AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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. ALF often affects young people and carries a very high mortality. The term ALF 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.

ALF is a broad term and encompasses both fulminant hepatic failure (FHF) and subfulminant hepatic failure (or late-onset hepatic failure). FHF 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 prior to 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 this 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 ALF in the United States. The outcome of ALF is related to the etiology, the degree of encephalopathy, and related complications. Unfortunately, despite aggressive treatment, many patients die from FHF. Prior to orthotopic liver transplantation (OLT) for FHF, the mortality rate was generally greater than 80%. Approximately 6% of OLTs performed in the United States are for FHF. 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.

Pathophysiology

The development of cerebral edema distinguishes FHF from portosystemic encephalopathy, although certain mechanisms appear to be common to both clinical entities (see Portal-Systemic Encephalopathy). Briefly, hyperammonemia may be involved in the development of cerebral edema. Another consequence of FHF is multisystem organ failure, which often is 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 FHF.

Many hemodynamic features of FHF may be mediated by elevated systemic concentrations of nitric oxide, which acts as a potent vasodilator. However, in this setting, cytokine profiles are deranged, and a distinct possibility exists that neurohumoral effects mediate extrahepatic organ dysfunction, with the circulatory manifestations simply representing epiphenomena. Elevated serum concentrations of bacterial endotoxin, tumor necrosis factor-a, and interleukin-1 and interleukin-6 have been found in FHF, but the specific roles of these inflammatory mediators are unclear.

The development of liver failure represents the final common outcome of a wide variety of potential causes, as the broad differential diagnosis suggests. 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. An active metabolite, N-acetyl-p-benzoquinoneimine (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 usually is 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

Incidence of FHF appears to be low, with approximately 2000 cases annually occurring in the United States. Drug-related hepatotoxicity comprises more than 50% of ALF 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 HBV, 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 FHF 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 FHF 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. The etiologic factor leading to hepatic failure and the development of complications is key. In general, the best prognoses occur in the absence of complications. Cerebral edema, renal failure, adult respiratory distress syndrome, bleeding, and sepsis pose challenges that reduce the probability of survival.

• Viral hepatitis: In patients with FHF 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 FHF as the result of other causes of viral hepatitis is much less favorable.
• Acetaminophen toxicity: FHF 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 to 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 FHF: In non-acetaminophen-induced FHF, a PT of greater than 100 seconds and any 3 of the following 5 criteria are independent predictors: (1) age younger than 10 years or older than 40 years, (2) FHF due to non-A, non-B, non-C hepatitis, halothane hepatitis, or idiosyncratic drug reactions, (3) jaundice present more 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 London 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 are proposed. Reduced levels of group-specific component (Gc)-globulin (a molecule that binds actin) are reported in FHF, and a persistently increasing PT portends death. These and other parameters are not validated widely yet.
• Wilson disease: When presenting as FHF 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

ALF is seen among all races. In the US multicenter study of ALF, the ethnic distribution included whites (74%), Hispanics (10%), African Americans (3%), Asians (5%), and Latin Americans (2%).

Sex

Viral hepatitis E and autoimmune liver disease are more common in women than in men. In the US multicenter study group, ALF was seen more often in women (73%) than in men.

Age

This may be pertinent to morbidity and mortality. Patients younger than 10 years and older than 40 years tend to fare relatively poorly. According to the US multicenter study group, women were older than men (39 y vs 32.5 y).

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

All patients with clinical or laboratory evidence of moderate or severe acute hepatitis should have immediate measurement of prothrombin time and careful evaluation of mental status. Patient 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 ALF.
• 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. 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 FHF accompanied by abdominal pain, suggests the possibility of hepatic vein thrombosis (Budd-Chiari syndrome).
• Hematemesis or melena may complicate the presentation of FHF as a result of upper gastrointestinal bleeding.
• Typically, patients are hypotensive and tachycardic as a result of the reduced systemic vascular resistance that accompanies FHF.
• This pattern is indistinguishable from septic shock. While this may be intrinsic to hepatic failure, considering the possibility of a superimposed infection (especially spontaneous bacterial peritonitis) is important.
• Table 1. Grading of Hepatic Encephalopathy
  
  

  Grade	level of Consciousness	Personality and Intellect	Neurologic Signs	Electroencephalogram Abnormalities
  0	Normal	Normal	None	None
  Subclinical	Normal	Normal	Abnormalities only on psychometric testing	None
  1	Day/night sleep reversal Restlessness	Forgetfulness Mild confusion Agitation Irritability	Tremor Apraxia Incoordination Impaired handwriting	Triphasic waves (5 Hz)
  2	Lethargy Slowed responses	Disorientation to time Loss of inhibition Inappropriate behavior	Asterixis Dysarthria Ataxia Hypoactive reflexes	Triphasic waves (5 Hz)
  3	Somnolence Confusion	Disorientation to place Aggressive behavior	Asterixis Muscular rigidity Babinski signs Hyperactive reflexes	Triphasic waves (5 Hz)
  4	Coma	None	Decerebration	Delta/slow wave activity

Causes

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

• Hepatitis A and B are the typical viruses causing viral hepatitis and may lead to hepatic failure. Hepatitis C rarely causes ALF. Hepatitis delta virus (co-infection or superinfection with HBV) can lead to FHF. HEV (often observed in pregnant women) in endemic areas is an important cause of FHF.
• Other atypical viruses can cause viral hepatitis and FHF.
• • Cytomegalovirus
  • Hemorrhagic fever viruses
  • Herpes simplex virus
  • Paramyxovirus
  • Epstein-Barr virus
• Incidence of acute fatty liver of pregnancy, frequently culminating in FHF, 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 FHF. The one major exception to this is the pregnant patient who develops HEV 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 FHF 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 usually is associated with preeclampsia.
• Incidence of FHF 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 FHF only rarely, though they are the most common form of drug reaction to lead to FHF (with the exception of acetaminophen poisoning).
• • Drug toxicity - Acetaminophen (also known as paracetamol and APAP)
    • Intentional or accidental overdose. In the US 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 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
    • 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 toxin
  • 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, eg, 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)
• Table 2. Differential Diagnosis of Hepatic Encephalopathy

• Consideration	Evaluation
  Structural lesions	Computed tomography
  Intracranial hemorrhage (epidural, subdural, subarachnoid, intraparenchymal) Cerebral infarct	Consider lumbar puncture after excluding mass if history or examination suggests subarachnoid hemorrhage or meningoencephalitis.
  Intracranial infections (encephalitis [herpes simplex virus, others], meningitis, intracerebral abscess, hydrocephalus)	Viral serologic testing
  Toxic or metabolic etiologies
  Drug intoxication (ethanol, salicylates, opioids, benzodiazepines, others)	Blood alcohol level Drug screen
  Delirium tremens
  Wernicke encephalopathy
  Hypoglycemia	Response to thiamine
  Ketoacidosis	Response to glucose
  Electrolyte disturbances	Blood glucose level
  Hypercapnia	Serum electrolytes
  Hypoxia	Arterial blood gas determination
  Postictal encephalopathy	EEG
  Other
  Functional psychoses	Psychiatric evaluation

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Acute fatty liver of pregnancy
Adult-onset Still disease
A phalloides mushroom poisoning
B cereus toxin
Fructose intolerance
Galactosemia
HELLP syndrome of pregnancy
Hemorrhagic viruses (Ebola virus, Lassa virus, Marburg virus)
Idiopathic drug reaction (hypersensitivity)
Neonatal iron storage disease
Paramyxovirus
Primary graft nonfunction (in liver transplant recipients)
Tyrosinemia
Yellow phosphorus poisoning
Acetaminophen poisoning

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• CBC count: Results may indicate thrombocytopenia.
• PT and/or INR
• • These tests are used to determine the presence or severity of coagulopathy.
  • They are sensitive markers of hepatic synthetic failure but rarely in the setting of suspected FHF.
  • They may be increased because of extrahepatic causes (vitamin K deficiency, disseminated intravascular coagulation [DIC], consumptive coagulopathy).
• Hepatic enzymes
• • Levels of the transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase [SGOT] and alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase [SGPT]) often are elevated dramatically as a result of severe hepatocellular necrosis.
  • In instances of acetaminophen toxicity (especially alcohol-enhanced), the AST level may be well over 10,000 U/L.
  • The alkaline phosphatase level may be normal or elevated.
• Serum bilirubin
  • By definition, this should be elevated in FHF. It climbs as hepatic dysfunction worsens.
  • Serum bilirubin elevated greater than 4 mg/dL suggests a poor prognosis in the setting of acetaminophen poisoning.
• Serum ammonia
  • This level may be elevated dramatically in patients with FHF. Arterial blood is the best way to measure ammonia.
  • The arterial serum ammonia level is most accurate, but venous ammonia levels are generally acceptable.
  • It does not exclude the possibility of another cause for mental status changes (notably increased ICP and seizures).
• Serum glucose: Levels may be very low and pose a serious hazard. This results from impairments in glycogen production and gluconeogenesis.
• Serum lactate
  • Arterial blood lactate levels either at 4 hours (>3.5) or at 12 hours (>3.0) are early predictors of outcome in acetaminophen-induced ALF. Levels are often elevated as a result of both impaired tissue perfusion (increases production) and decreased clearance by the liver.
  • An increased anion gap metabolic acidosis is associated with this condition (although it may be accompanied by a respiratory alkalosis as a result of hyperventilation).
• Arterial blood gases: These may reveal hypoxemia, which is a significant concern as a result of adult respiratory distress syndrome or other causes (eg, pneumonia).
• Serum creatinine: Levels may be elevated, signifying the development of hepatorenal syndrome or some other cause of acute renal failure.
• Blood cultures
• • Most patients develop some sort of infection during or prior to hospitalization. Patients are at risk of line sepsis and complications from all other invasive procedures.
  • Fungal infections are common, most likely as a result of decreased host resistance and antibiotic treatment.
  • Infection may be associated with bacteremia, but identifying and treating it early is important because the mortality from FHF increases significantly with the development of this serious complication.
• Serum-free copper
• • This is important to consider when Wilson disease must be excluded or confirmed. FHF from Wilson disease appears to be uniformly fatal without transplantation.
  • The diagnosis may be challenging because serum ceruloplasmin levels may be elevated as an acute phase reactant or depressed in a nonspecific fashion as a result of hepatic failure; therefore, copper studies are preferable but also may be confounded by impaired biliary excretion. This leads to increased urinary copper excretion by way of increased serum copper. In this setting, an increased serum-free (unbound) copper may be more reliable than any other study results.
• Serum phosphate
• • Levels may be low.
  • It has been hypothesized that people who rapidly regenerate will develop hypophosphatemia. Elevated phosphate levels suggest impaired regeneration.
• Viral serologies
• • HAV immunoglobulin M (IgM), hepatitis B surface antigen, and HBV anticore IgM serologies help determine acute infection with HAV or HBV.
  • HCV antibody testing may be negative for several weeks or months. Repeat testing may be necessary, but acute HCV as a cause of FHF appears to be exceedingly uncommon. If a strong index of suspicion exists, obtain hepatitis C viral load testing.
  • If hepatitis B surface antigen is positive (especially if the patient is a known intravenous [IV] drug abuser), consider HDV-IgM.
  • Other viral studies may be helpful in the posttransplant setting or when patients are otherwise heavily immunosuppressed. Other studies include cytomegalovirus viremia and cytomegalovirus antigenemia. Also consider herpes simplex virus.
• Autoimmune markers: ANA, ASMA, and immunoglobulin levels are important markers for a diagnosis of autoimmune hepatitis.
• Acetaminophen level
• • Obviously, this may have decreased by the time a patient presents with FHF, but it may be helpful for documentation purposes.
  • Acetaminophen–protein adducts are specific biomarkers of drug-related toxicity. These can be measured in blood. Recently, it has been shown that measurement of serum adducts improves diagnostic accuracy in patients with ALF. Measurement of acetaminophen–protein adducts is particularly useful to diagnose cases lacking historical data or other clinical information. 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 person who is an IV drug abuser.

Imaging Studies

• Liver ultrasound (Doppler)
• • This examination may establish the patency and flow in the hepatic vein (allowing exclusion of Budd-Chiari syndrome), hepatic artery, and the portal vein.
  • The examination 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.
  • It establishes the presence of ascites.
• Computed tomography scan or magnetic resonance imaging of the abdomen
• • These may be required for further definition of hepatic anatomy and to help the clinician exclude other intraabdominal processes, particularly if the patient has developed massive ascites, is obese, or if transplantation is being planned.
  • Intravenous contrast may compromise renal function. Consider performing a contrast-free study.
• Computed tomography scan of the head helps identify cerebral edema and exclude intracranial mass lesions (especially hematomas) that may mimic edema from FHF. Also consider and exclude subdural hematomas.

Other Tests

• Electroencephalogram: Consider this study in the evaluation of a patient with encephalopathy if seizures must be excluded.

Procedures

• Liver biopsy: 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.
• Intracranial pressure monitoring
• • When establishing a diagnosis of intracranial hypertension or cerebral edema, this approach is frequently necessary and has value in guiding management.
  • Typically, extradural catheters are safer than intradural catheters. Intradural catheters are somewhat more accurate and, in the hands of a neurosurgeon experienced with their use, may be equally safe.

Histologic Findings

Biopsy findings may be nonspecific, but, in general, they depend on the underlying etiology. Panlobular necrosis generally is observed as a result of idiosyncratic medication-induced hepatitis leading to FHF. Centrilobular necrosis is typical of acetaminophen-induced FHF, but panlobular injury also may be observed. Viral hepatitis typically shows 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 FHF but also is observed in acute fatty liver of pregnancy.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

The most important step is to identify the cause of liver failure. Prognosis of ALF is dependent on etiology. A few etiologies of ALF demand immediate and specific treatment. It is also critical to identify those patients who will be candidates for liver transplant.

The most important aspect of treatment is to provide good intensive care support. Patients with grade II encephalopathy should be transferred to ICU for monitoring. As the patient develops progressive encephalopathy, protection of the airway is important. Most patients with ALF tend to develop some degree of circulatory dysfunction. Careful attention should be paid to fluid management, hemodynamics, metabolic parameters, and surveillance of infection. Maintenance of nutrition and prompt recognition of gastrointestinal bleeding are crucial. Coagulation parameters, complete blood count, and metabolic panel should be checked frequently. Serum aminotransferases and bilirubin are generally measured daily to follow the course of infection. Intensive care management includes recognition and management of complications.

• Airway protection
  • As the patients with FHF drift deeper into coma, their ability to protect their airway from aspiration decreases. Patients who are in stage III coma should have a nasogastric tube for stomach decompression. When patients progress to stage III coma, the intubation should be performed.
  • Short-acting benzodiazepines in low doses (eg, midazolam 2-3 mg) may be used prior to intubation or propofol (50 mcg/kg/min) may be initiated before intubation and continued as an infusion. It is also known to decrease the cerebral blood flow and intracranial hypertension. It may be advisable to use endotracheal lidocaine prior to endotracheal suctioning.
• Encephalopathy and cerebral edema
  • Patients with grade I encephalopathy may sometimes be safely managed on a medicine ward. Frequent mental status checks should be performed with transfer to an ICU warranted with progression to grade II encephalopathy.
  • Head imaging with computerized tomography (CT) is used to exclude other causes of decline in mental status, such as intracranial hemorrhage.
  • 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 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.
  • 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 neurological changes, such as pupillary dilatation or signs of decerebration, are typically evident only late in the course.
  • CT of the brain does not reliably demonstrate evidence of edema, especially at early stages. A primary purpose of ICP monitoring is to detect elevations in ICP and reductions in cerebral perfusion pressure (CPP; calculated as mean arterial pressure minus ICP) so that interventions can be made to prevent herniation while preserving brain perfusion.
  • The ultimate goal of such measures is to maintain neurological integrity and prolong survival while awaiting receipt of a donor organ or recovery of sufficient functioning hepatocyte mass. Additionally, refractory ICH and/or decreased CPP is considered a contraindication to liver transplantation in many centers.
• Cardiovascular monitoring
  • Homodynamic derangements consistent with multiple organ failure occur in ALF. Hypotension (systolic, <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 GI blood loss. Homodynamic derangement resembles that of sepsis or cirrhosis with hepatorenal syndrome (low 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 filling pressure. If needed, dopamine or norepinephrine can be used to correct hypotension.
• Management of renal failure: Hemodialysis may significantly lower the mean arterial pressure such that cerebral perfusion pressure is compromised. Continuous veno-venous hemofiltration is preferred.
• Management of coagulopathy
• • In the absence of bleeding, it is not necessary to correct clotting abnormalities with fresh frozen plasma (FFP); the exception is when an invasive procedure is planned or with profound coagulopathy (INR >7). (PT and 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 increases it by 10%.) FFP of 15 mL/kg of body weight or 4 units correct deficiency. If fibrinogen is very low (<80 mg/dL), consider cryoprecipitation.
  • Recombinant factor VII A may be used in patients nonresponsive to FFP. It is used in a dose of 4 µg/kg 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 count is less than 10,000/µL or if an invasive procedure is being done and the platelet count is less than 50,000/µL. Six to 8 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.
• Managing poisonings (eg, acetaminophen, mushroom) requires specific treatment distinct from other, more general issues related to FHF.
• • Treat acetaminophen (paracetamol, APAP) overdose with NAC. Researchers theorize that this antidote works by a number of protective mechanisms. Early after overdose, NAC prevents the formation and accumulation of 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 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 regardless of the time since overdose. Therapy with NAC has been shown to decrease mortality in late-presenting patients with FHF (in the absence of acetaminophen in the serum).
  • A phalloides mushroom intoxication is much more common in Europe as well as in California. Treat with intravenous 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.

Surgical Care

Liver transplantation is the definitive treatment, but a detailed discussion is beyond the scope of this article. Preoperative management is emphasized here.

• 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.
• In the future, hepatocyte transplantation may provide long-term support, but it remains investigational. It has shown dramatic results in animal models of ALF.
• Artificial liver support systems
• • Artificial liver support systems can be divided into 2 major categories: biologic (bioartificial) and nonbiologic.
  • The bioartificial liver is composed of a dialysis cartridge with mammalian or porcine hepatocytes filling the extra capillary spaces. These devices have undergone controlled trials. One recent multicenter trial did report improved short-term survival for a subgroup of patients with ALF who were treated with a porcine hepatocyte based artificial liver.
  • 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, no synthetic capacity is provided.
  • 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 resins columns in the circuit cleanse and regenerate the albumin dialysate. Clinical studies have shown that it improves hyperbilirubinemia and encephalopathy.
  • Two other systems based on the removal of albumin bound toxins, the Prometheus using the principle of fractionated plasma separation and adsorption (FPSA) and the single pass albumin dialysis (SPAD), are also undergoing clinical studies for ALF.
  • Currently available liver support systems are not routinely recommended outside of clinical trials.

Consultations

Managing FHF is a team effort. Consultations in the areas of 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.

Diet

• Patients are, by necessity, nothing by mouth (NPO). They may require large amounts of intravenous 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).
• Restricting protein (amino acids) to 0.6 g/kg body weight per day was previously routine in the setting of hepatic encephalopathy, but this may not be necessary.

Activity

Bedrest is recommended.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Multiple medications may be necessary because of the wide variety of complications that may develop from FHF. Decreased hepatic metabolism and potential for hepatotoxicity become central issues. Antidotes that effectively bind or eliminate A phalloides toxin and toxic metabolites of acetaminophen are essential.

Acetaminophen ingestion of more than 10 g may be hepatotoxic due to formation of a highly reactive toxic intermediate metabolite, which ordinarily is metabolized further in the presence of glutathione to N-acetyl-p-aminophenol-mercaptopurate. Administering NAC permits restitution of intrahepatic glutathione. It is most effective when administered within 12-20 hours following overdose. Never administer aminoglycosides and NSAIDs because the potential for nephrotoxicity is exaggerated greatly in this setting.

Drug Category: Antidotes

Neutralize toxic agents.

Drug Name	Silibinin (Silibinin Plus)
Description	Water-soluble derivative of silymarin, which is active ingredient in herbal preparation milk thistle. Possesses antioxidant properties that may benefit liver disease management.
Adult Dose	20-50 mg/kg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Alcohol decreases effect
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Continued alcohol ingestion may damage liver

Drug Name	Activated charcoal (Actidose-Aqua, Liqui-Char, CharcoAid)
Description	If ingestion has been recent, Amanita toxin may be bound to charcoal and absorption prevented.
Adult Dose	50 g PO or NG tube
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies; do not use with sorbitol in fructose intolerance; sorbitol not recommended in children aged <1 y
Interactions	May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases adsorptive properties of activated charcoal)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Activated charcoal not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administering activated charcoal; after emesis with ipecac syrup, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black

Drug Name	N-acetylcysteine (Mucomyst, Mucosil)
Description	First DOC. Provides reducing equivalents to help restore depleted intrahepatic glutathione levels.
Adult Dose	Oral: Loading dose: 140 mg/kg PO Maintenance dose: 70 mg/kg PO q4h, beginning 4 h after loading dose, for a total of 17 maintenance doses If dose is vomited within 1 h of administration, readminister IV (patients >40 kg): Acute (8-10 h after ingestion): Loading dose: 150 mg/kg IV infused over 1 h; dilute in 250 mL D5W First maintenance dose: 50 mg/kg IV infused over 4 h; dilute in 500 mL D5W Second maintenance dose: 100 mg/kg IV infused over 16 h; dilute in 1000 mL D5W Each infusion immediately follows the previous; total treatment time 21 h Late presenting or chronic (>10 h after ingestion): Loading dose: 140 mg/kg IV infused over 1 h; dilute in 500 mL D5W Maintenance doses: 70 mg/kg IV q4h for at least 12 doses; dilute each dose in 250 mL D5W and infuse over minimum 1 h; total treatment time 48 h Decrease total volume of D5W if fluid restriction required
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Studies are inconclusive regarding administration with charcoal
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Possible GI distress

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Complications

• Infection
• • For patients with FHF, a wide variety of infectious complications may develop, just as in any patient admitted to the ICU with a debilitating illness.
  • Line sepsis and pneumonia are frequent.
  • Fungal and viral opportunistic infections may arise because of the patient's debilitation.
  • The patient may develop a sepsislike picture as a result of altered hemodynamics secondary to the liver failure alone. Because this development so closely mimics sepsis, it usually requires empiric broad-spectrum antibiotic coverage.
• Cerebral edema
• • The occurrence of cerebral edema and ICH in patients with ALF 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 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 homodynamic and renal parameters, as well as glucose, electrolytes, and acid/base status, become critical. Frequent neurological evaluation for signs of elevated intracranial pressure should be conducted.
  • Seizures, which may be seen as a manifestation of the process that leads to hepatic coma and ICH, should be controlled with phenytoin. Use of any sedative is discouraged in light of its effects on the evaluation of mental status. Only minimal doses of benzodiazepines should be used given their delayed clearance by the failing liver. Seizure activity may acutely elevate and may also cause cerebral hypoxia and, thus, contribute to cerebral edema.
  • Closely monitor ICP and neurologic status.
  • Most patients with FHF require prophylactic endotracheal intubation early in the course of the illness because of their impaired ability to maintain airways. This also allows the opportunity to manage intracranial hypertension with hyperventilation.
  • Mannitol is the mainstay of therapy, and a neurosurgical consultation is mandatory.
• Hepatic encephalopathy
• • Manage hepatic encephalopathy in the conventional way, by providing lactulose and avoiding sedatives.
  • Hepatic encephalopathy is not truly a complication because it is required for the diagnosis of FHF, but evolution to higher stages of hepatic encephalopathy may result in patients losing their abilities to maintain their airways.
  • Early endotracheal intubation is advisable (see Portal-Systemic Encephalopathy).
• Hemorrhage
• • This develops as a result of the profoundly impaired coagulation that manifests in these patients.
  • The transfusion requirements for coagulation products (fresh frozen plasma, platelets) may be enormous. Multiple transfusions with packed red blood cells may be needed.
  • Gastrointestinal bleeding may develop from esophageal, gastric, or ectopic varices as a result of portal hypertension. Portal hypertensive gastropathy and stress gastritis also may develop.
  • Any minor trauma may result in extensive percutaneous bleeding or internal hemorrhage.
  • Consider retroperitoneal hemorrhage if large transfusion requirements are not matched by an obvious blood loss.

Prognosis

• Prognosis is highly dependent on the inciting cause of FHF. Prognostic indices have been developed to identify patients who require liver transplantation. The development of complications is the other factor that largely determines survival.
• Viral hepatitis
• • Approximately 50-60% of patients with FHF due to HAV survive.
  • These patients account for a substantial proportion (10-20%) of the pediatric liver transplants in some countries, despite the relatively mild infection observed in many children infected with HAV.
  • The outcome for patients with FHF as the result of other causes of viral hepatitis is much less favorable.
• Acetaminophen toxicity
• • FHF 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) have increased mortality when compared to those with milder encephalopathy.
  • An arterial pH of less than 7.3 and either a PT greater than 100 seconds or serum creatinine greater than 300 mcg/mL (3.4 mg/dL) are independent predictors of a poor prognosis.
• Non–acetaminophen-induced FHF
• • A PT greater than 100 seconds and any 3 of the following 5 criteria are independent predictors: (1) age younger than 10 years or older than 40 years, (2) FHF due to non-A, non-B, non-C hepatitis, halothane hepatitis, or idiosyncratic drug reactions, (3) jaundice present more than 1 week before onset of encephalopathy, (4) PT greater than 50 seconds, or (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, developed at King's College Hospital in London, have been validated in other centers; however, significant variability occurs in the patient populations encountered at any center, and this heterogeneity may preclude widespread applicability.
  • Other prognosticating tests have been proposed. Reduced levels of Gc-globulin (a molecule that binds actin) have been reported in FHF, and a persistently increasing PT portends death. These and other parameters have not been widely validated yet.
• Wilson disease: Wilson disease presenting as FHF is almost uniformly fatal without OLT.

Patient Education

• 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.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to consider diagnosis of FHF and/or initiate appropriate timely referral to liver transplantation center

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Blake A Jones, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Jan 9, 2008