• ALF is defined as severe hepatic injury (as evidenced by elevated liver enzymes) with INR >1.5 and hepatic encephalopathy occurring <26 wk before presentation in a patient with no prior history of liver disease.
• Close to half of ALF is caused by drug ingestion, usually acetaminophen.
• Given the potential rapidity of deterioration, referral must be made as soon as possible to a liver transplant center.
• There should be a low threshold to start N-acetylcysteine.
• Coagulopathy should not be corrected unless life-threatening bleeding occurs or it is recommended by the liver transplant hepatologist.

• Initial treatment should focus on the patient’s mental status and managing encephalopathy.
  1. Grade I encephalopathy may be managed on a medical ward (neuro vital signs q4h).
  2. Grade II, III, and IV encephalopathy should be managed in an ICU (with elevated head of the bed to 30 degrees). Grade III and IV encephalopathy require intubation and mechanical ventilation.
  3. Decreased stimulation is important (avoiding sedatives; dimly lit, quiet room; no audible monitor alarms).
• A liver specialist should be notified urgently, and arrangements should be made for imminent transfer to a transplant center. Early transport is important, as the patient transport risks increase or even preclude transfer in later stages of encephalopathy.
• Nutritional support should be initiated early. A daily intake goal of 60 g of protein (or amino acids 0.8 to 1.2 g/kg/day) is recommended to prevent catabolism of protein stores. Enteral feeding should be initiated in patients with grade III or IV encephalopathy.
• Fluid support should be initiated if patient is not tolerating oral intake, or signs of hypoperfusion are present. Crystalloid solutions (normal saline in hypotensive patients, normal saline + 75 mEq/L NaCO₃ in acidotic patients, normal saline + dextrose in hypoglycemic patients) can be used.

• If encephalopathy progresses and cerebral edema develops leading to increased ICP, intravenous mannitol is recommended to reduce cerebral edema transiently. Prophylactic hyperventilation is not recommended in patients with ALF. Serum sodium should be maintained between 140 to 150 mmol/L. In patients with the highest risk of cerebral edema, hypertonic saline is recommended.
• Phenytoin can be used to manage seizures. In patients not responding to phenytoin, short-acting benzodiazepines may be used.
• Sedative medications should be avoided, as they are not cleared well and may mask signs of worsening encephalopathy or cerebral edema.
• Lactulose and rifaximin are not routinely recommended for encephalopathy treatment; neomycin should be avoided due to concerns of nephrotoxicity.
• Broad-spectrum antibiotics should be started immediately if infection is suspected. Sources usually include respiratory, urinary, and blood; there is no evidence for empiric antibiotic treatment. Antifungals should be initiated if no initial improvement with antibiotics occurs.
• In the case of persistent hypotension, norepinephrine is the initial vasopressor of choice; vasopressin can be added as a second pressor to maintain mean arterial pressure (MAP) >75 mm Hg. Persistent hypotension despite fluid resuscitation and pressor support should prompt concern for adrenal insufficiency.
• If dialysis is required for renal support, continuous mode is recommended over intermittent hemodialysis.
• Patients should receive stress ulcer prophylaxis, given the risk of gastrointestinal bleeding.
• Routine correction of thrombocytopenia or INR correction are not recommended in the absence of bleeding. However, in the setting of clinical bleeding or the need for a procedure with a high bleeding risk, plasma or clotting factors are recommended. Vitamin K should be given routinely since in patients with ALF vitamin K deficiency is common.
• Part of the pharmacologic treatment will be specific to the suspected etiology of ALF.
• If acetaminophen is the known or suspected cause, an IV acetylcysteine protocol should be initiated. N-acetylcysteine is not harmful and dramatically alters the course in acetaminophen toxicity, so there should be a low threshold to start, particularly in young patients or those with no known cause of ALF.
• The 20-h protocol is:
  1. Initial loading dose of 150 mg/kg IV given over 60 min followed by
  2. 12.5 mg/kg IV/h over 4 h followed by
  3. 6.25 mg/kg IV/h for 16 h.
• A repeat acetaminophen level and alanine transaminase (ALT) should be checked at hour 18 of NAC treatment. If either the acetaminophen level or the ALT is elevated, the 16-h portion of treatment (6.25 mg/kg) should be extended and another ALT, INR, or acetaminophen level should be checked every 12 h. The acetylcysteine can be stopped once the acetaminophen level is undetectable, INR <2, or ALT is shown to be either normal or decreasing. Additional information on acetaminophen overdose is available in the topic “Acetaminophen Poisoning.”
• N-acetylcysteine therapy outside of acetaminophen poisoning has been investigated, but evidence for the benefit is inconclusive. Its routine use is not currently recommended by practice guidelines and is center specific.⁸
• Liver support systems:
  1. Liver support systems have been trialed either to support the patient until the liver recovers or as a bridge to liver transplantation.
  2. High-volume plasma exchange can improve hepatic encephalopathy and transplant-free survival in a patient ineligible for liver transplantation, but no survival benefit has been shown for a patient undergoing liver transplantation with plasma exchange compared with supportive therapy alone.⁹
  3. The molecular absorbents recirculating system (MARS) is an artificial extracorporeal hepatic support system that allows albumin-bound toxins to be removed. MARS has been shown to improve hemodynamics and biochemical variables, and there is emerging evidence that MARS therapy is associated with higher transplant-free survival. However, the routine use of MARS is not currently recommended by practice guidelines.¹⁰
  4. Bioartificial support systems in the form of hepatocytes (human or other mammalian origin) have also been used in cartridges as part of extracorporeal systems. These have not shown any benefit, with or without transplantation.

• In patients with high-grade hepatic encephalopathy (HE) awaiting transplant, intracranial pressure (ICP) monitoring is recommended in centers with expertise in ICP monitoring.
• Neurologic examination every 1 to 4 h is recommended in the absence of ICP monitoring.
• Patients with suspected acetaminophen toxicity should have LFTs monitored every 12 h. Otherwise, LFTs can be monitored daily.
• Chemistry panels and prothrombin time/INR should be monitored every 8 to 12 h. Correction of coagulopathy should be avoided because it can interfere with assessment of liver function. In the setting of life-threatening bleeding, fresh frozen plasma (FFP) and recombinant factor VIIa can be considered.
• Point-of-care glucose should be checked every 4 h initially to evaluate for hypoglycemia. If hypoglycemia is detected, dextrose should be added to crystalloid solution.
• Because of the increased risk of infection, daily urine, sputum, and blood cultures, as well as chest x-ray examinations, should be checked even in the absence of signs or symptoms of infection.

• Overall mortality from ALF is 30% to 40% and has improved significantly over the last 20 yr.
• Transplant-free survival in ALF in the setting of acetaminophen, hepatitis A, shock liver, and pregnancy-related disease is >50%; for all other causes of ALF, transplant-free survival is <25%.
• Higher-grade hepatic encephalopathy and renal dysfunction in non-acetaminophen ALF predict worse survival.
• Multiple models have been developed to predict spontaneous recovery in ALF patients (King’s College criteria, Clichy criteria, MELD score, APACHE II score).
• The King’s College criteria form the basis of the model most commonly used for prognostication (Table 3).
• Transplantation:
  1. Patients with ALF are given the highest priority for liver transplantation. ALF accounts for only 10% of the U.S. liver transplants.
  2. Contraindications to listing include medical history of irreversible brain injury, psychiatric illness severe enough to affect patients’ survival or likelihood of compliance with medications, active sepsis, severe medical comorbidities including malignancy, increasing dependence on ventilator/inotropic support, acute substance abuse, previous episodes of self-harm (>5 episodes), refractory mental illness, and inadequate family support.
  3. For patients with alcoholic liver disease, many centers require a 6-mo abstinence period, but several transplant centers in North America and Europe have transplanted selected patients with alcoholic hepatitis who were unlikely to survive 6 mo.¹¹
  4. Mortality on the waiting list is 25%; 1-yr and 5-yr survival after transplantation are 73% and 67%, respectively.
  5. Various prognostic criteria used for liver transplantation in patients with fulminant hepatic failure are summarized in Box E6.

• Arterial pH <7.3 (irrespective of grade of encephalopathy) or
• PT >100 sec (INR >6.5) and
• Serum creatinine >3.4 mg/dl (>300 μmol/L) and
• Patients with grade III and IV hepatic encephalopathy

Acute form (delayed jaundice-encephalopathy <7 days):

• PT >100 sec (INR >6.5) (irrespective of grade of encephalopathy) or any three of the following variables:
• Aged <10 or >40 yr
• Non-A, non-B hepatitis, halothane hepatitis, idiosyncratic drug reactions
• Subacute form: Delayed encephalopathy >7 days
• Serum bilirubin 17.4 mg/dl (300 μmol/L)
• PT >50 sec