Acute Liver Failure

 

 Permissions and Reprints

Abstract

Acute liver failure (ALF) (sometimes referred to as fulminant hepatic failure) is a clinical syndrome from a variety of causes resulting from rapid loss in hepatocyte function, typically associated with coagulopathy and encephalopathy in a patient without preexisting liver disease or cirrhosis. Cerebral edema is a cardinal feature and may produce uncal herniation, yielding brain stem compression and death. The typical interval from onset of symptoms to onset of encephalopathy is 1 to 2 weeks, but cases evolving more slowly, up to 6 months, may still be included in the definition. ALF is rare, affecting 2000 patients annually in the United States, and comprises ∼7% of liver transplants annually. Currently, in the United States, acetaminophen accounts for ∼50% of all cases of ALF, but other etiologies include hepatitis, drug-induced liver injury, autoimmune hepatitis. Prior to the availability of liver transplantation (LT), mortality of ALF was extremely high, often exceeding 90%; most common causes of death were multiorgan failure, hemorrhage, infection, and cerebral edema. Fortunately, survival has improved considerably in the last 3 decades (overall survival now exceeds 60%). In large part, this improved survival reflects the option of LT but also reflects the high frequency of acetaminophen toxicity as a cause of ALF. In fact, most patients with ALF are not candidates for LT. Critical care of patients with ALF is key to their survival, and decisions must sometimes be made with inadequate information. We review standard practices (medical, pharmacological, and LT) and new research initiatives and findings for this interesting but vexing orphan disease. Particular attention will be paid to practical matters for clinicians to consider in approaching the ALF patient.

• References

• 1 Trey C, Davidson CS. The management of fulminant hepatic failure. In: Popper H, Schaffner F, eds. Progress in Liver Diseases. New York: Grune & Stratton; 1970: 282-298
  Google Scholar
• 2 Lee WM, Squires Jr RH, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: summary of a workshop. Hepatology 2008; 47 (4) 1401-1415
  CrossrefPubMedGoogle Scholar
• 3 Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet 2010; 376 (9736) 190-201
  CrossrefPubMedGoogle Scholar
• 4 Ostapowicz GA, Fontana RJ, Schiødt FV , et al; U.S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137 (12) 947-954
  CrossrefPubMedGoogle Scholar
• 5 Stravitz RT, Kramer AH, Davern T , et al; Acute Liver Failure Study Group. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med 2007; 35 (11) 2498-2508
  CrossrefPubMedGoogle Scholar
• 6 Stravitz RT, Kramer DJ. Management of acute liver failure. Nat Rev Gastroenterol Hepatol 2009; 6 (9) 542-553
  CrossrefPubMedGoogle Scholar
• 7 Lee WM, Schiødt FV. Fulminant hepatic failure. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff's Diseases of the Liver. 8th ed. Philadelphia: Lippincott-Raven; 1999: 879-895
  Google Scholar
• 8 Schiødt FV, Atillasoy E, Shakil AO , et al. Etiology and outcome for 295 patients with acute liver failure in the United States. Liver Transpl Surg 1999; 5 (1) 29-34
  CrossrefPubMedGoogle Scholar
• 9 Lee WM, Seremba E. Etiologies of acute liver failure. Curr Opin Crit Care 2008; 14 (2) 198-201
  CrossrefPubMedGoogle Scholar
• 10 Acharya SK, Dasarathy S, Kumer TL , et al. Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome. Hepatology 1996; 23 (6) 1448-1455
  CrossrefPubMedGoogle Scholar
• 11 Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995; 22 (3) 767-773
  CrossrefPubMedGoogle Scholar
• 12 Shakil AO, Kramer D, Mazariegos GV, Fung JJ, Rakela J. Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria. Liver Transpl 2000; 6 (2) 163-169
  PubMedGoogle Scholar
• 13 Schiødt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997; 337 (16) 1112-1117
  CrossrefPubMedGoogle Scholar
• 14 Larson AM, Polson J, Fontana RJ , et al; Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42: 1367-1372
  PubMedGoogle Scholar
• 15 Shayiq RM, Roberts DW, Rothstein K , et al. Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: an explanation for high acetaminophen dosage in humans without hepatic injury. Hepatology 1999; 29 (2) 451-463
  CrossrefPubMedGoogle Scholar
• 16 Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis 2007; 11 (3) 525-548, vi
  CrossrefPubMedGoogle Scholar
• 17 Davern II TJ, James LP, Hinson JA , et al; Acute Liver Failure Study Group. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 2006; 130 (3) 687-694
  CrossrefPubMedGoogle Scholar
• 18 James LP, Alonso EM, Hynan LS , et al; Pediatric Acute Liver Failure Study Group. Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause. Pediatrics 2006; 118 (3) e676-e681
  CrossrefPubMedGoogle Scholar
• 19 Khandelwal N, James LP, Sanders C, Larson AM, Lee WM ; and the Acute Liver Failure Study Group. Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure. Hepatology 2011; 53 (2) 567-576
  CrossrefPubMedGoogle Scholar
• 20 Watkins PB, Kaplowitz N, Slattery JT , et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006; 296 (1) 87-93
  CrossrefPubMedGoogle Scholar
• 21 U.S. Food and Drug Administration. FDA drug safety communication: prescription acetaminophen products to be limited to 325 mg per dosage unit: boxed warning will highlight potential for severe liver failure. http://www.fda.gov/Drugs/DrugSafety/ucm239821.htm . Accessed August 21, 2011
  PubMedGoogle Scholar
• 22 Harris G. F.D.A. plans new limits on painkillers. New York Times. January 13, 2011. http://www.nytimes.com/2011/01/14/health/policy/14fda.html?scp=1&sq=tylenol%20package&st=cse . Accessed August 21, 2011
  PubMedGoogle Scholar
• 23 Chalasani N, Fontana RJ, Bonkovsky HL , et al; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135 (6) 1924-1934, e1–e4
  CrossrefPubMedGoogle Scholar
• 24 Reuben A, Koch DG, Lee WM ; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52 (6) 2065-2078
  CrossrefPubMedGoogle Scholar
• 25 Dao DY, Hynan LS, Yuan HJ , et al; The Acute Liver Failure Study Group. Two distinct subtypes of hepatitis B virus-related acute liver failure are separable by quantitative serum IgM anti-HBc and HBV DNA levels. Hepatology 2011; Oct 10. doi:10.1002/hep24732. [Epub ahead of print]
  PubMedGoogle Scholar
• 26 Stravitz RT, Lefkowitch JH, Fontana RJ , et al; Acute Liver Failure Study Group. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology 2011; 53 (2) 517-526
  CrossrefPubMedGoogle Scholar
• 27 Korman JD, Volenberg I, Balko J , et al; Pediatric and Adult Acute Liver Failure Study Groups. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 2008; 48 (4) 1167-1174
  CrossrefPubMedGoogle Scholar
• 28 Rowbotham D, Wendon J, Williams R. Acute liver failure secondary to hepatic infiltration: a single centre experience of 18 cases. Gut 1998; 42 (4) 576-580
  CrossrefPubMedGoogle Scholar
• 29 Lee WM, Brown KE, Young NS , et al; Acute Liver Failure Study Group. Brief report: no evidence for parvovirus B19 or hepatitis E virus as a cause of acute liver failure. Dig Dis Sci 2006; 51 (10) 1712-1715
  CrossrefPubMedGoogle Scholar
• 30 Levitsky J, Duddempudi AT, Lakeman FD , et al; US Acute Liver Failure Study Group. Detection and diagnosis of herpes simplex virus infection in adults with acute liver failure. Liver Transpl 2008; 14 (10) 1498-1504
  CrossrefPubMedGoogle Scholar
• 31 Polson J, Lee WM ; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology 2005; 41 (5) 1179-1197
  CrossrefPubMedGoogle Scholar
• 32 Lee WM, Hynan LS, Rossaro L , et al; Acute Liver Failure Study Group. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009; 137 (3) 856-864, e1
  CrossrefPubMedGoogle Scholar
• 33 Oketani M, Ido A, Tsubouchi H. Changing etiologies and outcomes of acute liver failure: a perspective from Japan. J Gastroenterol Hepatol 2011; 26 (Suppl 1) 65-71
  CrossrefPubMedGoogle Scholar
• 34 Sorrell MF, Belongia EA, Costa J , et al. National Institutes of Health consensus development conference statement: management of hepatitis B. Ann Intern Med 2009; 150 (2) 104-110
  PubMedGoogle Scholar
• 35 Blei AT. Pathogenesis of brain edema in fulminant hepatic failure. Prog Liver Dis 1995; 13: 311-330
  PubMedGoogle Scholar
• 36 Jalan R. Pathophysiological basis of therapy of raised intracranial pressure in acute liver failure. Neurochem Int 2005; 47 (1-2) 78-83
  CrossrefPubMedGoogle Scholar
• 37 Larsen FS, Wendon J. Prevention and management of brain edema in patients with acute liver failure. Liver Transpl 2008; 14 (Suppl 2) S90-S96
  CrossrefPubMedGoogle Scholar
• 38 Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999; 29 (3) 648-653
  CrossrefPubMedGoogle Scholar
• 39 Vaquero J, Fontana RJ, Larson AM , et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl 2005; 11 (12) 1581-1589
  CrossrefPubMedGoogle Scholar
• 40 Parekh NK, Hynan LS, De Lemos J, Lee WM ; Acute Liver Failure Study Group. Elevated troponin I levels in acute liver failure: is myocardial injury an integral part of acute liver failure?. Hepatology 2007; 45 (6) 1489-1495
  CrossrefPubMedGoogle Scholar
• 41 Stravitz RT, Lisman T, Luketic VA , et al. Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography. J Hepatol 2012; 56 (1) 129-136
  CrossrefPubMedGoogle Scholar
• 42 Schiødt FV, Balko J, Schilsky MC, Harrison ME, Thornton A, Lee WM ; Acute Liver Failure Study Group. Thrombopoietin in acute liver failure. Hepatology 2003; 37 (3) 558-561
  CrossrefPubMedGoogle Scholar
• 43 O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97 (2) 439-445
  PubMedGoogle Scholar
• 44 Lee WM, Squires Jr RH, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: summary of a workshop. Hepatology 2008; 47 (4) 1401-1415
  CrossrefPubMedGoogle Scholar
• 45 Shouval DS, Mor E, Avitzur Y , et al. Living-related donor liver transplantation for children with fulminant hepatic failure in Israel. J Pediatr Gastroenterol Nutr 2009; 48 (4) 451-455
  CrossrefPubMedGoogle Scholar
• 46 Hanje AJ, Michaels A, Lee WM. Is N-acetylcysteine effective in all non-acetaminophen acute liver failure?. In: Jensen DM, , ed. Controversies in Hepatology. Philadelphia, PA: Slack; 2011
  Google Scholar
• 47 Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology 2009; 136 (7) 2159-2168
  CrossrefPubMedGoogle Scholar
• 48 Jalan R, Lee WM. Treatment of hyperammonemia in liver failure: a tale of two enzymes. Gastroenterology 2009; 136 (7) 2048-2051
  CrossrefPubMedGoogle Scholar
• 49 Davies NA, Wright G, Ytrebø LM , et al. L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats. Hepatology 2009; 50 (1) 155-164
  CrossrefPubMedGoogle Scholar
• 50 Ytrebø LM, Kristiansen RG, Maehre H , et al. L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure. Hepatology 2009; 50 (1) 165-174
  PubMedGoogle Scholar
• 51 Demetriou AA, Brown Jr RS, Busuttil RW , et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg 2004; 239 (5) 660-667 , discussion 667–670
  CrossrefPubMedGoogle Scholar
• 52 Jalan R, Sen S, Williams R. Prospects for extracorporeal liver support. Gut 2004; 53 (6) 890-898
  CrossrefPubMedGoogle Scholar
• 53 Liu J, Kjaergard LL, Als-Nielsen B, Gluud C. Artificial and bioartificial support systems for liver failure: a Cochrane Hepato-Biliary Group Protocol. Liver 2002; 22 (5) 433-438
  PubMedGoogle Scholar
• 54 Chari RS, Collins BH, Magee JC , et al. Brief report: treatment of hepatic failure with ex vivo pig-liver perfusion followed by liver transplantation. N Engl J Med 1994; 331 (4) 234-237
  CrossrefPubMedGoogle Scholar
• 55 Horslen SP, Hammel JM, Fristoe LW , et al. Extracorporeal liver perfusion using human and pig livers for acute liver failure. Transplantation 2000; 70 (10) 1472-1478
  CrossrefPubMedGoogle Scholar
• 56 Fukumitsu K, Yagi H, Soto-Gutierrez A. Bioengineering in organ transplantation: targeting the liver. Transplant Proc 2011; 43 (6) 2137-2138
  CrossrefPubMedGoogle Scholar