tbl 6: alcoholic liver disease Flashcards
Alcohol
- Ethanol (C2H5OH) is a primary alcohol – __________ is able to form hydrogen bonds in water, thus making ethanol water soluble
o ________________ allows it to be soluble in phospholipid biological membrane – concentration of alcohol can equalise rapidly between the tissue and plasma as it passes through biological membranes
o There is no specific plasma binding protein for alcohol
- Blood alcohol content (measured in g/L) – directly proportional on the impact on tissues as alcohol is soluble across membranes
o Alcohol is absorbed partially via the stomach, but the main absorption is at the small intestine (20 times more efficient the stomach)
o Ethanol then passes into the __________ and is then metabolised by first pass metabolism in the liver
o Blood alcohol content is impacted by _______________________________
§ Presence of fatty food in the stomach and duodenum delays gastric emptying – delays the peak rise of blood alcohol content and rate of elimination by the liver from the bloodstream
polar hydroxyl group;
Short carbon chain;
portal venous drainage;
the strength/ volume of alcohol and gastric emptying speed
Metabolism of alcohol – predominantly by hepatocytes in the liver, but some other organs can also metabolise alcohol. 3 mechanisms of oxidative alcohol mechanism yielding acetaldehyde:
1) Ethanol is catalysed by _______________ to acetaldehyde – results in reduction of NAD+ to NADH
2) Cytochrome P450 has an alternative route of producing acetaldehyde – involves direct reduction of O2 to generate ______________
§ This process occurs in both ____________ and occurs at higher alcohol levels – generates free radicals e.g. superoxides and peroxides
3) _____________ also converts ethanol to acetaldehyde in peroxisomes where H2O2 is present
- Acetaldehyde is then processed by aldehyde dehydrogenase, using NAD+ which is converted to NADH, to form acetate
- Acetate can then enter the citric cycle to yield CO2 and ATP
- Non-oxidative pathway of alcohol metabolism – occurs when fatty acid or phospholipid is added to alcohol
o Catalysed by enzymes such as _______________ to form fatty acid ethyl esters
alcohol dehydrogenase;
NADP+;
the liver and the brain;
Catalase;
fatty acid ethyl esterase
Genetic variation of alcohol and aldehyde dehydrogenases – numerous alleles
- ADH variations – physiologically insignificant
o ADH1B1 allele is common in black, Caucasians and has a Michaelis constant (Km) of 0.5 mM, Vmax of 4
o ADH1B2 allele is common in Chinese, Japanese and Jewish people and have a higher Km of 0.9mM and Vmax of 350.
- For ALDH, _____________ alleles are largely inactive – 50% of Taiwanese, Han Chinese and Japanese have this genotype
o Individuals who are hetero and especially homozygous for these alleles will have very high _____________ levels post-alcohol
o Acetaldehyde has side-effects if there is a build-up – such as nausea, headache and vomiting
o This has a protective function for the individual – tends to develop alcoholic avoidance behaviour due to the toxic side effects they experience after drinking
ALDH2*1/2;
acetaldehyde
Harmful consequences of ethanol metabolism
- Increased NADH:NAD+ ratio – production of reduced NADH leads to general reduction of ______________ of a cell and more oxygen is needed to return the cell (e.g. hepatocyte) to a baseline level, resulting in hypoxia
o Leads to direct activation of some ______________, encouraging lipid deposition in hepatocytes – basis of fatty liver in early progression of cirrhosis
- Acetaldehyde adduct formation – acetaldehyde is similar to formaldehyde, a carcinogen
o Acetaldehyde is relatively unstable and can bind to adjacent _______________ in the cell to form adducts
o May activate antibody and T cell responses
o Cytoskeletal membrane proteins of erythrocytes are more susceptible – ______________
o Amines e.g. neurotransmitters like dopamine, serotonin can bind – role in addictions - Reactive oxygen species
- Induction (enhancement) of cytochrome P450 system – a person is able to tolerate more alcohol
o Pharmacological disruption is clinically relevant such as increased metabolism of warfarin by YP450, leading to increased clearance and reduced effectiveness - Production of _________________ – via non-oxidative routes, may result in toxicity
o Evidence of direct damage to cardiac and pancreatic tissues
cytosolic environment;
fatty acid synthetic enzymes;
lipid and protein molecules;
macrocytosis;
fatty acid ethyl esters (FAEE)
Alcohol as a competitive inhibitor
- Methanol (CH3OH) is a common byproduct of distillation of alcohol, common component of paints and solvents and is a common biofuel – metabolised along the same pathway as alcohol by ADH and ALDH
o __________________ catalyses the conversion of methanol to formaldehyde which is then catalysed by aldehyde dehydrogenase to form formic acid
o Formic acid is highly toxic and causes CNS depression, blindness and death (methanol can also be directly excreted by the kidneys – slow, insignificant)
- Alcohol is used as a treatment for these patients who have methanol overdose – competitive inhibitor of alcohol dehydrogenase such that the methanol does not form formaldehyde
o Allows methanol to be excreted slowly via the kidneys and avoid formation of formic acid
Alcohol dehydrogenase;
Alcohol dependence – refers to a physical or psychological dependence on alcohol despite knowing the harmful side effects of it
- Development of a tolerance towards alcohol and experience withdrawal symptoms when they try to quit
- Physical withdrawal symptoms include tremor,
sweating, hallucination and fits and psychological withdrawal symptoms include depression, anxiety, irritability and insomnia
- These people often think about drinking in the morning and drinking starts to take priority over work, family and social events
- CAGE questionnaire – 4 questions to determine alcohol dependance
WHAT ARE THE 4 QUESTIONS?
o If 2 or more of the questions are yes, this test has an 77% sensitivity and 91% specificity of detecting alcohol abuse (4th question is the most important)
- Paddington alcohol test (normally conducted in A&E)
How often do you drink alcohol?
What is the most you will drink in a day?
Do you feel your attendance to A&E is related to your alcohol?
Have you felt the need to Cut down on drinking?
Have people Annoyed you by criticising your drinking?
Have you ever felt Guilty about drinking?
Have you ever felt you needed a drink first thing in the morning to steady your nerves or get rid of a handover (Eye-opener)?
Effects of alcohol on liver
- Alcoholic steatosis – occurs in 20% of heavy drinkers
o Benign, reversible and is due to lipid accumulation as a result of high NADH levels and stimulation of fatty acid synthase
o May have _______________ with slightly deranged LFT
- Alcoholic steatohepatitis – evidence of hepatocellular injuries, necrosis, areas of apoptosis, but no ___________ at this stage
- Alcoholic hepatitis – immune-mediated inflammatory response in the liver linked directly to alcohol, may be reversible if alcoholic intake is ceased.
- Cirrhosis – occurs in 10 to 15% of drinkers with steatosis
o Irreversible, progressive pattern of fibrosis (___________________ in the space of Disse)
o Prediction of cirrhosis – most powerful predictor is _________________________________ - Genetics and cirrhosis – certain ALD, ALDH combinations can be protective – genetic loci studies for susceptibility genes
o Understanding of genetic basis to cirrhosis is limited and likely polygenic – immunity, inflammation, handling of ROS etc - Perivenular fibrosis, periportal fibrosis, and cirrhosis – typical features of alcoholic fibrosis and often coexist with the findings of alcoholic hepatitis
Alcohol damage to other organs
- Alcohol can result in ____________________ – secondary to acetaldehyde adduct formation, fatty acid ethyl esters and fatty acid deposition within the cardiac tissue
- __________________ can also occur due to oxidative stress and toxic metabolites. A lot of the metabolic and toxic effects (e.g. ROS, acetaldehyde are systemic and not just limited to the liver
slightly enlarged liver;
fibrosis;
periportal and collagen deposition;
pre-existing hepatitis C and high levels of alcohol;
alcoholic cardiomyopathy;
Chronic pancreatitis
Effects of alcohol on liver
- Alcoholic steatosis – occurs in 20% of heavy drinkers
o Benign, reversible and is due to lipid accumulation as a result of high NADH levels and stimulation of fatty acid synthase
o May have _______________ with slightly deranged LFT
- Alcoholic steatohepatitis – evidence of hepatocellular injuries, necrosis, areas of apoptosis, but no ___________ at this stage
- Alcoholic hepatitis – immune-mediated inflammatory response in the liver linked directly to alcohol, may be reversible if alcoholic intake is ceased.
- Cirrhosis – occurs in 10 to 15% of drinkers with steatosis
o Irreversible, progressive pattern of fibrosis (___________________ in the space of Disse)
o Prediction of cirrhosis – most powerful predictor is _________________________________ - Genetics and cirrhosis – certain ALD, ALDH combinations can be protective – genetic loci studies for susceptibility genes
o Understanding of genetic basis to cirrhosis is limited and likely polygenic – immunity, inflammation, handling of ROS etc - Perivenular fibrosis, periportal fibrosis, and cirrhosis – typical features of alcoholic fibrosis and often coexist with the findings of alcoholic hepatitis
Alcohol damage to other organs
- Alcohol can result in ____________________ – secondary to acetaldehyde adduct formation, fatty acid ethyl esters and fatty acid deposition within the cardiac tissue
- __________________ can also occur due to oxidative stress and toxic metabolites. A lot of the metabolic and toxic effects (e.g. ROS, acetaldehyde are systemic and not just limited to the liver
slightly enlarged liver;
fibrosis;
periportal and collagen deposition;
pre-existing hepatitis C and high levels of alcohol;
alcoholic cardiomyopathy;
Chronic pancreatitis
Alcoholic cardiomyopathy – enlargement of the heart, thinning of cardiac wall muscles especially _________________
- ______________ and ____________ are implicated in this pathology
- Life-threatening condition as heart failure leads to pulmonary and peripheral oedemas, arrhythmias and death without cardiac transplantation
- Treatment – stop alcohol intake and to medically the cardiac failure with ______________________and defibrillator (for arrhythmia), and transplantation if all else fails to prevent premature death
left ventricle;
Fatty acid ethyl esters and acetaldehyde adducts;
ACE inhibitors, beta blockers
Alcohol and cancer
- There are about 14 million of cancer cases globally/year – expected to increase to 24 million/year by 2035
- The vast majority of these cancers are attributed to preventable lifestyle choices, mainly alcohol, smoking and obesity
- The GI tract (___________________________) as well as the breast all have alcohol as an independent risk factor for developing malignancies
- Mechanisms by which alcohol causes cancer – acetaldehyde toxicity, DNA methylation and oxidative stress (affecting DNA)
oral, pharynx, larynx, oesophagus, liver, colorectal
Pancreatitis due to alcohol
- Alcohol can cause acute pancreatitis and 70% of all chronic pancreatitis cases are due to alcohol – due to ________________________
- Results in the pancreas becoming calcified and non functional
o Loss of exocrine function (secretion of digestive enzymes) – ____________________
o The loss of endocrine function often leads to the patient developing diabetes
o The patient also suffers from chronic pain and is often _____________-
oxidative stress and reactive metabolites;
weight loss, steatorrhea and vitamin deficiencies;
opiate dependent
Foetal alcohol syndrome – combination of cognitive and behavioural deficits due to the impact on the developing brain of the foetus
- Possibly brought about by epigenetic factors such as DNA methylation and_______________, but is still poorly understood
- Presents with learning difficulty, language delay, lack of social boundaries and hyperactivity
o Many appear normal (no facial features) but have cognitive features
- Treatment – by psychologist, psychiatrist, speech and language therapist
o No cure – advice not to drink alcohol during pregnancy
o 2 out of every 1000 births were affected by foetal alcohol syndrome – leading cause of mental retardation in the Western world
o Accounts for 11% of total cost of all institutionalised mental health inpatients in America
histone modification
Long term alcohol exposure – also impedes numerous areas of cognition (memory, visuospatial and motor)
- In the long term, brain atrophy is common and leads to increased risk of ___________________
Wernicke’s encephalopathy – due to central nervous effects of Vitamin B deficiency, particularly Vitamin B1 (thiamine)
- Causes a classic triad of __________________________
- In hospitals, _________________(B vitamins/thiamine) is used in alcoholic patients who are admitted to prevent Wernicke’s Korsakoff’s syndrome – due to chronic thiamine deficiency
- Neurones particularly in mammillary bodies of the limbic system are irreversibly lost, resulting in _________________
- Loss of the ability to create new memories after the event that caused the amnesia (while long term memory is still preserved)
subdural haematoma;
confusion, ataxia (neurological sign consisting of lack of voluntary coordination of muscle movements) and ophthalmoplegia (paralysis of the muscles within or surrounding the eye);
Pabrinex;
anterograde amnesia
Recommended limits for alcohol
- ____________ for males and _________ for females (0 in pregnancy)
- 1 unit of alcohol is defined as __________ of pure alcohol – most drinks have alcohol by volume (ABV), around 5% for beer and 30 to 40% for hard liquors like vodka.
o A 750ml bottle of 13% Sauvignon blanc gives 13/100 x 750ml = 97.5ml alcohol or 9.75 units
Units = strength (ABV) x volume/1000
1 unit of alcohol represents the ___________________
- Advice for alcohol intake – alcohol diary
- The patient should have at least 2 days free of alcohol per week and it is important for them to read the label detailing the ABV
- Benefits of abstaining from drinking should also be detailed to the patient (e.g. cost saving, weight, energy, skin, fitness and sleep quality)
3 to 4 units/day;
2 to 3 units/day;
10ml (8g)
amount of alcohol that Is metabolised by an adult in 1 hour
