Acute Liver Failure

Practice Essentials

Acute liver failure is an uncommon condition in which rapid deterioration of liver function results in coagulopathy, usually with an international normalized ratio (INR) of greater than 1.5, and alteration in the mental status (encephalopathy) of a previously healthy individual. Acute liver failure often affects young people and carries a very high mortality.

The ultrasonogram shows a hyperechoic mass representing hepatocellular carcinoma.

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Ultrasonogram shows a hyperechoic mass representing hepatocellular carcinoma.

Signs and symptoms

Acute liver failure is a broad term that encompasses both fulminant hepatic failure and subfulminant hepatic failure (or late-onset hepatic failure). The term 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. The term subfulminant hepatic failure is reserved for patients with liver disease for up to 26 weeks before the development of hepatic encephalopathy.

Signs and symptoms of acute failure may include the following:

• Encephalopathy
• Cerebral edema: May lead to signs of increased intracranial pressure (ICP) (eg, papilledema, hypertension, bradycardia)
• Jaundice: Often present but not always
• Ascites: Potential for hepatic vein thrombosis with rapid development in the presence of fulminant hepatic failure accompanied by abdominal pain
• Right upper quadrant tenderness: Variably present
• Change in liver span: May be small due to hepatic necrosis or may be enlarged due to heart failure, viral hepatitis, or Budd-Chiari syndrome
• Hematemesis or melena: Due to upper gastrointestinal (GI) bleeding
• Hypotension and tachycardia: Due to reduced systemic vascular resistance

See Presentation for more detail.

Diagnosis

The most important step in the assessment of patients with acute liver failure is to identify the cause, because certain conditions necessitate immediate and specific treatment and affect prognosis. 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 the mental status. The presence of PT prolongation or mental status changes is grounds for hospital admission.

Laboratory testing

• Complete blood count: May reveal thrombocytopenia
• Coagulation studies: PT and/or international normalized ratio (INR)
• Liver function tests: Often elevated levels of aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT), alkaline phosphatase (ALP)
• Serum bilirubin level: Elevated
• Serum ammonia level: May be dramatically elevated (accuracy: arterial > venous level)
• Serum glucose level: May be dangerously low
• Serum (arterial) lactate level: Often elevated
• Arterial blood gas: May reveal hypoxemia
• Serum creatinine level: May be elevated
• Serum free copper and ceruloplasmin levels: Low levels in Wilson disease
• Serum phosphate level: May be low
• Acetaminophen and acetaminophen-protein adducts levels
• Drug screening: Consider in patients who are intravenous drug abusers
• Blood cultures: For patients with suspected infection
• Viral serologies: Consider for hepatitis A virus immunoglobulin M (IgM), hepatitis B surface antigen (HBsAg), hepatitis B virus anticore IgM; hepatitis C viral load testing; hepatitis D virus IgM if HBsAg is positive; in posttransplantation or immunosuppressed setting, consider studies for cytomegalovirus viremia, cytomegalovirus antigenemia, and herpes simplex virus
• Autoimmune markers (for autoimmune hepatitis diagnosis): Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and immunoglobulin levels

Other studies may include the following:

• Electroencephalography
• Intracranial pressure monitoring
• Percutaneous (contraindicated in the presence of coagulopathy) or transjugular liver biopsy

Imaging studies

• Hepatic Doppler ultrasonography
• Abdominal computed tomography (CT) scanning or magnetic resonance imaging without contrast
• Cranial CT scanning

See Workup for more detail.

Management

The most important aspect of treatment for acute liver failure is to provide good intensive care support, including the protection of the airways.^{[1, 2, 3, 4, 5]} Specific therapy is also dependent on the cause of the patient’s liver failure and the presence of any complications.

Pay careful attention to the patient’s fluid management and hemodynamics. It is crucial to monitor their metabolic parameters, assess for infection, maintain nutrition, and promptly recognize GI bleeding.

Pharmacotherapy

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

The following medications may be used in the management of acute liver failure:

• Antidotes (eg, penicillin G, silibinin, activated charcoal, N-acetylcysteine)
• Osmotic diuretics (eg, mannitol)
• Barbiturate agents (eg, pentobarbital, thiopental)
• Benzodiazepines (eg, midazolam)
• Anesthetic agents (eg, propofol)

Surgery

Liver transplantation is the definitive treatment for acute liver failure. In selected patients for whom no allograft is immediately available, consider support with a bioartificial liver. This is a short-term measure that only leads to survival if the liver spontaneously recovers or is replaced.^{[6, 7, 8, 9]}

Nonbiologic extracorporeal liver support systems, such as hemodialysis, hemofiltration, charcoal hemoperfusion, plasmapheresis, and exchange transfusions permit temporary liver support until a suitable donor liver is found. However, no controlled study has shown long-term benefit.

See Treatment and Medication for more details.

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Background

Acute liver failure (ALF) is an uncommon condition in which rapid deterioration of the 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 (AASLD) has produced guidelines on the management of acute liver failure in adults.^{[1, 2]}

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).

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 the systems remain a temporary measure and, to date, have had no impact on survival. Other investigational therapeutic modalities, including hypothermia, have been proposed but remain unproven.^{[10, 11]}

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 measures and the use of orthotopic liver transplantation have improved survival from less than 20% to approximately 60%.^{[12, 13]}

For patient education information, see the Infections Center and Digestive Disorders Center, as well as Hepatitis A (HAV, Hep A), Hepatitis B (HBV, Hep B), Hepatitis C (Hep C, HCV), and Cirrhosis.

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Pathophysiology

The development of cerebral edema is the major cause of morbidity and mortality in patients with acute liver failure.^{[10, 14, 15]} 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 endotoxins, tumor necrosis factor–alpha (TNF-α), 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 in intracranial blood volume and cerebral blood flow is a factor in acute liver failure. The increased cerebral blood flow results because of the 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 Differential 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.^{[13, 16, 17, 18]} 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 two different yet equally important settings. The first is an overdose (accidental or intentional) of acetaminophen. Acetaminophen ingestion of more than 10 g simply overwhelms the normal hepatic stores of glutathione, allowing reactive metabolites to escape.

The second and less obvious scenario occurs in 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 one to two 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.^[19]

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Etiology

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 coinfection 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
• Dengue virus ^[20]

Autoimmune hepatitis may also result in hepatic failure.

Hepatic failure in pregnancy

Acute fatty liver of pregnancy (AFLP) frequently culminates in fulminant hepatic failure.^[21]  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. Drug-induced liver injury (DILI) is a leading cause of emergent liver transplantation^[22] ; in Western nations, DILI is the primary cause of acute liver failure in adults.^[23]  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).^{[23, 24, 25]}

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.^[17] Chronic alcohol use may greatly increase the susceptibility to hepatotoxicity from acetaminophen because of depleted glutathione stores. Some patients with acute liver failure have unrecognized or uncertain acetaminophen toxicity. These cases have been diagnosed by highly specific acetaminophen-cysteine adducts assay. But this assay is currently not available for routine clinical use.

Fluoroquinolones are sometimes associated with mild, transient elevations in aminotransferase levels. In particular, moxifloxacin has been identified as presenting a risk for acute liver failure. A study by Paterson et al examined the risk of acute liver injury associated with the use of moxifloxacin relative to other antibiotics. Results showed an association between moxifloxacin and an increased risk of acute liver failure among adults aged 66 years or older with no history of liver disease who were admitted to the hospital for acute liver injury within 30 days of receiving a prescription for the antibiotic.^[26]

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)^[25]
• Anesthetic agents (halothane)
• Lipid-lowering medications (atorvastatin, lovastatin, simvastatin)
• Immunosuppressive agents (cyclophosphamide, methotrexate)
• Nonsteroidal anti-inflammatory agents (NSAIDs)
• Salicylates (ingestion of these agents may result in 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

In October 2013, the Centers for Disease Control and Prevention (CDC) issued a warning that the weight-loss and bodybuilding supplement OxyELITE Pro was associated with severe acute hepatitis and fulminant liver failure.^{[27, 28]}

Lo Re et al have proposed a new prognostic model to predict the risk of acute liver failure in patients with drug-induced liver injury that takes into consideration a patient's platelet count and total bilirubin level rather than the conventional use of alanine aminotransferase or aspartate aminotransferase and total bilirubin values used in Hy's law.^[29] They reported a high sensitivity of predicting acute liver failure with their model as compared with the low sensitivity but high specificity when Hy's law is used.

More recently, researchers in the United Kingdom and Denmark developed a statistical outcome prediction model to support decision making in patients with acetaminophen-induced acute liver failure.^[30] Variables include patients’ age, Glasgow coma scale, arterial pH and lactate levels, creatinine levels, international normalized ratio, and cardiovascular failure, as well as changes in INR and lactate levels.

Toxin-related hepatotoxicity

The following toxins are associated with dose-related toxicity:

• Amanita phalloides mushroom toxin^[31]
• 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 and lung, and 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.

• References

Epidemiology

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.^[32]

International statistics

In developed nations, acute liver failure has an estimated incidence of fewer than 10 cases per million people per year.^[33] 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 hepatitis B virus (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.^[32] 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 white persons (74%), Hispanics (10%), black persons (3%), Asians (5%), and Latin Americans (2%).^{[3, 17, 18]}

Acute liver failure in women

Viral hepatitis E and autoimmune liver disease are more common in women than in men.^[32] 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.

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Prognosis

Before the introduction of orthotopic liver transplantation (OLT) for fulminant hepatic failure, mortality 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 complications, which include cerebral edema, renal failure, adult respiratory distress syndrome (ARDS), coagulopathy, and infection.

Preoperative prognostic factors for liver transplantation survival in patients with acute liver failure appear to include the recipient's pretransplantation lowest pH and body mass index.^[34]  According to Hoyer et al, the recipient's lowest preoperative pH is also independently associated with inpatient mortality, in which the calculated cutoff is a pH of 7.26.^[34]

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 due to 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 the prognostic variables permit reasonable accuracy in determining the need for 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 level 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 three of the following five criteria are independent predictors^[35] 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 the onset of encephalopathy
• PT longer than 50 seconds
• Serum bilirubin level greater than 300 mmol/L (17.5 mg/dL)

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

The above criteria were developed at King's College Hospital in London^[35] 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,^{[36, 37]} and a persistently increasing PT portends death. These and other parameters have not been widely validated 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 the 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.

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History

The patient's history is valuable for suggesting the likely causes of acute liver failure and guiding appropriate interventions. If the patient is incapacitated, closely question family members, caretakers, and friends.

In taking the history, collect details on the following:

• 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 to risk factors for viral hepatitis (travel, transfusions, sexual contacts, occupation, body piercing)
• Exposure to hepatic toxins (mushrooms, organic solvents, phosphorus contained in fireworks).
• Evidence of complications (eg, renal failure, seizures, bleeding, infection)

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Physical Examination

Physical examination includes careful assessment and documentation of the patient's 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 heart failure, viral hepatitis, or Budd-Chiari syndrome.

The development of cerebral edema may ultimately 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 as a result of upper gastrointestinal bleeding may complicate fulminant hepatic failure.

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 presentation may be intrinsic to hepatic failure, it is important to consider the possibility of a superimposed infection (especially spontaneous bacterial peritonitis).

Assess the patient for signs of encephalopathy. See the table below.

Table. Grading of Hepatic Encephalopathy

View Table

See Table

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Approach Considerations

The most important step in patients with acute liver failure is to identify the cause.^{[38, 39]} Prognosis in acute liver failure is dependent on the etiology. Acute liver failure from certain causes demands immediate and specific treatment. It is also critical to identify those patients who will be candidates for liver transplantation.^{[38, 39]}

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 the mental status. Prolongation of the PT, an international normalized ratio (INR) above 1.5, or alteration in mental sensorium is grounds for hospital admission or transfer to a specialized unit.^[39]

A complete blood cell (CBC) count in patients with liver failure may reveal thrombocytopenia.

Consider electroencephalography in the evaluation of a patient with encephalopathy if seizures must be excluded.

American College of Gastroenterology guidelines for drug-induced liver injury

In 2014, the American College of Gastroenterology released new guidelines for the diagnosis and management of drug-induced liver injury.^{[38, 40]} Key points include the following^[38] :

• Drug-induced liver injury is a diagnosis of exclusion; a thorough history-taking and workup should be performed to rule out other possible etiologies
• Liver biopsy should be considered to help confirm the presence of drug-induced liver injury, if autoimmune hepatitis may be associated with the condition, and when immunosuppressive agents are being considered
• The widely used Roussel Uclaf Causality Assessment Method (RUCAM) scale may underestimate the risk of liver injury associated with herbal and dietary supplements

These guidelines also include an algorithm for the diagnosis of patients with suspected drug-induced liver injury and provide separate diagnostic pathways based on the type of liver damage (hepatocellular, mixed, or cholestatic) present.

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Laboratory Studies

Prothrombin time (PT)

The PT and/or the international normalized ratio (INR) are used to determine the presence and severity of coagulopathy. These are sensitive markers of hepatic synthetic failure and are usually abnormal in the setting of fulminant hepatic failure. Results may be worsened because of extrahepatic causes (eg, vitamin K deficiency, disseminated intravascular coagulation [DIC], consumptive coagulopathy).

Hepatic enzymes

The levels of the transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase [SGOT], and alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase [SGPT]) are often elevated dramatically as a result of severe hepatocellular necrosis.

In instances of acetaminophen toxicity (especially alcohol-enhanced), the AST and ALT levels may be well over 10,000 U/L. The alkaline phosphatase (ALP) level may be normal or mildly elevated.

Serum bilirubin

By definition, the serum bilirubin level should be elevated in fulminant hepatic failure. It climbs as hepatic dysfunction worsens. A serum bilirubin level that is elevated to greater than 4 mg/dL suggests a poor prognosis in the setting of acetaminophen poisoning.

Serum ammonia

The serum ammonia level may be elevated dramatically in patients with fulminant hepatic failure. The arterial serum ammonia level is the most accurate measurement, but venous ammonia levels are generally acceptable. An elevated serum ammonia level does not exclude the possibility of another cause for mental status changes (notably, increased intracranial pressure and seizures).

Serum glucose

Serum glucose levels may be dangerously low. This decrease results from impairments in glycogen production and gluconeogenesis.

Serum lactate

Arterial blood lactate levels, either at 4 hours (>3.5 mmol/L) or at 12 hours (>3.0 mmol/L), are early predictors of outcome in acetaminophen-induced acute liver failure. Blood lactate levels are often elevated as a result of both impaired tissue perfusion, which increases production, and decreased clearance by the liver.

Patients with elevated lactate levels may have an associated metabolic acidosis due to an increased anion gap. Alternatively, this condition may be accompanied by a respiratory alkalosis as a result of hyperventilation.

Arterial blood gases

Like pulse oximetry, arterial blood gas evaluation is valuable for identifying acid-base imbalances. However, because of significant disturbances in the acid-base balance, which are usually progressive, arterial blood gas evaluation is required, rather than only monitoring pulse oximetry. Placement of an arterial line is recommended.

Additionally, arterial blood gases may reveal hypoxemia, which is a significant concern as a result of adult respiratory distress syndrome (ARDS) or other causes (eg, pneumonia).

Serum creatinine

Serum creatinine levels may be elevated, signifying the development of hepatorenal syndrome or some other cause of acute renal failure.

Serum free copper

Patients with Wilson disease have low ceruloplasmin and total serum copper levels. However, ceruloplasmin acts as an acute-phase reactant as well as a copper transporter, and levels may be increased (eg, from active inflammation, pregnancy, or estrogen treatment) or depressed in a nonspecific fashion as a result of hepatic failure. Thus, determination of serum free copper (ie, non-ceruloplasmin–bound copper) is important when Wilson disease must be excluded or confirmed. Fulminant hepatic failure from Wilson disease appears to be uniformly fatal without transplantation.

The free copper level is determined by subtracting 3 times the ceruloplasmin level (mg/dL) from the total serum copper level (µg/dL). Normal free copper levels range from 1.3 to 1.9 µmol/L (8-12 µg/dl); in Wilson disease, levels exceed 3.9 µmol/L (>25 µg/dL).

Serum phosphate

Levels of serum phosphate may be low. It has been hypothesized that hypophosphatemia develops in people whose livers regenerate rapidly. Elevated phosphate levels suggest impaired regeneration.

Autoimmune markers

Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and immunoglobulin levels are important markers for the diagnosis of autoimmune hepatitis.

Acetaminophen studies

In patients with liver failure from acetaminophen toxicity, the acetaminophen level may have decreased by the time a patient presents with fulminant hepatic failure. Nevertheless, this assay may be helpful for documentation purposes.

Acetaminophen-protein adducts are specific biomarkers of acetaminophen-related toxicity. These can be measured in blood. Measurement of acetaminophen-protein adducts is particularly useful for diagnosis in cases lacking historical data or other clinical information.^[18]  Serum acetaminophen-protein adducts decrease in parallel to aminotransferases and can be detected up to 7 days.

Drug screen

Consider a drug screen in a patient who is an intravenous drug abuser.

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Blood Cultures

Most patients with acute liver failure develop infection during or before hospitalization. Patients are at risk of catheter sepsis and complications from all other invasive procedures. Fungal infections are common, most likely as a result of decreased host resistance and antibiotic treatment.^[41]

Infection may be associated with bacteremia. Early identification and treatment of bacteremia is important because the mortality from fulminant hepatic failure increases significantly with the development of this serious complication.

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Viral Serologies

Hepatitis A virus (HAV) immunoglobulin M (IgM), hepatitis B surface antigen (HBsAg), and hepatitis B virus (HBV) anticore IgM serologies help identify acute infection with HAV or HBV.

Hepatitis C virus (HCV) antibody test results may remain negative for several weeks or months. Repeat testing may be necessary, but acute HCV infection as a cause of fulminant hepatic failure appears to be exceedingly uncommon. If a strong clinical suspicion exists, obtain hepatitis C viral load testing.

If the HBsAg assay is positive, consider testing for hepatitis D virus (HDV) IgM. This test is particularly advisable if the patient is a known intravenous (IV) drug abuser.

Other viral studies may be helpful in the posttransplantation setting or when patients are otherwise heavily immunosuppressed. Such studies include cytomegalovirus viremia and cytomegalovirus antigenemia. Also consider herpes simplex virus (HSV).

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Liver Ultrasonography

A Doppler ultrasonography scan of the liver establishes the presence of ascites and may determine the patency and flow in the hepatic veins (allowing exclusion of Budd-Chiari syndrome), hepatic artery, and the portal vein.

Liver ultrasonography may not be necessary if an obvious explanation exists for the hepatic failure. However, it may assist the clinician in excluding the presence of a hepatocellular carcinoma or intrahepatic metastases (see the image below).

View Image

Ultrasonogram shows a hyperechoic mass representing hepatocellular carcinoma.

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Computed Tomography Scanning

Computed tomography (CT) scanning (or magnetic resonance imaging [MRI]) of the abdomen may be required for further definition of hepatic anatomy and to help the clinician exclude other intra-abdominal processes, particularly if the patient has developed massive ascites, if the patient is obese, or if transplantation is being planned.

Intravenous contrast media may compromise renal function. Consider performing a contrast-free study.

CT scanning of the head may help identify cerebral edema, although CT scans do not reliably demonstrate evidence of edema, especially at early stages. Head imaging with CT scanning is also used to exclude other causes of decline in the mental status, such as intracranial mass lesions (especially hematomas) that may mimic edema from fulminant hepatic failure. It can also exclude subdural hematomas (see the image below).

View Image

Subacute subdural hematoma with extension into the anterior interhemispheric cistern. Note that the sulci do not contain the spread of these hemorrhag....

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Liver Biopsy and Histologic Findings

A percutaneous liver biopsy is contraindicated in the setting of coagulopathy. However, a transjugular biopsy is helpful for diagnosis if autoimmune hepatitis, metastatic liver disease, lymphoma, or herpes simplex hepatitis is suspected. Liver biopsy findings may be nonspecific, but in general, the findings depend on the underlying etiology of the acute liver failure.

Liver biopsy specimens in patients with idiosyncratic medication-induced hepatitis leading to fulminant hepatic failure generally shows panlobular necrosis. In patients with acetaminophen-induced fulminant hepatic failure, centrilobular necrosis is typical but panlobular injury may also be observed.

Viral hepatitis typically produces a panlobular injury and may be difficult to distinguish from medication-induced hepatitis. The presence of microvesicular steatosis suggests certain medications (eg, valproic acid, salicylates in Reye syndrome) as a cause for fulminant hepatic failure, but this finding is also observed in acute fatty liver of pregnancy.

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Intracranial Pressure Monitoring

When establishing a diagnosis of intracranial hypertension or cerebral edema, intracranial pressure monitoring is frequently necessary. Monitoring also has value in guiding management.

Typically, extradural catheters are safer than intradural catheters. However, intradural catheters are somewhat more accurate and, in the hands of a neurosurgeon experienced with their use, may be equally safe.

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Approach Considerations

The most important aspect of treatment in patients with acute liver failure is to provide good intensive care support.^{[1, 2, 3, 4, 5, 38, 39]}  Patients with grade II encephalopathy should be transferred to the intensive care unit (ICU) for monitoring. As encephalopathy progresses, protection of the airway becomes increasingly important.

Most patients with acute liver failure tend to develop some degree of circulatory dysfunction. Careful attention should be paid to fluid management and hemodynamics.^{[38, 39]} Monitoring of metabolic parameters, surveillance for infection, maintenance of nutrition, and prompt recognition of gastrointestinal bleeding are crucial.

Coagulation parameters, complete blood cell count, and metabolic panel should be checked frequently. Serum aminotransferases and bilirubin are generally measured daily to follow the course of the disease.

Bed rest is recommended.

Consultations

Managing fulminant hepatic failure is a team effort. Consultations with specialists in intensive care, gastroenterology, infectious diseases, hematology, neurology, neurosurgery, and transplantation surgery may be needed to address the myriad complex issues that can confront the medical staff.

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Airway Protection

As patients with fulminant hepatic failure drift deeper into coma, the ability to protect their airway from aspiration decreases. Patients who are in stage III coma should have a nasogastric tube (NGT) inserted for stomach decompression. When patients progress to stage III coma, intubation should be performed.

Short-acting benzodiazepines in low doses (eg, midazolam, 2-3 mg) may be used before intubation, or propofol (50 mcg/kg/min) may be initiated before intubation and continued as an infusion. Propofol is also known to decrease the cerebral blood flow and intracranial hypertension (ICH). It may be advisable to use endotracheal lidocaine before endotracheal suctioning.

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Management of Encephalopathy and Cerebral Edema

Patients with grade I encephalopathy may sometimes be safely managed in a medicine ward. Frequent mental status checks should be performed, and transfer to an intensive care unit (ICU) is warranted with progression to grade II encephalopathy.

Sedation should be avoided if possible. Unmanageable agitation may be treated with short-acting benzodiazepines in low doses.

Patients should be positioned with the head elevated at 30°. Efforts should be made to avoid patient stimulation. Maneuvers that cause straining or, in particular, Valsalva-like movements may increase intracranial pressure (ICP).

There is increasing evidence that ammonia may play a pathogenic role in the development of cerebral edema. Reducing elevated ammonia levels with enteral administration of lactulose might help prevent or treat cerebral edema. In the late stages of encephalopathy, to reduce the risk of aspiration, avoid providing lactulose by mouth or nasogastric tube in the absence of endotracheal intubation.

The occurrence of cerebral edema and intracranial hypertension (ICH) in patients with acute liver failure is related to the severity of encephalopathy. Cerebral edema is seldom observed in patients with grades I-II encephalopathy. The risk of edema increases to 25-35% with progression to grade III and increases to 65-75% (or more) in patients reaching grade IV coma.

Patients in the advanced stages of encephalopathy require close follow-up care. Monitoring and management of the hemodynamic and renal parameters, as well as glucose, electrolytes, and acid/base status, become critical.^{[38, 39]} Frequent neurologic evaluation for signs of elevated ICP should be conducted.

Intracranial pressure monitoring

In patients with grade III or IV encephalopathy, consider placement of an ICP monitor. ICP monitoring helps in the early recognition of cerebral edema.

The clinical signs of elevated ICP, including hypertension, bradycardia, and irregular respirations (Cushing triad), are not uniformly present; these and other neurologic changes, such as papillary dilatation or signs of decerebration, are typically evident only late in the course. Computed tomography (CT) scanning of the brain does not reliably detect edema, especially in the early stages.

The primary purpose of ICP monitoring is to detect elevations in ICP and reductions in cerebral perfusion pressure (CPP; calculated as mean arterial pressure [MAP] minus ICP) so that interventions can be made to prevent herniation while preserving brain perfusion. The ultimate goal of such measures is to maintain neurologic integrity and to prolong survival while awaiting the receipt of a donor organ or recovery of sufficient functioning hepatocyte mass. Additionally, refractory ICH and/or decreased CPP are considered contraindications to liver transplantation in many centers.

If an ICP monitor is placed, ICP should be maintained below 20-25 mm Hg, if possible, with CPP maintained above 50-60 mm Hg. Support of systemic blood pressure may be required to maintain adequate CPP.

Management of intracranial hypertension

ICH is managed initially with the use of mannitol. Osmotic diuresis with intravenous (IV) mannitol is effective in the short term in decreasing cerebral edema. Administration of IV mannitol (in a bolus dose of 0.5-1 g/kg or 50-100 g) is recommended to treat ICH in acute liver failure. The dose may be repeated once or twice, as needed, provided that serum osmolality has not exceeded 320 mOsm/L. Volume overload is a risk with mannitol use in patients with renal impairment and may necessitate the use of dialysis to remove excess fluid.

If life-threatening ICH is not controlled with mannitol infusion and other general management as outlined above, hyperventilation may be instituted temporarily in an attempt to acutely lower the ICP and to prevent impending herniation. Hyperventilation to reduce the partial pressure of carbon dioxide in the blood (PaCO₂) to 25-30 mm Hg can quickly lower ICP via vasoconstriction, causing decreased cerebral blood flow, but this effect is short lived.

Other therapies used to decrease ICH but not routinely recommended may be considered in refractory ICH. These include hypertonic saline, barbiturates, and hypothermia.

A controlled trial of administration of 30% hypertonic saline, 5-20 mL/hour, to maintain serum sodium levels of 145-155 mmol/L in patients with acute liver failure and severe encephalopathy suggested that induction and maintenance of hypernatremia may be used to prevent the rise in ICP values.^[42]

Barbiturate agents (thiopental or pentobarbital) may also be considered when severe ICH does not respond to other measures; administration of these drugs has been shown to effectively decrease ICP. Significant systemic hypotension frequently limits their use and may necessitate additional measures to maintain adequate mean arterial pressure. Doses of barbiturates for ICH are as follows:

• Thiopental: 5-10 mg/kg IV loading dose, followed by 3-5 mg/kg IV infusion
• Pentobarbital: 3-5 mg/kg IV loading dose, followed by 1-3 mg/kg/h infusion

Moderate hypothermia (32-34°C) may prevent or control ICH in patients with acute liver failure. An external cooling blanket may be used to achieve this goal. Potential deleterious effects of hypothermia include increased risk of infection, coagulation disturbance, and cardiac arrhythmias.

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Hemodynamic Monitoring

Hemodynamic derangements consistent with multiple organ failure occur in acute liver failure. Hypotension (ie, systolic blood pressure < 80 mm Hg) may be present in 15% of patients. Most patients will require fluid resuscitation on admission. Intravascular volume deficits may be present on admission due to decreased oral intake or gastrointestinal blood loss.

Hemodynamic derangement resembles that of sepsis or cirrhosis with hepatorenal syndrome (low systemic vascular resistance [SVR] with normal or increased cardiac output). An arterial line should be placed for continuous blood pressure monitoring.

A Swan-Ganz catheter should be placed, and fluid replacement with colloid albumin should be guided by the filling pressure. If needed, dopamine or norepinephrine can be used to correct hypotension.

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Management of Coagulopathy

In the absence of bleeding, it is usually not necessary to correct clotting abnormalities with fresh frozen plasma (FFP). The exception is when an invasive procedure is planned or in the presence of profound coagulopathy (international normalized ratio [INR] >7).^[43]

Prothrombin time (PT) and partial thromboplastin time (PTT) become prolonged when plasma coagulation components are diluted to less than 30%, and abnormal bleeding occurs when they are less than 17%. One unit of FFP increases the coagulation factor by 5%; 2 units increase it by 10%. An FFP infusion of 15 mL/kg of body weight or 4 units will correct the deficiency. If the fibrinogen level is very low (< 80 mg/dL), consider administering cryoprecipitate.

Recombinant factor VIIa may be used in patients whose condition is nonresponsive to FFP. It is used in a dose of 4 µg/kg intravenous (IV) push over 2-5 minutes. PT is normalized in 20 minutes and remains normalized for 3-4 hours.

Platelet transfusions are not used until the platelet count is below 10,000/µL or if an invasive procedure is being done and the platelet count is less than 50,000/µL. Six to 8 units of random donor platelets (1 random donor unit platelet/10 kg) will increase the platelet count to greater than 50,000/µL. The platelet count should be checked after 1 hour and 24 hours. Transfused platelets survive 3-5 days.

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Management of Acetaminophen Toxicity

Treat acetaminophen (paracetamol, APAP) overdose with N-acetylcysteine (NAC).^[44] Researchers theorize that this antidote works by a number of protective mechanisms. Early after an overdose, NAC prevents the formation and accumulation of N-acetyl-p-benzoquinone imine (NAPQI), a free radical that binds to intracellular proteins, nonspecifically resulting in toxicity.

NAC increases glutathione stores, combines directly with NAPQI as a glutathione substitute, and enhances sulfate conjugation. NAC also functions as an anti-inflammatory and antioxidant and has positive inotropic and vasodilating effects, which improve the microcirculatory blood flow and oxygen delivery to tissues. These latter effects decrease morbidity and mortality once hepatotoxicity is well established.

The protective effect of NAC is greatest when administered within 8 hours of ingestion; however, when indicated, administer NAC regardless of the time since the overdose. Therapy with NAC has been shown to decrease mortality in late-presenting patients with fulminant hepatic failure (in the absence of acetaminophen in the serum).

If patients present within 4 hours of overdosing on acetaminophen, administer activated charcoal just prior to starting NAC.^{[1, 2]}

Never administer aminoglycosides or nonsteroidal anti-inflammatory drugs (NSAIDs) to patients with acetaminophen hepatotoxicity, because the potential for nephrotoxicity is greatly exaggerated in this setting.

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Mushroom Poisoning

Treat Amanita phalloides mushroom intoxication with intravenous (IV) penicillin G, even though its mode of action is unclear. Silibinin, a water-soluble derivative of silymarin, may be administered orally, and oral charcoal may be helpful by binding the mushroom toxin.

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Liver Transplantation

Liver transplantation is the definitive treatment in liver failure, but a detailed discussion is beyond the scope of this article. For more information on liver transplantation, see the Medscape articles Liver Transplants and Pediatric Liver Transplantation. The American Association for the Study of Liver Diseases (AASLD) has produced guidelines on the evaluation of adult and pediatric patients for liver transplantation,^{[45, 46, 47]}  as well as the long-term management of these patients.^{[48, 49]}  Preoperative management is emphasized in this section.

In selected patients for whom no allograft is immediately available, consider support with a bioartificial liver. This is a short-term measure that only leads to survival if the liver spontaneously recovers or is replaced.^{[6, 7, 8, 9]}

Artificial liver support systems can be divided into two major categories: biologic (bioartificial) and nonbiologic.

The bioartificial liver is composed of a dialysis cartridge with mammalian or porcine hepatocytes filling the extracapillary spaces. These devices have undergone controlled trials. One multicenter trial reported improved short-term survival for a subgroup of patients with acute liver failure who were treated with a porcine hepatocyte-based artificial liver.^[9]

Nonbiologic extracorporeal liver support systems, such as hemodialysis, hemofiltration, charcoal hemoperfusion, plasmapheresis, and exchange transfusions, have been used; however, no controlled study has shown long-term benefit.

These modalities permit temporary liver support until a suitable donor liver is found. Although extracorporeal hemoperfusion of charcoal and other inert substances provide some measure of excretory function, this technique provides no synthetic capacity.

Among the liver support systems currently available, albumin dialysis using the molecular adsorbent recirculating system (MARS) is the one that has been most extensively investigated. In this device, blood is dialyzed across an albumin-impregnated membrane against 20% albumin. Charcoal and anion exchange resin columns in the circuit cleanse and regenerate the albumin dialysate. Clinical studies have shown that this system improves hyperbilirubinemia and encephalopathy.

Two other systems based on the removal of albumin bound toxins are the Prometheus device, using the principle of fractionated plasma separation and adsorption (FPSA), and the single pass albumin dialysis (SPAD). A clinical trial is in the process of recruiting patients to compare the MARS and SPAD systems with regard to their biologic and clinical efficacy, pulsatility index of middle cerebral artery modification, and tolerance.^[50]

Currently available liver support systems are not routinely recommended outside of clinical trials. In the future, hepatocyte transplantation, which has shown dramatic results in animal models of acute liver failure, may provide long-term support, but this approach remains investigational.

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Diet

Patients with acute liver failure are, by necessity, on nothing by mouth (NPO) status. They may require large amounts of intravenous (IV) glucose to avoid hypoglycemia.

When enteral feeding via a feeding tube is not feasible (eg, as in a patient with paralytic ileus), institute total parenteral nutrition (TPN). (See also Nutritional Requirements of Adults Before Transplantation and Nutritional Requirements of Children Prior to Transplantation.) Restricting protein (amino acids) to 0.6 g/kg body weight per day was previously routine in the setting of hepatic encephalopathy. However, this may not be necessary.

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Complications

Potential complications of acute liver failure include seizures, hemorrhage, infection, renal failure, and metabolic imbalances.

Seizures

Seizures, which may be seen as a manifestation of the process that leads to hepatic coma and intracranial hypertension (ICH), should be controlled with phenytoin. The use of any sedative is discouraged in light of its effects on the evaluation of the mental status. Only minimal doses of benzodiazepines should be used, given their delayed clearance by the failing liver. Seizure activity may acutely elevate the ICH and may also cause cerebral hypoxia and, thus, contribute to cerebral edema.

Hemorrhage

Hemorrhage develops as a result of the profoundly impaired coagulation that manifests in patients with acute liver failure. Gastrointestinal bleeding may develop from esophageal, gastric, or ectopic varices as a result of portal hypertension. Portal hypertensive gastropathy and stress gastritis may also develop. Any minor trauma may result in extensive percutaneous bleeding or internal hemorrhage.

The first step in management is to correct coagulopathy. The transfusion requirements for coagulation products (fresh frozen plasma [FFP], platelets) may be enormous. Multiple transfusions with packed red blood cells may be needed. Consider retroperitoneal hemorrhage if large transfusion requirements are not matched by an obvious blood loss.

Infection

Periodic surveillance cultures should be performed to detect bacterial and fungal infections. Empiric broad-spectrum antibiotics and antifungals should be given in the following circumstances:

• Progressive encephalopathy (start antibiotics in all patients listed for transplantation)
• Signs of systemic inflammatory response syndrome (SIRS) (temperature, >38°C or < 36°C; white blood cell [WBC] count, >12,000/μL or < 4,000/μL; pulse rate, >90 bpm)
• Persistent hypotension

Piperacillin/tazobactam (Zosyn) and fluconazole should be the initial antimicrobial choice. In hospital-acquired intravenous (IV) catheter infections, consider vancomycin.

Renal failure

Acute renal failure is a frequent complication in patients with acute liver failure and may be due to dehydration, hepatorenal syndrome, or acute tubular necrosis.^[39] To preserve renal function, maintain adequate blood pressure, avoid nephrotoxic medications and nonsteroidal anti-inflammatory agents (NSAIDs), and promptly treat infections.

When dialysis is needed, continuous (ie, continuous venovenous hemodialysis [CVVHD]) rather than intermittent renal replacement therapy is preferred. Hemodialysis may significantly lower the mean arterial pressure such that cerebral perfusion pressure is compromised.

Metabolic imbalances

Alkalosis and acidosis occur in acute liver failure. Identify and treat the underlying cause. Base deficits can be corrected by THAM solution (tromethamine injection), which prevents a rise in carbon dioxide, osmolality, and serum sodium.

Severe hypoglycemia occurs in approximately 40% of patients with fulminant hepatic failure. Although hypoglycemia occurs more frequently in children, blood sugar needs to be monitored in adult patients as well. Blood sugars should be maintained in the range of 60-200 mg/dL, using 10% dextrose solution.

Phosphate, magnesium, and potassium levels tend to be low in acute liver failure. Frequent supplementation is required.

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Medication Summary

Multiple medications may be necessary in patients with acute liver failure because of the wide variety of complications that may develop from fulminant hepatic failure. Decreased hepatic metabolism and the potential for hepatotoxicity become central issues. In patients with liver failure from Amanita phalloides or acetaminophen toxicity, antidotes that effectively bind or eliminate the relevant toxins are essential.

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Penicillin G (Pfizerpen)

• Dosing, Interactions, etc.

Clinical Context:  Intravenous penicillin G is the drug of choice for the treatment of mushroom poisoning from Amanita phalloides. Its mode of action is unclear in this setting.

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Silibinin (Silibinin Plus)

• Dosing, Interactions, etc.

Clinical Context:  Silibinin is a water-soluble derivative of silymarin, which is the active ingredient in the herbal preparation milk thistle. This agent possesses antioxidant properties that may benefit liver disease management.

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Activated charcoal (Actidose-Aqua, Liqui-Char, CharcoAid)

• Dosing, Interactions, etc.

Clinical Context:  In patients who have recently ingested Amanita phalloides, activated charcoal may bind the toxin and prevent absorption.

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N-acetylcysteine (Mucomyst, Mucosil)

• Dosing, Interactions, etc.

Clinical Context:  N-acetylcysteine is the drug of choice in acetaminophen overdose. N-acetylcysteine provides reducing equivalents to help restore depleted intrahepatic glutathione levels.

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Class Summary

Antidotes neutralize toxic agents and neutralize or counteract any form of poisoning.

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Mannitol (Osmitrol)

• Dosing, Interactions, etc.

Clinical Context:  Osmotic diuresis with intravenous mannitol is effective in the short term for decreasing cerebral edema. Administration of intravenous mannitol (in a bolus dose of 0.5-1 g/kg or 50-100 g) is recommended to treat intracranial hypertension in acute liver failure. The dose may be repeated once or twice, as needed, provided that the serum osmolality has not exceeded 320 mOsm/L. Volume overload is a risk with mannitol use in patients with renal impairment and may necessitate the use of dialysis to remove the excess fluid.

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Class Summary

Intracranial hypertension in acute liver failure is managed initially by the use of osmotic diuretics such as mannitol.

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Pentobarbital (Nembutal)

• Dosing, Interactions, etc.

Clinical Context:  Pentobarbital is a short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties. It may be used at high dosages to induce barbiturate coma for the treatment of refractory increased ICP. The recommended dose is 3-5 mg/kg intravenously as a loading dose, followed by infusion at 1-3 mg/kg/h intravenously.

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Thiopental (Pentothal)

Clinical Context:  Thiopental is an ultra–short-acting central nervous system depressant that decreases intracranial pressure. The recommended dose of thiopental for intracranial hypertension is 5-10 mg/kg as a loading dose, followed by an infusion of 3-5 mg/kg intravenously.

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Class Summary

Barbiturate agents such as thiopental and pentobarbital may be considered when severe intracranial hypertension does not respond to other measures. Administration has been shown to effectively decrease intracranial pressure (ICP). Significant systemic hypotension frequently limits their use and may necessitate additional measures to maintain adequate mean arterial pressure.

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Midazolam

• Dosing, Interactions, etc.

Clinical Context:  Midazolam is a shorter-acting benzodiazepine sedative-hypnotic useful in patients requiring acute and/or short-term sedation. Midazolam is used for sedation for mechanically ventilated patients. It is given through continuous intravenous infusion for sedation of intubated and mechanically ventilated patients.

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Class Summary

As patients with fulminant hepatic failure drift deeper into coma, the ability to protect their airway from aspiration decreases. Short-acting benzodiazepines in low doses may be used before intubation.

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Propofol (Diprivan)

• Dosing, Interactions, etc.

Clinical Context:  Propofol is a sedative-hypnotic that decreases the cerebral blood flow and intracranial hypertension. Propofol (50 mcg/kg/min) may be initiated before intubation and continued as an infusion.

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Class Summary

Anesthetic agents such as propofol have sedative and hypnotic effects that are used for induction.

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