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Overall, the most common causes of acute liver failure are

• Viruses, primarily hepatitis B

• Drugs and toxins, most commonly acetaminophen

In countries with poor sanitation, viral hepatitis is usually considered the most common cause; in countries where there is effective sanitation, toxins are usually considered the most common cause.

Overall, the most common viral cause is hepatitis B, often with hepatitis D coinfection; 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, 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 antibiotics (notably, amoxicillin/clavulanate), halothane, iron compounds, isoniazid, nonsteroidal anti-inflammatory drugs (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

• Autoimmune hepatitis

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 values on liver 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 blood pressure 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 blood urea nitrogen (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 white blood cells and killer cells. Bacterial translocation from the gastrointestinal tract increases. Respiratory and urinary tract infections and sepsis are common; pathogens can be bacterial, viral, or fungal.

• Metabolic: Both 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.

Characteristic manifestations are altered mental status (usually part of portosystemic encephalopathy) and jaundice. Manifestations of chronic liver disease such as ascites argue against the acuity of the condition but can be present in subacute liver failure. 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. Despite prolonged international normalized ratio (INR), bleeding is rare unless patients are in disseminated intravascular coagulation (DIC). This is because patients with acute liver failure have a re-balanced distribution of pro- and anticoagulant factors and, if anything, these patients are more frequently hypercoagulable (1, 2).

• Prolongation of international normalized ratio (INR) to ≥ 1.5 and clinical manifestations of encephalopathy in patients without prior history of chronic liver disease

• 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 without underlying chronic liver disease or cirrhosis have acute onset of jaundice and/or elevated transaminases that is accompanied by coagulopathy and mental status changes. Patients with known liver disease who acutely decompensate are not considered to have acute liver failure but rather acute-on-chronic liver failure, which has different pathophysiology from that of acute liver failure.

Laboratory tests to confirm the presence and severity of liver failure include liver enzyme and bilirubin levels and INR. Acute liver failure is usually considered confirmed if sensorium is altered and 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 complete blood count (CBC), serum electrolytes (including calcium, phosphate, and magnesium), renal function tests, and urinalysis. If acute liver failure is confirmed, arterial blood gases (ABGs), and blood type and screen should also be done. Plasma ammonia is recommended to help predict prognosis because higher ammonia levels (> 150 to 200) predict increased risk of cerebral edema (1). 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 cerebral edema or less likely intracranial bleeding.

To determine the cause of acute liver failure, clinicians should take a complete history of toxins ingested, including prescription and over-the-counter 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, anti–smooth muscle antibodies, immunoglobulin levels)

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

• Recent travel to countries where sanitation is poor: Tests for hepatitis A, B, D, and E

• Females of child-bearing age: Pregnancy testing

• Age < 40, hemolytic anemia, and a pattern showing a low alkaline phosphatase level with alkaline phosphatase/total bilirubin ratio < 4 and the aspartate aminotransferase (AST) level greater than the alanine aminotransferase (ALT) level, with elevations in ALT and AST (although usually < 2000): check ceruloplasmin level 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. Because of the high risk of infection, the American Association for the Study of Liver Diseases (AASLD) suggests considering surveillance blood cultures every 48 hours. Routine laboratory testing (eg, daily INR, 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 every 2 hours in patients with severe encephalopathy).

• Supportive measures

• N-Acetylcysteine for acetaminophen toxicity

• Sometimes liver transplantation

(See also the American Association for the Study of Liver Diseases [AASLD] practice guideline Management of Acute Liver Failure: Update 2011 and the European Association for the Study of the Liver Practical Guidelines on the Management of Acute [Fulminant] Liver Failure.)

Whenever possible, patients should be treated in an intensive care unit 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. There is no evidence that treatments such as lactulose or rifaximin help alleviate encephalopathy in acute liver failure, although they are useful in portosystemic encephalopathy. Also, lactulose can cause ileus and produce gas that distends the intestines, which can be problematic if laparotomy is needed (eg, for liver transplantation) (1). 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. (However, mannitol is contraindicated with acute kidney injury and serum osmolality must be checked before giving a second dose.)

• 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. However, no data indicate that ICP monitoring impacts mortality (2). Goals of treatment are an ICP of < 20 mm Hg and a cerebral perfusion pressure of > 50 mm Hg.

• To reduce cerebral edema: Renal replacement therapy in acute liver failure helps clear ammonia and predicts reduced mortality if initiated early. The European Association for the Study of the Liver (EASL) guidelines on acute liver failure recommend consideration of renal replacement therapy in patients with liver failure and markedly elevated ammonia and/or progressive encephalopathy (1).

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 or if an invasive procedure is planned. Fresh frozen plasma is otherwise avoided because it may result in volume overload and worsening of cerebral edema. Also, when fresh frozen plasma is used, clinicians cannot follow changes in international normalized ratio (INR), which are important because INR 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 gastrointestinal bleeding.

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

Acute acetaminophen toxicity 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-year survival rates of about 84% (3). 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 (Acute Physiologic Assessment and Chronic Health Evaluation 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).

Further information regarding acute liver failure can be found in the European Association for the Study of the Liver (EASL) guidelines.

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 years

• PT: Worse when INR 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 (for example, 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.