Acute Liver Failure

Background

• Acute liver failure, otherwise known as fulminant liver disease, is a loss of liver function that occurs rapidly over days to weeks with a duration of illness < 26 weeks, resulting in:
  • any degree of hepatic encephalopathy
  • liver-related coagulopathy (prothrombin time prolonged by 4-6 seconds or INR > 1.5)
• The presentation of acute liver failure may be classified as:
  • Hyperacute: characterized by severe coagulopathy, moderate intracranial hypertension, and progression from jaundice to encephalopathy typically in < 1 week. Examples of hyperacute presentation include acute acetaminophen toxicity (the most common cause of acute liver failure in the United States and Europe) and acute hepatitis A or E.
  • Acute: characterized by moderately severe coagulopathy, mild-to-moderate intracranial hypertension, and progression from jaundice to encephalopathy in 1-4 weeks. Acute presentations may be seen in almost all of the etiologies of acute liver failure.
  • Subacute: characterized by mild coagulopathy, severe jaundice, and progression to encephalopathy in 4-12 weeks. A subacute presentation is associated with nonacetaminophen drug toxicity. Many drugs can cause acute liver failure with most cases presenting within 6 months of starting the medication but this must be a diagnosis of exclusion.
• Other causes of acute liver failure include other viruses such as hepatitis B and D and Herpes, vascular ischemia in the setting of shock; Budd-Chiari syndrome (hepatic vein thrombosis); Wilson disease; poisoning from toxic Amanita mushrooms, herbs, and supplements; autoimmune hepatitis; extensive metastatic liver disease; and HELLP syndrome. Wilson disease and Budd-Chiari are generally chronic or subacute disorders but rarely may present as acute liver failure, when coagulopathy or encephalopathy develop within 26 weeks of recognized onset of those diseases.
• Conditions with underlying chronic liver disease, such as "acute alcoholic hepatitis," are not classified as acute liver failure.

Evaluation

• All patients with possible acute liver failure (such as patients presenting with severe acute hepatitis) should have an immediate measurement of prothrombin time and careful evaluation of mental status.
• Obtain laboratory testing to assess for the most common etiologies and severity of systemic dysfunction, particularly renal function.. Testing should include liver and renal function tests, electrolytes, phosphate, glucose, toxicology screen, serum acetaminophen level, complete viral hepatitis serologies (hepatitis A IgM, HBcAB IgM, HEV IgM), complete blood count, amylase, lipase, arterial blood gas with lactate, arterial ammonia, pregnancy test, HIV, and antinuclear antibody (ANA), antismooth muscle antibody (ASMA), and immunoglobulin levels.
  • For patients < 40 years old, obtain serum ceruloplasmin and copper levels. Consider a 24-hour urine copper measurement, particularly if ceruloplasmin is low.
  • Aminotransferase levels > 3,500 units/L are suggestive but neither diagnostic nor pathognomonic of acetaminophen toxicity.
  • A low alkaline phosphatase to bilirubin ratio (< 4) and/or hemolysis suggests Wilson disease.
  • Consider herpes simplex induced liver failure in pregnant or immunocompromised patients and those with fever, leukopenia, markedly elevated ALT, or skin vesicles. Infection happens in otherwise healthy individuals and without any of the above findings.
• Consider imaging studies ( in patients with ALF, particularly in patients with a history of cancer, massive hepatomegaly, or suspected acute hepatic vein thrombosis (Weak recommendation). Be cautious with contrast if renal function is impaired, and consider ultrasound with Doppler for some patients.
• Consider liver biopsy (usually performed via the transjugular route due to coagulopathy) if the etiology remains unclear after recommended testing (Weak recommendation).
• If an acetaminophen ingestion:
  • Determine the amount and time of the initial ingestion. Acetaminophen toxicity usually occurs with ingestions of > 10 g/day, such as suicidal intent. Plot the acetaminophen level on an overdose curve to assess for the likelihood of toxicity.
  • Recognize that staggered ingestions of 3-4g/day over time may present as acute liver failure with undetectable acetaminophen levels. People with preexisting liver damage, such as from fatty liver or alcohol use, are more prone to accidental overdose and may have a worse prognosis.

Management

• Contact a transplantation center and plan to transfer appropriate patients early in the evaluation process (Strong recommendation), especially patients with acetaminophen toxicity and any of these warning blood test results or signs which have developed within a 24-hour period:
  • arterial pH < 7.3 or increasing lactate not responsive to fluids
  • oliguria or worsening creatinine levels
  • INR > 3.0
  • grade 2 or worse hepatic encephalopathy (somnolence or flapping tremor present)
• For all patients with acute liver failure:
  • Admit to a monitored ICU bed.
  • Carefully monitor and maintain the patient’s metabolic status including hydration, electrolytes, oxygenation, and nutrition. Be aware of a tendency towards hypoglycemia and hyponatremia, both of which may present with mental status changes, develop rapidly, and have a worse prognosis..
  • Monitor for signs and symptoms of elevated intracranial pressure and treat with 30 degree head elevation and a mannitol bolus (0.5-1 g/kg) for the first-line therapy with close monitoring for serum hyperosmolarity and hypernatremia.
  • Monitor for infection and have a low threshold to give prophylactic antibiotics if signs of an infection or continued deterioration are present.
  • Administer prophylaxis for gastrointestinal bleeding with a proton pump inhibitor or H2 blocker.
  • Correct coagulopathy and thrombocytopenia prior to invasive procedures or if there is active bleeding.
  • Treat seizures immediately with short-acting benzodiazepines plus levetiracetam, as seizure activity raises intracranial pressure. Do not use prophylactic phenytoin for seizure prevention as evidence is limited and conflicting, and phenytoin is one of the causes of drug-induced liver failure.
  • Manage encephalopathy with a quiet environment and avoid oversedation, use low-dose benzodiazepines only if absolutely necessary, and consider airway protection as needed.
    • If lactulose is used, use with caution and do not induce diarrhea because it may worsen volume status and increase bowel distention, complicating subsequent transplant surgery.
    • Endotracheal intubation may be needed for severe encephalopathy.
  • Consider administration of N-acetylcysteine (NAC) at admission if acute liver failure etiology is unclear and while waiting for lab and imaging results due to general safety profile and emerging evidence of benefit in non-acetaminophen induced acute liver failure with early hepatic encephalopathy.
• For acetaminophen ingestion:
  • Give activated charcoal if ingestion is < 4 hours prior to presentation (Strong recommendation).
  • Start NAC promptly if toxic levels of acetaminophen are known or there is a suspected staggered ingestion (Strong recommendation). If time of, or the initial dose of acetaminophen is unknown, assume a dose of 150 mg/kg or > 12 g for plotting on the acetaminophen toxicity dose curve at the 4-hour mark.
  • Consider discontinuation of NAC if the acetaminophen level is determined to be below the toxicity line for acute ingestion. For an ingestion in the toxic range, a complete course of NAC should be given.
• For poisonous mushroom ingestion:
  • Consider gastric lavage and activated charcoal via nasogastric tube in patients with recent ingestion (evidenced by severe gastrointestinal symptoms).
  • Provide fluid resuscitation and closely monitor renal function.
  • Consider silibinin IV in symptomatic patients within 48 hours of ingestion - initial dose 5 mg/kg IV over 1 hour; then 20 mg/kg 24-hour continuous infusion (diluted in 5% glucose to a concentration of 2 mg silibinin/mL) for 3 days.
  • Consider penicillin G 300,000-1,000,000 units/kg/day IV (Weak recommendation).
  • Transplantation is often the only life-saving option.
• For drug-induced hepatotoxicity:
  • Discontinue all nonessential medications.
  • Consider NAC.
  • Corticosteroids are indicated if a drug hypersensitivity immunoallergic reaction is suspected (such as drug rash with eosinophilia and systemic symptoms [DRESS] syndrome).
• For acute failure due to viral hepatitis:
  • Provide supportive care.
  • Consider the nucleoside analogs entecavir or tenofovir in patients with hepatitis B viremia, particularly if future liver transplant is a possibility .
• For Wilson disease acute liver failure:
  • Immediately contact transplant center for consideration of transfer, evaluation and listing for emergency transplant (Strong recommendation).
  • Treatments to lower copper and prevent further hemolysis include albumin dialysis, continuous hemofiltration, plasmapheresis, and plasma exchange.
• For Budd-Chiari syndrome, consider anticoagulation and evaluate for emergency TIPS versus transfer to transplant center.
• For suspected herpes virus infection, consider antivirals while awaiting test results.
• For autoimmune acute liver failure consider prednisone 40-60 mg/day (Weak recommendation).