Lecture 3 - Alcohol Mediated Injury Flashcards
What are the ways that toxic substances can get in to the body?
Skin
Lungs
GI tract
What types of disease are caused by alcohol?
Steatosis
Alcohol hepatitis
Cirrhosis
NB alcohol has effects all over the body
What is the toxin in alcohol?
Ethanol
But predominantly: Acetaldehyde (metabolite of ethanol)
What is the difference in terms of effect on the body with alcohol consumed in great and small amounts?
Great amounts: • brain dysfunction • chronic gastritis • pancreatitis • cardiomyopathy
In moderation • increased fibrinolyses • decreased thrombosis • increased HDL • decreased atherosclerosis formation • decreased osteoporosis • decreased kidney stone formation
Which cancers does alcohol cause?
Mouth
Larynx
Liver
etc.
Describe metabolism of alcohol in the liver
- CYPs
- alcohol dehydrogenase
- catalase
Describe the absorption of alcohol
- Consumption
- Absorbed directly through GIT
- Blood stream
- Metabolism in the liver
- Excretion
Compare ADH levels in men and women
Men have more ADH than women
Alcohol dehydrogenase
Where are CYPs in the hepatocytes?
Microsomes / smooth ER
Where is ADH in hepatocytes?
Cytosol
What is the role of the peroxisomes?
Location of catalase
Metabolism of alcohol
What are some harmful biproducts of alcohol metabolism?
Reactive oxygen species
Free radicals
NADH
List the order of parts of the brain affected by alcohol
The cortex: higher order functions
Limbic system: emotions, memory
Cerebellum: motor control
Lower brain stem: breathing, BP
What is ethanol predominantly metabolised into?
Acetaldehyde
At what blood alcohol level leads to coma/fatal respiratory arrest?
0.3-0.4 gl/dl
What is another name for ‘sleepiness’?
Narcosis
Describe the effects of alcohol on the stomach
Acute gastritis
• acute inflammation
• haemorrhage
• sloughing of mucosa
What are some chronic effects of alcohol?
- Alcoholism
- Altered fatty acid metabolism
- Steatosis
- Hepatitis
- Cirrhosis
What changes occur to hepatocytes due to fatty acids?
‘Fatty liver’
Many small lipid droplets in the cytoplasm of the liver
Reversible
What are some acute effects of alcohol?
- ‘Party syndrome’ (effects on CNS)
- Acute gastritis
- Steatosis
Describe the changes to fatty acid metabolism due to chronic alcohol consumption
Increased synthesis of:
• Fatty acids
• Triglycerides
• Ketone bodies
Increased deposition of dietary fatty acids in the hepatocytes (in the cytoplasm)
Describe the changes to fatty acid metabolism due to chronic alcohol consumption.
Why is this bad?
Increased synthesis of: • Fatty acids • Triglycerides • Ketone bodies Reduction in: • Proteins which absorb triglycerides (such as lipoproteins and apoproteins)
Increased deposition of dietary fatty acids in the hepatocytes (in the cytoplasm)
Bad because:
• Ketone bodies are inherently toxic
• There is increased fatty acids circulating in the body
What is hepatitis?
Reversible?
Inflamed liver
Early exposure
Reversible
What is alcoholism?
Chronic consumption of doses great enough to injure socially, mentally, physically
Describe the structure of a liver lobule
- hexagonal
- ventral hepatic venule
- branches of hepatic portal vein
- bile ducts
- branches of hepatic artery
- connective tissue
Under what conditions does cirrhosis occur?
Continued exposure to alcohol
Progresses from steatosis or hepatitis
What is the microscopic unit of the liver?
Liver lobule
Describe blood flow in a liver lobule
From the border, into the central venule
Which structure is very important for the stability of the liver lobule?
Connective tissue
Compare histology of fatty liver with a healthy liver
- lipid droplets
* fibrotic tissue
Which structure in the liver is most at risk during chronic alcohol consumption?
Connective tissue
What are Kupffer cells?
Resident macrophages in the liver
What causes the inflammation in hepatitis?
Cytokine release from Kupffer cells
What is cirrhosis?
A combination of : • necrosis • inflammation • fibrosis • regeneration
There is a finite number of times that the liver tissue can be damaged and regenerate.
What are ‘new epitopes’ in cirrhosis?
Brought about by changes caused by acetaldehyde
Induce immune response
What are the green spots in cirrhosis?
- fibrotic tissue
* bile accumulation
What are Mallory bodies?
What is their role in hepatitis ?
Intermediate filaments
They are a histological feature of hepatitis. They stain pink.
Why does hepatocellular carcinoma occur?
Continuous regeneration involves much cell proliferation
In some cess, this leads to carcinoma
Describe the function of nodules in liver cirrhosis
Non functional
Describe the function of Stellate cells
Once activated, they proliferate into myofibroblasts that lay down much fibrotic tissue
• fibrogenesis
• contraction
(scarring…)
Which cell responds to the cytokines from Kupffer cells?
Stellate cells
These are there liver stem cells
What is the effect of alcohol on pulmonary immunity?
Decreased immunity
More prone to infection
Describe what happens to the connection between hepatic portal veins and central venues during liver cirrhosis
Fibrotic connection, instead of sinusoids between cells
What are there effects of alcohol on other organs?
Pancreatitis
Wernicke syndrome
Foetal alcohol syndrome
What is the main way that toxic substances are introduced to our bodies?
- Compound introduced to our bodies
- Metabolism, to form toxic metabolites
→ Toxicity
What are some cytotoxic pharmaceuticals?
- paracetamol
- therapeutic drugs
- aspirin
- oral contraceptives
What are some recreational drugs that introduce toxic substances to our bodies?
- cigarettes
- alcohol (ethanol)
- recreational drugs: cocaine, heroin etc.
What are the ways that toxins cause damage?
- direct covalent binding
- toxic metabolite formation
- free radical formation
What types of disease are cirrhosis, fatty liver syndrome, and hepatitis?
Tissue remodelling
What are CYPs?
Cytochrome P450 enzymes in the liver
What types of disease are cirrhosis, steatosis, and hepatitis?
Tissue remodelling
Which molecule elicits the acute effects of alcohol?
Acetaldehyde
Which chronic conditions of the liver are reversible, and which are irreversible?
Reversible: • steatosis • hepatitis Irreversible: • cirrhosis
What are the features of steatosis?
- lipid droplets in cytoplasm of hepatocytes
* perivenular fibrosis
Why does alcohol cause hepatitis?
- increased ROS
- lipid peroxidation
- decreased glutathione
- mitochondrial damage
- cytokine release from Kupffer cells
What are the symptoms of alcoholic hepatitis?
- jaundice
- liver tenderness
- fever
What is glutathione?
The major antioxidant in the body
What are the changes occurring in hepatitis?
- necrosis
- neutrophil infiltrate
- perivenular fibrosis
What effect does acetaldehyde have on the cytoskeleton?
Acetaldehyde forms complexes with protein, which disrupt the cytoskeleton and membrane
What is fibrosis and when does it occur?
It is a process whereby collagen is laid down
It occurs in response to injury
What processes do the cytokines released by Kupffer cells bring about?
- Chemotaxis
- Contraction
- Hepatocyte death
- Proliferation
- Fibrogenesis
Where do dietary fatty acids accumulate with chronic alcohol consumption?
In the cytoplasm of hepatocytes
