluconeogenesis due to liver damage & reduced muscle mass
• How does the metabolism of alcohol occur in the liver?

  ethanol (C2H5OH) + alcohol dehydrogenase + NAD+ -> acetaldehyde (CH3CHO) + NADH

  result in high NADH:NAD+ ratio in cytosol

  acetaldehyde transported to mitchondria to be oxidised:

  acetaldehyde (CH3CHO) + aldehyde dehydrogenase + NAD+ -> acetic acid (CH3COOH) + NADH

  result in high NADH:NAD+ ratio in mitochondria
• What are the metabolic consequences of alcohol metabolism?

  ethanol metabolism in liver increases NADH + H+ and shifts the equilibrium of the reactions below to the left

  reduces availability of substrates for entry into gluconeogenesis to maintain plasma glucose levels

  
• How does the biochemistry of alcohol metabolism work?

  • increased NADH concentration causes increased rate of reduction of pyruvate to lactate; less oxaloacetate made; less gluconeogenesis; causes hypoglycaemia
  • increased lactate levels; causes lactic acidaemia
  • increased acetate production; more Acetyl Coa; more fatty acid synthesis; more triglycerides; causes hyperlipidoma

  
• What are the symptoms of alcohol-induced hypoglycaemia?

  fall in blood glucose leads to stress response (rapid heart beat, clammy skin) to enhance stimulation of gluconeogenesis via adrenaline & glucagon

  rapid breathing due to metabolic acidosis (because of XS lactic acid)
• What are the effects of long-term alcohol consumption on lipid metabolism?

  high levels of NADH inhibit fatty acid oxidation and signal fatty acid synthesis

  TGs accumulate in liver -> 'fatty liver'

  
• How is the progression of fatty liver disease like?

  progress over 3 stages:

  1. inflammation of liver (damage to tissues; steatohepatitis)
  2. fibrosis (scar tissue formation at sites of damage)
  3. Cirrhosis (extensive scar tissue replaces healthy tissue)

  
• What are the effects of long-term alcohol consumption on the efficiency of ethanol metabolism?

  accumulation of Acetyl CoA due to high levels of NADH inhibiting citrate synthase and alpha-ketoglutarate dehydrogenase so Acetyl CoA can't be metabolised
• What are the two consequences of accumulation of Acetyl CoA?

  1. Production of ketone bodies; released into blood; makes blood even more acidic along with high lactate levels
  2. Processing of acetate in liver becomes inefficient, leading to build up of acetaldehyde (highly toxic)
• How does alcohol-induced hepatomegaly (enlarged liver) occur?

  alcohol consumption decreases activity of proteosome

  leads to accumulation of protein, causing enlarged liver

  decreased proteosome activity increases oxidative stress

  
• What are the causes of alcohol-induced thiamine (vitamin B1) deficiency?

  50% of alcoholics with liver disease will have thiamine deficiency

  symptoms: anorexia, irritability, difficulties with short-term memory

  causes: malnourishment, ethanol interferes with GI absorption, hepatic dysfunction, which hinders storage and activation to thiamine pyrophosphate
• Why is thiamine (vitamin B1) deficiency an important condition?

  thiamine is a cofactor for many enzymes; Pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, PPP pathway enzyme Transketolase

  has short half life so deficiency can occur rapidly during depletion
• What are glycogen storage diseases?

  inherited diseases

  glycogen stores affected by defects in either:

  • enzymes of synthesis
  • enzymes of degradation

  all autosomal recessive except IX (sex-linked)

  all result in production of an abnormal amount / type of glycogen
• What are the types of glycogen storage disease?

  Type 0: Glycogen synthase

  Type I (von Gierke's disease): G6Pase

  Type II (Pompe's disease): a-1,4 glucosidase in lysosomes

  Type III (Cori's disease): Debranching enzyme

  Type IV (Andersen's disease): Branching enzyme

  Type V (McArdle's syndrome): Glycogen phosphorylase
• What is Von Gierke's disease?

  most common GSD

  Glucose 6 phosphatase deficiency in liver, kidneys, intestines

  (G6P -> free glucose + Pi), so catalyses the terminal reaction of glycogenolysis and gluconeogenesis

  result in impaired glucose export & high levels of G6P in liver & kidney

  hypoglycaemia that does not respond to glucagon

  symptoms: intervals between feeds increase, infants sleep through night, illness prevents normal feeding routine
• What does high levels of G6P in liver and kidney due to Von Gierke's disease result in?

  abnormal levels of glycogen accumulation causing enlargement of liver and kidneys

  increased glycolysis causing lactic acidosis

  increased fatty acid, TG and VLDL synthesis
• How is metabolism in Von Gierke's disease?

  • hyperglucogonaemia (release glucagon) and adrenaline to compensate; result in mobilisation of fat stores and release of fatty acids
  • conversion of fatty acids to TGs and VLDL; accumulation of fat in liver & hyperlipidaemia, may lead to hepatoma, accumulation of fat in cheeks and buttocks
  • enlarged livers/kidneys, stunted growth, severe tendencies to hypoglycaemia, hyperlactaemia and hyperlipidemia
  • may also have hyperuricaemia due to hyperlactaemia as lactic acid competes for kidney transport mechanisms