Hypoglycaemia Flashcards
Hypoglycaemia
Blood glucose level of below 4mM (72mg/dL)
Symptoms develop at higher level if there is a rapid fall
A rapid fall may produce sweating, tachycardia and agitation - activation of SNS & release of adrenaline and glucagon
Signs & Symptoms
Symptoms: moodiness, faitness, numbness in arms and hands, blurred vision, confusion, memory loss, dizziness & lethargy
Serious consequences relate to effects on brain - seizures, coma..
Loss of consciousness occurs at 2.5mM
Rapid restoration of blood glucose essential to prevent brain damage
Causes
Fasting/exercise
Excess of exogenous/endogenous insulin
Inhibition of endogenous glucose production - alcohol
Hypernatraemia/hypovolaemia/pathologies such as adrenal insufficiency
Alcohol induced hypoglycaemia
Develops several hours after alcohol ingestion
Occurs on depletion of glycogen stores when blood glucose is reliant on hepatic gluconeogenesis
In the short-term (24 hours): consumption of alcohol = additional stresses on gluconeogenesis, as alcohol is metabolised primarily in the liver by an unregulated process
In the long-term (years): gluconeogenesis may be decreased by liver damage and reduced muscle mass (longer term)
Metabolism of alcohol
Ethanol -> acetaldehyde - using alcohol dehydrogenase (and NAD+ converted to NADH) - occurs in cytoplasm
Acetaldehyde -> acetic acid - using same enzyme & NAD+ -> NADH - occurs in mitochondria
Results in high levels of NADH in cytosol and mitochondria
The NADH pushes the equilibrium of certain equations to the right, resulting in high levels of lactate, malate and glycerol-3-phosphate
This reduces the availability of substrates for gluconeogenesis needed to maintain plasma glucose
Symptoms of alcohol induced hyppoglycaemia
Occurs when glycogen stores are depleted - gluconeogenesis required
Fall in blood glucose leads to stress response in order to enhance gluconeogenesis stimulation with glucagon and adrenaline
Metabolic acidosis due to excess lactic acid leads to rapid breathing
Long term alcohol consumption - effects on lipid metabolism
High levels of NADH inhibit fatty acid oxidation; instead stimulate fatty acid synthesis.
TGs accumulate in the liver causing ‘fatty liver’ and are also exported as VLDL.
Fatty liver disease can progress over time in 3 stages:
Inflammation (steatohepatitis).
Scar tissue forms at sites of damage (fibrosis).
Extensive scar tissue replaces healthy tissue (known as cirrhosis of the liver).
Long term alcohol consumption - effects on efficiency of ethanol metabolism
Acetate produced from EtOH - converted into acetyl-CoA
Further processing of acetyl-CoA in TCA cycle prevented because high levels of NADH inhibits both citrate synthase and α-ketoglutarate dehydrogenase
Accumulation of acetyl CoA has two consequences: Production of ketone bodies, released into blood and exacerbates the already acidic conditions resulting from high lactate levels; & processing of acetate in the liver becomes inefficient, leading to build-up of acetaldehyde, which is highly toxic
Other effects of alcohol
Hepatomegaly: alcohol decreases activity of proteosome -> accumulation of protein causes enlargement. Decreased proteasome activity also increases oxidative stress
Thiamine (B1) Deficiency: in 50% of alcoholics, symptoms are anorexia, irritability and short term memory loss; causes are malnourishment, problems with GI absorption, hepatic dysfunction; thiamine is a cofactor for many enzymes (eg pyruvate dehydrogenase and one in PPP); thiamine also has short half-life - 10-20 days, so deficiency = rapid depletion
Glycogen Storage Diseases
Inherited diseases in which the stores of glycogen are affected by defects in either the enzymes of synthesis or degradation of glycogen.
Many different types depending on which enzyme is affected
They are all autosomal recessive except for type IX which is sex-linked
All result in the production of an abnormal amount or abnormal type of glycogen
Overall frequency of 1:20000-1:40000 births.
May affect any of the enzymes involved in glycogen synthesis and breakdown
Type I, II, III, IV, V
Type I. von Gierke’s disease - Affects mainly the liver and kidneys caused by a deficiency in glucose 6-phosphatase.
Type II. Pompe’s disease
Alpha-1,4 glucosidase activity deficiency in the lysosomes. One of worst. Causes death by cardiorespiratory failure
Type III. Cori’s disease - The amylo 1,6 glucosidase (de-branching enzyme) is deficient - hypoglycaemia. Symptoms often disappear at puberty.
Type IV Andersen’s disease - One of the most severe. Liver glycogen in normal amounts but comprises long unbranched chains that have low solubility. Sufferers rarely live beyond 5 years.
Type V. McArdle’s syndrome - Affects muscle glycogen phosphorylase (liver enzyme is normal). Muscle cannot break down glycogen (which accumulates); sufferers have a low tolerance to exercise and fatigue easily, with painful muscle cramps after exercise. Otherwise normal life-span
Type I in detail
Most common – 25% OF GSDs
Deficiency of glucose-6-phosphatase in liver, kidneys and intestines.
G-6-P -> GLUCOSE + Pi
Catalyzes the terminal reaction of glycogenolysis and gluconeogenesis.
Results in impaired export of glucose from the liver from these two pathways between meals, causes hypoglycaemia that does not respond to glucagon.
Symptoms appear when intervals between feeds increases and infants sleep through the night, or when illness prevents normal feeding routine.
High levels of G-6-P in liver and kidney - which is metabolised to lactic acid/converted to glycogen or lipid
This results in abnormal glycogen levels (enlargement of liver/kidneys), increased glycolysis (-> lactic acidosis) and increased fatty acid/TG/VLDL synthesis
Metabolism of Von Gierke’s Disease
Body attempts to compensate for hypoglycaemia by releasing glucagon (hyperglucagonaemia) and adrenaline -> mobilisation of fat stores and release of fas.
Conversion of fatty acids to TGs and VLDL in the liver resulting in accumulation of fat in liver and hyperlipidaemia. May lead to hepatomas. Accumulation of fat in cheeks and buttocks.
Patients suffer with enlarged livers and/or kidneys, stunted growth, severe tendencies to hypoglycaemia (convulsions), hyperlactaemia and hyperlipidemia.
May also have hyperuricaemia as a result of hyperlactaemia as lactic acid in the blood competes for kidney transport mechanisms
Management of Von Gierke’s Disease
Aim of treatment is to correct hypoglycaemia and maintain normoglycaemia
Young infants can be fed glucose through nasogastric tubes while older children are fed glucose drinks at 2-3 hour intervals night and day to prevent fall in blood glucose and cerebral damage
Uncooked cornstarch may be used to prolong period between feeds.
Restrict dietary lipids
Liver transplant
