AASLD position paper: The management of acute liver failure
Authors: Julie Polson, William M. Lee
Journal: Hepatology (2005)

These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of recently-published world literature on the topic [Medline search], (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines,1 (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the AGA Policy Statement on Guidelines,2 (4) the experience of the authors in the specified topic. ALF, acute liver failure; NAC, N-acetylcysteine; HELLP, Hemolysis, Elevated Liver Enzymes, Low Platelets syndrome; ICH, intracranial hypertension; ICP, intracranial pressure; CT, computerized tomography; US ALFSG, United States Acute Liver Failure Study Group; CPP, cerebral perfusion pressure; MAP, mean arterial pressure; SIRS, systemic inflammatory response syndrome; FFP, fresh frozen plasma; rFVIIa, recombinant activated factor; GI, gastrointestinal; H2, histamine-2; PPI, proton pump inhibitors; CVVHD, continuous venovenous hemodialysis; APACHE, Acute Physiology and Chronic Health Evaluation; AFP, alpha fetoprotein; MELD, Model for End-stage Liver Disease. Intended for use by physicians, the recommendations in this document suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. This document has been designated as a Position Paper, since the topic contains more data based on expert opinion than on randomized controlled trials and thus is not considered to have the emphasis and certainty of a Practice Guideline. Nevertheless, it serves an important purpose of facilitating proper and high level patient care and we have characterized the quality of evidence supporting each recommendation, in accordance with the Practice Guidelines Committee of the AASLD recommendations used for full Practice Guidelines (Table 13). These recommendations are fully endorsed by the AASLD. Acute liver failure (ALF) is a rare condition in which rapid deterioration of liver function results in altered mentation and coagulopathy in previously normal individuals. U.S. estimates are placed at approximately 2,000 cases per year.4 The most prominent causes include drug-induced liver injury, viral hepatitis, autoimmune liver disease and shock or hypoperfusion; many cases (≈20%) have no discernible cause.5 Acute liver failure often affects young persons and carries a high morbidity and mortality. Prior to transplantation, most series suggested less than 15% survival. Currently, overall short-term survival with transplantation is greater than 65%.5 Because of its rarity, ALF has been difficult to study in depth and very few controlled therapy trials have been performed. As a result, standards of intensive care for this condition have not been established. The most widely accepted definition of ALF includes evidence of coagulation abnormality, usually an INR ≥1.5, and any degree of mental alteration (encephalopathy) in a patient without preexisting cirrhosis and with an illness of <26 weeks duration.6 Patients with Wilson disease, vertically-acquired HBV, or autoimmune hepatitis may be included in spite of the possibility of cirrhosis if their disease has only been recognized for <26 weeks. A number of other terms have been used including fulminant hepatic failure and fulminant hepatitis or necrosis. Acute liver failure is a better overall term that should encompass all durations up to 26 weeks. Terms used signifying length of illness such as hyperacute (<7 days), acute (7-21 days) and subacute (>21 days and <26 weeks) are not particularly helpful since they do not have prognostic significance distinct from the cause of the illness. For example, hyperacute cases may have a better prognosis but this is because most are due to acetaminophen toxicity.5 All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have immediate measurement of prothrombin time and careful evaluation for subtle alterations in mentation. If the prothrombin time is prolonged by ≈4-6 seconds or more (INR ≥1.5) and there is any evidence of altered sensorium, the diagnosis of ALF is established and hospital admission is mandatory. Since the condition may progress rapidly, with changes in consciousness occurring hour-by-hour, early transfer to the intensive care unit (ICU) is preferred once the diagnosis of ALF is made. History taking should include careful review of possible exposures to viral infection and drugs or other toxins. If severe encephalopathy is present, the history may be provided entirely by the family or may be unavailable. In this setting, limited information is available, particularly regarding possible toxin/drug ingestions. Physical examination must include careful assessment and documentation of mental status and a search for stigmata of chronic liver disease. Jaundice is often but not always seen at presentation. Right upper quadrant tenderness is variably present. Inability to palpate the liver or even to percuss a significant area of dullness over the liver can be indicative of decreased liver volume due to massive hepatocyte loss. An enlarged liver may be seen early in viral hepatitis or with malignant infiltration, congestive heart failure, or acute Budd-Chiari syndrome. History or signs of cirrhosis should be absent as such features suggest underlying chronic liver disease, which may have different management implications. Furthermore, the prognostic criteria mentioned below are not applicable to patients with acute-on-chronic liver disease. Initial laboratory examination must be extensive in order to evaluate both the etiology and severity of ALF (Table 2). In addition to coagulation parameters, early testing should include routine chemistries (especially glucose as hypoglycemia may be present and require correction), arterial blood gas measurements, complete blood counts, blood typing, acetaminophen level and screens for other drugs and toxins, viral hepatitis serologies (most prominently A and B), tests for Wilson disease, autoantibodies (anti-nuclear and anti-smooth muscle antibodies) and a pregnancy test in females. Plasma ammonia, preferably arterial,7, 8 may also be helpful. A liver biopsy, most often done via the transjugular route because of coagulopathy, may be indicated when certain conditions such as autoimmune hepatitis, metastatic liver disease, lymphoma, or herpes simplex hepatitis are suspected. As the evaluation continues, several important decisions must be made: whether to admit the patient to an ICU, whether to transfer the patient to a transplant facility, and (if already at a transplant center) whether and when to place the patient on the list for transplantation. For patients in a non-transplant center, the possibility of rapid progression of ALF makes early consultation with a transplant facility critical. Specific prognostic indicators may point toward the need for transplantation. For patients with acetaminophen-related ALF in particular, an arterial pH of <7.3 should prompt immediate consideration for transfer to a transplant center and placement on a transplant list.9 Patients with altered mentation should generally be admitted to an ICU. Planning for transfer to a transplant center should begin in patients with grade I or II encephalopathy (Table 2) because they may worsen rapidly. Early transfer is important as the risks involved with patient transport may increase or even preclude transfer once stage III or IV encephalopathy develops. Evaluation for transplantation should begin as early as possible. In these critically ill patients with potential for rapid deterioration it is necessary to make treatment plans promptly. Social and financial considerations are unavoidably tied to the overall clinical assessment where transplantation is contemplated. It is important to inform the patient's family or other next of kin of the potentially poor prognosis and to include them in the decision-making process. Patients with ALF should be admitted and monitored frequently, preferably in an ICU (III). Contact with a transplant center and plans to transfer appropriate patients with ALF should be initiated early in the evaluation process (III). The precise etiology of ALF should be sought to guide further management decisions (III). Etiology of ALF provides one of the best indicators of prognosis,5 and also dictates specific management options. Acetaminophen hepatotoxicity is suggested by historic evidence for excessive ingestion either as an intended suicidal overdose or the inadvertent use of supra-therapeutic quantities of pain medications. Acetaminophen is a dose-related toxin; most ingestions leading to ALF exceed 10 gm/day. However, severe liver injury can occur rarely when doses as low as 3-4 gm/day are taken.10 Very high aminotransferases may be seen; serum levels exceeding 3,500 IU/L are highly correlated with acetaminophen poisoning11 and should prompt consideration of this etiology even when historic evidence is lacking. Because acetaminophen is the leading cause of ALF (at least in the United States and Europe) and there is an available antidote, acetaminophen levels should be drawn in all patients presenting with ALF. Low or absent acetaminophen levels do not rule out acetaminophen poisoning since the time of ingestion may be remote or unknown, especially when overdose may have been unintentional and/or occurred over several days. If acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation, activated charcoal may be useful for gastrointestinal decontamination. While it is most effective if given within one hour of ingestion,12 it may be of benefit as long as 3 to 4 hours after ingestion.13 Administration of activated charcoal (standard dose 1g/kg orally, in a slurry) just prior to administration of N-acetylcysteine does not reduce the effect of N-acetylcysteine.13 N-acetylcysteine (NAC), the antidote for acetaminophen poisoning, has been shown to be effective and safe for this purpose in numerous controlled trials.15-18 The standard acetaminophen toxicity nomogram19 may aid in determining the likelihood of serious liver damage, but cannot be used to exclude possible toxicity due to multiple doses over time, or altered metabolism in the alcoholic or fasting patient.20 Given these considerations, administration of NAC is recommended in any case of ALF in which acetaminophen overdose is a suspected or possible cause. NAC should be given as early as possible, but may still be of value 48 hours or more after ingestion.21 NAC may be given orally (140 mg/kg by mouth or nasogastric tube diluted to 5% solution, followed by 70 mg//kg by mouth q 4 h × 17 doses) and has few side effects (occasional nausea, vomiting, rare urticaria or bronchospasm). In patients with ALF oral administration may often be precluded (for instance, by active gastrointestinal bleeding or worsening mental status), and NAC may be administered intravenously (loading dose is 150 mg/kg in 5% dextrose over 15 minutes; maintenance dose is 50 mg/kg given over 4 hours followed by 100 mg/kg administered over 16 hours). Allergic reactions may be successfully treated with discontinuation, antihistamines22 and epinephrine for bronchspasm. For patients with known or suspected acetaminophen overdose within 4 hours of presentation, give activated charcoal just prior to starting NAC (I). Begin NAC promptly in all patients where the quantity of acetaminophen ingested, serum drug level or rising aminotransferases indicate impending or evolving liver injury (II-1). NAC may be used in cases of acute liver failure in which acetaminophen ingestion is possible or when knowledge of circumstances surrounding admission is inadequate (III). Mushroom Poisoning (usually Amanita phalloides) may cause ALF, and the initial history should always include inquiry concerning recent mushroom ingestion. There is no available blood test to confirm the presence of these toxins, but this diagnosis should be suspected in patients with a history of severe gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal cramping), which occur within hours to a day of ingestion. If these effects are present, it may be early enough to treat patients with gastric lavage and activated charcoal via naso-gastric tube. Fluid resuscitation is also important. Traditionally, very low rates of survival have been reported without transplantation,23 but more recently complete recovery has been described with supportive care and medical treatment.24 Penicillin G and silibinin (silymarin or milk thistle) are the accepted antidotes despite no controlled trials proving their efficacy.23, 25, 26 While some reports have not found penicillin G to be helpful,27 enough efficacy has been reported to warrant consideration of the drug (given intravenously in doses of 300,000 to 1 million units/kg/day) in patients with known or suspected mushroom poisoning.28 Silibinin has generally been reported to be more successful than penicillin G, although penicillin G has been used more frequently in the United States.27, 28 Silibinin/silymarin is not available as a licensed drug in the United States, although it is widely available in Europe and South America. In the United States, it is commercially available as milk thistle extracts, tablets, capsules or tincture. These products usually contain 70%-80% silymarin, although there is no governmental regulation of such herbal supplements; silymarin concentrations may vary considerably between preparations and manufacturers.29 When used for treatment of mushroom poisoning, silymarin has been given in average doses of 30-40 mg/kg/day (either intravenously or orally) for an average duration of 3 to 4 days.26 N-acetylcysteine is often combined with these other therapies, but has not been shown to be effective in animal studies30; nevertheless, case reports have described its use as a part of overall management.31 In ALF patients with known or suspected mushroom poisoning, consider administration of penicillin G and silymarin (III). Patients with acute liver failure secondary to mushroom poisoning should be listed for transplantation, as this procedure is often the only lifesaving option (III). A variety of medications have been associated with acute liver injury. Before implicating a particular substance, history should include careful listing of all agents taken, the time period involved, and the quantity ingested. Drugs other than acetaminophen rarely cause dose-related toxicity. Most examples of idiosyncratic drug hepatotoxicity occur within the first 6 months after drug initiation. A potentially hepatotoxic medication that has been used continually for more than 1 to 2 years is unlikely to cause de novo liver damage. Certain herbal preparations and other nutritional supplements have been found to cause liver injury,32 so inquiry about such substances should be included in a complete medication history. There are no specific antidotes for idiosyncratic drug reactions; corticosteroids are not indicated unless a drug hypersensitivity reaction is suspected. Determination of a particular medication as the cause of ALF is a diagnosis of exclusion. Other causes of ALF should still be ruled out even if a drug is suspected. Any presumed or possible offending agent should be stopped immediately where possible. Classes of drugs commonly implicated include antibiotics, non-steroidal anti-inflammatory agents and anti-convulsants (Table 3). Obtain details (including onset of ingestion, amount and timing of last dose) concerning all prescription and non-prescription drugs, herbs and dietary supplements taken over the past year (III). Determine ingredients of non-prescription medications whenever possible (III). In the setting of acute liver failure due to possible drug hepatotoxicity, discontinue all but essential medications (III). Hepatitis serological testing should be done for identification of acute viral infection (Table 2) even when another putative etiology is identified. Viral hepatitis has become a relatively infrequent cause of ALF (United States: 12%; hepatitis B – 8%, hepatitis A – 4%).5 Acute hepatitis D may occasionally be diagnosed in a hepatitis B positive individual. Although controversial, hepatitis C alone does not appear to cause ALF.5, 33 Hepatitis E is a significant cause of liver failure in countries where it is endemic, and tends to be more severe in pregnant women.33, 34 This virus should be considered in anyone with recent travel to an endemic area such as Russia, Pakistan, Mexico, or India. With acute viral hepatitis, as with many other etiologies of ALF, care is mainly supportive. Of note, the nucleoside analog lamivudine (and possibly adefovir), used widely in the treatment of chronic hepatitis B, may be considered in patients with acute hepatitis B, although these drugs have not been subjected to a controlled trial35 in acute disease. Acute liver failure due to reactivation of hepatitis B may occur in the setting of chemotherapy or immunosuppression. Recent evidence suggests that patients found to be positive for HBsAg who are to begin such therapy should be treated prophylactically with a nucleoside analog, and that such treatment should be continued for 6 months after completion of immunosuppressive therapy (please refer to the AASLD Practice Guideline on Management of Chronic Hepatitis B, Update of Recommendations36). Herpes virus infection rarely causes ALF. Immunosuppressed patients or pregnant women (usually in the third trimester) are at increased risk, but occurrences of herpes virus ALF have been reported in healthy individuals.33, 37, 38 Skin lesions are present in only about 50% of cases. Liver biopsy is helpful in making the diagnosis. Treatment should be initiated with acyclovir for suspected or documented cases.37, 38 Other viruses such as varicella zoster39 have occasionally been implicated in causing hepatic failure. Viral hepatitis A- and B- (and E-) related acute liver failure must be treated with supportive care as no virus-specific treatment has been proven effective (III). Nucleoside analogs should be given prior to and continued for 6 months after completion of chemotherapy in patients with Hepatitis B surface antigen positivity to prevent reactivation/acute flare of disease (III). Patients with known or suspected herpes virus or varicella zoster as the cause of acute liver failure should be treated with acyclovir (III). Wilson disease is an uncommon cause of ALF (2%-3% of cases in the US ALFSG). Early identification is critical because the fulminant presentation of Wilson disease is considered to be uniformly fatal without transplantation. The disease typically occurs in young patients, accompanied by the abrupt onset of hemolytic anemia with serum bilirubin levels >20 mg/dL. Due to the presence of hemolysis, the indirect-reacting bilirubin is often markedly elevated along with the total bilirubin. Kayser-Fleischer rings are present in about 50% of patients presenting with ALF due to Wilson disease.40 Serum ceruloplasmin is typically low, but may be normal in up to 15% of cases and is often reduced in other forms of ALF; high serum and urinary copper levels as well as hepatic copper measurement may confirm the diagnosis. Very low serum alkaline phosphatase or uric acid levels are hints to suggest Wilson disease in the absence of other indicators. A high bilirubin (mg/dL) to alkaline phosphatase (IU/L) ratio (>2.0) is a reliable albeit indirect indicator of Wilson disease in this setting.40, 41 Renal function is often impaired as the released copper can cause renal tubular damage. Treatment to acutely lower serum copper and to limit further hemolysis should include albumin dialysis, continuous hemofiltration, plasmapheresis or plasma exchange. Initiation of treatment with penicillamine is not recommended in ALF as there is a risk of hypersensitivity to this agent; acute lowering of the copper is more effectively accomplished using direct plasma copper reduction techniques, especially when renal function is impaired.40 Although such copper lowering measures should be considered, recovery is infrequent without transplantation.40, 42 Wilson disease is one of the special circumstances in which patients may already have evidence of cirrhosis and still be considered to have a diagnosis of ALF when rapid deterioration occurs. Please refer to the AASLD Practice Guideline on Wilson Disease for more detailed information regarding the diagnosis and management of patients with this condition.40 Diagnostic tests for Wilson disease should include ceruloplasmin, serum and urinary copper levels, total bilirubin/alkaline phosphatase ratio, slit lamp examination for Kayser-Fleischer rings, and hepatic copper levels when liver biopsy is feasible (III). Patients in whom Wilson disease is the likely cause of acute liver failure must be immediately placed on the liver transplant list (III). With autoimmune hepatitis as with Wilson disease, patients may have unrecognized preexisting chronic disease and yet still be considered as having ALF. Such patients represent the most severe form of the disease, and would generally fall into the category of patients recommended for corticosteroid therapy as outlined by the AASLD Practice Guidelines for the Diagnosis and Treatment of Autoimmune Hepatitis (although ALF is not specifically discussed in that document).43 Although some patients may be responsive to steroid therapy, others require transplantation.44, 45 Autoantibodies may be absent making a definitive diagnosis difficult. Liver biopsy may be helpful if findings include presence of severe hepatic necrosis accompanied by interface hepatitis, plasma cell infiltration and hepatocyte rosettes. Initiation of steroid therapy may constitute a therapeutic trial for some patients (prednisone starting at 40-60 mg/day),43 although placement on the transplant list is indicated. When autoimmune hepatitis is suspected as the cause of acute liver failure, liver biopsy should be considered to establish this diagnosis (III). Patients with acute liver failure due to autoimmune hepatitis should be treated with corticosteroids (prednisone, 40-60 mg/day) (I). Patients should be placed on the list for transplantation even while corticosteroids are being administered (III). A small number of women near the end of pregnancy will develop rapidly progressive hepatocyte failure that has been well characterized46-49 and associated with increased fetal or maternal mortality. A variety of presentations may be seen, generally confined to the last trimester. The triad of jaundice, coagulopathy, and low platelets may occasionally be associated with hypoglycemia. Features of pre-eclampsia such as hypertension and proteinuria are common. Steatosis documented by imaging studies supports the diagnosis. The Oil-red O staining technique best demonstrates hepatic steatosis on biopsy. Intrahepatic hemorrhage and/or hepatic rupture constitute rare emergent situations requiring rapid resuscitation and intervention. Early recognition of these syndromes and prompt delivery are critical in achieving good outcomes. Recovery is typically rapid after delivery, and supportive care is the only other treatment required. Post-partum transplantation has occasionally been necessary, however.50 Pregnancy (especially in the third trimester) appears to increase the risk of ALF due to herpes virus, which should be treated with acyclovir (see section on acute viral infection).37 It is important to keep in mind that ALF in pregnant women may also be caused by entities not necessarily related to the pregnant state. For acute fatty liver of pregnancy or the HELLP syndrome, consultation with obstetrical services and expeditious delivery are recommended (III). A syndrome often referred to as "shock liver" occurs after cardiac arrest, a period of significant hypovolemia/hypotension, or in the setting of severe congestive heart failure.51 Documented hypotension is not always found. Drug-induced hypotension or hypoperfusion may be observed with long-acting niacin,52 or with cocaine,53 or methamphetamine.54 Other physical findings may be lacking, but evidence of cardiac dysfunction may be elicited via echocardiogram.55 Aminotransferase levels will be markedly elevated and respond rapidly to stabilization of the circulatory problem. Simultaneous onset of renal dysfunction and muscle necrosis may be noted. The ability to manage heart failure or other causes of ischemia successfully will determine outcome for these patients, and transplantation is seldom indicated. In ALF patients with evidence of ischemic injury cardiovascular support is the treatment of choice (III). The Budd-Chiari syndrome (acute hepatic vein thrombosis) can also present as ALF. Abdominal pain, ascites and striking hepatomegaly are often present. The diagnosis should be confirmed with hepatic imaging studies (computed tomography, doppler ultrasonography, venography, magnetic resonance venography). In the presence of significant liver failure, transplantation may be required as opposed to venous decompression.56 As malignancy-associated hypercoagulability is one of the causes of Budd-Chiari syndrome, it is important to rule out underlying cancer prior to transplantation of these patients. Hepatic vein thrombosis with hepatic failure is an indication for liver transplantation, provided underlying malignancy is excluded (II-3). Malignant infiltration of the liver may cause ALF. Massive hepatic enlargement may be seen. Diagnosis should be made by imaging and biopsy, and treatment appropriate for the underlying malignant condition is indicated. Transplantation is not an option for such patients.57, 58 Acute severe hepatic infiltration occurs with breast cancer,59, 60 small cell lung cancers,61 lymphoma58 and melanoma.62 In patients with acute liver failure who have a previous cancer history or massive hepatomegaly, consider underlying malignancy and obtain imaging and liver biopsy to confirm or exclude the diagnosis (III). When the etiology of ALF cannot be determined after routine evaluation, biopsy using a transjugular approach may be helpful in diagnosing malignant infiltration, autoimmune hepatitis, certain viral infections and Wilson disease. Lack of a clear diagnosis suggests that the history may have been inadequate regarding toxin or drug exposures. If the etiological diagnosis remains elusive after extensive initial evaluation, liver biopsy may be appropriate to attempt to identify a specific etiology that might influence treatment strategy (III). While patients with ALF represent a heterogeneous group, they have consistent clinical features, and share the common disease process of acute hepatocyte loss and its sequelae. Despite decades of research, however, no agent or therapy that is beneficial to all patients with ALF has been found. Systemic corticosteroids are ineffective in this condition.63-65 Because most patients with ALF tend to develop some degree of circulatory dysfunction, agents that may improve hemodynamics have been of particular interest. While prostacyclin and other prostaglandins have appeared promising in some reports,66, 67 others have not supported their efficacy in ALF.68 NAC may improve systemic circulation parameters in patients with ALF,69 but this was not observed in all studies.70 NAC has been shown to improve liver blood flow and function in patients with septic shock.71 Use of NAC in all forms of ALF cannot be justified based on current evidence. A large, multi-center, randomized, double-blind controlled trial of intravenous NAC versus placebo for non-acetaminophen ALF is currently under way. Because there is no proven therapy for ALF in general, management consists of intensive care support once treatments for specific etiologies have been initiated. While some patients with evidence of acute liver injury but without significant coagulopathy or encephalopathy may be monitored on a medicine ward, any patient with altered mental status warrants admission to an ICU as the condition may deteriorate quickly. Careful attention must be paid to fluid management, hemodynamics and metabolic parameters as well as surveillance for and treatment of infection. Maintenance of nutrition and prompt recognition and resuscitation of gastrointestinal bleeding are crucial as well. Coagulation parameters, complete blood counts, metabolic panels (including glucose) and arterial blood gas should be checked frequently. Serum aminotransferases and bilirubin are generally measured daily to follow the course of the condition, however changes in aminotransferase levels correlate poorly with prognosis. See Table 4. Cerebral edema and intracranial hypertension (ICH) have long been recognized as the most serious complications of ALF.72 Uncal herniation may result and is uniformly fatal. Cerebral edema may also contribute to ischemic and hypoxic brain injury, which may result in long-term neurological deficits in survivors.73 The pathogenic mechanisms leading to the development of cerebral edema and ICH in ALF are not entirely understood. It is likely that multiple factors are involved, including osmotic disturbances in the brain and heightened cerebral blood flow due to loss of cerebrovascular autoregulation. Inflammation and/or infection, as well as factors yet unidentified may also contribute to the phenomenon.74 Several measures have been proposed and used with varying success to tackle the problem of cerebral edema and the associated ICH in patients with ALF. Some interventions are supported by more evidence than others; no uniform protocol has been established. The occur