Alcoholic Liver Disease Flashcards
Causes of liver disease
Alcohol consumption Viral infections e.g. hepatitis Inherited disease e.g. Wilson's Vascular abnormalities Toxins, cancer, biliary tract disorders, infections, etc.
What is the recommended number of units per week in UK?
14 units
What classifies as ‘binge drinking’
> 6 units in a single session
- major cause for A&E admissions
What are the short term affects of alcohol on the body?
1) Loss of inhibition (impaired judgement)
2) Decreased respiratory rate
3) GI disturbances
4) Loss of consciousness
5) Impotence (inability to take effective action)
6) Acute poisoning
7) Complexion/effect on appearance
8) Unintentional injuries
What are the long term effects of alcohol on the body?
1) Liver disease
2) Cancer
3) Pancreatitis
4) GI ulceration
5) Osteoporosis (malabsorption)
6) Infertility
7) Heart disease and stroke due to cholesterol
8) Increased blood pressure
9) Obesity
10) Dementia
Stages of liver disease
Healthy liver
Fatty liver (steatosis)
Fibrosis
Cirrhosis
How is alcohol metabolised?
Alcohol dehydrogenase to acetaldehyde
Acetaldehyde dehydrogenase to acetic acid
Further metabolised to fatty acids
What happens to alcohol metabolism in chronic consumption?
Impaired efficiency of aldehyde dehydrogenase
1) Build up of acetaldehyde = inflammation, necrosis (inflammatory immune response- protein function)
2) Acetaldehyde = inhibits alcohol dehydrogenase (increased levels of circulating alcohol- causes effects to persist for longer)
Upregulation of CYP450 2E1
- Microsomal ethanol oxidising system responsible for ~10% in low consumption
- High consumption = increased free radicals produced causing further damage
What is fatty liver?
Is it reversible? What does it effect?
Accumulation of fat in the hepatocytes
- due to disruption of metabolic pathways
Reversible and rarely symptomatic
- doesn’t effect metabolism of food/drugs
What is the form of acute alcoholic hepatitis that is commonly caused by alcohol consumption? (AAH)
Steatohepatitis
What is steatohepatitis?
Accumulation of fat + hepatocellular injury
- inflammation and fibrosis
- can cause liver pain, vomiting, confusion
- improves with abstinence (though many will still develop cirrhosis despite)
What is thought to be the mechanisms of injury for steatohepatitis?
Poorly understood
- oxidative stress
- aldehyde accumulation
- altered protein function
What is fibrosis/cirrhosis?
Inflammation + fibrogenesis + collagen deposition
- the more episodes of inflammation, the more likely it is to develop
- irreversible, unlike acute episodes
- direct injury from free radicals and expression of inflammatory cytokines
- may exhibit signs of decompensation
- abstinence is key in management
Will cirrhosis occur in all patients with multiple episodes of inflammation?
No, dependent on individuals
Increased susceptibility depends on:
- genetics
- age
- gender
- BMI
- race
- consumption patterns
Give the outline of the management plan for patients admitted with AAH
1) Treat withdrawal symptoms and seizures if they occur
2) Treat the inflammatory component of AAH
3) Treat any complications of both liver disease and alcohol use
4) Treat malnutrition/malabsorption
5) Abstinence
Treatment (AAH) for malnutrition and behavioural changes (delusions, agitation, confusion)
Sedatives and vitamin supplement
- e.g. Chlordiazepoxide (BZ) + Pabrinex (injection)
Chlordiazepoxide
- anti-convulsant and sedative
- slow onset means lower risk of dependency
- symptom triggered dosing
- if chronic end stage patients, give oxazepam/lorazepam (shorter t1/2)
Why might shorter-acting BZs be used?
BZs are metabolised by the liver
- effects may last much longer than desired
Why is Pabrinex used?
Many patients will have poor diet
- vitamin deficient (high carbs, low protein, vitamins and minerals)
- malabsorption in intestinal mucosa (corrosion of lining)
- thiamine deficiency (vitamin B = polyneuritis- motor/sensory effects)
What can thiamine deficiency lead to?
1) Wernicke’s encephalopathy (mimics dementia)
- vitamin B reserves used up
- leads to nstagmus (involuntary rapid eye movements), ataxia (loss control of body movements), learning/memory impairment
2) Korsakoff syndrome
Dosing for Pabrinex?
1-3 pairs BD/TDS
- Avoid IM if coagulopathic
- IV also available
What are the typical signs of acute alcoholic hepatitis?
Signs of decompensation
Enlarged liver (hepatomegaly)
Fever
Leucocytosis (increased WBC)
Lab signs of AAH
Increased: WBC Neutrophil count AST INR Bilirubin
If signs indicate AAH, but also raised creatinine?
Hepato-renal syndrome
- indication for liver transplant (poor prognostic marker)
Scoring systems used for AAH
MELD
Lille
- albumin, bilirubin, INR, creatinine
- recalculate as treatment progresses
Pharmacological treatment for AAH
1) Pabrinex/Chlordiazepoxide
2) Corticosteroids e.g. prednisolone 7 days/ pentoxifylline (inhibits TNFa, phosphodiesterase inhibitor)
NB: Pentoxifylline: less evidence based, more experience based for prescriber
Currently in clinical trials:
- anti-TNF biologics
- antioxidants
- colchicine etc.
What systems does alcohol effect and how?
Dysregulation GABA + Glutamine
GABA system
- normally, facilitates GABAergic neurotransmission, leading to inhibition
- chronically: body adapts and reduces GABA receptors to counteract alcohol-induced increase in activity
Endogenous opioid system (dopamine)
- increases release of endorphins to stimulate dopamine release
Glutamine system
- inhibits excitatory glutaminergic function
- chronically: upregulated NMDA receptors to increase glutamate functioning
What happens if alcohol is suddenly withdrawn?
CNS hyperactivity
- can lead to seizures
Treatment for abstinence?
1) Psychological treatments (counselling, therapy)
2) Pharmacological treatment
- Acamprosate
- Disulfram
- Naltrexone (opioid antagonist)
What is the mechanism of Acamprosate?
1st line treatment
- stimulates GABAergic neurotransmission
- antagonise effects of excitatory amino-acid neurotransmission
- no liver metabolism nor sedation
What is the mechanism and profile of Disulfram?
Irreversibly inhibits aldehyde dehydrogenase
- increased levels of acetaldehyde exacerbate the effects of alcohol, causing patient to refrain from further alcohol intake
- nausea, flushing, headache, palpitations
- metabolised by liver, excreted by kidneys
Benefit is debatable, and relies on patient being compliant
What are the significant interactions with disulfram?
What are the ADR’s associated with disulfram?
Phenytoin
Hepatotoxicity
What is the mechanism and profile of Naltrexone?
Opioid antagonist
- decrease the affects of alcohol (causes increased opioid activity)
- reduce craving and consumption
- metabolised liver; excreted kidneys
- ADR: hepatoxocity
