Acute_Liver_Failure_Update_2011（AASLD）

POSITION PAPER AASLD Position Paper: The Management of Acute Liver Failure: Update 2011 William M. Lee, MD,1 Anne M. Larson, MD,2 and R. Todd Stravitz, MD3 Preamble These recommendations provide a data-supported approach. They are based on the following: 1) Formal review and analysis of recently-published world litera- ture on the topic [Medline search]; 2) American Col- lege of Physicians Manual for Assessing Health Prac- tices and Designing Practice Guidelines;1 3) guideline policies, including the AASLD Policy on the Develop- ment and Use of Practice Guidelines and the AGA Policy Statement on Guidelines;2; and 4) the experi- ence of the authors in the specified topic. Intended for use by physicians, the recommenda- tions 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 docu- ment has been designated as a Position Paper, since the topic contains more data based on expert opinion than on randomized controlled trials and is thus 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 1)3 These recommendations are fully endorsed by the AASLD. Introduction Acute liver failure (ALF) is a rare condition in which rapid deterioration of liver function results in altered mentation and coagulopathy in individuals without known pre-existing liver disease. U.S. esti- mates are placed at approximately 2,000 cases per year.4,5 A recent estimate from the United Kingdom was 1-8 per million population.6 The most promi- nent causes include drug-induced liver injury, viral hepatitis, autoimmune liver disease and shock or hy- poperfusion; many cases (�15%) have no discernible cause.7 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 (one year) including those undergoing transplantation is greater than 65%.7 Because of its rarity, ALF has been difficult to study in depth and very few con- trolled therapy trials have been performed. As a result, standards of intensive care for this condition have not been established although a recent guideline provides some general directions.8 Definition The most widely accepted definition of ALF includes evidence of coagulation abnormality, usually an International Normalized Ratio (INR) �1.5, and any degree of mental alteration (encephalopathy) in a patient without preexisting cirrhosis and with an illness of <26 weeks’ duration.9 Patients with Wilson disease, vertically-acquired hepatitis B virus (HBV), or autoim- mune hepatitis may be included in spite of the possi- bility of cirrhosis if their disease has only been recog- nized for <26 weeks. A number of other terms have Abbreviations: ALF, acute liver failure; NAC, N-acetylcysteine; HELLP, Hemolysis, Elevated Liver Enzymes, Low Platelets syndrome; gm/day, grams per day; gm/kg, grams per kilogram; ICH, intracranial hypertension; ICP, intracranial pressure; INR, international normalized ratio; CT, computerized tomography; US ALFSG, United States Acute Liver Failure Study Group; CPP, cerebral perfusion pressure; MAP, mean arterial pressure; mg/dL, milligrams per deciliter, 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; AFP, alpha fetoprotein; MELD, Model for End-stage Liver Disease; mg/kg, milligrams per kilogram; IU/L, international units per liter; From the 1University of Texas, Southwestern Medical Center at Dallas, 5959 Harry Hines Boulevard, HP4.420E, Dallas, TX 75390-8887; 2Director, Swedish Liver Center, Swedish Health Systems, 1101 Madison Street #200, Seattle WA 98104-1321; 3Virginia Commonwealth University, Section of Hepatology, PO Box 980341, 1200 East Broad Street, Richmond, VA 23298 Copyright VC 2011 by the American Association for the Study of Liver Diseases. Potential conflict of interest: Dr. William Lee has advisory relationships with Eli Lilly, Cumberland, Novartis, Forest Labs and Gilead and receives research support from Bristol-Myers Squibb, Cumberland, Gilead, Globeimmune, Merck, Vertex, Novartis, Boehringer Ingelheim, Anadys and Siemens. Dr. Anne Larson and Dr. R. Todd Stravitz have nothing to report. 1 been used for this condition, including fulminant he- patic 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 popular but not particularly help- ful since they do not have prognostic significance dis- tinct from the cause of the illness. For example, hyper- acute diseases tend to have a better prognosis, but this is because most are due to acetaminophen toxicity or ischemic hepatopathy, both of which have good initial recovery rates.7 Diagnosis and Initial Evaluation All patients with clinical or laboratory evidence of 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 diagno- sis of ALF is established and hospital admission is mandatory. Since the condition may progress rapidly, patients determined to have any degree of encephalop- athy should be transferred to the intensive care unit (ICU) and contact with a transplant center made to determine if transfer is appropriate. Transfer to a trans- plant center should take place for patients with grade I or II encephalopathy (Table 5) because they may wor- sen 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. History taking should include careful review of pos- sible 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. Limited historical information, particularly regarding possible toxin/drug ingestions, complicates the initial assessment and may be responsible for many indeterminate diagnoses.10 Physical examination should include a mental status examination and a search for stigmata of chronic liver disease. Jaundice is often but not always seen at presentation and may be absent in acetaminophen cases early on. Right upper quadrant tenderness is variably present. Inability to palpate the liver or even to percuss a significant area of dullness over the liver may indicate decreased liver vol- ume. An enlarged liver may be seen early in viral hepa- titis but is particularly noteworthy for malignant infil- tration, congestive heart failure, or acute Budd-Chiari syndrome. History or signs suggesting underlying chronic liver disease should have different management implications. Furthermore, the prognostic criteria men- tioned 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). Early testing should include routine chemis- tries (especially glucose, as hypoglycemia may be pres- ent and require correction), arterial blood gas measure- ments, complete blood counts, blood typing, acetaminophen level and screens for other drugs and toxins, viral serologies (Table 2), tests for Wilson dis- ease, autoantibodies, and a pregnancy test in females. Plasma ammonia, preferably arterial, may also be help- ful.11,12 Liver biopsy, most often done via the transjug- ular route because of coagulopathy, is indicated when certain conditions such as autoimmune hepatitis, Table 1. Quality of Evidence on Which a Recommendation Is Based3 Grade Definition I Randomized controlled trials II-1 Controlled trials without randomization II-2 Cohort or case-control analytic studies II-3 Multiple time series, dramatic uncontrolled experiments III Opinions of respected authorities, descriptive epidemiology Table 2. Initial Laboratory Analysis Prothrombin time/INR Chemistries sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate glucose AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin creatinine, blood urea nitrogen Arterial blood gas Arterial lactate Complete blood count Blood type and screen Acetaminophen level Toxicology screen Viral hepatitis serologies anti-HAV IgM, HBsAg, anti-HBc IgM, anti-HEV§, anti-HCV, HCV RNA*, HSV1 IgM, VZV Ceruloplasmin level# Pregnancy test (females) Ammonia (arterial if possible) Autoimmune Markers ANA, ASMA, Immunoglobulin levels HIV-1, HIV-2‡ Amylase and lipase *Done to recognize potential underlying infection. #Done only if Wilson disease is a consideration (e.g., in patients less than 40 years without another obvious explanation for ALF); in this case uric acid level and bilirubin to alkaline phosphatase ratio may be helpful as well. ‡Implications for potential liver transplantation. §If clinically indicated. 2 LEE, LARSON, AND STRAVITZ HEPATOLOGY, September 2011 metastatic liver disease, lymphoma, or herpes simplex hepatitis are suspected, but is not required to deter- mine prognosis. Imaging may disclose cancer or Budd Chiari syndrome but is seldom definitive. The pres- ence of a nodular contour can be seen in ALF and should not be interpreted as indicating cirrhosis in this setting. Once at the transplant facility, the patient’s suitabil- ity for transplantation should be assessed.13 Evaluation for transplantation should begin as early as possible, even before the onset of encephalopathy if possible. Social and financial considerations are unavoidably tied to the overall clinical assessment where transplan- tation is contemplated. It is also important to inform the patient’s family or other next of kin of the poten- tially poor prognosis and to include them in the deci- sion-making process. Recommendations 1. Patients with ALF should be hospitalized and monitored frequently, preferably in an ICU (III). 2. Contact with a transplant center and plans to transfer appropriate patients with ALF should be initiated early in the evaluation process (III). 3. The precise etiology of ALF should be sought to guide further management decisions (III). Determining Etiologies and Specific Therapies Etiology of ALF provides one of the best indicators of prognosis, and also dictates specific management options.6,7 Acetaminophen Hepatotoxicity Acetaminophen hepatotoxicity is suggested by his- toric evidence for excessive ingestion either as an intended suicidal overdose or the inadvertent use of su- pra-therapeutic quantities of pain medications. Acet- aminophen is a dose-related toxin; most ingestions leading to ALF exceed 10 gm/day (�150 mg/kg). However, severe liver injury can occur rarely when doses as low as 3-4 gm/day are taken.14 Very high aminotransferase levels are typically seen; serum levels exceeding 3,500 IU/L are highly correlated with acet- aminophen poisoning and should prompt considera- tion of this etiology even when historic evidence is lacking.15 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.7 However, low or absent levels of the parent com- pound, acetaminophen, do not rule out hepatotoxicity since the time of ingestion may be relatively remote or unknown, especially when overdose may have been unintentional or occurred over several days.10 If acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation, acti- vated charcoal may be useful for gastrointestinal decon- tamination. While it is most effective if given within one hour of ingestion,16 it may be of benefit as long as 3 to 4 hours after ingestion.17 Administration of acti- vated charcoal (standard dose 1 gm/kg orally, in a slurry) just prior to administration of N-acetylcysteine does not reduce the effect of N-acetylcysteine.17 N-ace- tylcysteine (NAC), the antidote for acetaminophen poi- soning, has been shown to be effective and safe for this purpose in numerous controlled trials.18,19 The standard acetaminophen toxicity nomogram20 may aid in deter- mining the likelihood of serious liver damage, but can- not be used to exclude possible toxicity due to multiple doses over time, when the time of ingestion is unknown, or when altered metabolism occurs such as in the alcoholic or fasting patient.21 Given these consid- erations, administration of NAC is recommended in any case of ALF in which acetaminophen overdose is a suspected or possible cause; specific indications that acetaminophen may be the culprit include very high aminotransferases and low bilirubin levels, in the ab- sence of apparent hypotension or cardiovascular col- lapse.10 NAC should be given as early as possible, but may still be of value 48 hours or more after ingestion.22 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 x 17 doses) and has few side effects (nausea and vomiting particularly with rapid infusion or oral NAC,23 rare urticaria or broncho- spasm). Allergic reactions are infrequent and are suc- cessfully treated with discontinuation, antihistamines and epinephrine if bronchospasm is present.24 Oral administration has largely been replaced by intravenous administration (loading dose is 150 mg/kg in 5% dex- trose over 15 minutes; maintenance dose is 50 mg/kg given over 4 hours followed by 100 mg/kg administered over 16 hours or 6 mg/kg/hr). Controversy exists over when to stop use of NAC, whether a standard 72-hour period is optimal or continuation until liver chemistry values have improved. Recommendations 4. For patients with known or suspected acet- aminophen overdose within 4 hours of presentation, give activated charcoal just prior to starting NAC dosing (I). HEPATOLOGY, September 2011 LEE, LARSON, AND STRAVITZ 3 5. 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). 6. 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 but aminotransferases sug- gest acetaminophen poisoning (III). Non-acetaminophen Acute Liver Failure For patients whose disease appears to be caused by etiologies other than acetaminophen, N-acetylcysteine may improve outcomes. In a randomized, controlled trial, NAC appeared to improve spontaneous survival when given during early coma stages (grades I and II) in the setting of non-acetaminophen acute liver failure including, for example, drug-induced liver injury and hepatitis B.23 Mushroom Poisoning Mushroom Poisoning (usually Amanita phalloides) may cause ALF, and the initial history should always include inquiry concerning recent mushroom inges- tion. 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 gastroin- testinal symptoms (nausea, vomiting, diarrhea, abdom- inal 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 acti- vated charcoal via nasogastric tube. Fluid resuscitation is also important. Traditionally, very low rates of sur- vival have been reported without transplantation,25 but more recently complete recovery has been described with supportive care and medical treatment.26 Penicil- lin G and silibinin (silymarin or milk thistle) are the accepted antidotes despite a lack of controlled trials proving their efficacy.27-30 While some reports have not found penicillin G to be helpful,29 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.30 Silibinin has generally been reported to be more successful than penicillin G, although penicillin G has been used more frequently in the United States.31,32 Silibinin is not available as a licensed drug in the United States, although it is widely available in Europe and South America. Emergency application can be made to receive the medication rap- idly in the United States. When used for treatment of mushroom poisoning, silibinin has been given in aver- age doses of 30-40 mg/kg/day (either intravenously or orally) for an average duration of 3 to 4 days.28 NAC is often combined with these other therapies, but has not been shown to be effective in animal studies;30 nevertheless, case reports have described its use as a part of overall management. Recommendation 7. In ALF patients with known or suspected mushroom poisoning, consider administration of penicillin G and N-acetylcysteine (III). 8. Patients with acute liver failure secondary to mushroom poisoning should be listed for transplan- tation, as this procedure is often the only lifesaving option (III). Drug Induced Liver Injury (DILI) Many prescription and over-the-counter medications have been associated with acute liver injury and liver failure. A careful drug history should include listing of all agents taken, the time period involved, and the quantity or dose ingested. Determination of a particu- lar medication as the cause of ALF is a diagnosis of exclusion; guidelines for assessment of causality have recently been proposed by the Drug-Induced Liver Injury Network.33 Drugs other than acetaminophen rarely cause dose-related toxicity. Most examples of idi- osyncratic 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, weight loss agents and other nutritional supplements have been found to cause liver injury, so inquiry about such sub- stances should be included in a complete medication history.34-35 There are no specific antidotes for idiosyn- cratic drug reactions; corticosteroids are not indicated unless a drug hypersensitivity such as the ‘drug rash with eosinophilia and systemic symptoms’ (DRESS) syndrome or an autoimmune reaction is suspected.36 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 antibi- otics, non-steroidal anti-inflammatory agents and anti- convulsants (Table 3). Recommendations 9. Obtain details (including onset of ingestion, amount and timing of last dose) concerning all pre- scription and non-prescription drugs, herbs and die- tary supplements taken over the past year (III). 4 LEE, LARSON, AND STRAVITZ HEPATOLOGY, September 2011 10. Determine ingredients of non-prescription medications whenever possible (III). 11. In the setting of acute liver failure due to pos- sible drug hepatotoxicity, discontinu