eMedicine Specialties > Gastroenterology > Liver

Acute Liver Failure

Author: Gagan K Sood, MD, Associate Professor, Department of Medicine and Surgery, Baylor College of Medicine
Contributor Information and Disclosures

Updated: Jun 25, 2009

Introduction

Background

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 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 and 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.

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 virus (HBV), or autoimmune hepatitis may be included in spite of the possibility of cirrhosis if their disease has been less than 26 weeks.

Drug-related hepatotoxicity is the leading cause of acute liver failure in the United States. The outcome of acute liver failure is related to the etiology, the degree of encephalopathy, and related complications. Unfortunately, despite aggressive treatment, many patients die from fulminant hepatic failure.^1,2  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 approximately a survival rate of 60%.

The development of liver support systems provides some promise for this particular circumstance, 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.^3,4

For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles Hepatitis A, Hepatitis B, Hepatitis C, and Cirrhosis.

Pathophysiology

The development of cerebral edema is the major cause of morbidity and mortality of patients suffering from acute liver failure.^3,5,6 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. 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 among high ammonia, glutamine, and raised ICH has been reported in humans.

Another phenomenon that has been involved in acute liver failure is the increase of intracranial blood volume and cerebral blood flow. 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. However, in this setting, cytokine profiles are also deranged. Elevated serum concentrations of bacterial endotoxin, tumor necrosis factor-alpha (TNF-a), and interleukin-1 (IL-1) and -6 (IL-6) have been found in fulminant hepatic 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.

The development of liver failure represents the final common outcome of a wide variety of potential causes, as the broad differential diagnosis suggests (see Other Problems to Be Considered). A complete discussion is beyond the scope of this article, and the reader is directed to consult the literature dealing specifically with these underlying etiologic factors. However, mechanisms of acetaminophen hepatotoxicity are worth discussing briefly.

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.^2,7,8,9 An active metabolite, N -acetyl-p-benzoquinone-imine (NAPQI), appears to mediate much of the damage to liver tissue by forming covalent bonds with cellular proteins. Therefore, the presence of highly reactive free radicals following acetaminophen ingestion poses a threat to the liver parenchyma, but it is usually addressed adequately by intrahepatic glutathione reserves. The reduced glutathione quenches the reactive metabolites and acts to prevent nonspecific oxidation of cellular structures that may 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. This simply overwhelms the 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.

Frequency

United States

The incidence of fulminant hepatic failure appears to be low, with approximately 2000 cases annually occurring in the United States. Drug-related hepatotoxicity comprises 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 disease, autoimmune hepatitis, Wilson disease, fatty liver of pregnancy, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome.

International

Acetaminophen or paracetamol overdoses are prominent causes of FHF in Europe and, in particular, Great Britain. In the developing world, acute HBV infection dominates as a cause of fulminant hepatic failure because of the high prevalence of HBV. 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.

Mortality/Morbidity

Several factors contribute to morbidity and mortality in cases of liver failure.

The etiologic factor leading to liver failure and the development of complications are the main determinants of 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 OLT. Patients presenting with deep coma (hepatic encephalopathy grades 3-4) on admission have increased mortality compared with 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 predictors¹⁰ : (1) age younger than 10 years or older than 40 years; (2) fulminant hepatic failure due to non-A, non-B, non-C hepatitis; halothane hepatitis; or idiosyncratic drug reactions;, (3) jaundice present longer than 1 week before onset of encephalopathy; (4) PT greater than 50 seconds; and (5) serum bilirubin greater than 300 mmol/L (17.5 mg/dL). Once these patients are identified, arrange appropriate preparations for OLT.
  • The above criteria were developed at King's College Hospital in London¹⁰ 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. Reduced levels of group-specific component (Gc)-globulin (a molecule that binds actin) are reported in fulminant hepatic failure,^11,12 and a persistently increasing PT portends death. These and other parameters are not validated widely yet.
• Wilson disease: When this condition presents as fulminant hepatic failure without OLT, it is almost uniformly fatal.
• Age: Patients younger than 10 years and older than 40 years tend to fare relatively poorly.
• Rate of development and degree of encephalopathy: A short time from jaundice (usually the first unequivocal sign of liver disease recognized by the patient or family) to encephalopathy is associated paradoxically 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.

Race

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%).^8,9,13

Sex

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.

Age

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. According to a US multicenter study group, women with acute liver failure were older (39 y) than men (32.5 y).

Clinical

History

All patients with clinical or laboratory evidence of moderate or severe acute hepatitis should have immediate measurement of prothrombin time (PT) and careful evaluation of mental status. The patients should be admitted to the hospital if there is alteration in mental sensorium or prothrombin time is prolonged.

• Clinical features may be self-evident and lead to a rapid diagnosis of acute liver failure.
• The patient history is valuable for guiding appropriate interventions.
  • If the patient is incapacitated, closely question family members and friends.
  • Detail the date of onset of jaundice and encephalopathy, alcohol use, medication use (prescription and illicit or recreational), herbal or traditional medicine use, family history of liver disease (Wilson disease), exposure risk factors for viral hepatitis (travel, transfusions, sexual contacts, occupation, body piercing), and toxin ingestion (mushrooms, organic solvents, phosphorus contained in fireworks).
  • Determine if any complications have developed.

Physical

• Physical examination includes careful assessment and documentation of mental status and search for stigmata of chronic liver disease. Jaundice is often but not always present. Right upper quadrant tenderness is variably present. The liver span may be small, indicative of significant loss of volume due to hepatic necrosis. An enlarged liver may be seen with congestive heart failure, viral hepatitis, or Budd-Chiari syndrome.
• Development of cerebral edema ultimately may give rise to manifestations of increased intracranial pressure (ICP), including papilledema, hypertension, and bradycardia.
• The rapid development of ascites, especially if observed in a patient with fulminant hepatic failure accompanied by abdominal pain, suggests the possibility of hepatic vein thrombosis (Budd-Chiari syndrome).
• Hematemesis or melena may complicate the presentation of fulminant hepatic failure as a result of upper gastrointestinal (GI) bleeding.
• Typically, patients are hypotensive and tachycardic as a result of the reduced systemic vascular resistance that accompanies fulminant hepatic failure, a pattern that is indistinguishable from septic shock. Although this may be intrinsic to hepatic failure, considering the possibility of a superimposed infection (especially spontaneous bacterial peritonitis) is important.

Table. Grading of Hepatic Encephalopathy

Open table in new window

Causes

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

• Hepatitis A and B are the typical viruses that cause viral hepatitis and may lead to hepatic failure. Hepatitis C rarely causes acute liver failure. HDV (co-infection or superinfection with HBV) can lead to fulminant hepatic failure. HEV (often observed in pregnant women) in endemic areas is an important cause of fulminant hepatic failure.
• Other atypical viruses can cause viral hepatitis and fulminant hepatic failure.
  • Cytomegalovirus
  • Hemorrhagic fever viruses
  • Herpes simplex virus
  • Paramyxovirus
  • Epstein-Barr virus
• The incidence of acute fatty liver of pregnancy, frequently culminating in fulminant hepatic failure, has been estimated to be 0.008% (typically in the third trimester; preeclampsia develops in approximately 50% of these patients). However, 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 HEV infection and in whom an exposure history is usually remarkable for travel and/or residence in the Middle East, India and the subcontinent, Mexico, or other endemic areas. In these patients, progression to fulminant hepatic failure is unfortunately common and often fatal. In the United States, it is relatively uncommon but must be considered in the appropriate setting.
• The HELLP syndrome occurs in 0.1-0.6% of pregnancies and is usually associated with preeclampsia.
• Incidence of fulminant hepatic failure following other liver diseases is less well established.
• Many drugs (both prescription and illicit) are implicated in the development of FHF. The list provided is incomplete, and only the more common agents are identified. Consult an appropriate pharmacy reference text if concerns exist regarding a specific medication. 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).
  • Drug toxicity – Acetaminophen (also known as paracetamol and APAP)
    • 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.
    • Dose-related toxicity
    • May have greatly increased susceptibility to hepatotoxicity with depleted glutathione stores in the setting of chronic alcohol use (consider increased susceptibility due to chronic alcohol use)
  • Prescription medications (idiosyncratic hypersensitivity reactions)
    • Antibiotics (ampicillin-clavulanate, ciprofloxacin, doxycycline, erythromycin, isoniazid, nitrofurantoin, tetracycline)
    • Antivirals (fialuridine)
    • Antidepressants (amitriptyline, nortriptyline)
    • Antidiabetics (troglitazone)
    • Antiepileptics (phenytoin, valproate)
    • Anesthetic agents (halothane)
    • Lipid-lowering medications (atorvastatin, lovastatin, simvastatin)
    • Immunosuppressive agents (cyclophosphamide, methotrexate)
    • Nonsteroidal anti-inflammatory agents (NSAIDs)
    • Salicylates (Reye syndrome)
    • Oral hypoglycemic agents (troglitazone)
    • Others (disulfiram, flutamide, gold, propylthiouracil)
  • Illicit drugs
    • Ecstasy (3,4-methylenedioxymethamphetamine [MDMA])
    • Cocaine (may be the result of hepatic ischemia)
  • Herbal or alternative medicines
    • Ginseng
    • Pennyroyal oil
    • Teucrium polium
    • Chaparral or germander tea
    • Kawakawa
• The following toxins are associated with dose-related toxicity:
  • Amanita phalloides mushroom toxin¹⁴
  • Bacillus cereus toxin
  • Cyanobacteria toxin
  • Organic solvents (eg, carbon tetrachloride)
  • Yellow phosphorus
• The following are vascular causes of hepatic failure:
  • Ischemic hepatitis (consider especially if 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)
• The following metabolic diseases can cause hepatic failure:
  • Acute fatty liver of pregnancy
  • Alpha1 antitrypsin deficiency
  • Fructose intolerance
  • Galactosemia
  • Lecithin-cholesterol acyltransferase deficiency
  • Reye syndrome
  • Tyrosinemia
  • Wilson disease
• Autoimmune disease (autoimmune hepatitis) can cause hepatic failure.
• Malignancy can cause of hepatic failure.
  • 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)
• The following are miscellaneous causes of hepatic failure:
  • Adult-onset Still disease
  • Heat stroke
  • Primary graft nonfunction (in liver transplant recipients)

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