Something she ate?

The blood tests show profoundly deranged LFTs. This is a mixed picture of LFT derangement, with transaminitis being more pronounced. The AST:ALT ratio <1. This is specific for hepatocellular damage, with differentials including ischaemic hepatitis, hepato-toxins or viral hepatitis.

Fulminant hepatitis (Hôpital Beaujon classification¹), or hyperacute hepatitis (Kings College criteria²), depending on the classification used, is diagnosed based on the time from jaundice to encephalopathy. In this case, the timeline of symptoms onset (from asymptomatic to encephalopathy within 2 days) made this a case of fulminant hepatitis.

Coagulation studies also need to be done to assess the synthetic function of the liver. A ‘liver screen’ should also be considered. This typically includes:

• Viral hepatitis screen (Hepatitis A/B/C serology, Epstein Barr Virus (EBV), Cytomegalovirus (CMV)
• Autoimmune screen (Anti-Mitochondrial Antibodies (AMA), Antinuclear Antibodies (ANA), Anti-Smooth Muscle Antibodies (ASMA), p-Anti-Neutrophil Cytoplasmic Antibodies (p-ANCA), IgM/IgG)
• Alpha-1 antitrypsin
• Screen for infiltrative diseases (copper level, ceruloplasmin, ferritin)
• Blood paracetamol level

Glucose and ammonia levels would also be useful to confirm complications of acute liver failure.

Other investigations to consider include imaging of the liver with ultrasound and computerised tomography (CT) to assess for any changes to the liver parenchyma or vasculature, such as portal vein thrombosis or Budd Chiari Syndrome (hepatic venous outflow obstruction).

In this case, the history pointed towards mushroom poisoning. Most cases of mushroom poisoning are self-limiting episodes of gastrointestinal upset. Whilst very rare, severe mushroom toxicity can occur and can even be fatal.

There are many different syndromes associated with mushroom poisoning in Australia including cholinergic, hallucinogenic, glutaminergic, disulfram-like and hepatotoxic³. The hepatotoxic mushrooms result from 3 different types of cyclopeptide (amatoxin, phallotoxin and virotoxin). Symptoms usually start between 6 and 24 hours after ingestion of the mushrooms containing these peptides (delayed, rather than early, onset).

Amanita phalloides, more commonly known as the death cap mushroom, is the most commonly eaten poisonous mushroom in Victoria. It usually grows under oak trees and its distinguishing features include a smooth, yellowish-green to brown cap, white gills, white stem, membranous skirt on stem and cup-like structure around the base of the stem⁴. It contains amatoxin, which irreversibly binds to RNA polymerase II, thus inhibiting DNA transcription, resulting in arrest of protein synthesis and eventually cell necrosis⁵. Patients with suspected Amanita phalloides poisoning should be managed in consultation with a clinical toxicology service and should be referred to a liver transplant centre if they fail to improve.

Other causes of fulminant liver failure are

• Viruses (for example, Hepatitis A, B, C, EBV, CMV)
• Autoimmune
• Alcoholic
• Toxins
• Others- Acute fatty liver of pregnancy, Haemolysis, Elevated Liver enzymes and Low Platelets (HELLP) Syndrome, Budd Chiari, ischaemic hepatitis, infiltrative diseases e.g., Wilson’s disease

West Haven criteria⁶ classify the severity of hepatic encephalopathy:

• Grade I- Changes in behaviour with minimal change in level of consciousness
• Grade II- Gross disorientation, drowsiness, asterixis present, inappropriate behavior
• Grade III- Marked confusion, incoherent speech, somnolence but arousable to vocal stimuli
• Grade IV- Comatose, unresponsive to pain

This patient is highly likely to have amatoxin-mediated hepatoxicity from Amanita phalloides mushroom poisoning. Management priorities^3,7,8 are as follows:

Resuscitation to address immediate life threats (if present):

• Airway – patients are often obtunded and require intubation for airway protection
• Breathing- Hyperventilate to aim for a low-normal PaCO2 for neuroprotection
• Circulation- Patients should receive IV fluid resuscitation, particularly if significant diarrhoea/vomiting causing hypovolaemic shock. Vasopressors such as noradrenaline are often required (systemic vasodilation is common in hepatic failure).
• Disability- treat hypoglycaemia if present.

Supportive care and monitoring

• Prioritise short-acting agents, avoid medications that accumulate in hepatic failure
• Usually ICU measures (e.g. FASTHUGS)
• 4H therapy for hepatic failure

Investigations (as discussed previously)

Decontamination and Enhanced Elimination

• Multidose activated charcoal be beneficial in an alert and compliant patient to enhance elimination as amatoxin undergoes enterohepatic circulation. The timeframe for administration of charcoal post Amanita phalloides poisoning may be up to 48 hours⁹. This should be discussed with a toxicologist.

Antidotes and specific therapies

• Silibinin an antidote used in cases of Amanita phalloides poisoning¹⁰. It is a milk-thistle extract and works by competing with amatoxins for transmembrane transport, thus inhibits amatoxin uptake by hepatocytes. The recommended dose is 5mg/kg by IV infusion over 1 hour, then 20mg/kg/day for up to 3 days.
• If silibilin is unavailable, alternatives such as rifampicin (600 mg IV daily) or benzylpenicillin (600mg/kg/day in divided doses for first day) may be used⁹.
• N- Acetylcysteine is also used, with the same infusion protocol as for paracetamol toxicity⁹.

Disposition

• Admission to ICU and early discussion with a hepatologist to identify patients who are likely to require (and are candidates for) a liver transplant.

A key cause of mortality in acute liver failure is cerebral oedema. The exact pathophysiology is complex, but an important factor is the accumulation of metabolic toxins such as ammonia.

Quadruple-H therapy is a combined neuroprotective approach to manage cerebral oedema¹¹. It refers to hypernatraemia, hyperventilation, haemodialysis, and induced hypothermia. It should be instituted in all patients with high grade encephalopathy requiring intubation.

Hyperventilation

Patients with liver failure often have a high respiratory rate at baseline. Aiming for a PaCO2 at lower limit of normal, i.e., 35mmHg, in a ventilated patient reduces cerebral hyperaemia. Aggressive hyperventilation should be avoided as it leads to severe vasoconstriction which can lead to cerebral ischaemia.

Hypernatraemia

Osmotherapy, with hypertonic saline (23.4% sodium chloride at 1-10ml/hr through a dedicated Central Venous Catheter (CVC) lumen), reduce cerebral oedema and intracranial pressure by causing the efflux of water from brain tissue into the bloodstream. Aim Na 148-152 mmol/L.

Haemofiltration

Haemofiltration has a role not only in supporting the kidneys, but also as a neuroprotective strategy. It clears ammonia, allows fluid removal, and facilitates management of electrolyte. A higher than usual dialysis dose of 40-60ml/kg/hr should be prescribed.

Hypothermia

Aiming for a lower core temp (35 ^oC) reduces cerebral metabolic rate and cerebral blood flow. This can be achieved by using cooling blankets or adjusting the CRRT circuit.

The King’s College Criteria² can be used to risk stratify patients and identify those who will require a liver transplantation. If the patient’s trajectory is concerning, early referral to a liver transplant centre is crucial, even before she meets King’s College criteria.

Alternatively, the Model for End-Stage Liver Disease (MELD) score¹² can be used. It predicts 90-day mortality and is calculated based on serum Na, creatinine, bilirubin, and INR, and whether the patient has received dialysis in the past week. The higher the MELD score, the higher the predicted mortality.