Acute Liver Failure — Clinical Case

DCE Long Case

Patient profile

Ms C is a 19-year-old university student who presents with a one-week history of progressive jaundice, confusion, easy bruising and dark urine. She has a family history of Wilson disease (her sister was diagnosed two years ago) but has never been screened herself. [1]

Presenting concern: Over the past week she has noticed yellowing of her eyes and skin, dark tea-coloured urine, increasing tiredness, difficulty concentrating, and several unexplained bruises on her arms. Over the last 48 hours she has become drowsy and her flatmates noticed she was confused and repetitive in conversation. She presented to the emergency department after a flatmate found her difficult to rouse in the morning. [1]

Past medical history: Nil significant. No prior liver disease. Menarche at 13; regular cycles until 3 months ago when they became irregular (hyperoestrogenism from Wilson liver disease). No medications, no alcohol, no recreational drugs, no herbal supplements. [1]

Family history: One sister (age 22) diagnosed with Wilson disease two years ago, on penicillamine with stable disease. Parents are first cousins (consanguinity increases autosomal recessive disease risk). One brother (age 16) not tested. No family history of other liver or neurological disease. [1]

Social: Third-year biomedical science student; lives with flatmates; non-smoker; minimal alcohol; no recent travel; no mushroom foraging. [1]

Examination:

• Drowsy but rousable to voice, Glasgow Coma Scale 13 (opens eyes to voice, obeys commands, confused speech). Temperature 37.1. Pulse 96 regular. Blood pressure 100/60. Respiratory rate 18. SpO2 97 per cent room air.
• Icteric sclerae and generalised jaundice. Pallor consistent with anaemia. Several bruises on the forearms.
• Fetor hepaticus. Flapping tremor (asterixis) on sustained wrist extension. NO spider naevi, NO palmar erythema, NO gynaecomastia, NO parotid enlargement — the absence of chronic liver disease stigmata.
• Abdomen: tender liver edge palpable 2 cm below the costal margin. No ascites. No splenomegaly.
• Neurological: grade 2 encephalopathy (drowsy, disoriented, asterixis). No focal deficits. No Kayser-Fleischer rings visible to the naked eye (slit-lamp pending). [1]

Investigations:

• AST 1800 U/L; ALT 1500 U/L; bilirubin 280 (conjugated 180); albumin 28; ALP 35 (low for the degree of injury); gamma-GT 40.
• INR 3.8; fibrinogen 1.4 g/L.
• Haemoglobin 72 g/L; reticulocytes 8 per cent; direct Coombs test NEGATIVE; blood film: polychromasia and schistocytes.
• Caeruloplasmin 0.08 g/L (low, reference 0.20 to 0.60); 24-hour urinary copper 480 micrograms (high, reference below 40).
• Creatinine 110 micromol/L; urea 6.5; glucose 3.5 (low-normal); phosphate 0.6.
• Arterial blood gas: pH 7.38; lactate 2.8 mmol/L; bicarbonate 22.
• Sodium 134; potassium 4.2.
• HBsAg negative, anti-HBc IgM negative, anti-HAV IgM negative, anti-HEV IgM negative, HSV PCR negative.
• ANA negative, smooth muscle antibody negative, IgG 14 (normal).
• Paracetamol level undetectable. Salicylate undetectable. Beta-hCG negative.
• Doppler ultrasound: patent hepatic veins, portal vein and hepatic artery. Liver diffusely echogenic with coarse texture. No ascites. Small spleen (12 cm). [1]

Candidate's opening statement (SASPOP)

"This is Ms C, a 19-year-old university student presenting with a one-week history of progressive jaundice, confusion and easy bruising, found to have acute liver failure — coagulopathy (INR 3.8) and grade 2 encephalopathy within 26 weeks, without pre-existing liver disease — secondary to Wilson disease, confirmed by the pathognomonic combination of Coombs-negative haemolytic anaemia (haemoglobin 72, reticulocytes 8 per cent, negative Coombs), a low alkaline phosphatase of 35 (counterintuitively low for the degree of liver injury), a caeruloplasmin of 0.08, and a 24-hour urinary copper of 480 micrograms. She has a family history of Wilson disease in her sister, which she was never screened for, and her parents are consanguineous. Her main problems are the Wilson disease acute liver failure, which has a near-universal medical mortality and requires urgent liver transplant; the grade 2 encephalopathy with the risk of cerebral oedema; the coagulopathy (which I am NOT correcting because it is a prognostic marker); the Coombs-negative haemolytic anaemia; and the genetic implications for her family. My priorities are to admit her to the liver ICU, start chelation and N-acetylcysteine empirically, manage her encephalopathy and complications, and refer her urgently for liver transplant — the only curative option for Wilson ALF." [1]

Structured problem list (numbered, prioritised)

1. Wilson disease acute liver failure — INR 3.8, grade 2 encephalopathy, Coombs-negative haemolysis, low ALP, low caeruloplasmin, high urinary copper; near-universal medical mortality without transplant.
2. Grade 2 encephalopathy — risk of progression to grade 3 to 4 and cerebral oedema (the leading cause of death in ALF).
3. Coagulopathy (INR 3.8, fibrinogen 1.4) — prognostic marker driving the King's College Criteria; not to be routinely corrected.
4. Coombs-negative haemolytic anaemia (haemoglobin 72) — copper-mediated red cell membrane damage.
5. Genetic and family implications — autosomal recessive; consanguineous parents; untested brother and obligate-carrier parents. [1]

Integrated management plan

Step 1 — Urgent liver transplant referral: [1]

The single most important action. Wilson disease ALF has a medical mortality approaching 100 percent — chelation rarely reverses established failure, and there is no medical therapy that can halt the copper-mediated destruction once ALF is established [2]. Transplant is curative because the donor liver has normal ATP7B copper-transporting ATPase and normal copper handling. Contact the transplant unit immediately for workup: blood group, imaging, psychosocial assessment, listing and donor matching. Do not wait for the formal King's College Criteria to be met — the cause itself is the poor prognostic factor. A patient who meets the criteria and does not receive a transplant has a survival of around 20 percent; with transplant, one-year survival exceeds 75 percent [1].

Step 2 — ICU supportive care: [1]

Admit to the liver ICU. Secure the airway if encephalopathy deepens to grade 3. Establish arterial and central access with hourly GCS and pupillary monitoring. For cerebral oedema prophylaxis: elevate the head to 30 degrees, maintain normocapnia (PaCO2 35 to 40), normoglycaemia, normothermia, and use hypertonic saline to a serum sodium of 145 to 155 if she progresses to grade 3 to 4. Mannitol 0.5 g/kg for established intracranial hypertension. Do NOT use corticosteroids — they are ineffective for the cytotoxic cerebral oedema of ALF [9].

For the coagulopathy: give vitamin K 10 mg IV. Do NOT routinely correct the INR with FFP — it is the prognostic marker that drives the King's College Criteria and the transplant decision [8]. Reserve FFP, cryoprecipitate (to a fibrinogen above 1.5 g/L) and platelets for active bleeding or immediately before invasive procedures. Use prothrombin complex concentrate for rapid pre-procedure reversal if needed.

For the haemolysis: cross-match blood and transfuse for symptomatic anaemia or a haemoglobin below 70. Correct any hypoglycaemia with 10 per cent dextrose. Use continuous renal replacement therapy (not intermittent) if renal failure develops. Surveil for infection with daily cultures and a low threshold for broad-spectrum antibiotics. [1]

Step 3 — Chelation and N-acetylcysteine: [1]

Start the 21-hour IV N-acetylcysteine regimen empirically (150 mg/kg over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours) because it has a transplant-free survival benefit in early-stage non-acetaminophen ALF [6]. Start chelation with penicillamine (or trientine if penicillamine is contraindicated) — acknowledging that it rarely reverses established ALF but is standard practice while awaiting transplant. The chelation will also help with the copper load and the haemolysis.

Step 4 — The aetiological confirmation: [1]

The diagnosis is confirmed by the pathognomonic combination: Coombs-negative haemolytic anaemia, low ALP (ALP-to-bilirubin ratio below 2), low caeruloplasmin (0.08 g/L), and high 24-hour urinary copper (480 micrograms). Arrange slit-lamp examination for Kayser-Fleischer rings (present in the majority, though not visible to the naked eye in this patient). Consider ATP7B genetic testing for confirmation and for family screening. A liver biopsy is not required to confirm the diagnosis in the ALF setting and is hazardous given the coagulopathy. [1]

Step 5 — Genetic counselling and family screening: [1]

Wilson disease is autosomal recessive. Her parents are consanguineous (first cousins), which increases the risk of autosomal recessive disease. Her sister is already diagnosed. Her brother (age 16) has never been tested — he has a 25 percent chance of being affected and should be screened urgently with caeruloplasmin, 24-hour urinary copper, slit-lamp examination and ATP7B genetic testing. Parents are obligate carriers. Involve the clinical genetics team. [1]

Probing questions the examiner would ask

Q: Why is her alkaline phosphatase normal at 35 when her bilirubin is 280? [1]

A: "This is a characteristic feature of Wilson disease ALF. The ratio of alkaline phosphatase to bilirubin (in international units) is typically below 2, which is a validated discriminator for Wilson disease. The mechanism relates to the copper-mediated inhibition of alkaline phosphatase synthesis and the dominance of haemolysis in the bilirubin elevation. A normal or low ALP in a young patient with severe liver injury and jaundice should trigger a Wilson workup immediately [2]."

Q: Why does she have a Coombs-negative haemolytic anaemia? [1]

A: "The copper released from the necrotic liver enters the circulation and damages red cell membranes, causing a non-immune (Coombs-negative) haemolytic anaemia. The reticulocyte count is high because the bone marrow is responding. The Coombs test is negative because this is not antibody-mediated — it is direct copper toxicity to the red cells. This combination — ALF plus Coombs-negative haemolysis plus low ALP — is virtually pathognomonic for Wilson disease." [1]

Q: How do you apply the King's College Criteria in this patient? [1]

A: "For non-paracetamol ALF, the criteria are INR above 6.5 alone, OR any three of age under 10 or over 40, non-A non-B or drug cause, jaundice to encephalopathy above 7 days, INR above 3.5, bilirubin above 300 [1]. She does not yet meet these — her INR is 3.8 (above 3.5 but not above 6.5), her bilirubin is 280 (below 300), and she is under 40. However, for Wilson disease specifically, the cause itself is a poor prognostic factor and the near-universal medical mortality means transplant referral is mandatory regardless of the formal criteria. I would not delay referral waiting for the criteria to be met [7]."

Q: She needs a central line but her INR is 3.8 and fibrinogen is 1.4. How do you manage this? [1]

A: "Give vitamin K 10 mg IV, and use prothrombin complex concentrate for rapid pre-procedure reversal rather than fresh frozen plasma — it is volume-sparing and faster. Give cryoprecipitate to raise the fibrinogen above 1.5 g/L. I would NOT give routine prophylactic FFP in the absence of bleeding or procedures, because it destroys the prognostic value of the INR. The key insight: the coagulopathy of ALF is a rebalanced state — the patient loses both procoagulant and anticoagulant factors, so the INR overstates the bleeding risk. Thromboelastography often shows a normal or even hypercoagulable tracing despite a high INR [8]."

Q: She progresses to grade 4 encephalopathy with hypertension and bradycardia. How do you manage the cerebral oedema? [1]

A: "The Cushing reflex (hypertension with bradycardia) is the sign of raised intracranial pressure. I would elevate the head to 30 degrees, ensure normocapnia, normoglycaemia and normothermia, give hypertonic saline to a serum sodium of 145 to 155, give mannitol 0.5 g/kg IV bolus (monitoring the osmolal gap), and consider induced hypothermia to 33 to 34 degrees or intracranial pressure monitoring in grade 4. I would NOT use corticosteroids — they are ineffective for the cytotoxic cerebral oedema of ALF, unlike the vasogenic oedema of brain tumours [9]. I would intubate and ventilate for airway protection and controlled ventilation. This is the leading cause of death in ALF and the window for transplant is closing — I would escalate the transplant urgency."

Q: How do you counsel her family about the genetics and the missed screening? [1]

A: "Wilson disease is autosomal recessive, caused by mutations in the ATP7B gene. Her sister was diagnosed two years ago, which should have triggered family screening — the missed opportunity is a source of family guilt that I would address with compassion and without blame. Her parents are consanguineous first cousins, which increases the risk of autosomal recessive disease. Her brother (age 16) has a 25 percent chance of being affected and must be screened urgently with caeruloplasmin, 24-hour urinary copper, slit-lamp examination and genetic testing. If he is affected (even if presymptomatic), he needs lifelong chelation to prevent liver and neurological disease. I would involve the clinical genetics team and arrange a family meeting once the acute situation is stabilised." [1]

Communication and shared decision-making

"I would speak with Ms C, if she is rousable, and with her family under the doctrine of necessity (she is in grade 2 encephalopathy and may lack full capacity). I would explain the diagnosis in plain language: her body cannot handle copper properly because of a genetic condition she shares with her sister, and the copper has built up and severely injured her liver. I would be honest that the only way to save her life is a liver transplant, that the next 48 hours are critical, and that the medical team has contacted the transplant unit urgently. I would address the family's guilt about the missed screening with compassion — the priority now is the transplant, not recrimination. I would involve the transplant coordinator, hepatology, surgery, anaesthesia, intensive care and psychiatry, and I would document the shared decisions and review them as her clinical picture evolves. I would arrange family screening for her brother and genetic counselling for the wider family." [1]

Outcome and follow-up

Ms C is admitted to the liver ICU. N-acetylcysteine is started empirically, penicillamine is commenced, vitamin K is given, and the transplant unit is contacted within the first hour. Her encephalopathy stabilises at grade 2, her INR peaks at 4.5 and her bilirubin at 310 over the next 24 hours, and she is listed for urgent transplant. A suitable deceased-donor graft becomes available on day 3. She undergoes orthotopic liver transplant without complication. The explanted liver shows established cirrhosis with massive copper deposition (consistent with longstanding subclinical Wilson disease that decompensated acutely). Post-transplant, her encephalopathy resolves within 48 hours, her INR normalises, and her haemolysis ceases as the copper load is cleared. She is started on standard immunosuppression (tacrolimus, mycophenolate, prednisolone). Her brother is screened and found to have Wilson disease (presymptomatic) and started on chelation. At one year she is well, has returned to university, and her transplanted liver is functioning normally. She does not require copper chelation post-transplant because the donor liver has normal copper handling. [1]