PBL 5- Wernickes-Korsacoff Flashcards
Where does first pass metabolism occur for alcohol?
- Stomach
- Liver ( 80-85%)
- 3-10% of alcohol is excreted unmetabolised in breath, urine and sweat
Why is the BAC different to the content of alcohol in the drink?
some is metabolised by FPM
When is BAC first detectable and when does it reach its peak?
- Detectable within 5 minutes
* Peak is after 30-90 minutes
What causes the effects of alcohol?
- the metabolites of alcohol
* Dependent on environmental factors
Why does the BAC stop rising after a while?
• The enzymes that are metabolising alcohol are saturated
How much individual variation is there for alcohol metabolism?
What contributes towards this?
• 3 fold variation in absorption, distribution, metabolism and elimination
Attributed to:
• Genetic variation in alcohol metabolizing enzymes
• Gender and age
○ Increased BAC in women (lower ADH, lower liver intake and less water volume)
○ Increased BAC in older people
• Speed of gastric emptying
○ Increased emptying (ie food intake) decreases the BAC
• Drinking pattern
○ Decreased metabolism in chronic alcoholism
• Drugs and smoking
What is the MAIN oxidative pathway of alcohol metabolism?
ADH pathway : Major pathway of metabolism
• Ethanol is converted to acetaldehyde via Alcohol Dehydrogenase (ADH) in the cytosol
○ Converts NAD to NADH as side product
○ Mostly occurs via Class 1 ADH in the liver however some genetic variation can change the affinity of the enzyme for alcohol.
○ In chronic drinking you can start to use Class 3.
○ Gastric mucosa have Class IV ADH
• Acetaldehyde is then converted to acetate via Acetaldehyde dehydrogenase (ALDH) in the mitochondria
○ Converts NAD to NADH
○ ALDH 2 is the predominant isoform
○ Asian populations have a polymorphism in the ALDH2 and have a reduced rate of metabolism- leads to an accumulation of acetaldehyde
• Acetate then enters the circulation
What accumulates in excessive drinking and why?
- Toxic acetaldehyde accumulation
* Saturation of Acetaldehyde
What pathway is induced in large alcohol consumption?
Microsomal ethanol oxidising system (MEOS)
• Induced 4-10 fold by large alcohol consumption ○ In a normal person this pathway has a low affinity so makes up a small amount of oxidation in the liver ○ Can occur in other tissues- brain • Contributes to alcohol tolerance (metabolic adaption) • Mediated by CYP 450 • Converts Ethanol + NADPH + o2 to Acetaldehyde • Occurs in the microsomes in the ER membrane
Risks:
• Used up a lot of O2
○ Can cause oxidative stress due to increased ROS formation
• Same enzymes used to metabolise drugs and other compounds
○ Causes increased hepatotoxicity of drugs like acetominophen
What oxidative pathway increases in the fasted state?
Where is this pathway predominant?
Catalase mediated alcohol metabolism
• Usually a marginal pathway except when in the fasted state • Converts ethanol + hydrogen peroxide to acetaldehyde via CATALASE ○ Hydrogen peroxide is sourced through beta oxidation of fatty acids in the liver • Occurs in peroxisomes
Major pathway in the BRAIN
• Because ADH is not physiologically active in the brain
• Small amounts are done by CYP 450 pathway
What is the main alcohol metabolism pathway in the brain?
- Catalase mediated alcohol oxidation
- Done in Peroxisomoes
- Converts Brain ETOH to brain Acetalaldehyde and then acetate
What is the non oxidative pathway of alcohol metabolism?
- only occurs in high BAC
- Not well understood
- Found in chronic alcohol abuse
- Develop alcoholic pancreatitis
- There is a low ADH level in the pancreas so the non oxidative pathway is used
- It is a marker of acute and chronic ethanol consumption
What is the recommended alcohol consumption?
• MEN ○ No more than 4 drinks per day ○ No more than 14 a week • Women ○ No more than 3 drinks on any day ○ No more than 7 drinks per week
Low risk limits may be lower for individuals due to genetic and environmental differences
What are the beneficial effects of alcohol consumption?
• Rosveratrol is concentrated in skin and seeds of grapes
• Lowers risk of CVD
• Protects against atherosclerosis
• Mechanisms
○ Anti-oxidant
○ Anti-thrombotic activity ( inhibits thromboxane synthesis and platelet aggregation, increases vasodilation)
○ Inhibits oxidation of LDL cholesterol and increases HDL cholesterol
What causes the toxicity of heavy drinking?
Accumulation of acetaldehyde
What occurs in accumulation of acetyl dehyde?
• Alcohol sensitivity in the periphery
○ Facial flushing, throbbing in head an neck
○ Headache, nausea, vomiting
○ Sweating, thirst, chest pain, palpitation
○ Dyspnea, hyperventilation, tachycardia
○ Hypotension, syncope, marked uneasiness
○ Weakness, vertigo, blurred vision, confusion
What are the health effects of heavy alcohol use?
• Thiamin deficiency • Vitamin B6 and folate deficiency • Disease risk increased: ○ Arthritis ○ Cancer ○ Foetal alcohol syndrome ○ Heart disease ○ Hypoglycaemia ○ Infertility ○ Kidney disease ○ Liver disease § Fatty liver § Fibrosis due to excessive accumulation of ECM proteins - collagen type 1 § Progression to cirrhosis after 10-20 years ○ Nervous disorders ○ Malnutrition ○ Obesity
What is the interaction between ethanol toxicity and malnutrition?
Causes primary and secondary malnutriation
• Primary
○ Replaces other nutrients
○ Empty calories (7.1 hcal/g)
• Secondary
○ Direct toxic effects on GI tract and liver
○ Maldigestion and malabsorption
How does liver injury occur in heavy drinking?
• chronic alcohol leads to increased gut permeability and therefore an increase in endotoxins
• Activation of Kupffer cells
○ Largest group of liver macrophages
○ Responsible for the immune response
• Increase in the number of cytokines and ROS
○ Inflammatory response
○ Oxidative stress
○ Activation of hepatic stellate cells
• Start to proliferate, migrate and sythesize more matrix collagen type 1
○ Stellate cells usually store vitamin A
○ Usually maintain the ECM
• Liver scarring and fibrosis
• Deterioration of liver function
What are the detrimental effects of the oxidation of alcohol for each pathway?
What is the effect of this?
• ADH pathway
○ Increase NADH: NAH ratio
○ Indirect formation of ROS due to the excess NADH needing to be oxidised by mitochondria
• CYP 450 pathway
○ Increase ROS formation due to increase in MEOS CYP2EI
• All
○ Acetaldehyde adducts formation
○ Excess acetaldehyde combines with protein, DNA or lipids to form a new compound - adducts
○ Produce Acetaldehyde which needs NAD to be metabolised- effect on NAD/NADH ratio
Effects of Adducts:
○ Are toxic
○ Interferes with protein function and secretion
○ Impaired DNA repari- carcinogenesis
○ Membrane alterations
○ Secretion of inflammatory chemokines- due to unknown substance
○ Liver damage
Effects of Oxidative stress
• Due to increased MEOS pathway forming ROS
• Due to increased NADH excess which is oxidised by mitochondria to NAD
• ETC components reduced creating ROS
• Initially the liver can buffer this through antioxidants like glutathione
• When depleted hepatocytes become damaged
Effects of NADH formation:
• Altered carbohydrate Metabolism
○ Inhibition of the TCA cycle
○ No gluconeogenesis and depletion of glycogen stores
○ Leads to hypoglycaemia
○ Increase in lactate leads to lactic acidosis
• Altered fatty acid metabolism
○ Decreased metabolism and increased FA synthesis
○ Acetyl coa does not go into TCA cycle and accumulates
○ Formation of lipids, cholesterol and ketone bodies induced
○ Aft accumulates in the liver causing Fatty liver and hyperlipidaemia
• Causes a redox state due to mitochondria oxidising excess NADH
• Hypoxia in perivenous hepatocytes
○ Excess NADH oxidised in mitochondria requires increase in O2 uptake
• Liver damage
What are the effects of BAC on brain function?
• Alcohol drinking markedly reduces brain metabolism
• Damage in heavy drinkers is worse in thiamin deficiency
• Brain shrinkage
○ Decreased white and grey matter volume
○ White matter loss can be partially reversed by alcohol abstinence
• Permanent neuronal loss
○ Superior frontal association cortex
○ Cerebellum
○ Mammillary bodies of the hypothalamus
○ Dorsomedial nucleus within the thalamus
○ Amygdala
What are the effects of alcohol on Neurotransmitters?
- Inhibits excitatory glutaminergic neurotransmission
- Agonist of GABA a receptors = increased GABA release
- Increased serotonin transmission
- Activation of opioid or cannabinoid receptors
- Increased dopamine release
- Complex regulatory interactions
Chronic use induces neuroadaptive responses in various NT systems resulting in
• Alcohol tolerance
• Alcohol withdrawal symptoms
• Alcohol dependence- relapse drinking behaviour
What is Vitamin B1 found in?
- fortified breads and creals
- Fish
- Lean meats
- Milk
What is the difference between dry beri beri and wet beri beri?
Lesions in the CNS
Dry = peripheral neuropathy
Wet = similar to congestive heart failure
How frequent is Thiamine deficiency in alcoholics?
• 25-80%
What is the importance of Thiamine in metabolism?
• Thiamine is an essential cofactor for many cellular reactions ○ Nucleic acid synthesis ○ Myelin ○ Protein synthesis • Critical for conversion of carbohydrates to energy ○ Glycolysis • Critical for CNS function ○ Synthesis of ACH ○ Synthesis of GABA
What are the effects of thiamine deficiency?
• major factor causing brain damage in alcoholics
○ After 10 years of heavy drinking 40% of alcoholics develop cerebellar degeneration
• Wernickes encephalopathy (lesions in CNS)
• Korsakoffs psychosis
• Beri Beri (Lesions in PNS)
Due to : • Altered cerebral energy metabolism ○ Decreased activity of KGDH ○ Impaired glucose metabolism ○ Lactic acidosis • Oxidative stress and inflammation ○ BBB disruption ○ Brain oedema in vulnerable cerebral areas • Impaired neurotransmitter function
How common is Korsacoffs psychosis?
• 80-90% of alcoholics with WE develop Korsakoffs psychosis
