Alcohol metabolism, alcoholic liver disease and alcoholism Flashcards
Define alcohol
“Alcohol” is non-specific, and includes methanol, ethanol, propanol etc.
In usual parlance, however, alcohol often means ethanol.
How is ethanol distributed and lost?
Ethanol is water soluble – so distribution to lean body mass only
Some endogenous production
Approx 10% lost through breath/urine – rest metabolised
Metabolism nearly all in liver some in brain, pancreas and stomach
Complete the equation
What are alcohol dehydrogenase polymorphisms?
Several isoforms of this enzyme are present, with variable activity in individuals depending on genetic makeup, gender and other factors.
For example, individuals of Asian descent who have the B2 ADH isoform, metabolise ethanol 20% faster than northern Europeans who posses the B1 ADH.
What is NAD role in alcohol metabolism and what is the consequence of this?
Both alcohol dehydrogenase and aldehyde dehydrogenase reactions reduce NAD to NADH
Increases:
lactate:pyruvate ratio
beta-hydroxybutyrate:acetoacetate ratio
Inhibits:
Glycolysis
Citric acid cycle – ketogenesis
Fatty acid oxidation
Gluconeogenesis
What is oxidant stress?
Lipid peroxidation which is associated with both acute tissue damage & fibrosis
Free radicals attack cellular & mitochondrial DNA causing deletions & mutations
What is 1 unit?
1 Unit = 10mL or 8g of pure alcohol
In 2016 the safe limit was reduced to ___U per week for both genders in at least ___ doses.
14 units
3 doses
Legal limit for driving in the UK is blood ethanol ≤ ___mg/dL.
Legal limit for driving in the UK is blood ethanol ≤ 80mg/dL.
≤ 2-3 units in females
≤ 3-4 units in men
Why should pregant women not drink alcohol?
Pregnant women or women trying to conceive should not drink alcohol. Ethanol crosses the placenta. Alcohol can seriously affect foetal development (foetal alcohol syndrome).
What is alcoholic ketoacidosis?
Metabolic acidosis with increased anion gap.
Typically occurs in chronic alcoholics who binge with little nutrition intake.
What is the pathophysiology of alcoholic ketoacidosis?
Glycogen depletion/inhibited gluconeogenesis
Lipolysis and ketones increased (beta hydroxybutyrate) Insulin suppressed
Extracellular volume depletion/dehydration/stress - increase counter regulatory hormones further supressing insulin
How does alcohol cause hypoglycaemia?
Ethanol causes hypoglycaemia through:
- decreased intake of glucose (CHO)
- depletion of glycogen
- blockade of gluconeogenesis
Prompt treatment with glucose is life-saving
Need to give parenteral thiamine as well to prevent CNS damage in case there is also thiamine deficiency
What endocrine issues can alcohol cause?
- Decreased testosterone (testicular atrophy)
- Pseudo Cushings
- Metabolic Syndrome and Dyslipidaemia
What general nutrition issues can alcohol cause?
- Low calcium (diet, decreased vitamin D)
- Low phosphate (diet, increased PTH)
- Low Mg, K (diet, urinary loss, hyperaldosteronism)
What LFTs change in alcohol?
- Gamma Glutamyl Transferase (GGT) increased by liver enzyme induction
- Transaminases (ALT and AST) increased by hepatocellular damage
- Globulin increased in cirrhosis
- Bilirubin & INR increased and albumin decreased by liver failure
What are the causes of thiamine deficiency?
- Ethanol interferes with GI absorption
- Hepatic dysfunction, which hinders storage and activation
- Malnourishment
What other relevant blood tests would you do for an alcohol patient?
- Macrocytosis – raised MCV in a full blood count
- Raised serum ferritin concentration
- Hyperuricaemia
- Hypertriglyceridaemia
- Increased carbohydrate-deficient transferrin or CDT
How does alcohol cause hypertension?
- impairment of the baroreceptors (which sense blood pressure)
- increase of sympathetic activity
- stimulation of the renin-angiotensin-aldosterone system
- an increase in plasma cortisol
- an increase of intracellular calcium with subsequent increase in vascular reactivity
- endothelial e.g. inhibition of endothelium-dependent nitric oxide production
Which zone of the liver lobule
Gets the most oxygen?
Does the most metabolism?
What features on liver biopsy increase the risk of progression?
Increased risk of progression
Microvesicular fatty change
Extend of fibrosis
Amount of MD bodies
Intrahepatic cholestasis
What are the pathological features of alcoholic liver disease?
What is macrovesicular steatosis?
What is microvesicular steatosis?
What is balloning?
Steatohepatitis
What does this show?
Steatohepatitis: Mallory denk bd
What are the fibrosis/cirrhosis mechanisms?
inflammation and necrosis cause increase in cytokines and growth factors (TGF-beta, MCP-1) that activate fibroblasts/myofibroblasts to deposit collagen (Disse’s space)
centrilobular fibrosis - reversible
septal fibrosis - increasingly irreversible
What does this show?
Macronodular cirrhosis/portal hypertension
What does this show?
Cirrhosis and hepatocellular carcinoma
What are portal hypertension consequences?
impaired intestinal function and malabsorption
splenomegaly with anaemia and thrombocytopenia
portal bypass circulations:
haemorrhoids (v. iliaca)
caput medusae (paraumbilical veins)
oesophageal veins (varices)
vasodilatation and compensatory increase in cardiac output
toxic metabolites (NH3, fatty acids, biogenic amines) bypass the liver and may cause portosystemic (hepatic) encephalopathy
What is the management for alcohol withdrawal patients?
ØDeal with immediate problem of patient at risk to himself and others. e.g. Environmental considerations, Benzodiazepine
ØReducing course of chlordiazepoxide /diazepam
ØPabrinex iv tds
ØIncrease ‘obs’ and possibly ‘special’ the patient
ØWhen better requires alcohol counselling, review of social situation, liaise with GP etc..
What is alcohol withdrawal?
- Physiological dependence
- The ‘need’ to drink to avoid unpleasant symptoms - ‘Relief Drinking’
- Delirium Tremens
What are the symptoms of withdrawal?
- Tremor/shaking
- Sweating
- Tachycardia
- Nausea
- Agitation
- Siezures
- Visual hallucinations
What are the different methods of alcohol withdrawal?
•Planned:
- in community
- in hospital/detox facility
•Unplanned:
- known alcohol problems + another
medical problem
- alcohol history not known in patient
presenting with a separate problem
Why is an alcohol history important for all inpatients?
- High index of suspicion of unplanned alcohol withdrawal
- Often occurs 2-3 days after admission
How can you tell if someone is an alcoholic?
- CAGE questions
- AUDIT questionnaire
What drugs are used to manage alcohol withdrawal?
- CHLORDIAZEPOXIDE – used at RSCH & PRH
- DIAZEPAM
What are the potential hazards of alcohol withdrawal syndrome?
- Severe liver disease - precipitation of hepatic encephalopathy
- Respiratory depression
- Reluctance to prescribe more
Concomitant alcohol consumption
What are the core features of delerium?
- Disturbance of consciousness
- Change in cognition or a perceptual disturbance (hallucination)
- Tendency to fluctuate.
- Behaviour overactive or underactive
- Other features: disorganized thinking, poor memory, delusions and mood lability
What are the causes of delerium?
- Any infection (esp. in elderly)
- Drug side effect
- Hypoxia
- Drug overdose
- Alcohol intoxication
- Wernicke encephalopathy
- Hypoglycaemia
- Meningitis / encephalitis
- Psychiatric illness
- Head injury
- Constipation (elderly)
- Hepatic encephalopathy
Emergency GP referral:
- 31 yr old woman - jaundice abdominal distension
- 6 yrs alcohol dependence - 3L 7.5% cider per day Relief drinking
- Recent siezure
Bilirubin 197mmol/L (< 21)
Albumin 29g/L (35-52)
INR 2.6 (0.9 – 1.1)
Diagnosis: SEVERE alcoholic hepatitis
What is wenicke-korsakoff syndrome?
- Wernicke’s Encephalopathy
- Korsakoff’s Psychosis
What are the dietary sources of thiamine (vit b1)
Wheat
Yeast
Nuts
Oatmeal
Potatoes
Pork
Marmite
THIAMINE - VIT B1
- Daily nutrient requirement approx. ___mg
- Body stores of approx. ___mg
- Deficiency starts after about ______ of thiamine free diet
- Daily nutrient requirement approx. 1mg
- Body stores of approx. 30mg
- Deficiency starts after about 1 month of thiamine free diet
What is the role of thiamine?
Glucose and lipid metabolism
Production of amino acids
Production of glucose derived neurotransmitters
What are the causes of thiamine deficiency?
•Alcoholism commonest cause
(inadequate intake, inhibition of active intestinal absorption by alcohol and malnutrition)
- Chronic vomiting e.g. hyperemesis gravidarum
- Famine
What is wernickes encephalopathy?
Classic Triad:
- Confusion
- Eye Signs - opthalmoplegia and nystagmus
- Ataxia
Only seen in 10% of cases
Underdiagnosed
What are the consequences of wernickes encephalopathy?
- Brain damage:
- Multiple small haemorrhages especially in upper brainstem, hypothalamus and thalamus, mamillary bodies
- 20% mortality if untreated
What is korsakoffs pyschosis?
- Permanent brain damage
- Severe short term memory loss
- Confabulation
How can wernicke-korsakoffs syndrome be prevented?
- Can be precipitated / rapidly worsened with introduction of nutrition or administration of IV 5% dextrose
- Any available thiamine in brain is utilised in the metabolism of glucose leading to sudden complete deficiency
- GIVE PARENTERAL THIAMINE BEFORE DEXTROSE OR NUTRITION
- (NB confused/comatose patient in A&E)
- ALWAYS CHECK GLUCOSE LEVEL FIRST
What is the treatment for wernicke-korsakoffs syndrome?
•PABRINEX:
-Thiamine 250mg + others
- Give IV for 2-5 days depending on response
- Rarely causes anaphylaxis
- Continue oral thiamine and other vitamins after initial treatment
