Acute liver failure — defining the syndrome, King's College Criteria and N-acetylcysteine viva

Interpretation

The examiner opens: "A patient is admitted with confusion and jaundice, an INR of 4, AST 6000, and a recent paracetamol overdose. Talk me through how you would define and manage this syndrome."^[1]

• The diagnosis is acute liver failure (ALF) — the defining triad is severe acute liver injury plus coagulopathy (INR at least 1.5) plus encephalopathy, all within 26 weeks, in a patient without pre-existing cirrhosis. The accepted exceptions to the "no chronic disease" rule are Wilson's disease and reactivation of chronic hepatitis B.
• Encephalopathy is the cardinal feature that separates ALF from severe acute hepatitis; a raised INR alone with preserved consciousness is not ALF.

Key points

The examiner will probe each of these; be ready to defend them at viva depth:

1. Syndromic classification (O'Grady, 1993) — by the interval from jaundice to encephalopathy: hyperacute (under 7 days, paracetamol), acute (8–28 days), subacute (29 days to 26 weeks).^[4] Paradoxically, hyperacute ALF has the highest risk of cerebral oedema but the best transplant-free survival — if the patient survives the insult, hepatocyte regeneration restores function.
2. King's College Criteria reproduced verbatim — for paracetamol ALF: arterial pH below 7.3 after fluid resuscitation, OR all three of INR over 6.5, creatinine over 300 micromol/L, grade III–IV encephalopathy. For non-paracetamol ALF: INR over 6.5 alone, OR any three of age under 10 or over 40, unfavourable cause (non-A non-B, drug, halothane), interval over 7 days, INR over 3.5, bilirubin over 300 micromol/L. Meeting criteria = urgent transplant referral.^[2]
3. N-acetylcysteine (NAC) — mechanism: paracetamol is metabolised by CYP2E1 to the toxic NAPQI, detoxified by glutathione; overdose depletes glutathione, NAPQI causes zone-3 (centrilobular) necrosis, and NAC repletes glutathione. Dose: 150 mg/kg IV over 1 h, then 50 mg/kg over 4 h, then 100 mg/kg over 16 h. Give to ALL paracetamol-induced ALF regardless of timing, and the Lee 2009 trial showed IV NAC improves transplant-free survival in non-paracetamol ALF too.^[5]
4. Pathophysiology of cerebral oedema — ammonia, no longer cleared, crosses into astrocytes; glutamine synthetase converts it to glutamine; the astrocyte swells (cytotoxic oedema) → raised ICP → brainstem herniation, the leading cause of death. Manage with head of bed 30 degrees, hypertonic saline (target Na 145–155), mannitol 0.5 g/kg, and continuous renal replacement therapy.
5. Five priorities of ICU management — (1) ICU + identify/treat cause; (2) encephalopathy/cerebral oedema; (3) coagulopathy/hypoglycaemia (do NOT prophylactically correct INR); (4) circulation/infection/renal; (5) early transplant referral.^[1]
6. Prognosis — depends on cause, age and speed of onset; paracetamol and hepatitis A do best, indeterminate/drug/Wilson's worst without transplant; overall survival with modern ICU and transplantation now exceeds 70 percent.
7. Aetiology clues — young + Coombs-negative haemolysis + Kayser–Fleischer rings + ALP:bilirubin ratio below 2 = Wilson's; third-trimester pregnancy + hypoglycaemia + high ammonia = AFLP (deliver the baby); mushroom foraging + delayed GI phase then hepatorenal failure = Amanita (silibinin + penicillin).

References

1. Stravitz RT, Lee WM. Acute liver failure. Lancet 2019.^[1]
2. O'Grady JG, et al. Early indicators of prognosis in fulminant hepatic failure (King's College Criteria). Gastroenterology 1989.^[2]
3. O'Grady JG, et al. Acute liver failure: redefining the syndromes. Lancet 1993.^[4]
4. Lee WM, et al. IV N-acetylcysteine in non-acetaminophen ALF. Gastroenterology 2009.^[5]

References4ShowHide

1. [1]Stravitz RT, Lee WM. Acute liver failure. Lancet, 2019.PMID 31498101
2. [2]O'Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology, 1989.PMID 2490426
3. [4]O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet, 1993.PMID 8101303
4. [5]Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology, 2009.PMID 19524577