Acute Liver Failure 

Acute liver failure (ALF) is an uncommon condition in which the rapid deterioration of liver function results in coagulopathy and alteration in the mental status of a previously healthy individual. Acute liver failure often affects young people and carries a very high mortality.

The term acute liver failure is used to describe the development of coagulopathy, usually with an international normalized ratio (INR) of greater than 1.5, and any degree of mental alteration (encephalopathy) in a patient without preexisting cirrhosis and with an illness of less than 26 weeks' duration.

Acute liver failure is a broad term that encompasses both fulminant hepatic failure (FHF) and subfulminant hepatic failure (or late-onset hepatic failure). Fulminant hepatic failure is generally used to describe the development of encephalopathy within 8 weeks of the onset of symptoms in a patient with a previously healthy liver. Subfulminant hepatic failure is reserved for patients with liver disease for up to 26 weeks before the development of hepatic encephalopathy.

There are important differences between FHF in children and FHF in adults. For example, in children with FHF, encephalopathy may be absent, late, or unrecognized. For a full discussion of the diagnosis and management of pediatric FHF, see Fulminant Hepatic Failure. The American Association for the Study of Liver Diseases has produced guidelines on the management of acute liver failure in adults.^[1]

Some patients with previously unrecognized chronic liver disease decompensate and present with liver failure; although this is not technically FHF, discriminating such at the time of presentation may not be possible. Patients with Wilson disease, vertically acquired hepatitis B, or autoimmune hepatitis may be included in spite of the possibility of cirrhosis if their disease has been manifest for less than 26 weeks.

The most important step in the assessment of patients with acute liver failure is to identify the cause, as certain causes demand immediate and specific treatment (see Workup). Drug-related hepatotoxicity, especially from acetaminophen, is the leading cause of acute liver failure in the United States (see Etiology).

The most important aspect of treatment is to provide good intensive care support. Careful attention should be paid to fluid management and hemodynamics. Monitoring of metabolic parameters, surveillance for infection, maintenance of nutrition, and prompt recognition of gastrointestinal bleeding are crucial (see Treatment and Management).

Various medications may be necessary because of the variety of complications that occur from fulminant hepatic failure. In specific cases, antidotes that effectively bind or eliminate toxins are essential (see Medication).

The development of liver support systems provides some promise for patients with FHF, although it remains a temporary measure and, to date, has no impact on survival. Other investigational therapeutic modalities, including hypothermia, have been proposed but remain unproven.^{[2, 3]}

The outcome of acute liver failure is related to the etiology, the degree of encephalopathy, and related complications (see Prognosis). Although mortality from FHF remains significantly high, improved intensive care and use of orthotopic liver transplantation have improved survival from less than 20% to approximately 60%.^{[4, 5]}

For patient education information, see eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center, as well as Hepatitis A, Hepatitis B, Hepatitis C, and Cirrhosis.

The development of cerebral edema is the major cause of morbidity and mortality in patients with acute liver failure.^{[2, 6, 7]} The etiology of this intracranial hypertension (ICH) is not fully understood, but it is considered to be multifactorial.

Briefly, hyperammonemia may be involved in the development of cerebral edema. Brain edema is thought to be both cytotoxic and vasogenic in origin.

Cytokine profiles are also deranged. Elevated serum concentrations of bacterial endotoxin, tumor necrosis factor–alpha (TNF-α), and interleukin (IL)–1 and IL-6 have been found in fulminant hepatic failure.

Cytotoxic edema

Cytotoxic edema is the consequence of impaired cellular osmoregulation in the brain, resulting in astrocyte edema. Cortical astrocyte swelling is the most common observation in neuropathologic studies of brain edema in acute liver failure.

In the brain, ammonia is detoxified to glutamine via amidation of glutamate by glutamine synthetase. The accumulation of glutamine in astrocytes results in astrocyte swelling and brain edema. There is clear evidence of increased brain concentration of glutamine in animal models of acute liver failure. The relationship between high ammonia and glutamine levels and raised ICH has been reported in humans.

Vasogenic factors

An increase of intracranial blood volume and cerebral blood flow is a factor in acute liver failure. The increased cerebral blood flow results because of disruption of cerebral autoregulation. The disruption of cerebral autoregulation is thought to be mediated by elevated systemic concentrations of nitric oxide, which acts as a potent vasodilator.

Multisystem organ failure

Another consequence of fulminant hepatic failure is multisystem organ failure, which is often observed in the context of a hyperdynamic circulatory state that mimics sepsis (low systemic vascular resistance); therefore, circulatory insufficiency and poor organ perfusion possibly either initiate or promote complications of fulminant hepatic failure.

Acetaminophen hepatotoxicity

The development of liver failure represents the final common outcome of a wide variety of potential causes, as the broad differential diagnosis suggests (see Diagnosis). As with many drugs that undergo hepatic metabolism (in this case, by cytochrome P-450), the oxidative metabolite of acetaminophen is more toxic than the drug.^{[5, 8, 9, 10]} The highly reactive active metabolite N -acetyl-p-benzoquinone-imine (NAPQI) appears to mediate much of the acetaminophen-related damage to liver tissue by forming covalent bonds with cellular proteins.

Ordinarily, NAPQI is metabolized in the presence of glutathione to N -acetyl-p-aminophenol-mercaptopurine. Glutathione quenches this reactive metabolite and acts to prevent nonspecific oxidation of cellular structures, which might result in severe hepatocellular dysfunction.

This mechanism fails in 2 different yet equally important settings. The first is an overdose (accidental or intentional) of acetaminophen. Acetaminophen ingestion of more than 10 g simply overwhelms normal hepatic stores of glutathione, allowing reactive metabolites to escape.

The second and less obvious scenario occurs with a patient who consumes alcohol regularly. This does not necessarily require a history of alcohol abuse or alcoholism. Even a moderate or social drinker who consistently consumes 1-2 drinks daily may sufficiently deplete intrahepatic glutathione reserves. This results in potentially lethal hepatotoxicity from what is otherwise a safe dose of acetaminophen (below the maximum total dose of 4 g/d) in an unsuspecting individual.Patients with acute liver failure may have unrecognized or uncertain acetaminophen toxicity.^[11]

Numerous causes of fulminant hepatic failure exist, but hepatotoxicity due to acetaminophen and idiosyncratic drug reactions is the most common cause in the United States. For nearly 15% of patients, the cause remains indeterminate.

Viral hepatitis may lead to hepatic failure. Hepatitis A and B account for most of these cases. In the developing world, acute hepatitis B virus (HBV) infection dominates as a cause of fulminant hepatic failure because of the high prevalence of the disease.

Hepatitis C rarely causes acute liver failure. Hepatitis D, as a co-infection or superinfection with hepatitis B virus, can lead to fulminant hepatic failure. Hepatitis E (often observed in pregnant women) in endemic areas is an important cause of fulminant hepatic failure.

Atypical causes of viral hepatitis and fulminant hepatic failure include the following:

• Cytomegalovirus
• Hemorrhagic fever viruses
• Herpes simplex virus
• Paramyxovirus
• Epstein-Barr virus

Autoimmune hepatitis may also result in hepatic failure.

Hepatic failure in pregnancy

Acute fatty liver of pregnancy (AFLP) frequently culminates in fulminant hepatic failure. AFLP typically occurs in the third trimester; preeclampsia develops in approximately 50% of these patients. AFLP has been estimated to occur in 0.008% of pregnancies.

The most common cause of acute jaundice in pregnancy is acute viral hepatitis, and most of these patients do not develop fulminant hepatic failure. The one major exception to this is the pregnant patient who develops hepatitis E virus infection, in whom progression to fulminant hepatic failure is unfortunately common and often fatal.

The exposure history in patients with hepatitis E is usually remarkable for travel and/or residence in the Middle East, India and the subcontinent, Mexico, or other endemic areas. In the United States, hepatitis E is relatively uncommon but must be considered in the appropriate setting.

The HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome occurs in 0.1-0.6% of pregnancies. It is usually associated with preeclampsia and may rarely result in liver failure.

Drug-related hepatotoxicity

Many drugs (both prescription and illicit) are implicated in the development of fulminant hepatic failure. The more common agents are discussed below.

Idiosyncratic drug reactions may occur with virtually any medication. Fortunately, these appear to lead to fulminant hepatic failure only rarely, although they are the most common form of drug reaction to lead to fulminant hepatic failure (with the exception of acetaminophen poisoning).

Acetaminophen (also known as paracetamol and N -acetyl-p-aminophenol [APAP]) may lead to liver failure as a result of intentional or accidental overdose. In the US Acute Liver Failure (ALF) study, unintentional acetaminophen use accounted for 48% of cases, whereas 44% of cases were due to intentional use; in 8% of cases, the intention was unknown. Chronic alcohol use may greatly increase susceptibility to hepatotoxicity from acetaminophen because of depleted glutathione stores. Some patients with acute liver failure have unrecognized or uncertain acetaminophen toxicity. These case have been diagnosed by highly specific acetaminophen-cysteine adducts assay. But this assay is currently not available for routine clinical use.

Prescription medications that have been associated with idiosyncratic hypersensitivity reactions include the following:

• Antibiotics (ampicillin-clavulanate, ciprofloxacin, doxycycline, erythromycin, isoniazid, nitrofurantoin, tetracycline)
• Antidepressants (amitriptyline, nortriptyline)
• Antiepileptics (phenytoin, valproate)
• Anesthetic agents (halothane)
• Lipid-lowering medications (atorvastatin, lovastatin, simvastatin)
• Immunosuppressive agents (cyclophosphamide, methotrexate)
• Nonsteroidal anti-inflammatory agents (NSAIDs)
• Salicylates (as a result of Reye syndrome)
• Others (disulfiram, flutamide, gold, propylthiouracil)

Illicit drugs that have been associated with idiosyncratic hypersensitivity reactions include the following:

• Ecstasy (3,4-methylenedioxymethamphetamine [MDMA])
• Cocaine (may be the result of hepatic ischemia)

Herbal or alternative medicines that have been associated with idiosyncratic hypersensitivity reactions include the following:

• Ginseng
• Pennyroyal oil
• Teucrium polium
• Chaparral or germander tea
• Kawakawa

Toxin-related hepatotoxicity

The following toxins are associated with dose-related toxicity:

• Amanita phalloides mushroom toxin^[12]
• Bacillus cereus toxin
• Cyanobacteria toxin
• Organic solvents (eg, carbon tetrachloride)
• Yellow phosphorus

A phalloides mushroom intoxication is much more common in Europe and in California than in the remainder of the United States.

Vascular causes

The following are vascular causes of hepatic failure:

• Ischemic hepatitis (consider especially in the setting of severe hypotension or recent hepatic tumor chemoembolization)
• Hepatic vein thrombosis (Budd-Chiari syndrome)
• Hepatic veno-occlusive disease
• Portal vein thrombosis
• Hepatic arterial thrombosis (consider posttransplant)

Metabolic causes

The following metabolic diseases can cause hepatic failure:

• Alpha1-antitrypsin deficiency
• Fructose intolerance
• Galactosemia
• Lecithin-cholesterol acyltransferase deficiency
• Reye syndrome
• Tyrosinemia
• Wilson disease

Malignancies

Malignancies that can cause hepatic failure include the following:

• Primary liver tumor (usually hepatocellular carcinoma, rarely cholangiocarcinoma)
• Secondary tumor (extensive hepatic metastases or infiltration from adenocarcinoma, such as breast, lung, melanoma primaries [common]; lymphoma; leukemia)

Miscellaneous

Miscellaneous causes of hepatic failure include adult-onset Still disease, heatstroke, and primary graft nonfunction in liver transplant recipients.

The incidence of fulminant hepatic failure appears to be low in the United States, with approximately 2000 cases annually. Drug-related hepatotoxicity accounts for more than 50% of acute liver failure cases, including acetaminophen toxicity (42%) and idiosyncratic drug reactions (12%). Nearly 15% of cases remain of indeterminate etiology. Other causes seen in the United States are hepatitis B, autoimmune hepatitis, Wilson disease, fatty liver of pregnancy, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome.

International statistics

Acetaminophen (paracetamol) overdoses are prominent causes of fulminant hepatic failure in Europe and, in particular, Great Britain. Hepatitis delta virus (HDV) superinfection is much more common in developing countries than in the United States because of the high rate of chronic HBV infection.

Hepatitis E virus (HEV) is associated with a high incidence of fulminant hepatic failure in women who are pregnant and is of concern in pregnant patients living in or traveling through endemic areas. These regions include, but are not limited to, Mexico and Central America, India and the subcontinent, and the Middle East.

Racial distribution of acute liver failure

Acute liver failure is seen among all races. In a US multicenter study of acute liver failure, the ethnic distribution included whites (74%), Hispanics (10%), blacks (3%), Asians (5%), and Latin Americans (2%).^{[9, 10, 13]}

Acute liver failure in women

Viral hepatitis E and autoimmune liver disease are more common in women than in men. In a US multicenter study group, acute liver failure was seen more often in women (73%) than in men, and women with acute liver failure were older (39 y) than men (32.5 y).

Age and liver failure

Age may be pertinent to morbidity and mortality in those with acute liver failure. Patients younger than 10 years and older than 40 years tend to fare relatively poorly.

Before orthotopic liver transplantation (OLT) for fulminant hepatic failure, the mortality rate was generally greater than 80%. Approximately 6% of OLTs performed in the United States are for fulminant hepatic failure. However, with improved intensive care, the prognosis is much better now than in the past, with some series reporting a survival rate of approximately 60%.

The etiologic factor and the development of complications are the main determinants of outcome in acute liver failure. Patients with acute liver failure caused by acetaminophen have a better prognosis than those with an indeterminate form of the disorder. Patients with stage 3 or 4 encephalopathy have a poor prognosis. The risk of mortality increases with the development of any of the complications, which include cerebral edema, renal failure, adult respiratory distress syndrome (ARDS), coagulopathy, and infection.

Viral hepatitis

In patients with fulminant hepatic failure due to hepatitis A virus (HAV), survival rates are greater than 50-60%. These patients account for a substantial proportion (10-20%) of the pediatric liver transplants in some countries despite the relatively mild infection that is observed in many children infected with HAV. The outcome for patients with fulminant hepatic failure as the result of other causes of viral hepatitis is much less favorable.

Acetaminophen toxicity

Fulminant hepatic failure due to acetaminophen toxicity generally has a relatively favorable outcome, and prognostic variables permit reasonable accuracy in determining the need for orthotopic liver transplantation (OLT). Patients in deep coma (hepatic encephalopathy grades 3-4) on admission have a higher mortality than patients with milder encephalopathy. An arterial pH of lower than 7.3 and either a prothrombin time (PT) greater than 100 seconds or serum creatinine greater than 300 mcg/mL (3.4 mg/dL) are independent predictors of poor prognosis.

Non-acetaminophen-induced fulminant hepatic failure

In non-acetaminophen-induced fulminant hepatic failure, a PT of greater than 100 seconds and any 3 of the following 5 criteria are independent predictors^[14] of a poor prognosis:

• Age younger than 10 years or older than 40 years
• Fulminant hepatic failure due to non-A, non-B, non-C hepatitis; halothane hepatitis; or idiosyncratic drug reactions
• Jaundice present longer than 1 week before onset of encephalopathy
• PT greater than 50 seconds
• Serum bilirubin greater than 300 mmol/L (17.5 mg/dL)

In patients who meet 3 or more of these criteria, preparations for OLT should be arranged.

The above criteria were developed at King's College Hospital in London^[14] and have been validated in other centers. However, significant variability occurs in terms of the patient populations encountered at any center, and this heterogeneity may preclude widespread applicability.

Many other prognosticating tests have been proposed. The combination of reduced levels of group-specific component (Gc)-globulin (a molecule that binds actin) is reported in fulminant hepatic failure,^{[15, 16]} and a persistently increasing PT portends death. These and other parameters are not validated widely yet.

Wilson disease

Wilson disease that presents as fulminant hepatic failure is almost uniformly fatal unless the patient undergoes OLT.

Onset of encephalopathy

Paradoxically, rapid progression from onset of jaundice (usually the first unequivocal sign of liver disease recognized by the patient or family) to encephalopathy is associated with improved survival. When this interval is less than 2 weeks, patients have hyperacute liver failure. Although the grade of encephalopathy is a prognostic factor in cases of acetaminophen overdose, it does not correlate with outcome in other settings.