Evidence ratings (Grades I, II-1, II-2, II-3, and III) are defined at the end of the "Major Recommendations" field.
Diagnosis and Initial Evaluation
- Patients with acute liver failure (ALF) should be admitted and monitored frequently, preferably in an intensive care unit (ICU) (Grade III).
- Contact with a transplant center and plans to transfer appropriate patients with ALF should be initiated early in the evaluation process (Grade III).
- The precise etiology of ALF should be sought to guide further management decisions (Grade III).
Table. Initial Laboratory Analysis
- Prothrombin time/international normalized ratio (INR)
- Chemistries
- sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate
- glucose
- aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, gamma glutamyl transpeptidase (GGT), total bilirubin, albumin
- creatinine, blood urea nitrogen
- Arterial blood gas
- Arterial lactate
- Complete blood count
- Blood type and screen
- Acetaminophen level
- Toxicology screen
- Viral hepatitis serologies
- anti-hepatitis A (HAV) IgM, hepatitis B surface antigen (HBSAg), anti-hepatitis B core antibody (anti-HBc IgM), antibody to hepatitis E (anti-HEV#), and antibody to hepatitis C (anti-HCV*)
- Ceruloplasmin level**
- Pregnancy test (females)
- Ammonia (arterial if possible)
- Autoimmune markers
- antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), Immunoglobulin levels
- Human immunodeficiency virus (HIV) status***
- Amylase and lipase
* Done to recognize potential underlying infection
** Done only if Wilson disease is a consideration (e.g., in patients less than 40 years without another obvious explanation for ALF); in this case uric acid level and bilirubin to alkaline phosphatase ratio may be helpful as well.
*** Implications for potential liver transplantation
# If clinically indicated.
Determining Etiologies and Specific Therapies
Acetaminophen Hepatotoxicity
- For patients with known or suspected acetaminophen overdose within 4 hours of presentation, give activated charcoal just prior to starting N-acetylcysteine (NAC) (Grade I).
- Begin NAC promptly in all patients where the quantity of acetaminophen ingested, serum drug level, or rising aminotransferases indicate impending or evolving liver injury (Grade II-1).
- NAC may be used in cases of acute liver failure in which acetaminophen ingestion is possible or when knowledge of circumstances surrounding admission is inadequate (Grade III).
Mushroom Poisoning
- In ALF patients with known or suspected mushroom poisoning, consider administration of penicillin G and silymarin (Grade III).
- Patients with acute liver failure secondary to mushroom poisoning should be listed for transplantation, as this procedure is often the only lifesaving option (Grade III).
Drug Induced Hepatotoxicity
- Obtain details (including onset of ingestion, amount, and timing of last dose) concerning all prescription and non-prescription drugs, herbs and dietary supplements taken over the past year (Grade III).
- Determine ingredients of non-prescription medications whenever possible (Grade III).
- In the setting of acute liver failure due to possible drug hepatotoxicity, discontinue all but essential medications (Grade III) (See Table 3 "Some Drugs Which May Cause Idiosyncratic Liver Injury to ALF" in the original guideline.)
Viral Hepatitis
- Viral hepatitis A- and B- (and E-) related acute liver failure must be treated with supportive care as no virus-specific treatment has been proven effective (Grade III).
- Nucleoside analogs should be given prior to and continued for 6 months after completion of chemotherapy in patients with Hepatitis B surface antigen positivity to prevent reactivation/acute flare of disease (Grade III).
- Patients with known or suspected herpes virus or varicella zoster as the cause of acute liver failure should be treated with acyclovir (Grade III).
Wilson Disease
- Diagnostic tests for Wilson disease should include ceruloplasmin, serum and urinary copper levels, total bilirubin/alkaline phosphatase ratio, slit lamp examination for Kayser-Fleischer rings, and hepatic copper levels when liver biopsy is feasible (Grade III).
- Patients in whom Wilson disease is the likely cause of acute liver failure must be immediately placed on the liver transplant list (Grade III).
Autoimmune Hepatitis
- When autoimmune hepatitis is suspected as the cause of acute liver failure, liver biopsy should be considered to establish this diagnosis (Grade III).
- Patients with acute liver failure due to autoimmune hepatitis should be treated with corticosteroids (prednisone, 40-60 mg/day) (Grade I).
- Patients should be placed on the list for transplantation even while corticosteroids are being administered (Grade III).
Acute Fatty Liver of Pregnancy/Hemolysis, Elevated Liver Enzymes, Low Platelets (HELLP) Syndrome
- For acute fatty liver of pregnancy or the HELLP syndrome, consultation with obstetrical services and expeditious delivery are recommended (Grade III).
Acute Ischemic Injury
- In ALF patients with evidence of ischemic injury, cardiovascular support is the treatment of choice (Grade III).
Budd-Chiari Syndrome
- Hepatic vein thrombosis with hepatic failure is an indication for liver transplantation, provided underlying malignancy is excluded (Grade II-3).
Malignant Infiltration
- In patients with acute liver failure who have a previous cancer history or massive hepatomegaly, consider underlying malignancy and obtain imaging and liver biopsy to confirm or exclude the diagnosis (Grade III).
Indeterminate Etiology
- If the etiological diagnosis remains elusive after extensive initial evaluation, liver biopsy may be appropriate to attempt to identify a specific etiology that might influence treatment strategy (Grade III).
Therapy: General Considerations
Central Nervous System and Intracranial Pressure Monitoring
- In early stages of encephalopathy, sedation should be avoided if possible. Lactulose may be used, but concern has been raised about increasing bowel distention during the subsequent transplant procedure (Grades II-2, III).
- In patients progressing to grade III or IV encephalopathy, the head should be elevated to 30 degrees, and endotracheal intubation should be performed (Grade III).
- Seizure activity should be treated with phenytoin and low-dose benzodiazepines (Grade III).
- Although there is no consensus among the centers and experts, intracranial pressure (ICP) monitoring is mainly considered for patients who are listed for transplantation (Grade III).
- In the absence of ICP monitoring, frequent evaluation for signs of intracranial hypertension are needed to identify early evidence of uncal herniation (Grade III).
- In the event of intracranial hypertension, mannitol should be given and hyperventilation may be considered in order to temporarily reduce the ICP, but prophylactic use of these interventions is not helpful and therefore not recommended (Grade I).
- Short-acting barbiturates may be considered for refractory intracranial hypertension (Grade III).
- Corticosteroids should not be used to control elevated ICP in patients with acute liver failure (Grade I).
Infection
- Periodic surveillance cultures should be performed to detect bacterial and fungal infections as early as possible and prompt treatment should be initiated accordingly (Grades II-2, III).
- Prophylactic antibiotics and anti-fungals may be considered but have not been shown to improve overall outcomes (Grades II-2, III).
Coagulopathy
- Replacement therapy for thrombocytopenia and/or prolonged prothrombin time is recommended only in the setting of hemorrhage or prior to invasive procedures (Grade III).
Gastrointestinal (GI) Bleeding
- Patients with ALF in the intensive care unit should receive prophylaxis with H2 blocking agents or proton pump inhibitors (PPIs) (or sucralfate as a second-line agent) for acid-related gastrointestinal bleeding associated with stress (Grades I, III).
Hemodynamics/Renal Failure
- Careful attention must be paid to fluid resuscitation and maintenance of adequate intravascular volume in patients with acute liver failure (Grade III).
- If dialysis support is needed for acute renal failure, it is recommended that a continuous mode rather than an intermittent mode be used (Grade I).
- Pulmonary artery catheterization should be considered in a hemodynamically unstable patient to ensure that appropriate volume replacement has occurred (Grade III).
- Systemic vasopressor support with agents such as epinephrine, norepinephrine, or dopamine but not vasopressin should be used if fluid replacement fails to maintain mean arterial pressure (MAP) of 50-60 mm Hg (Grades III, II-1).
Metabolic Concerns
- Metabolic homeostasis must be carefully maintained in patients with acute liver failure. Overall nutritional status as well as glucose, phosphate, potassium and magnesium levels should be monitored frequently, with expeditious correction of derangements (Grade III).
Table: Intensive Care of ALF
| Cerebral Edema/Intracranial Hypertension |
Grade I/II Encephalopathy
- Consider transfer to liver transplant facility and listing for transplantation
- Brain computed tomography (CT): rule out other causes of decreased mental status; little utility to identify cerebral edema
- Avoid stimulation, avoid sedation if possible
- Antibiotics: surveillance and treatment of infection required; prophylaxis possibly helpful
- Lactulose: possibly helpful
Grade III/IV Encephalopathy
- Continue management strategies listed above
- Intubate trachea (may require sedation)
- Elevate head of bed
- Consider placement of intracranial pressure (ICP) monitoring device
- Immediate treatment of seizures required; prophylaxis of unclear value
- Mannitol: use for severe elevation of intracranial pressure or first clinical signs of herniation
- Hyperventilation: effects short-lived; may use for impending herniation
|
| Infection |
- Surveillance for and prompt antimicrobial treatment of infection required
- Antibiotic prophylaxis possibly helpful but not proven
|
| Coagulopathy |
- Vitamin K: give at least one dose
- Fresh frozen plasma (FFP): give only for invasive procedures or active bleeding
- Platelets: give for platelet counts <10,000/mm3 or invasive procedures
- Recombinant activated factor VII: possibly effective for invasive procedures
- Prophylaxis for stress ulceration: give histamine-2 receptor blocker or proton pump inhibitor
|
| Hemodynamics/Renal Failure |
- Pulmonary artery catheterization
- Volume replacement
- Pressor support (dopamine, epinephrine, norepinephrine) as needed to maintain adequate mean arterial pressure
- Avoid nephrotoxic agents
- Continuous modes of hemodialysis if needed
- N-acetylcysteine, prostacyclin: effectiveness unknown
- Vasopressin: not helpful in ALF; potentially harmful
|
| Metabolic Concerns |
- Follow closely: glucose, potassium, magnesium, phosphate
- Consider nutrition: enteral feedings if possible or total parenteral nutrition
|
Transplantation and Prognosis
Transplantation
- Urgent hepatic transplantation is indicated in acute liver failure where prognostic indicators suggest a high likelihood of death (Grade II-3).
Liver Support Systems
- Currently available liver support systems are not recommended outside of clinical trials; their future in the management of ALF remains unclear (Grades I, II-1).
Prognosis
- Currently available prognostic scoring systems do not adequately predict outcome and determine candidacy for liver transplantation. Reliance entirely upon these guidelines is thus not recommended (Grades II-2, II-3, III).
Definitions:
Grade I: Randomized controlled trials
Grade II-1: Controlled trials without randomization
Grade II-2: Cohort or case-control analytic studies
Grade II-3: Multiple time series, dramatic uncontrolled experiments
Grade III: Opinions of respected authorities, descriptive epidemiology
