Paracetamol overdose

Contents

Mechanism of Toxicity

At therapeutic doses, paracetamol is metabolised by:

  • Glucuronidation (~55%): UDP-glucuronosyltransferase → glucuronide conjugate (non-toxic)
  • Sulphation (~30%): sulphotransferase → sulphate conjugate (non-toxic)
  • CYP oxidation (~10–15%): CYP2E1 (primarily) and CYP3A4 → NAPQI (N-acetyl-p-benzoquinone imine), a highly reactive electrophile

NAPQI is normally detoxified by conjugation with glutathione → mercapturic acid → renally excreted. This pathway is non-toxic and the liver has abundant glutathione reserves.

In Overdose

Glucuronidation and sulphation become saturated → proportionally more paracetamol is shunted through CYP oxidation → NAPQI production overwhelms glutathione stores.

Free NAPQI:

  • Binds covalently to hepatocyte proteins → mitochondrial dysfunction → centrilobular (zone 3) necrosis
  • Zone 3 has the highest CYP2E1 activity and lowest glutathione reserves

The result: fulminant hepatocellular necrosis, peaking 72–96h post-ingestion.

Risk Factors for Hepatotoxicity

Hepatotoxicity at a given dose is increased by:

Risk factor Mechanism
Chronic alcohol use CYP2E1 induction ↑ NAPQI production; glutathione depletion
Enzyme-inducing drugs (phenytoin, carbamazepine, phenobarbital, rifampicin, isoniazid) CYP induction → ↑ NAPQI
Malnutrition / anorexia / eating disorders Depleted glutathione reserves
HIV/AIDS Glutathione depletion
Fasting Reduced glutathione synthesis

Current UK practice (MHRA 2012): a single nomogram treatment line is used regardless of risk factors; the previously used "high-risk" line was withdrawn as it was causing under-treatment. All patients with concentration above the standard treatment line should receive NAC.

Clinical Course and Staging

Phase Timing Features
I — Prodrome 0–24h Nausea, vomiting, malaise, abdominal pain; no jaundice; can appear well
II — Latent 24–72h Apparent improvement; rising AST/ALT begins; INR may start to rise; subclinical liver injury
III — Hepatotoxicity 72–96h Peak LFT abnormality; jaundice; coagulopathy (PT/INR key marker); AKI (direct renal tubular toxicity); encephalopathy in severe cases; MODS
IV — Recovery or ALF Days 4–14 Either resolution (most patients) or progression to acute liver failure (rare but life-threatening)

Assessment and Investigations

  • Paracetamol concentration: 4h post-ingestion minimum (any time if >4h); plot on nomogram — treatment if above line (100 mg/L at 4h)
  • INR/PT: most sensitive marker of hepatic synthetic function; rises earlier than bilirubin in ALF
  • ALT/AST: peak at 72–96h; ALT >1000 IU/L = significant hepatotoxicity
  • Creatinine and eGFR: direct nephrotoxicity; rises with severe hepatotoxicity (hepatorenal syndrome)
  • Bicarbonate and lactate: acid-base status; metabolic acidosis in severe ALF (important in KCC)
  • Blood glucose: hepatic gluconeogenesis fails in ALF → hypoglycaemia

Staggered ingestion / unknown time of ingestion:

  • Exact timing may be unclear (intentional overdose, binge over hours)
  • If >150 mg/kg estimated (or 12g total), or history unreliable: treat with NAC empirically; do not withhold while awaiting concentration
  • Never delay NAC in a sick patient while awaiting results

N-Acetylcysteine (NAC)

Mechanism

  • Glutathione precursor: replenishes intracellular glutathione, allowing NAPQI detoxification
  • Direct antioxidant: reacts directly with NAPQI in severe overdose
  • Anti-inflammatory: reduces hepatic inflammatory injury in established hepatotoxicity
  • Most effective within 8 hours of ingestion; still beneficial in established hepatotoxicity (different mechanism)

UK Standard Three-Bag Regimen

Bag Dose Volume Rate
1 150 mg/kg 200 mL 5% dextrose Over 60 min
2 50 mg/kg 500 mL 5% dextrose Over 4h
3 100 mg/kg 1000 mL 5% dextrose Over 16h

(A simplified two-bag regimen — 100 mg/kg/2h then 200 mg/kg/16h — is used in some centres based on SNAP trial data, with equivalent efficacy and fewer anaphylactoid reactions.)

Anaphylactoid Reactions

  • Occur in ~5–15% during bag 1 (flushing, urticaria, bronchospasm); peak in first 15 min
  • Not a true IgE-mediated allergy — histamine release from mast cells is rate-related
  • Management: slow infusion rate, antihistamine (chlorphenamine 10 mg IV); rarely require NAC discontinuation; restart at a slower rate once resolved
  • Asthmatics at slightly higher risk of bronchospasm

Duration of NAC

  • If no hepatotoxicity develops: complete 21h regimen and discharge if concentration sub-therapeutic
  • If hepatotoxicity develops (rising ALT/INR): continue NAC infusion (at bag 3 rate) until LFTs improving and INR <2 — this may be days

King's College Criteria (KCC)

For referral to a liver transplant unit in paracetamol-induced acute liver failure:

**Arterial pH <7.30** after adequate resuscitation (>24h post-ingestion, regardless of encephalopathy grade)

OR all three of:

INR >6.5 (PT >100 seconds)
Creatinine >300 µmol/L
Grade III or IV hepatic encephalopathy

  • Sensitivity ~70%, specificity ~90% for poor outcome without transplantation
  • Serum lactate >3.5 mmol/L at 12h (pre-NAC) or >3 mmol/L at 12–24h after NAC has been incorporated into some modified KCC with improved sensitivity
  • Serum phosphate >1.2 mmol/L at 48–96h (reflects hepatic regeneration failure) also adds prognostic value

Important: refer early, before all three criteria are simultaneously met. A patient clearly progressing towards meeting criteria, or with severe acidosis, should be referred proactively.

Acute Liver Failure — ICU Management

Coagulopathy

  • INR/PT is the best marker of hepatic synthetic function
  • Do not replace with FFP unless there is active bleeding or an invasive procedure — FFP masks the prognostic marker (INR) without improving outcomes
  • Vitamin K: give parenterally (hepatocytes not functioning; oral absorption unreliable)

Encephalopathy

  • Grade I–II: confusion, altered behaviour
  • Grade III–IV: stupor, coma — airway at risk; intubate at grade III
  • Lactulose: minimal evidence in ALF (mechanism is of benefit in cirrhosis); oral laxatives may be used
  • Avoid excessive sedation (confounds grade assessment)
  • Cerebral oedema: complication of high-grade encephalopathy; raised ICP can occur; consider ICP monitoring in grade IV; hypertonic saline, head positioning, mannitol

Hypoglycaemia

  • Hepatic gluconeogenesis and glycogenolysis fail in ALF
  • Monitor blood glucose hourly; treat aggressively with 50% dextrose or 10% dextrose infusion
  • Target glucose 4–8 mmol/L

Renal failure

  • AKI common (direct tubular toxicity + hepatorenal physiology)
  • Early RRT; haemofiltration preferred (haemodynamic instability common); avoid intermittent HD in unstable patients

Infection

  • Immunoparesis in ALF: high risk of bacterial and fungal infection; surveillance cultures; low threshold for broad-spectrum antibiotics; prophylactic antifungals in severe ALF

Liver support devices

  • MARS (Molecular Adsorbents Recirculating System): albumin dialysis; removes protein-bound toxins; bridge to transplantation or recovery; no proven mortality benefit in RCT data for ALF overall; used in selected centres

Viva Questions

1. Explain the mechanism of paracetamol hepatotoxicity and why glutathione is central to it.

Paracetamol is metabolised mainly by glucuronidation and sulphation to non-toxic conjugates. A small fraction (~10–15%) is oxidised by CYP2E1 and CYP3A4 to NAPQI — a highly reactive electrophile. In normal circumstances, NAPQI is immediately conjugated with glutathione, forming a non-toxic mercapturic acid which is excreted. In overdose, the glucuronidation and sulphation pathways saturate, driving proportionally more paracetamol through CYP oxidation. NAPQI production overwhelms glutathione stores. Free NAPQI binds covalently to hepatocyte proteins, particularly in zone 3 of the hepatic acinus (which has the highest CYP2E1 expression and lowest glutathione concentration), causing mitochondrial dysfunction and centrilobular necrosis. This is why glutathione replenishment (via NAC) is the cornerstone of treatment, and why risk factors that either induce CYP2E1 or deplete glutathione (chronic alcohol, enzyme-inducing drugs, malnutrition) increase hepatotoxicity risk at any given dose.

2. How effective is NAC and does it matter when it is given?

NAC is most effective when given within 8 hours of ingestion — at this stage it replenishes glutathione stores, preventing free NAPQI from accumulating and virtually eliminates the risk of hepatotoxicity. Efficacy falls significantly with later administration but NAC remains beneficial even in established hepatotoxicity (>24–48h): it reduces morbidity and mortality through mechanisms including direct antioxidant scavenging and anti-inflammatory effects, and there is evidence it improves transplant-free survival even in patients with ALF. Therefore NAC should never be withheld on the basis of late presentation. In practice: any patient with a concentration above the treatment nomogram line should receive the full 21-hour course regardless of time since ingestion; any patient with established hepatotoxicity (elevated ALT, rising INR) should receive ongoing NAC infusion until LFTs are improving and INR is falling, regardless of the initial concentration.

3. What are the King's College Criteria for paracetamol-induced ALF and how do you use them in practice?

The King's College Criteria identify patients unlikely to survive without liver transplantation: arterial pH <7.30 after adequate resuscitation, or the combination of INR >6.5, creatinine >300 µmol/L, and grade III-IV encephalopathy. These carry approximately 70% sensitivity and 90% specificity for mortality without transplantation. In practice, they are referral criteria, not rigid transplantation criteria. Patients should be referred to a specialist liver unit early — ideally before all criteria are fully met — as transfer logistics take time and clinical condition can deteriorate rapidly. Falling pH, rapidly rising INR, or worsening encephalopathy are all indications to contact the liver centre proactively. Listing decisions involve the liver transplant team, and additional factors are considered including likelihood of recovery, transplant contraindications, and patient preferences. FFP should not be used to correct coagulopathy as it masks the INR, which is a key prognostic marker; replace clotting factors only for active bleeding or invasive procedures.

4. A patient presents 16 hours after a paracetamol overdose. The paracetamol concentration is undetectable but their INR is 3.2 and ALT is 4,200 IU/L. How do you manage them?

This patient has established hepatotoxicity — significant enough to have taken 16 hours to develop this degree of injury. The undetectable concentration is irrelevant at this stage; the damage is done. Management: (1) Start NAC immediately (if not already running) — continue at bag 3 rate (100 mg/kg/16h) and repeat until INR <2 and ALT is falling; (2) Monitor closely: 4-hourly INR, creatinine, glucose, and acid-base; (3) Contact the regional liver unit — this patient with INR 3.2 and elevated transaminases is at risk of progressing to ALF; early referral is appropriate before KCC criteria are fully met; (4) Correct hypoglycaemia aggressively — monitor blood glucose hourly; (5) Avoid FFP (masks prognosis); give vitamin K parenterally; (6) Assess for grade of encephalopathy regularly — any deterioration in mental status triggers re-evaluation and possible intubation at grade III; (7) Consider N-acetylcysteine extended infusion and initiate organ support as needed. The trajectory over the next 12–24h will determine whether transplant listing becomes necessary.