Acute Liver Failure
Background
Definition and pathophysiology
- Hepatocellular dysfunction causing coagulopathy (INR ≥1.5) and encephalopathy in someone without known liver disease.
- In existing disease, it is known as acute decompensated liver disease. However, some causes of chronic liver disease can present with ALF.
- Usually happens when at least ⅔ liver damaged.
- Time scale: hyperacute (<1 week), acute (2-4 weeks), or subacute (1-3 months). Hyperacute actually has better long-term outcome if the immediate crisis is survived.
Causes
- Overdose: paracetamol (commonest UK cause), alcohol (though usually considered acute on chronic).
- Viral: usually hepatitis A or B. The commonest global cause of ALF. Atypical causes: CMV, HSV, EBV.
- Seronegative hepatitis: no cause found, including no hepatitis A, B, or C.
- Drugs: phenytoin, sodium valproate, isoniazid, nitrofurantoin, sulfonamides, co-amoxiclav.
- Metabolic: Wilson's, Reye's.
- Vascular: ischaemic hepatitis, Budd-Chiari syndrome.
- Pregnancy: fatty liver of pregnancy, HELLP.
Signs and symptoms
- Non-specific: tired, nausea, anorexia, weight loss.
- Hepatic: abdominal or RUQ pain, jaundice, fetor hepaticus (pear drop smell), hepatic encephalopathy.
Investigations
- ↑LFTs
- ↓Synthetic function: ↑PT/INR (early sign), ↓albumin, ↓glucose (↓gluconeogenesis).
- FBC: infection (↑WBC), haemolytic anaemia in Wilson's (↓Hb).
- ABG: acidosis due to reduced hepatic clearance of lactate.
- U+E: AKI is a potential complication.
Cause-specific tests:
- Paracetamol levels.
- Viral serology.
- Auto-antibodies: ANA, ASMA, AMA, ANCA.
- Ceruloplasmin and 24h urine copper (Wilson's).
- β-hCG
Imaging:
- Abdo US with doppler: hepato/splenomegaly, cirrhosis, hepatic vein thrombosis.
- CXR to check for aspiration pneumonia in those with ↓consciousness.
Complications and prognosis
- Cerebral oedema. Commonest cause of death in ALF. ↑ICP leads to brain hypoperfusion and/or coning.
- Sepsis and shock.
- AKI
Mortality by cause (remember, in cases which have already led to ALF):
- Hep A: 30%.
- Paracetamol OD: 50%.
- Hep B: 70%.
- Wilson's: 99%.
Paracetamol overdose
Pathophysiology
- The usual paracetamol metabolism pathways – glucuronidation or sulfation – are rapidly saturated.
- The other pathway – via the cytochrome P450 isoenzymes CYP2E1 and CYP3A4 – generates toxic NAPQI. The body can only detoxify a small amount with endogenous glutathione.
- Risk is increased by malnutrition, concomitant enzyme inducer use (enzyme-inducing anti-epileptics, rifampicin), or chronic alcoholism (also causes enzyme induction). Reduces potentially toxic level from 12 g to 7.5 g.
Signs and symptoms
- Symptoms takes up to 3 days to develop.
- Early features: non-specific abdo pain, nausea and vomiting, altered clotting.
- Later features: jaundice, RUQ pain, ALF, encephalopathy.
- Presentation is often pre-symptomatic, among those who have regretted their OD (or been brought in by others).
Investigations
- Basic bloods: FBC, LFTs, U+E, coag, albumin, glucose.
- Serum paracetamol levels should be measured ≥4 hours post-ingestion, as they take time to peak.
- ABG: lactic acidosis if severe, due to NAPQI inhibition of aerobic respiration and ↓hepatic clearance of lactate.
Management
- N-acetylcysteine (NAC) IV is the antidote, and is most effective within 8 hours. Usually a 24 hour infusion.
- Methionine PO is 2nd-line.
- Activated charcoal if <1 hour from ingestion.
- Transplantation indications (King's College Criteria): pH <7.3 24h post ingestion, or all 3 of {INR >6.5 (PT >100 sec) and creatinine >300 μmol/l (3.4 mg/dL) and grade 3-4 encephalopathy}.
- Correct any hypoglycaemia, but seek specialist advice before correcting INR.
Prognosis and complications
- Acute liver failure.
- AKI: develops at 3-7 days.
- Death: usually occurs 3-6 days post-ingestion. Occurs in <1%, but in 50% of those who develop ALF.
- Poor prognostic indicators: ↑ or rising PT, ↓pH, ↑lactate, ↑BR, grade 3/4 encephalopathy, ↑creatinine.
N-acetylcystine (NAC)
Mechanism
- A glutathione precursor, allowing detoxification of NAPQI.
- Completely prevents ALF if given <8 hours.
Management
- Give if serum paracetamol above the treatment line >4 hours post-ingestion. If >24 hours since ingestion, give if any paracetamol detected or there is abnormal liver function.
- Ideally give within 8 hours of ingestion but still useful later. If >8 hours, treat before levels are known.
- Give 3 IV infusions over 21 hours (the first within 1 hour), mixed with 5% glucose.
- NAC can be stopped after this, provided paracetamol levels are below the treatment line and bloods (LFTs, INR, renal function) have normalised.
Side effects
- Vomiting. Give antiemetic IV (e.g. ondansetron).
- Anaphylactoid reaction (15%). Dose-related histamine release, causing urticaria, wheeze, and ↓BP. Stop NAC, give chlorphenamine (± steroids, adrenaline), then re-start. If only mild skin reaction, just reduce infusion.
- Coagulopathy
Hepatic encephalopathy
Pathophysiology
- ↑Ammonia due to reduced hepatic clearance.
- Ammonia crosses blood-brain-barrier, is absorbed by astrocytes, and is converted to glutamine.
- Glutamine increases intracellular osmotic pressure, causing cell swelling and cerebral oedema.
- Also interferes with neurotransmitter synthesis and electrical function.
- Due to acute liver failure, decompensated cirrhosis, or post-TIPS procedure.
Grades
- Mildly altered mental status.
- Asterixis and lethargy.
- Upper motor neuron signs, disorientation, sleepiness.
- Coma.
Management
- Lactulose ± phosphate enemas to reduce ammonia production by gut bacteria.
- Rifaximin to kill gut bacteria.
- Both therapies should be continued long-term for secondary prevention.
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