A guide to managing acute liver failure

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ABSTRACTNearly 2,000 cases of acute liver failure occur each year in the United States. This disease carries a high mortality rate, and early recognition and transfer to a tertiary medical care center with transplant facilities is critical. This article reviews the definition, epidemiology, etiology, and management of acute liver failure.


  • In the United States, the most common cause of acute liver failure is acetaminophen toxicity, followed by viral hepatitis.
  • Testing for the cause of acute liver failure needs to start as soon as possible so that specific treatment can be initiated and the patient can be placed on the transplant list if needed.
  • Acetylcysteine and either a proton pump inhibitor or a histamine H2 receptor blocker should be given to all patients with acute liver failure. Liver transplant is the cornerstone of therapy in patients not responding to other treatments.
  • There are a number of prognostic scores for acute liver failure, but each has limitations.



When the liver fails, it usually fails gradually. The sudden (acute) onset of liver failure, while less common, demands prompt management, with transfer to an intensive care unit, specific treatment depending on the cause, and consideration of liver transplant, without which the mortality rate is high.

This article reviews the definition, epidemiology, etiology, and management of acute liver failure.


Acute liver failure is defined as a syndrome of acute hepatitis with evidence of abnormal coagulation (eg, an international normalized ratio > 1.5) complicated by the development of mental alteration (encephalopathy) within 26 weeks of the onset of illness in a patient without a history of liver disease.1 In general, patients have no evidence of underlying chronic liver disease, but there are exceptions; patients with Wilson disease, vertically acquired hepatitis B virus infection, or autoimmune hepatitis can present with acute liver failure superimposed on chronic liver disease or even cirrhosis.

The term acute liver failure has replaced older terms such as fulminant hepatic failure, hyperacute liver failure, and subacute liver failure, which were used for prognostic purposes. Patients with hyperacute liver failure (defined as development of encephalopathy within 7 days of onset of illness) generally have a good prognosis with medical management, whereas those with subacute liver failure (defined as development of encephalopathy within 5 to 26 weeks of onset of illness) have a poor prognosis without liver transplant.2,3


There are nearly 2,000 cases of acute liver failure each year in the United States, and it accounts for 6% of all deaths due to liver disease.4 It is more common in women than in men, and more common in white people than in other races. The peak incidence is at a fairly young age, ie, 35 to 45 years.


The most common cause of acute liver failure in the United States and other Western countries is acetaminophen toxicity, followed by viral hepatitis. In contrast, viral hepatitis is the most common cause in developing countries.5

Acetaminophen toxicity

Patients with acetaminophen-induced liver failure tend to be younger than other patients with acute liver failure.1 Nearly half of them present after intentionally taking a single large dose, while the rest present with unintentional toxicity while taking acetaminophen for pain relief on a long-term basis and ingesting more than the recommended dose.6

After ingestion, 52% to 57% of acetaminophen is converted to glucuronide conjugates, and 30% to 44% is converted to sulfate conjugates. These compounds are nontoxic, water-soluble, and rapidly excreted in the urine.

However, about 5% to 10% of ingested acetaminophen is shunted to the cytochrome P450 system. P450 2E1 is the main isoenzyme involved in acetaminophen metabolism, but 1A2, 3A4, and 2A6 also contribute.7,8 P450 2E1 is the same isoenzyme responsible for ethanol metabolism and is inducible. Thus, regular alcohol consumption can increase P450 2E1 activity, setting the stage under certain circumstances for increased acetaminophen metabolism through this pathway.

Reprinted from Schilling A, Corey R, Leonard M, Eghtesad B. Acetaminophen: old drug, new warnings. Cleve Clin J Med 2010; 77:19–27.
Figure 1.

Metabolism of acetaminophen through the cytochrome P450 pathway results in production of N-acetyl-p-benzoquinone imine (NAPQI), the compound that damages the liver. NAPQI is rendered nontoxic by binding to glutathione, forming NAPQI-glutathione adducts. Glutathione capacity is limited, however. With too much acetaminophen, glutathione becomes depleted and NAPQI accumulates, binds with proteins to form adducts, and leads to necrosis of hepatocytes (Figure 1).9,10

Acetylcysteine, used in treating acetaminophen toxicity, is a substrate for glutathione synthesis and ultimately increases the amount of glutathione available to bind NAPQI and prevent damage to hepatocytes.11

Acetaminophen is a dose-related toxin. Most ingestions leading to acute liver failure exceed 10 g/day (> 150 mg/kg/day). Moderate chronic ingestion, eg, 4 g/day, usually leads to transient mild elevation of liver enzymes in healthy individuals12 but can in rare cases cause acute liver failure.13

Whitcomb and Block14 retrospectively identified 49 patients who presented with acetaminophen-induced hepatotoxicity in 1987 through 1993; 21 (43%) had been taking acetaminophen for therapeutic purposes. All 49 patients took more than the recommended limit of 4 g/day, many of them while fasting and some while using alcohol. Acute liver failure was seen with ingestion of more than 12 g/day—or more than 10 g/day in alcohol users. The authors attributed the increased risk to activation of cytochrome P450 2E1 by alcohol and depletion of glutathione stores by starvation or alcohol abuse.

Advice to patients taking acetaminophen is given in Table 1.

Other drugs and supplements

A number of other drugs and herbal supplements can also cause acute liver failure (Table 2), the most common being antimicrobial and antiepileptic drugs.15 Of the antimicrobials, antitubercular drugs (especially isoniazid) are believed to be the most common causes, followed by trimethoprim-sulfamethoxazole. Phenytoin is the antiepileptic drug most often implicated in acute liver failure.

Statins can also cause acute liver failure, especially when combined with other hepatotoxic agents.16

The herbal supplements and weight-loss agents Hydroxycut and Herbalife have both been reported to cause acute liver failure, with patients presenting with either the hepatocellular or the cholestatic pattern of liver injury.17 The exact chemical in these supplements that causes liver injury has not yet been determined.

The National Institutes of Health maintains a database of cases of liver failure due to medications and supplements at The database includes the pattern of hepatic injury, mechanism of injury, management, and outcomes.

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