Acute liver failure

Acute liver failure (ALF) is a severe condition seen in individuals without previous hepatic disease, and it is characterized by rapidly progressive liver injury, hepatic encephalopathy, and impaired synthetic function, which results in coagulopathy. If these features occur in individuals with prior hepatic disease, it is considered acute-on-chronic liver failure. The most common causes are infections (e.g., viral hepatitis) and drug toxicity (e.g., acetaminophen ingestion). Hepatic encephalopathy may be accompanied by jaundice and nonspecific symptoms such as nausea, vomiting, and fatigue. The diagnosis is confirmed by identifying an elevation of hepatic enzymes and an altered coagulation panel in patients with encephalopathy. Clinicians should maintain a high index of suspicion and aim to confirm the diagnosis as quickly as possible in order to start management early. Patients with ALF are usually critically ill and require admission to a critical care unit for extensive supportive treatment. The prognosis is poor, and most patients require urgent liver transplantation as definitive treatment.

• Acute liver failure (ALF): a condition characterized by a rapidly progressive (within a period of 26 weeks) and severe acute liver injury, defined as impairment of synthetic function (i.e., coagulopathy) and encephalopathy, in an individual without previous hepatic disease
  • Subtypes are defined according to the amount of time it takes for encephalopathy to develop. ^[1][2][3]
    • Hyperacute liver failure: 0–1 weeks
    • Acute (fulminant) liver failure: 1–3 weeks
    • Subacute liver failure: Encephalopathy develops slowly, after ∼ 3 weeks and up to ∼ 26 weeks from the onset of other symptoms.
• Chronic liver disease (CLD): a condition characterized by progressive deterioration of hepatic function over at least 26–28 weeks (∼ 6 months), e.g., cirrhosis. ^[2]
• Acute decompensation of CLD: An episode of acute worsening of chronic liver disease manifestations (e.g., ascites, hepatic encephalopathy, GI bleeding, jaundice, infection), which can be due to a precipitant or progression of the underlying illness. ^[4]
• Acute-on-chronic liver failure (ACLF): A distinct syndrome involving acute decompensation of CLD accompanied by multiorgan failure and significant short-term mortality. ^[4][5][6]

Acute liver failure is idiopathic in 20–45% of cases, more commonly in patients with the subacute subtype. ^[1][10]

Presentation is mostly nonspecific and clinicians should maintain a high index of suspicion in patients who acutely develop the following symptoms: ^[1][2][3]

• Signs of hepatic encephalopathy (e.g., altered level of consciousness, asterixis )
• Symptoms of cerebral edema ^[11]
• Nausea, vomiting
• Fatigue, lethargy, malaise
• Jaundice, pruritus
• Anorexia
• Abdominal pain: may be located in the RUQ or diffuse, secondary to ascites
• Features of the underlying etiology (e.g., Kayser-Fleischer rings in Wilson disease)

In hyperacute liver failure, jaundice is usually minimal and the predominant presentation is encephalopathy, which can delay diagnosis and management.

Routinely consider ALF in patients presenting with acute encephalopathy.

• Severe acute hepatitis without liver failure
• Chronic liver disease with superimposed illness
• Other encephalitis or encephalopathy, e.g., drugs and toxins, uremic encephalopathy (See “Altered mental status and coma.”)
• Sepsis
• See also “Jaundice and cholestasis.”

The differential diagnoses listed here are not exhaustive.

Recommendations in this article are consistent with the 2011 update of the American Association for the Study of Liver Diseases (AASLD) position paper on the management of ALF. ^[3][12]

Approach ^[1][3][12]

The aim of initial management is metabolic and hemodynamic stability, which provides the best conditions for hepatic regeneration.

• Unstable patients: Begin emergency stabilization (i.e., using the ABCDE approach) prior to diagnostic confirmation if severely ill upon presentation (see “Stabilization” for details).
• Suspected ALF: Obtain liver chemistries, coagulation panel, and perform a detailed neurologic assessment.
  • Consider alternate diagnoses if there is no evidence of hepatocellular injury, i.e., normal liver chemistries (see Differential diagnoses”).
  • ALF is confirmed if all the following are present:
    • Abnormal liver chemistries
    • Altered coagulation parameters
    • Any degree of encephalopathy
• Confirmed ALF: See “Diagnostics” and “Treatment” for details.
  • Identify liver transplant candidates early and refer them immediately to a transplant center if necessary.
  • Admit to a critical care unit. ^[13]
  • Begin aggressive supportive care: e.g., volume repletion, ICP monitoring, treatment of hypoglycemia and electrolyte disturbances.
  • Identify and treat the underlying cause.
  • Consider starting N-Acetylcysteine.
  • If the cause is medication- or substance-induced, notify the local poison control center.

The diagnosis of ALF requires the presence of hepatic injury (elevated aminotransferases), encephalopathy, and coagulopathy (INR > 1.5).

Acute liver failure can cause multiorgan dysfunction which requires system-based management in a critical care unit. ^[8]

Stabilization ^[1][3][12]

• Immediate hemodynamic support: Restore volume and perfusion early to avoid or reduce organ damage.
  • Initiate volume repletion with normal saline.
  • Titrate to MAP > 75 mm Hg. ^[12]
  • Start vasopressors if nonresponsive to fluids.
    • First-line: norepinephrine
    • Second-line: Consider adding vasopressin. ^[12]
  • Consider hydrocortisone for persistent hypotension.
  • Start hemodynamic monitoring (e.g., BP and urinary output) to adjust therapy.
• Respiratory support
  • Secure airway as needed.
  • Consider early intubation (especially in patients with rapidly progressing encephalopathy).
  • See “Intubation of patients with high ICP” and “Ventilation strategy for elevated ICP.”
  • Start clinical and SpO2 monitoring and consider serial ABG.
• Management of encephalopathy and increased ICP: ^[1][12][14]
  • Consider early intubation.
  • Refer early for liver transplantation.
  • Control hyperammonemia: Consider lactulose . ^[2][15]
  • Begin neuroprotective measures and ICP management as needed.
    • Target CPP 60–80 mm Hg ^[12]
    • Consider osmotic therapy and temperature control.
    • Refractory cases: Consider indomethacin . ^[1]
  • Monitoring: Assess clinical signs of encephalopathy and ammonia levels.
  • Consider intracranial pressure monitoring only in patients with signs of increased ICP.

↑ ICP and severe hepatic encephalopathy account for 20–35% of mortality in patients with ALF. Early screening and treatment are essential to improve survival. ^[8][10]

Supportive care ^[1][3][12]

• Metabolic and nutritional support
  • Optimize nutrition: for patients in a catabolic state, optimize weight-based protein intake enterally or via TPN.
  • Electrolyte repletion and treatment of hypoglycemia as needed
  • Avoid hypotonic fluids (may result in hyponatremia).
  • Consider glucose infusion with a target glucose ∼ 140 mg/dL. ^[1][14]
  • Consider serial CMP monitoring.
• Hemostasis ^[1][14][16]
  • Correct coagulopathy if there is active bleeding or need for invasive procedures, usually using a combination of: ^[16][17]
    • Fresh frozen plasma (most common)
    • Recombinant factor VIIa
    • Cryoprecipitate (for hypofibrinogenemia < 100 mg/dL)
    • Vitamin K
    • Platelets (e.g., for severe thrombocytopenia)
    • See “Transfusion” for dosages.
  • Consider stress ulcer prophylaxis to prevent GI bleeding.
  • Consult hematology for specialized management.
  • Monitor coagulation studies and consider using viscoelastic hemostatic assays.
• Management of kidney injury
  • Optimize hemodynamic support.
  • Consider renal replacement therapy.
  • See also “Acute kidney injury” and “Hepatorenal syndrome.”
  • Monitor urine output and consider serial renal function tests.
• Infection control: patients with ALF are at increased risk of sepsis.
  • Begin infection control and prevention measures based on individual risk (e.g., consider isolation).
  • Consider antibiotic prophylaxis. ^[13]
  • Screen for and start empiric antibiotics for sepsis if suspected.
  • Monitor with frequent clinical assessments (e.g., vital signs, qSOFA).
  • Consider serial biomarkers (e.g., CBC, CRP, ESR).

Diagnostic studies in ALF are used to confirm the diagnosis and assess the extent of associated organ failure. When the patient is stable, diagnostic studies also aid in the identification of the underlying cause if still unknown.

Laboratory studies ^[3][12]

Common findings include:

• CBC: : typically platelet count ≤ 150,000/mm³; other findings are variable and depend on the underlying etiology.
• Liver chemistries
  • Significantly elevated aminotransferases
  • Hyperbilirubinemia
• BMP
  • Hypoglycemia (common)
  • Electrolyte disturbances (e.g., hyponatremia, hypokalemia, hypophosphatemia)
  • ↑ BUN and creatinine if acute kidney injury or hepatorenal syndrome is present
• Coagulation panel
  • Prolonged prothrombin time (INR ≥ 1.5)
  • The presence of other derangements (e.g., hypofibrinogenemia) is variable.
  • Consider thromboelastogram for a global assessment of coagulation.
• ABG or VBG : Findings vary depending on the underlying etiology (see “Acid-base disorders” for more information). ^[18]
  • Acidosis: secondary to lactic acidosis , uremia, or toxic metabolites
  • Alkalosis: secondary to hypoalbuminemic acidosis or respiratory alkalosis
  • Lactate: commonly elevated, marker of severe disease
• Serum ammonia (preferably arterial): frequently elevated; values > 150 micromol/L are associated with a higher risk of increased ICP.
• LDH: typically elevated in early stages of acute liver injury

Imaging ^[19]

Imaging is not routinely indicated and may not provide any additional diagnostic information, but it is often part of the general diagnostic workup of acutely ill patients.

• Abdominal imaging: Findings vary as ALF progresses.
  • Early findings
    • Abdominal x-ray: may show hepatomegaly
    • Abdominal ultrasound: liver echogenicity may be heterogeneously decreased (usually a sign of necrosis); possible presence of ascites
    • Doppler ultrasound: can be useful to identify the underlying cause (e.g., portal vein thrombosis, hepatic ischemia)
    • CT/MRI abdomen with contrast: usually shows diffuse enhancement (e.g., in necrosis), may show ascites and/or hepatomegaly
  • Findings in late stages: In patients who have been sick for at least seven days, ultrasound, CT, or MRI may show a nodular surface, which can be mistaken for cirrhosis.
• Additional imaging: Consider CT head to rule out other causes of altered mental status or coma.

Do not mistake the nodular appearance of a regenerating necrotic liver for cirrhosis, as this may delay urgent management!

Identifying the underlying cause ^[12][15][20]

The etiology of ALF may be evident after taking the patient history (e.g., acetaminophen overdose), or it may require further investigation. In many cases, the etiology remains unknown even after an extensive evaluation. ^[1]

• Laboratory studies
  • Screen the following viral serologies in all patients: hepatitis A (IgM), hepatitis B (surface antigen and core IgM), hepatitis C (antibodies), and hepatitis E (IgG and possibly RNA testing)
    • Consider PCR for EBV, CMV, adenovirus, and HSV.
    • Consider VZV (IgM) in immunocompromised patients or those with a vesicular rash.
  • Toxicology screen: measure acetaminophen levels and consider screening for other measurable hepatotoxic drugs, e.g., phenytoin.
  • Consider testing for more uncommon etiologies based on clinical suspicion.
    • Ceruloplasmin and copper studies for Wilson disease ^[20]
    • Serum IgG levels and autoimmune markers for autoimmune hepatitis
    • α-fetoprotein for suspected malignancy
    • Pregnancy test in suspected HELLP syndrome
  • Hematologic studies (e.g., blood smear, Coombs test) may show abnormalities, e.g., hemolytic anemia in Wilson disease. ^[21]
• Liver biopsy ^[20][21]
  • Indications
    • To distinguish between ALF and chronic liver disease if the diagnosis is uncertain.
    • The suspected underlying etiology requires specific management (e.g., autoimmune hepatitis, malignancy).
  • Findings: specific to each underlying etiology; necrosis and regeneration are commonly seen.
  • Complications: significant risk of bleeding

In ALF, the significant risks of performing a liver biopsy may outweigh the benefits, as most patients require a liver transplant regardless of biopsy results.

Urgent liver transplantation remains the standard of care for ALF. ^[3]

Liver transplant ^[22]

• Consider liver transplant in most patients, as a high proportion do not recover with supportive therapy alone (see “Prognosis”).
• Use prognostic scoring systems (e.g., MELD score, King's College criteria) to risk-stratify patients' need and urgency of transplantation.
• Consult the transplant team early and, if necessary, transfer candidates to a transplant center without delay.
• Treat any complications arising during the waiting period, e.g., cerebral edema, acute kidney injury, sepsis, coagulopathy (see “Management”).

Scoring systems

• There are multiple methods available to predict which patients will likely require a liver transplant, and these are mostly based on clinical and laboratory parameters.
• Commonly used scores
  • King's College criteria: provides indications for liver transplant ^[10][22]
  • MELD (for patients older than 12 years of age) and PELD (for pediatric patients) : prioritizes patients waiting for a transplant

Treatment of the underlying cause ^[10]

Specific measures may improve the prognosis when the cause of ALF is identified, for example:

• Autoimmune hepatitis: Consider a trial of steroids on a case-by-case basis, weighing the increased risk of infection against the likely benefit.
• Viral hepatitis: Certain antivirals (e.g., for hepatitis B) can improve the prognosis.
  • Hepatitis B: tenofovir or entecavir
  • CMV hepatitis: ganciclovir or valganciclovir ^[23]
  • HSV hepatitis: acyclovir ^[24]
• Amanita phalloides intoxication
  • Contact Poison Control.
  • GI decontamination: Consider gastric lavage or activated charcoal if indicated.
  • Optimize hydration.
  • Consider N-acetylcysteine, silibinin, and penicillin G as antidotes. ^[3]
• Pregnancy-related liver disease: Urgent delivery of the fetus is indicated.
• Acetaminophen toxicity: Treat with N-acetylcysteine.

N-acetylcysteine (NAC) ^[1][3]

• Indicated in all patients with ALF due to confirmed or suspected acetaminophen toxicity.
• Consider in patients with confirmed or suspected mushroom poisoning, e.g., Amanita phalloides.
• Can be considered in patients with other causes of ALF (not routine). ^[1]
• Dosage and administration
  • 21-hour IV NAC regimen
  • 72-hour oral NAC regimen
  • Consider extending therapy on a case-by-case basis depending on clinical and laboratory evaluations.

Administer N-acetylcysteine as early as possible if indicated, i.e., before hepatic encephalopathy becomes severe. ^[8]

• Advances in management have improved outcomes for ALF patients, but prognosis remains poor (overall mortality of 30–40%) and is worse for ALF of indeterminate etiology. ^[1][13].
• Survival without liver transplant depends on etiology ^[13]
  • Acetaminophen toxicity, hepatitis A, ischemic hepatitis, pregnancy-related (e.g., HELLP syndrome, AFLP): ≥ 50%
  • All other etiologies: < 25%
• Survival with liver transplant: ∼ 65–84% at 1 year ^[10]