Acute Liver Failure

 

  • Background

    Aka fulminant hepatic failure.

    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

    General bloods:

    • ↑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

    Complications:

    • 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

    1. Mildly altered mental status.
    2. Asterixis and lethargy.
    3. Upper motor neuron signs, disorientation, sleepiness.
    4. 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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