Not Found

Find information on medical topics, symptoms, drugs, procedures, news and more, written for the health care professional.

Acute Liver Failure

(Fulminant Liver Failure)

By Steven K. Herrine, MD, Professor of Medicine, Division of Gastroenterology and Hepatology, and Vice Dean for Academic Affairs, Sidney Kimmel Medical College at Thomas Jefferson University

Click here for
Patient Education

Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive, sometimes with liver transplantation and/or specific therapies (eg, N-acetylcysteine for acetaminophen toxicity).

Liver failure can be classified in several ways, but no system is universally accepted (see Table: Classification of Liver Failure*).

Classification of Liver Failure*



Common Findings

Acute (fulminant)

  • 2 wk after jaundice appears

  • 8 wk in a patient with no prior liver disease

Often cerebral edema

Subacute (subfulminant)

Encephalopathy develops within 6 mo but later than in acute liver failure.

Renal failure, portal hypertension (more common than in acute liver failure)


Encephalopathy develops after 6 mo.

Often caused by cirrhosis

*No classification system is universally accepted.


Overall, the most common causes of acute liver failure are

  • Viruses

  • Drugs and toxins

In developing countries, viral hepatitis is usually considered the most common cause; in developed countries, toxins are usually considered the most common cause.

Overall, the most common viral cause is hepatitis B; hepatitis C is not a common cause. Other possible viral causes include cytomegalovirus, Epstein-Barr virus, herpes simplex virus, human herpesvirus 6, parvovirus B19, varicella-zoster virus, hepatitis A virus (rarely), hepatitis E virus (especially if contracted during pregnancy), and viruses that cause hemorrhagic fever (see Overview of Arbovirus, Arenavirus, and Filovirus Infections).

The most common toxin is acetaminophen; toxicity is dose-related . Predisposing factors for acetaminophen-induced liver failure include preexisting liver disease, chronic alcohol use, and use of drugs that induce the cytochrome P-450 enzyme system (eg, anticonvulsants). Other toxins include amoxicillin/clavulanate, halothane, iron compounds, isoniazid, NSAIDs, some compounds in herbal products, and Amanita phalloides mushrooms (see Liver Injury Caused by Drugs). Some drug reactions are idiosyncratic.

Less common causes include

  • Vascular disorders

  • Metabolic disorders

Vascular causes include hepatic vein thrombosis (Budd-Chiari syndrome), ischemic hepatitis, portal vein thrombosis, and hepatic sinusoidal obstruction syndrome (also called hepatic veno-occlusive disease), which is sometimes drug- or toxin-induced. Metabolic causes include acute fatty liver of pregnancy, HELLP syndrome (hemolysis, elevated liver function tests, and low platelets), Reye syndrome, and Wilson disease. Other causes include autoimmune hepatitis, metastatic liver infiltration, heatstroke, and sepsis. The cause cannot be determined in up to 20% of cases.


In acute liver failure, multiple organ systems malfunction, often for unknown reasons and by unknown mechanisms. Affected systems include

  • Hepatic: Hyperbilirubinemia is almost always present at presentation. The degree of hyperbilirubinemia is one indicator of the severity of liver failure. Coagulopathy due to impaired hepatic synthesis of coagulation factors is common. Hepatocellular necrosis, indicated by increased aminotransferase levels, is present.

  • Cardiovascular: Peripheral vascular resistance and BP decrease, causing hyperdynamic circulation with increased heart rate and cardiac output.

  • Cerebral:Portosystemic encephalopathy occurs, possibly secondary to increased ammonia production by nitrogenous substances in the gut. Cerebral edema is common among patients with severe encephalopathy secondary to acute liver failure; uncal herniation is possible and usually fatal.

  • Renal: For unknown reasons, acute kidney injury occurs in up to 50% of patients. Because BUN level depends on hepatic synthetic function, the level may be misleadingly low; thus, the creatinine level better indicates kidney injury. As in hepatorenal syndrome, urine sodium and fractional sodium excretion decrease even when diuretics are not used and tubular injury is absent (as may occur when acetaminophen toxicity is the cause).

  • Immunologic: Immune system defects develop; they include defective opsonization, deficient complement, and dysfunctional WBCs and killer cells. Bacterial translocation from the GI tract increases. Respiratory and urinary tract infections and sepsis are common; pathogens can be bacterial, viral, or fungal.

  • Metabolic: Metabolic and respiratory alkalosis may occur early. If shock develops, metabolic acidosis can supervene. Hypokalemia is common, in part because sympathetic tone is decreased and diuretics are used. Hypophosphatemia and hypomagnesemia can develop. Hypoglycemia may occur because hepatic glycogen is depleted and gluconeogenesis and insulin degradation are impaired.

  • Pulmonary: Noncardiogenic pulmonary edema may develop.

Symptoms and Signs

Characteristic manifestations are altered mental status (usually part of portosystemic encephalopathy), bleeding, purpura, jaundice, and ascites. Other symptoms may be nonspecific (eg, malaise, anorexia) or result from the causative disorder. Fetor hepaticus (a musty or sweet breath odor) and motor dysfunction are common. Tachycardia, tachypnea, and hypotension may occur with or without sepsis. Signs of cerebral edema can include obtundation, coma, bradycardia, and hypertension. Patients with infection sometimes have localizing symptoms (eg, cough, dysuria), but these symptoms may be absent.


  • Prolongation of PT and/or clinical manifestations of encephalopathy in patients with hyperbilirubinemia and elevated aminotransferase levels

  • To determine the cause: History of drug use, exposure to toxins, hepatitis virus serologic tests, autoimmune markers, and other tests based on clinical suspicion

Acute liver failure should be suspected if patients have acute jaundice, unexplained bleeding, or changes in mental status (possibly suggesting encephalopathy) or if patients with known liver disease quickly deteriorate in any way.

Laboratory tests to confirm the presence and severity of liver failure include liver enzyme and bilirubin levels and PT. Acute liver failure is usually considered confirmed if sensorium is altered or PT is prolonged by > 4 sec or if INR is > 1.5 in patients who have clinical and/or laboratory evidence of acute liver injury. Evidence of cirrhosis suggests that liver failure is chronic.

Patients with acute liver failure should be tested for complications. Tests usually done during the initial evaluation include CBC, serum electrolytes (including calcium, phosphate, and magnesium), renal function tests, and urinalysis. If acute liver failure is confirmed, ABGs, amylase and lipase, and blood type and screen should also be done. Plasma ammonia is sometimes recommended for diagnosing encephalopathy or monitoring its severity. If patients have hyperdynamic circulation and tachypnea, cultures (blood, urine, ascitic fluid) and chest x-ray should be done to rule out infection. If patients have impaired or worsening mental status, particularly those with coagulopathy, head CT should be done to rule out intracranial bleeding.

To determine the cause of acute liver failure, clinicians should take a complete history of toxins ingested, including prescription and OTC drugs, herbal products, and dietary supplements. Tests done routinely to determine the cause include

  • Viral hepatitis serologic tests (eg, IgM antibody to hepatitis A virus [IgM anti-HAV], hepatitis B surface antigen [HBsAg], IgM antibody to hepatitis B core antigen [IgM anti-HBcAg], antibody to hepatitis C virus [anti-HCV])

  • Autoimmune markers (eg, antinuclear antibodies [ANA], anti–smooth muscle antibodies, immunoglobulin levels)

Other testing is done based on findings and clinical suspicion, as for the following:

  • Recent travel to developing countries: Tests for hepatitis A, B, D, and E

  • Females of child-bearing age: Pregnancy testing

  • Age < 40 and relatively normal aminotransferase levels: Ceruloplasmin level to check for Wilson disease

  • Suspicion of a disorder with structural abnormalities (eg, Budd-Chiari syndrome, portal vein thrombosis, liver metastases): Ultrasonography and sometimes other imaging

Patients should be monitored closely for complications (eg, subtle changes in vital signs compatible with infection), and the threshold for testing should be low. For example, clinicians should not assume worsening mental status is due to encephalopathy; in such cases, head CT and often bedside glucose testing should be done. Routine laboratory testing (eg, daily PT, serum electrolytes, renal function tests, blood glucose, and ABGs) should be repeated frequently in most cases. However, testing may need to be more frequent (eg, blood glucose q 2 h in patients with severe encephalopathy).


Prediction of prognosis can be difficult. Important predictive variables include

  • Degree of encephalopathy: Worse when encephalopathy is severe

  • Patient age: Worse when age is < 10 or > 40 yr

  • PT: Worse when PT is prolonged

  • Cause of acute liver failure: Better with acetaminophen toxicity, hepatitis A, or hepatitis B than with idiosyncratic drug reactions or Wilson disease

Various scores (usually King's College criteria or Acute Physiologic Assessment and Chronic Health Evaluation II [APACHE II] score) can predict prognosis in populations of patients but are not highly accurate for individual patients.


  • Supportive measures

  • N-Acetylcysteine for acetaminophen toxicity

  • Sometimes liver transplantation

(See also the American Association for the Study of Liver Disease’s practice guideline Management of Acute Liver Failure: Update 2011.)

Whenever possible, patients should be treated in an ICU at a center capable of liver transplantation. Patients should be transported as soon as possible because deterioration can be rapid and complications (eg, bleeding, aspiration, worsening shock) become more likely as liver failure progresses.

Intensive supportive therapy is the mainstay of treatment. Drugs that could worsen manifestations of acute liver failure (eg, hypotension, sedation) should be avoided or used in the lowest possible doses.

For hypotension and acute kidney injury, the goal of treatment is maximizing tissue perfusion. Treatment includes IV fluids and usually, until sepsis is excluded, empiric antibiotics. If hypotension is refractory to about 20 mL/kg of crystalloid solution, clinicians should consider measuring pulmonary capillary wedge pressure to guide fluid therapy. If hypotension persists despite adequate filling pressures, clinicians should consider using pressors (eg, dopamine, epinephrine, norepinephrine).

For encephalopathy, the head of the bed is elevated 30° to reduce risk of aspiration; intubation should be considered early. When selecting drugs and drug doses, clinicians should aim to minimize sedation so that they can monitor the severity of encephalopathy. Propofol is the usual induction drug for intubation because it protects against intracranial hypertension and has a brief duration of action, allowing rapid recovery from sedation. Lactulose may be helpful for encephalopathy, but it is not given by mouth or nasogastric tube to patients who have altered mental status unless they are intubated; the dose is 50 mL q 1 to 2 h po until patients have ≥ 2 stools/day, or 300 mL in 1 L of saline can be given rectally. Measures are taken to avoid increasing intracranial pressure (ICP) and avoid decreasing cerebral perfusion pressure:

  • To avoid sudden increases in ICP: Stimuli that could trigger a Valsalva maneuver are avoided (eg, lidocaine is given before endotracheal suctioning to prevent the gag reflex).

  • To temporarily decrease cerebral blood flow: Mannitol (0.5 to 1 g/kg, repeated once or twice as needed) can be given to induce osmotic diuresis, and possibly brief hyperventilation can be used, particularly when herniation is suspected.

  • To monitor ICP: It is not clear whether or when the risks of ICP monitoring (eg, infection, bleeding) outweigh the benefits of being able to detect cerebral edema early and being able to use ICP to guide fluid and pressor therapy; some experts recommend such monitoring if encephalopathy is severe. Goals of treatment are an ICP of < 20 mm Hg and a cerebral perfusion pressure of > 50 mm Hg.

Seizures are treated with phenytoin; benzodiazepines are avoided or used only in low doses because they cause sedation.

Infection is treated with antibacterial and/or antifungal drugs; treatment is started as soon as patients show any sign of infection (eg, fever; localizing signs; deterioration of hemodynamics, mental status, or renal function). Because signs of infection overlap with those of acute liver failure, infection is likely to be overtreated pending culture results.

Electrolyte deficiencies may require supplementation with sodium, potassium, phosphate, or magnesium.

Hypoglycemia is treated with continuous glucose infusion (eg, 10% dextrose), and blood glucose should be monitored frequently because encephalopathy can mask the symptoms of hypoglycemia.

Coagulopathy is treated with fresh frozen plasma if bleeding occurs, if an invasive procedure is planned, or possibly if coagulopathy is severe (eg, INR > 7). Fresh frozen plasma is otherwise avoided because it may result in volume overload and worsening of cerebral edema. Also, when it is used, clinicians cannot follow changes in PT, which are important because PT is an index of severity of acute liver failure and is thus sometimes a criterion for transplantation. Recombinant factor VII is sometimes used instead of or with fresh frozen plasma in patients with volume overload. Its role is evolving. H2 blockers may help prevent GI bleeding.

Nutritional support may be necessary if patients cannot eat. Severe protein restriction is unnecessary; 60 g/day is recommended.

Acute acetaminophen overdose is treated with N-acetylcysteine. Because chronic acetaminophen toxicity can be difficult to diagnose, use of N-acetylcysteine should be considered if no cause for acute liver failure is evident. Whether N-acetylcysteine has a slight beneficial effect on patients with acute liver failure due to other conditions is under study.

Liver transplantation results in average 1-yr survival rates of about 80%. Transplantation is thus recommended if prognosis without transplantation is worse. However, prediction is difficult and scores, such as King's College criteria and the APACHE II score, are not sufficiently sensitive and specific to be used as the only criteria for transplantation; thus, they are used as adjuncts to clinical judgment (eg, based on risk factors).

Key Points

  • The most common causes of acute liver failure are viral hepatitis (in developing countries) and drugs and toxins (in developed countries).

  • Acute liver failure is characterized by jaundice, coagulopathy, and encephalopathy.

  • Confirm the diagnosis by finding prolongation of PT or clinical manifestations of encephalopathy in patients with hyperbilirubinemia and elevated aminotransferase levels.

  • Determine the cause by assessing history of drug use and exposure to toxins and doing hepatitis virus serologic tests, autoimmune markers, and other tests based on clinical suspicion.

  • Treat complications intensively, usually in an ICU.

  • Consider N-acetylcysteine for acetaminophen-induced liver failure and liver transplantation for patients with poor prognostic factors (eg, age < 10 or > 40, severe encephalopathy, severe prolongation of PT, idiosyncratic drug reaction, Wilson disease).

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • No US brand name