Alcohol Metabolism and Alcohol-Induced Liver Disease Flashcards
how is ethanol usually metabolised?
Ethanol (alcohol dehydrogenase) -> Acetaldehyde
NAD+ -> NADH
Acetaldehyde (aldehyde dehydrogenase) -> Acetate
NAD+ -> NADH
what happens to acetate after metabolism?
doesn’t stay in the blood - fuel, especially in heart & skeletal muscle
what is the outline of glucose metabolism in the liver?
Glucose -> pyruvate -> acetyl CoA
- > fatty acids
- > TCA cycle -> Co2 and water
glycolsis = glucose -> Co2 and water gluconeogenesis = Co2 and water -> glucose
what is the outline of liver fatty acid catabolism?
Fatty acid release from triacylglycerol
in adipose tissue -> Transport to liver -> Fatty acid oxidation (β-oxidation) -> Acetyl CoA -> TCA Cycle -> Carbon Dioxide + Water
what is the outline of liver fatty acid synthesis?
Acetyl CoA -> Fatty acid synthesis -> Triacylglycerol synthesis -> Release as part of VLDL
what are the consequences for metabolising a lot of ethanol?
NAD+ used up & NADH accumulates
Inhibition of all other reactions that use NAD+ as hydrogen atom/electron acceptor
Inhibition of pathways that contain these reactions
what pathways are affected by extensive ethanol metabolism?
TCA Cycle
β-Oxidation
Gluconeogenesis
what happens when β-Oxidation is inhibited?
Uses nad+ as electron acceptor – production of fatty acids slows down
what 3 mechanisms is blood glucose levels maintained by?
Diet
Breakdown of stored glucose (glycogen)
Gluconeogenesis
how is alcohol-induced hypoglycaemia caused?
Inhibition of gluconeogenesis – increases risk of being unable to maintain blood glucose concentration – risk of hypoglycaemia
Alcohol takes gluconeogenesis – diet and glycogen stand. If they don’t = alcohol-induced hypoglycaemia
who is at risk of alcohol-induced hypoglycaemia?
Alcohol abusers – chronic under nourishment
Those who exercise vigorously & fail to eat before consuming alcohol
if well-nourished, what is the fuel source?
glucose
if under-nourished, what is the fuel source?
fatty acids
what occurs in well-nourished fat metabolism?
Liver converts glucose to acetyl CoA as normal, but acetyl CoA then converted into fatty acids because TCA cycle inhibited
Fatty acids incorporated into triacylglycerol & exported into blood on VLDL -> hypertriacylglyerolaemia
what occurs in under-nourished/fasting fat metabolism?
Fatty acids arriving at liver unable to be used as fuel due to decrease in β-oxidation = incorporated into triacylglycerol instead
Excess triacylglycerol tends to accumulate in liver as under nutrition also problems with export mechanism
when does acetaldehyde toxicity occur?
if substantial ethanol concentration achieved or if aldehyde dehydrogenase activity low
what are the consequences of acetaldehyde toxicity?
Catecholamine release in heart rate & facial flushing
Reaction of acetaldehyde with proteins
dysfunction
what does MEOS stand for?
Microsomal Ethanol Oxidising System
what does MEOS do?
Oxidises ethanol to acetaldehyde
Can generate ROS
what is MEOS induced by?
ethanol
in what situations is MEOS Likely to Catalyse Oxidation of a Significant Amount of Alcohol?
Binge drinking – normal pathway saturated
Alcohol abusers – higher levels of MEOS because induced by ethanol
what other enzymes are involved in ethanol metabolism?
Aldehyde Oxidase & Xanthine Oxidase
what do Aldehyde Oxidase & Xanthine Oxidase do?
Oxidise acetaldehyde to acetate
Can generate ROS
when are Aldehyde Oxidase & Xanthine Oxidase significant?
Only of significance in individuals with low aldehyde dehydrogenase activity
what nutritional issues are there about carbohydrates?
ethanol metabolised less efficiently than carbohydrate
carbohydrate content highly variable, and most alcoholic drinks except beer very low in protein and vitamins
what nutritional issues are there about iron content?
iron content can be high, especially in wine
what nutritional issues are there about vitamins and calcium?
intakes of various vitamins and of calcium, iron and fibre tend to be low in alcoholics
what nutritional issues are there about absorption transport?
absorption transport, storage and/or metabolism of vitamins and minerals can be altered, especially in alcohol-induced liver diease
what digestive problems are associated?
• acute gastritis and duodenitis • diarrhoea • malabsorption • fibrosis of parotid glands decrease in salivary flow* • lack of bile salts* *seen in cirrhosis
what are the stages of alcohol-induced liver disease?
Stage I Fatty liver
Stage II Steatohepatitis
Stage III Cirrhosis
what is stage 1 alcohol-induced liver disease?
Characterised by fatty deposits - triacylglycerol form
what is stage 2 alcohol-induced liver disease?
fatty liver and inflammation
characterised by disruption of liver architecture, swelling and death of liver cells and accumulation of lymphocytes and phagocytes
what is stage 3 alcohol-induced liver disease?
characterised by fibrosis (scarring) of the liver
entire liver affected and architecture disrupted
fibres divide the liver into nodules
in alcoholic cirrhosis, nodules relatively smaller and more numerous than in other types of cirrhosis
what are the risk factors for alcohol-induced liver disease?
- excessive ethanol consumption >160g (16 units)/day for at least 5 years
- female sex – females achieve a higher blood ethanol concentration following ingestion of a defined ingested dose
•genetics
−>1 gene involved
−associations with genes encoding alcohol-metabolising enzymes and proteins that control collagen synthesis
•Nutrition
−Increased susceptibility if deficient in protein and/or calories
•Hepatitis B or C infection – predispose to alcohol causing problems
what are presenting signs and symptoms of alcohol-induced liver disease?
- Non specific digestive problems e.g. anorexia, diarrhoea, vague upper right quadrant abdominal pain
- Concern about effect of alcoholism, e.g. depression, poor work performance
- Physical signs, e.g. tender hepatomegaly tremors and other features of alcoholism
what are typical lab findings of alcohol-induced liver disease?
- Increase in mean red cell volume
- Due to folate deficiency or toxic effect of acetaldehyde on bone marrow
- Increase in serum activities of gamma glutamyl transferase (GGT), alanine transferase (ALT) and aspartate aminotransferase (AST)
- GGT induced by ethanol
- ALT and AST indicate cellular damage
- ALT>AST
- ^ in serum procollagen III peptide
how is ROS produced from ethanol metabolism?
production of hydrogen peroxide via MEOS action on ethanol, or aldehyde oxidase/xanthine oxidase action on acetaldehyde
what are the consequence of ROS production from ethanol metabolism?
ROS inhibit lipid export from liver - may contribute to lipid accumulation
Lipid peroxides alter membrane properties - may contribute to cell lysis
Some evidence that lipid peroxides induce collagen production - may contribute to fibrogenesis
what evidence is there that ROS production is linked to alcohol-induced liver disease?
Susceptibility of rats to alcohol-induced liver damage increased by feeding diet rich in polyunsaturated fatty acids
Lipid peroxidation products in serum & red cells of cirrhotic alcoholics correlated with ethanol intake & extent of liver damage
Alcoholics exhibit early in plasma concentrations of antioxidant vitamins with onset of cirrhosis
decrease in hepatic antioxidants concentrations in subjects with alcohol-induced liver injury
Toxic effect of carbon tetrachloride in rat liver enhanced by chronic ethanol feeding
Alcohol-induced damage reduced by drugs that protect liver against toxins which generate ROS
what is the role of MEOS in alcohol-induced liver disease?
Hepatic distribution of enzyme & tissue damage correlated
Susceptibility of rats to alcohol-induced liver damage correlated with inducibility of this enzyme
