Paracetamol Toxicity — Clinical Case

DCE Long Case

Patient profile

Mr D is a 38-year-old unemployed man who presents to the emergency department 14 hours after ingesting 24 g of paracetamol as a single dose during an alcohol binge, after his partner of six years left him. [1]

Presenting concern: He ingested 48 tablets of 500 mg paracetamol (24 g) at around 10 pm the previous evening, together with approximately half a bottle of vodka. He vomited twice overnight and slept. This morning he was found drowsy on the floor by a friend, complaining of right upper quadrant pain and nausea, and was brought to the emergency department. He admits to the overdose and says he "wanted to end it." [1]

Past medical history: Alcohol use disorder (120 g per day for 8 years, two previous detoxifications, no seizures or delirium tremens), depression (diagnosed 3 years ago, not on treatment after defaulting from his general practitioner), a previous paracetamol overdose at age 34 (treated with NAC, full recovery), and malnutrition (body mass index 19). No known chronic liver disease has been formally diagnosed. [1]

Medications: Nil regular. He has defaulted from sertraline (previously 50 mg daily) and takes no other prescribed or over-the-counter medications. [1]

Family history: Father with alcohol use disorder (deceased, liver failure at age 55); mother alive with hypertension; one sister with depression. No children. [1]

Social: Unemployed for 2 years (previously a labourer); lives alone in a rented flat after his partner left 2 weeks ago; smokes 20 cigarettes per day; illicit cannabis use. Limited social supports; the friend who found him is present. [1]

Examination:

• Drowsy but rousable to voice, Glasgow Coma Scale 14 (opens eyes to voice, obeys commands, confused speech). Temperature 36.9. Pulse 98 regular. Blood pressure 108/66. Respiratory rate 18. SpO2 96 per cent room air.
• Icteric sclerae; mild jaundice over the face and chest. Fetor hepaticus.
• A liver flap (asterixis) on sustained wrist extension. Several bruises on the forearms.
• Palmar erythema; no spider naevi or gynaecomastia (acute rather than chronic picture).
• Abdomen: tender hepatomegaly with a liver edge palpable 3 cm below the costal margin; no ascites; no splenomegaly; bowel sounds present.
• No focal neurological signs; no signs of chronic liver disease beyond the palmar erythema. [1]

Investigations:

• AST 1200 U/L; ALT 980 U/L; bilirubin 62 (conjugated 38); albumin 32; gamma-GT 180 (chronic alcohol).
• INR 3.4; prothrombin time 38 seconds; fibrinogen 2.1 g/L.
• Creatinine 180 micromol/L; urea 9.2; eGFR 38; sodium 134; potassium 3.4; magnesium 0.6; phosphate 0.5.
• Arterial blood gas: pH 7.32; PaCO2 32; PaO2 88; bicarbonate 16; base excess minus 8; arterial lactate 4.2 mmol/L.
• Glucose 3.1 mmol/L.
• Paracetamol level 90 mg/L (drawn 14 hours after ingestion); salicylate undetectable; ethanol 0.05 per cent.
• Beta-hCG negative. Amylase normal.
• Full blood count: haemoglobin 132; white cell count 11.2; platelets 145.
• Chest X-ray: clear. ECG: sinus tachycardia, normal. [1]

Candidate's opening statement (SASPOP)

"This is Mr D, a 38-year-old unemployed man presenting 14 hours after a 24 g single paracetamol overdose during an alcohol binge, with established stage 2 to 3 paracetamol-induced hepatotoxicity — transaminitis, coagulopathy, hypoglycaemia, mild encephalopathy and acute kidney injury — in a high-risk host with chronic alcohol use and malnutrition. The picture is consistent with a single acute ingestion (the nomogram applies, and his level of 90 mg/L at 14 hours lies above the high-risk 150 mg/L treatment line extrapolated to that time). His main problems are the paracetamol-induced acute liver injury, which I am treating with N-acetylcysteine and monitoring against the King's College Criteria; his high-risk profile from chronic alcohol (CYP2E1 induction and glutathione depletion); the acute kidney injury; the risk of alcohol withdrawal during admission; and the psychosocial crisis of deliberate self-harm with a previous overdose. My priorities are to give NAC immediately, correct his hypoglycaemia and volume status, admit to a high-dependency bed, monitor for progression to acute liver failure, notify the transplant unit early given his high lactate, and manage his alcohol withdrawal and psychiatric risk." [1]

Structured problem list (numbered, prioritised)

1. Single acute paracetamol overdose with established hepatotoxicity — 24 g (well above the 10 g threshold), 14 hours post-ingestion, AST 1200 and INR 3.4.
2. High-risk patient — chronic alcohol use and malnutrition (CYP2E1 induction, glutathione depletion); the 150 mg/L treatment line applies.
3. Approaching acute liver failure — coagulopathy, hypoglycaemia, high lactate (4.2), mild encephalopathy; close to but not yet meeting King's College Criteria.
4. Acute kidney injury (creatinine 180) — direct NAPQI tubular injury plus hepatorenal physiology.
5. Alcohol use disorder with withdrawal risk — 120 g per day; previous detoxifications; malnutrition; magnesium and phosphate depletion.
6. Depression and deliberate self-harm — previous overdose; relationship breakdown; unemployment; needs psychiatric assessment once medically stable. [1]

Integrated management plan

Step 1 — Immediate antidote and resuscitation: [1]

Start the 21-hour intravenous N-acetylcysteine regimen immediately — 150 mg/kg in 200 mL of 5 per cent dextrose over 1 hour, then 50 mg/kg in 500 mL over 4 hours, then 100 mg/kg in 1000 mL over 16 hours, totalling 300 mg/kg over 21 hours [2]. Do not wait for any further testing — he is 14 hours in with established injury and a detectable level above the high-risk line. Give 10 per cent dextrose for the hypoglycaemia (glucose 3.1) and check glucose hourly; hypoglycaemia reflects impaired gluconeogenesis and is a poor prognostic sign. Give cautious crystalloid for the volume depletion and to refine the lactate as a prognostic marker, then reassess. Activated charcoal is futile at 14 hours because the drug has long since been absorbed.

Step 2 — Monitoring and risk stratification: [1]

Admit to a high-dependency or ICU bed. Repeat INR, AST, ALT, creatinine, lactate, pH and glucose every 4 to 6 hours. Track the King's College Criteria continuously: for paracetamol-induced acute liver failure, transplant referral is indicated if either arterial pH below 7.3 after fluid resuscitation, OR all three of INR above 6.5, creatinine above 300 and grade 3 to 4 encephalopathy are present [4]. His arterial lactate of 4.2 mmol/L is above the 3.5 mmol/L early-admission threshold that Bernal showed identifies non-survivors a median of 6 hours before the formal criteria declare themselves [6], so notify the liver transplant unit now, before he formally meets the criteria. Send a full septic screen and exclude alternative or additional causes (viral serology, autoimmune markers, Doppler of the hepatic vessels).

Step 3 — Continuing NAC and managing adverse reactions: [1]

Given his established hepatotoxicity, continue NAC beyond 21 hours using the modified prolonged regimen (the third-bag rate repeated) until the INR is below 1.3 and falling, the AST is falling, the paracetamol level is below 10 mg/L, and he is clinically well. Keays showed that IV NAC improves survival, reduces cerebral oedema and reduces the need for inotropes even after fulminant hepatic failure is established [5]. If he develops a reaction during the loading bag (urticaria, flushing, bronchospasm — up to 20 per cent, non-IgE-mediated and rate-related), stop the infusion, give chlorphenamine and hydrocortisone if moderate, and restart at a slower rate once settled [7]. Reserve permanent cessation for genuine anaphylaxis, managed with intramuscular adrenaline.

Step 4 — Acute liver failure complications (if he progresses): [1]

Manage encephalopathy with lactulose, head-of-bed elevation, avoidance of sedatives, and intubation for grade 4 or airway protection. For cerebral oedema use mannitol 0.5 g/kg or hypertonic saline to a sodium of 145 to 155, neuroprotection (normocapnia, normoglycaemia, normothermia), and consider intracranial pressure monitoring in grade 4. Do NOT routinely correct the INR with fresh frozen plasma — it is the prognostic marker that drives the transplant decision; give vitamin K 10 mg and reserve correction for active bleeding or before procedures. Correct hypoglycaemia (10 per cent dextrose) and hypophosphataemia (phosphate replacement). Support renal failure with continuous renal replacement therapy if needed. Surveil for infection with cultures and a low threshold for broad-spectrum antibiotics (sepsis precipitates encephalopathy and is frequently fatal). [1]

Step 5 — Alcohol withdrawal and comorbidity: [1]

Start a symptom-triggered benzodiazepine regimen using CIWA-Ar scoring, give parenteral thiamine 100 mg IV daily before any glucose to prevent Wernicke encephalopathy, correct potassium, magnesium and phosphate, and involve the addiction medicine and dietetics teams. His malnutrition worsens glutathione depletion and hepatic regeneration, so nutrition is part of the acute plan. Continue his smoking and cannabis use management as appropriate to the inpatient setting. [1]

Step 6 — Psychiatry and safety: [1]

Once medically stable, involve the psychiatric liaison team for formal risk assessment and a safety plan, addressing his depression, his previous overdose, the relationship breakdown and his unemployment. Arrange follow-up with mental health and addiction services, advise the pharmacist and general practitioner on limited dispensing of paracetamol and any paracetamol-containing combination products, and document the shared decisions. Communicate with his friend and (with his consent) his family about the clinical course and the safety plan. [1]

Probing questions the examiner would ask

Q: His INR rises to 7.5, creatinine to 310, and he progresses to grade 3 encephalopathy, with arterial pH 7.28. What do you do? [1]

A: "He now meets the King's College Criteria on both limbs — arterial pH below 7.3, and the full triad of INR above 6.5 with creatinine above 300 and grade 3 to 4 encephalopathy. Either alone is sufficient for referral. I would urgently refer him to the liver transplant unit, continue NAC, manage his acute liver failure in ICU, and arrange the transplant workup — blood group, imaging, psychosocial assessment. The King's College Criteria, derived from the 1989 cohort, remain the best-validated tool for paracetamol-induced acute liver failure [4]. A patient who meets the criteria and does not receive a transplant has a survival of around 20 per cent; with transplant, one-year survival exceeds 75 per cent."

Q: How does the lactate help you make the transplant decision earlier? [1]

A: "Bernal showed that arterial lactate above 3.5 mmol/L on early admission, or above 3.0 mmol/L after fluid resuscitation, identifies non-survivors with accuracy similar to the King's College Criteria combined, but a median of 6 hours earlier — 4 hours versus 10 hours [6]. In Mr D, whose admission lactate is 4.2, I would contact the transplant unit before he formally meets the criteria, to buy time for workup and transfer. The lactate is an early-warning adjunct to the criteria, not a replacement."

Q: He is 20 minutes into the NAC loading bag when he develops widespread urticaria, wheeze and oxygen saturation of 90 per cent. How do you respond? [1]

A: "This is a moderate-to-severe non-IgE-mediated rate-related reaction to NAC. I would stop the infusion immediately, give high-flow oxygen, chlorphenamine 10 mg IV and hydrocortisone 100 mg IV, and assess airway and breathing. With oxygen desaturation and bronchospasm I would treat this as an anaphylactoid reaction and give intramuscular adrenaline 0.5 mg, with ICU involvement. Once settled I would discuss with toxicology about re-challenging at a much slower rate, because the antidote is essential and most reactions are rate-related. Permanent cessation is reserved for genuine anaphylaxis that cannot be controlled [7]."

Q: How would your management differ if he had taken the paracetamol as 6 g daily over four days rather than a single dose? [1]

A: "The nomogram would not apply — it is valid only for a single acute ingestion with a known time [1]. I would treat empirically with NAC because he has a detectable paracetamol level and AST elevation. Staggered overdose carries a worse prognosis despite smaller individual doses, and the King's College Criteria have reduced sensitivity in this group [8], so I would have a lower threshold for early transplant referral. Otherwise the supportive care is the same."

Q: Why is chronic alcohol use a high-risk factor for paracetamol toxicity? [1]

A: "Two mechanisms. Chronic alcohol induces CYP2E1, the enzyme that generates the toxic metabolite NAPQI, so more of the drug is shunted down the toxic pathway. And chronic alcohol use with malnutrition depletes hepatic glutathione, the protective molecule that detoxifies NAPQI. The net effect is more NAPQI production and less capacity to detoxify it, which is why these patients are managed on the lower 150 mg/L treatment line rather than the 200 mg/L standard line [7]. Note that acute alcohol co-ingestion does not reliably protect through competitive CYP2E1 inhibition, and should not change the threshold."

Q: He wants to leave against medical advice. How do you respond? [1]

A: "I would first assess his capacity — he is encephalopathic (grade 2) and under the influence of alcohol, which is likely to impair his capacity to refuse life-saving treatment. If he lacks capacity, I would treat in his best interest under the doctrine of necessity, using the mental health or guardianship legislation as applicable. If he regains capacity and continues to refuse, I would explore his reasons, explain the consequences honestly, offer a lower-intensity alternative if appropriate (there is none here — NAC is essential), involve a senior colleague and the psychiatry and ethics teams, and document the assessment and the decision carefully. Where there is a clear suicide intent and impaired capacity, detention under mental health legislation for assessment and treatment may be appropriate." [1]

Communication and shared decision-making

"I would speak with Mr D once he is rousable, and with his friend and family with his consent, in plain language. I would explain that the paracetamol has injured his liver, that we are giving an antidote called N-acetylcysteine that works by replenishing a protective chemical in the liver, and that his chronic alcohol use has made him more vulnerable. I would be honest that the next 48 hours are critical and that we have involved the liver transplant team because his blood tests show serious injury. I would address his distress and the relationship breakdown directly, reassure him that the psychiatric team will support him, and involve his friend and family in a safety plan before discharge. I would document the shared decisions, give written information, arrange named follow-up, and ensure the general practitioner and pharmacist are involved in limiting future access to paracetamol." [1]

Outcome and follow-up

With continued NAC, supportive care and close monitoring, Mr D's INR peaks at 4.8 and then falls over the next 48 hours; his AST peaks at 2400 and falls; his encephalopathy resolves; and he does not meet the King's College Criteria. He undergoes an alcohol withdrawal managed with symptom-triggered diazepam, receives thiamine and nutritional support, and has a psychiatric review that restarts an antidepressant and arranges outpatient mental health and addiction follow-up. His liver function tests return to normal by six weeks, and he is counselled on safe paracetamol dosing (no more than 2 to 3 g per day given his alcohol use). He recovers fully — the liver regenerates because the periportal hepatocytes are spared — with no residual chronic liver disease from this single episode. [1]