Acute Liver Failure — Viva Defence

Long Case Viva Defence

The scenario

A 19-year-old university student presents with a one-week history of progressive jaundice, confusion, easy bruising and dark urine. She has no prior medical history. Her sister was diagnosed with Wilson disease two years ago but the patient has never been tested. On examination she is icteric, drowsy but rousable with a flapping tremor, has a tender liver edge and several bruises. Bloods: AST 1800, ALT 1500, INR 3.8, bilirubin 280, ALP 35, albumin 28, haemoglobin 72, reticulocytes 8 per cent, Coombs test negative, caeruloplasmin 0.08 g/L, 24-hour urinary copper 480 micrograms, creatinine 110, glucose 3.5. She is in grade 2 encephalopathy. [1]

Opening statement (SASPOP)

"This is Ms C, a 19-year-old university student presenting with a one-week history of progressive jaundice, confusion and bruising, found to have acute liver failure — coagulopathy 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, a low alkaline phosphatase of 35 (counterintuitively low for the degree of 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. Her main problems are the Wilson disease acute liver failure (which has a near-universal medical mortality and requires urgent 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." [1]

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.
3. Coagulopathy (INR 3.8) — prognostic marker, not to be routinely corrected.
4. Coombs-negative haemolytic anaemia (haemoglobin 72) — copper-mediated red cell damage.
5. Genetic and family implications — autosomal recessive; siblings require screening. [1]

Integrated management plan

Pillar 1 — Urgent transplant referral: "I would contact the liver transplant unit immediately. Wilson disease ALF has a medical mortality approaching 100 percent and transplant is the only cure [2]. The workup — blood group, imaging, psychosocial assessment, listing and donor matching — takes time, and the window for salvage is narrow. I would not wait for the formal King's College Criteria to be met because the cause itself is a 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]."

Pillar 2 — ICU supportive care: "I would admit her to the liver ICU, secure the airway if encephalopathy deepens, and establish arterial and central access with hourly GCS and pupillary monitoring. For cerebral oedema prophylaxis I would elevate the head to 30 degrees, maintain normocapnia, normoglycaemia and normothermia, and use hypertonic saline to a serum sodium of 145 to 155 if she progresses to grade 3 to 4. I would NOT use corticosteroids — they are ineffective for the cytotoxic cerebral oedema of ALF [9]. For the coagulopathy I would give vitamin K 10 mg IV and NOT routinely correct the INR with FFP, because it is the prognostic marker that drives the transplant decision [8]. I would reserve blood products for active bleeding or pre-procedure. I would correct any hypoglycaemia, use continuous renal replacement therapy if needed, and surveil for infection."

Pillar 3 — Chelation and NAC: "I would 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]. I would start chelation with penicillamine or trientine, acknowledging that it rarely reverses established ALF but is standard practice while awaiting transplant."

Pillar 4 — Transfusion and the haemolysis: "I would cross-match blood and transfuse for symptomatic anaemia or a haemoglobin below 70. The haemolysis is caused by the released copper damaging red cell membranes; it is NOT immune-mediated, which is why the Coombs test is negative. The haemolysis will resolve after transplant or hepatic recovery." [1]

Pillar 5 — Genetic counselling: "Wilson disease is autosomal recessive. Her sister is already diagnosed. Her parents are obligate carriers. Any other siblings have a 25 percent chance of being affected and should be screened with caeruloplasmin, 24-hour urinary copper, slit-lamp examination and genetic testing. I would 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 is incompletely understood but 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 to the haemolysis. The Coombs test is negative because this is not an antibody-mediated process — 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 [2]."

Q: She is 19 years old. How do you counsel her family about the genetics? [1]

A: "Wilson disease is autosomal recessive, caused by mutations in the ATP7B gene on chromosome 13. Both her parents are obligate carriers. Each sibling has a 25 percent chance of being affected and a 50 percent chance of being a carrier. Her sister is already diagnosed — the family history was there and the patient was never screened, which is a missed opportunity. I would arrange screening of all siblings with caeruloplasmin, 24-hour urinary copper, slit-lamp examination for Kayser-Fleischer rings, and ATP7B genetic testing if available. Affected siblings (even if presymptomatic) need lifelong chelation to prevent liver and neurological disease." [1]

Q: What is her prognosis without transplant? [1]

A: "Near-universal medical mortality. Wilson disease ALF is one of the few causes where the medical mortality approaches 100 percent — the liver is destroyed by copper-mediated mitochondrial injury and there is no medical therapy that can reverse it once ALF is established. Chelation may help in the chronic presymptomatic or early stage but not in fulminant presentation. The only option is urgent liver transplant, which is curative because the donor liver has normal ATP7B and normal copper handling. One-year post-transplant survival exceeds 75 percent [7]."

Q: How do you manage her INR of 3.8 if she needs a central line? [1]

A: "I would give vitamin K 10 mg IV and use prothrombin complex concentrate (PCC) rather than fresh frozen plasma for rapid pre-procedure reversal, because PCC is volume-sparing and faster. 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]."

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 — that her body cannot handle copper properly, that the copper has built up and injured her liver severely, and that the only way to save her life is a liver transplant. I would be honest 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 and reassure them that the priority now is the transplant. I would involve the transplant coordinator, hepatology, surgery, anaesthesia and psychiatry, and I would document the shared decisions and review them as her clinical picture evolves." [1]

Short Case Discussion — Encephalopathy Grading and Abdominal Examination

Instruction: "Examine this patient's abdomen and assess for encephalopathy." [1]

Systematic examination routine

1. End of bed — jaundice, drowsiness, agitation, asterixis, the rate and depth of breathing, bruising, any monitoring or lines.
2. Hands and arms — liver flap (asterixis on sustained wrist extension), palmar erythema, bruising, finger-prick marks.
3. Face and chest — fetor hepaticus (sweet musty breath), icteric sclerae, spider naevi (ABSENT in pure ALF — their presence suggests chronic disease), gynaecomastia (absent in ALF), parotid enlargement (absent in ALF).
4. Abdomen — tender hepatomegaly (acute hepatitis, paracetamol injury), small or absent liver (massive necrosis), ascites (uncommon in ALF, common in Budd-Chiari), splenomegaly (suggests portal hypertension and chronic disease).
5. Neurological — grade the encephalopathy, assess GCS, check for signs of cerebral oedema (Cushing reflex, pupillary changes, posturing) in grade 4. [1]

Key physical signs the patient demonstrates (for this case)

• Icteric sclerae and jaundice
• Drowsy but rousable, with asterixis (grade 2 encephalopathy)
• Fetor hepaticus
• Tender liver edge palpable 2 cm below the costal margin
• Bruising on the arms
• NO spider naevi, NO palmar erythema, NO gynaecomastia — the absence of chronic liver disease stigmata is consistent with acute, not chronic, liver failure
• Haemoglobin 72 — the pallor of haemolysis [1]

Presentation template

"I examined Ms C, a 19-year-old woman who is drowsy but rousable at the end of the bed, icteric, with a flapping tremor on sustained wrist extension consistent with grade 2 hepatic encephalopathy. She has fetor hepaticus. The pulse is 96 regular, blood pressure 100/60, and her Glasgow Coma Scale is 13. The hands show a liver flap and several bruises but no palmar erythema. There are NO spider naevi and NO gynaecomastia — the absence of chronic liver disease stigmata is consistent with acute, not chronic, liver failure. The abdomen reveals a tender liver edge palpable 2 cm below the costal margin, with no ascites and no splenomegaly. The neurological examination is consistent with grade 2 encephalopathy. These findings, with an INR of 3.8 and an AST of 1800 in a young woman with Coombs-negative haemolysis and a low caeruloplasmin, are consistent with Wilson disease acute liver failure. I would monitor the encephalopathy grade and the INR against the King's College Criteria, and I would refer her urgently for transplant." [1]

Discussion questions

Q: How do you grade hepatic encephalopathy, and why does the grade matter? [1]

A: "I use the West Haven classification: grade 0 is covert (only on psychometric testing); grade 1 is mild confusion, altered sleep rhythm, and a shortened attention span; grade 2 is lethargy, disorientation and asterixis; grade 3 is marked somnolence or semi-stupor, responsive to stimuli, with gross disorientation; grade 4 is coma. The grade matters for three reasons: it is a prognostic marker (higher grades have worse outcomes); it is a component of the King's College Criteria for paracetamol ALF (grade 3 to 4 with INR above 6.5 and creatinine above 300); and it is the trigger for cerebral oedema prophylaxis — the risk of cerebral oedema rises sharply in grade 3 to 4, reaching 80 percent in grade 4 [8]."

Q: Why are there no spider naevi in this patient? [1]

A: "Spider naevi, palmar erythema, gynaecoomastia and parotid enlargement are stigmata of CHRONIC liver disease — they develop over months to years of altered oestrogen metabolism in cirrhosis. In acute liver failure, the liver injury is too recent for these stigmata to have developed, so their ABSENCE is itself a key sign that this is acute, not chronic, liver failure. If I saw spider naevi and splenomegaly in this patient, I would reconsider the diagnosis and think of acute decompensation of chronic liver disease instead [2]."

Q: What signs would make you concerned about cerebral oedema in grade 4 encephalopathy? [1]

A: "The Cushing reflex — hypertension with bradycardia and irregular breathing — is the classic sign of raised intracranial pressure. Other signs: pupillary changes (sluggish, then fixed and dilated from uncal herniation), decerebrate or decorticate posturing, and a falling Glasgow Coma Scale. These are indications for urgent neuroprotection — hypertonic saline, mannitol, head elevation, normocapnia — and for contacting the transplant unit, because the window is closing. Cerebral oedema is the leading cause of early death in ALF [9]."

Q: How would you distinguish this Wilson ALF from acute decompensation of autoimmune hepatitis? [1]

A: "Autoimmune hepatitis can present de novo as ALF, and both occur in young women. The discriminating features: autoimmune hepatitis has positive ANA, smooth muscle antibody and a high IgG, and typically a higher ALP; Wilson disease has the Coombs-negative haemolysis, the low ALP, the low caeruloplasmin and the high urinary copper. A liver biopsy (transvenous, given the coagulopathy) would show plasma cell infiltration and interface hepatitis in autoimmune disease, versus copper deposition and cirrhosis in Wilson. Management also differs — autoimmune ALF may respond to corticosteroids (though the response in fulminant presentation is unreliable and should not delay transplant), while Wilson ALF requires urgent transplant [7]."

Q: When would you use corticosteroids for cerebral oedema, and when are they contraindicated? [1]

A: "Corticosteroids (dexamethasone, methylprednisolone) are effective for the VASOGENIC cerebral oedema of brain tumours, abscesses and bacterial meningitis, where the blood-brain barrier is disrupted. They are INEFFECTIVE and not recommended for the CYTOTOXIC cerebral oedema of acute liver failure, where the problem is astrocyte swelling from glutamine accumulation (ammonia is metabolised by astrocyte glutamine synthetase to glutamine, which accumulates and causes osmotic swelling). For ALF cerebral oedema, I use hypertonic saline, mannitol, head elevation, normocapnia and normoglycaemia, and consider induced hypothermia or intracranial pressure monitoring in grade 4 [9]."