Liver disease - acute
Description
- Spectrum: acute hepatitis -> severe acute liver injury -> acute liver failure (ALF)
Definitions
- Acute liver failure = all three, in a patient without pre-existing liver disease:
1. INR >=1.5 (coagulopathy)
2. Any degree of hepatic encephalopathy
3. Onset within a defined short window (classically <26 weeks)
- Jaundice is usually present but is not part of the definition
- Severe acute liver injury = coagulopathy without encephalopathy - not yet ALF
By interval jaundice -> encephalopathy
| Interval | Typical cause | Cerebral oedema | |
|---|---|---|---|
| Hyperacute | <7 days | Paracetamol, HAV/HEV, ischaemic | Highest risk |
| Acute | 8-28 days | HBV | Intermediate |
| Subacute | 29 days - 12 weeks | Drug (non-paracetamol), seronegative | Low (but worst transplant-free survival) |
- Counter-intuitive: the more hyperacute the presentation, the better the spontaneous survival
Epidemiology
- Rare: ~1-6 per million per year in developed countries
- Paracetamol is the commonest cause in Australia, the UK and the US
- Viral hepatitis dominates in the developing world
- Transplantation required in ~25-30% of ALF
- Paracetamol is the leading agent in intentional self-poisoning presentations to Australian EDs
Aetiopathogenesis
Causes
- Drugs/toxins
- Paracetamol - most common overall
- Idiosyncratic DILI: antituberculous (isoniazid, rifampicin, pyrazinamide), antiepileptics (valproate, phenytoin, carbamazepine), antibiotics (augmentin - the commonest idiosyncratic DILI, flucloxacillin, nitrofurantoin), statins, herbal/complementary, MDMA, cocaine
- Amanita phalloides mushroom
- Viral - HAV, HBV (+/- HDV), HEV (fulminant in pregnancy, ~20% mortality in 3rd trimester), HSV/VZV (immunocompromised, often anicteric, very high transaminases), EBV, CMV
- Vascular - ischaemic hepatitis ("shock liver"), Budd-Chiari, veno-occlusive disease
- Pregnancy - acute fatty liver of pregnancy, HELLP
- Metabolic - Wilson disease (presents as ALF in young people; look for haemolysis, low ALP, ALP:bilirubin ratio <4)
- Autoimmune hepatitis - acute severe presentation
- Malignant infiltration (lymphoma, breast), heat stroke, sepsis
- Seronegative/indeterminate ~15%
Paracetamol mechanism
- Normal: >90% glucuronidation/sulfation; small fraction via CYP2E1 -> NAPQI, detoxified by glutathione
- Overdose or depleted glutathione -> NAPQI accumulates -> centrilobular (zone 3) necrosis
- Acetylcysteine replenishes glutathione - hence the time-dependence
- Higher risk: chronic alcohol (CYP2E1 induction), malnutrition/fasting, anorexia, enzyme inducers, chronic illness
Diagnosis
Paracetamol overdose - the numbers
- Toxic dose:
- >10 g or 200 mg/kg in a single 24 h period, OR
- >6 g or 150 mg/kg/24 h sustained over the preceding 48 h, OR
- >4 g/day (100 mg/kg/day) plus abdominal pain or nausea/vomiting
- Serum paracetamol at 4 h post-ingestion plotted on the nomogram; treatment line 150 mg/L (1000 micromol/L) at 4 h
- Concentration taken before 4 h cannot be interpreted
- Liver injury may not be clinically or biochemically apparent for up to 24 h - a normal ALT at presentation means nothing
- Staggered ingestion or unknown timing -> treat and check paracetamol + ALT
Assessing severity in any acute liver injury
- INR is the best marker of synthetic function
- Reflects factor VII - shortest half-life (~4-6 h) of the vitamin K-dependent factors
- Albumin half-life ~20 days - useless acutely. Bilirubin reflects excretion, not synthesis
- Correct with vitamin K first to exclude deficiency as the cause
- Encephalopathy grading I-IV; grade III-IV -> intubate, ICU
- Fulminant picture: progressive jaundice, fetor hepaticus, fever, anorexia, vomiting, abdominal pain, asterixis
- Rising lactate, hypoglycaemia, acidosis, renal failure = deteriorating
Aetiological workup - send at presentation
- Paracetamol level, alcohol, drug history incl. complementary and recreational
- Viral: HAV IgM, HBsAg + anti-HBc IgM, HCV RNA, HEV IgM, HSV/VZV/CMV/EBV PCR
- Autoimmune: ANA, ASMA, anti-LKM, IgG
- Wilson: caeruloplasmin, serum/urinary copper, slit lamp, haemolysis + low ALP
- Pregnancy test; Doppler US of hepatic veins and portal vein
- Liver biopsy (transjugular) only if the cause remains unclear
Management
A. Paracetamol overdose
Verified against the MJA guidelines for the management of paracetamol poisoning in Australia and New Zealand (updated edition).
Decontamination
- Activated charcoal if:
- Within 2 h of a toxic ingestion (>10 g or 200 mg/kg), OR
- Up to 4 h after a massive overdose (>30 g) or a modified-release preparation
- Charcoal is not the emergency - acetylcysteine within 8 h is. Never delay NAC to give charcoal
Acetylcysteine - two-bag regimen (has replaced the three-bag)
- 200 mg/kg over 4 h, then 100 mg/kg over 16 h
- Fewer anaphylactoid reactions than the old 3-bag regimen, same efficacy
- Give if: level above the nomogram line; presentation >8 h after a toxic dose (start empirically, stop if level below line); staggered/unknown ingestion; any evidence of hepatotoxicity
- Massive overdose (level >2x the nomogram line) -> double the second bag to 200 mg/kg over 16 h
- Near-100% hepatoprotection if started within 8 h; still beneficial late, including in established ALF
- Anaphylactoid reaction = rate-related, not allergy - slow or pause the infusion, antihistamine, then restart. Not a contraindication
- Continue beyond 20 h if ALT still rising, INR >1.3, or paracetamol still detectable
B. Acute liver failure - supportive
- Discuss with a transplant centre early - before criteria are met
- ICU; intubate for grade III-IV encephalopathy
- N-acetylcysteine for non-paracetamol ALF too - improves transplant-free survival in early-grade encephalopathy
- Glucose infusion - hypoglycaemia is common and silent in the encephalopathic patient
- Cerebral oedema (hyperacute > subacute): head up 30 degrees, normocapnia, normothermia, hypertonic saline/mannitol; ammonia >150-200 micromol/L predicts intracranial hypertension
- Do not correct INR prophylactically - it is the prognostic marker; only give factors for bleeding or before a procedure
- Sepsis: low threshold for cultures and empirical antibiotics; SIRS may be non-infective
- Renal replacement therapy (continuous) - also clears ammonia
- Avoid sedation where possible; avoid nephrotoxins; PPI for stress ulcer prophylaxis
C. Cause-specific
- HBV -> entecavir/tenofovir; HSV -> aciclovir; Amanita -> silibinin, penicillin G
- Autoimmune -> corticosteroids (but do not delay transplant)
- Wilson -> transplant; chelation is too slow in ALF
- Budd-Chiari -> anticoagulation, TIPS
- Pregnancy-related (AFLP, HELLP) -> deliver
D. Transplantation - King's College Criteria
Paracetamol:
- Arterial pH <7.3 after resuscitation, OR all three of:
- INR >6.5 (PT >100 s)
- Creatinine >300 micromol/L
- Grade III-IV encephalopathy
- Lactate >3.5 after early resuscitation (or >3.0 after full resuscitation) added as a criterion
Non-paracetamol:
- INR >6.5 (PT >100 s) alone, OR any three of:
- Age <10 or >40
- Aetiology: seronegative, drug reaction, halothane
- Jaundice -> encephalopathy interval >7 days
- INR >3.5 (PT >50 s)
- Bilirubin >300 micromol/L
- Highly specific, poorly sensitive - meeting criteria mandates listing; not meeting them does not exclude it
Associations
- Chronic alcohol use - CYP2E1 induction + glutathione depletion -> paracetamol toxicity at therapeutic doses
- Malnutrition, anorexia nervosa, prolonged fasting - dec glutathione
- Enzyme inducers (rifampicin, phenytoin, carbamazepine, St John's wort)
- Pregnancy - HEV, AFLP, HELLP
- Immunosuppression - HSV/VZV, HBV reactivation
- Antituberculous therapy, complementary and herbal medicines, bodybuilding supplements
- Ask specifically about mushroom foraging and "natural" preparations - patients do not volunteer them
Natural history & complications
- Overall transplant-free survival ~40-60%; ~25-30% transplanted; overall survival with transplant ~80% at 1 year
Prognosis by cause
- Best spontaneous recovery: paracetamol, HAV, ischaemic hepatitis, pregnancy-related
- Worst: seronegative, idiosyncratic DILI, Wilson disease, Budd-Chiari, autoimmune - usually need transplant
Complications
- Cerebral oedema and intracranial hypertension - the leading cause of death in hyperacute ALF
- Sepsis and multiorgan failure - the leading cause overall
- Hypoglycaemia; lactic acidosis
- Hepatorenal / acute kidney injury (~50%)
- Bleeding (less than the INR suggests - a rebalanced coagulopathy)
- Circulatory failure with low SVR mimicking sepsis
- Pancreatitis, bone marrow suppression, aplastic anaemia (seronegative hepatitis)
- If recovery: complete regeneration, no chronic liver disease (except Wilson, autoimmune, and chronic HBV)
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