Skip Navigation

Nephrology Dialysis Transplantation 2007 22(Supplement 8):viii5-viii8; doi:10.1093/ndt/gfm650
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gotthardt, D.
Right arrow Articles by Sauer, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gotthardt, D.
Right arrow Articles by Sauer, P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Fulminant hepatic failure: etiology and indications for liver transplantation

Daniel Gotthardt1, Carina Riediger1, Karl Heinz Weiss1, Jens Encke1, Peter Schemmer2, Jan Schmidt2 and Peter Sauer1

1Department of Internal Medicine IV, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg and 2Department of Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany

Correspondence to: Daniel Gotthardt, Department of Internal Medicine IV, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Email: Daniel_Gotthardt{at}med.uni-heidelberg.de



   Abstract
Top
 Abstract
Main Text
 References
 
Fulminant hepatic failure is characterized by the development of severe liver injury with impaired synthetic capacity and encephalopathy in patients with previous normal liver or at least well compensated liver disease. The etiology of fulminant hepatic failure refers to a wide variety of causes, of which toxin-induced or viral hepatitis are most common. In spite of specific therapeutic options in distinctive etiologies, orthotopic liver transplantation is the only therapy proven to improve patient survival in the majority of patients. The outcome is determined by the complications like severe coagulopathy, infections, renal impairment or increased intracranial pressure. The decision for transplantation depends on the possibility of spontaneous hepatic recovery, which may be estimated by several factors. The most important variables for predicting the need of transplantation in fulminant hepatic failure are the degree of encephalopathy, patients age and the underlying cause of liver failure.

Keywords: fulminant hepatic failure; liver transplantation



   Main Text
Top
 Abstract
 Main Text
References
 
Overview
Fulminant hepatic failure (FHF) or acute liver failure (ALF) is defined as the rapid development of acute liver injury with severe impairment of the synthetic function and hepatic encephalopathy in a patient without obvious, previous liver disease. The time interval of onset of symptoms like jaundice and the appearance of encephalopathy led to several definitions of FHF [1,2]. Although hyper acute, fulminant and subfulminant hepatic failure may differ in their clinical features, like the incidence of cerebral edema, renal failure or portal hypertension, in clinical practice the different sub-definitions were not generally accepted [3].

FHF is not one of the major indications for orthotopic liver transplantations (OLT), but remains the only therapeutic option for patients, without sufficient regeneration of hepatocytes proven to improve survival. Before liver transplantation had become a reasonable option survival rates of acute liver failure were as low as 15%, but had achieved rates of 60% up to 80% in different series in the last decade [4]. Since the liver is capable of regenerating to a large extent and in several cases the underlying cause of hepatocyte injury may be removed or at least can be controlled with supportive medical therapy, FHF in principle may resolve in a complete recovery. The decision for transplantation depends upon the estimation of the probability of spontaneous recovery and may be very difficult, weighing the advantages of an early transplantation against the disadvantages of an unnecessary transplantation with all consequences. Therefore prognostic scores have been developed as decision support systems for indication and optimal time point of liver transplantation. Overall about 5 to 10% of annual liver transplantations are due to acute liver failure. In the UNOS/OPTN registry, in 2004, 491 out of 5845 transplantations were due to FHF (8.4%) [5]. In 2005 in the German registry 87 out of 1401 transplantations were reported to be associated with FHF (6.2%) [6] (see Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1. Indications for Liver transplantations

 
Etiology of acute liver failure
Generally FHF is defined by reduced synthesis parameters of the liver, usually INR ≥ 1.5 and reduced detoxification resulting in any degree of encephalopathy. This is accepted by the exclusion of preexisting cirrhosis and a duration of a liver disease for less than 26 weeks [1]. If FHF is due to autoimmune hepatitis, Wilson's disease, and vertically acquired HBV infection, the possibility of preexisting cirrhosis may be neglected, if the disease has been known for less than 26 weeks [7]. FHF can result from a wide variety of causes, but viral or toxin-induced hepatitis are the most common (see Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2. Etiology of fulminant hepatic failure

 
Drug induced liver failure
One of the most common causes of FHF is a substance that by itself is cytotoxic or after metabolizing is able to trigger a cascade of cytotoxic and/or autoimmune phenomena. The most important drug is acetaminophen not accounting only for the majority of drug induced ALF, but also being the most common reason for acute liver failure. In several cases the incidence of acetaminophen induced FHF varies among geographic regions, which mostly is due to the local incidence of the different forms of viral hepatitis [4,8,9]. Mushroom poisoning such as Amanita phalloides can cause acute liver failure as well, which should be excluded explicitly during initial evaluation of suspected patients. These intoxications are often preceded by severe gastrointestinal disease, like abdominal pain, diarrhea and vomiting.

Viral hepatitis
Hepatitis B is probably the most common viral cause of FHF and the incidence may be underestimated, since precore or pre-S mutant viruses may escape by routine serology [9]. The overall incidence varies widely in different reports, again reflecting the overall incidence of viral hepatitis in different geographic regions. Since there is evidence, that new antiviral treatment strategies against HBV may avoid fatal liver failure, the reduced possibility of complete immune response leading to elimination of HBV, led to an ongoing controversy of the initiation of antiviral treatment [10]. Although hepatitis A is the most common cause of acute viral hepatitis, a progression to FHF is observed in rare cases. Hepatitis C virus seems to be a cause of FHF only in a few cases. [4, 11]. Hepatitis E, which is more severe in pregnant women and is endemic in specific areas can cause FHF, thus travel history is important during initial presentation [12,13]. Other viral infections leading to ALF and requiring OLT have been described, e.g. Herpes Virus, but are often caused by immunosuppressive treatment, which was initiated before.

Vascular origin
The different blood supply related to the liver can be involved in FHF. Budd-Chiari syndrome, hepatic vein thrombosis, which is more common in females with a medium age of 35 may lead to FHF. [14,15]. Portal vein thrombosis may be the reason for FHF, but often is associated with cirrhosis of the liver or a pancreatic process. Veno-occlusive disease i.e. in the course of hematopoetic cell transplantation and ischemic hepatitis due to reduced arterial perfusion can also be a reason for FHF. Therefore abdominal imaging including assessment of arterial, portal and venous perfusion is strongly recommended starting with ultrasound examination. In most cases further imaging modalities like CT-scan or MRI are required.

Wilson's disease
A rare cause of acute liver failure is an acute manifestation of Wilson's disease (WD). It can occur as FHF or as acute-on-chronic event. Together with autoimmune hepatitis it is generally considered that WD comply with the criteria of acute liver failure, although in most cases a chronic disease is present, which has not been recognized. Therefore a manifest liver fibrosis or even cirrhosis is not considered to be an exclusion criteria for listing as an acute liver failure.

Rare causes of ALF
A number of metabolic related disorders other than Wilson's disease have been reported to be associated with FHF including acute fatty liver of pregnancy and Reye's syndrome. In addition FHF has also been reported in patients with autoimmune hepatitis, sepsis or malignant infiltration of the liver. The etiology of FHF can be determined in up to 80% of cases [3], which is important since it may influence treatment options and may help to determine the prognosis and requirement of OLT.

Treatment options
The management of patients with FHF requires a thorough infrastructure and understanding to deal with the complications that may be present, including renal failure, circulatory dysfunction, coagulopathy, gastrointestinal bleeding, encephalopathy, cerebral edema and metabolic disturbances like metabolic acidosis and hypoglycemia. In the course of these complexities, patients with FHF should be managed in an intensive care unit and should be transferred as soon as possible to centers with a liver transplant program [16]. Liver transplantation remains the main promising option of treatment of FHF. However, depending on the etiology, specific therapies may be used. For example, N-acetylcysteine can significantly improve prognosis of patients with acetaminophen intoxication [17]. Other interventions may be helpful in other specific settings as: forced diuresis, silibilin and activated charcoal in patients with amanita phalloides poisoning. Due to the development of new antiviral medication Hepatitis B virus infection can be treated even in the acute phase [18]. Acyclovir may improve prognosis in patients with herpes virus infection and FHF. Transjugular intrahepatic portosystemic stent shunt is the treatment of choice in patients presenting with FHF due to acute Budd-Chiari syndrome. Liver support systems that substitute in part the functions including detoxification and homeostasis of metabolism have been developed and tested. The efficacy has been demonstrated in only a small number of patients [19].

Prognostic scores and indication for orthotopic liver transplantation
In patients with FHF, the decision to transplant depends on the probability of spontaneous hepatic recovery, which is variable and cannot be predicted reliably. The most important factors for predicting survival in FHF are the degree of encephalopathy, the patient's age, and the cause of FHF. As an example, spontaneous recovery is more likely with lower grades of encephalopathy [20], which is between 65 to 70 percent in patients with encephalopathy grade I-II and is less than 20 percent in patients with encephalopathy grade IV [20]. Patients older than 40 or less than 10 years are less likely to show spontaneous recovery compared to patients between these ages. Patients with FHF due to acetaminophen intoxication, hepatitis A, hepatitis B have a better prognosis than those with idiosyncratic drug reactions or Wilson's disease [21]. Several other variables have been used to predict the probability of recovery but their predictive value have not been established so far: the prothrombin time in addition with serum bilirubin concentration and arterial pH [22], low serum phosphate levels [23], high arterial ammonia levels [24]. Liver histology has not been shown to be reliable for predicting recovery, and is not recommended routinely in patients with FHF [25].

Statistical models have been developed for predicting the outcome in patients with FHF [26–29]. The most commonly used scoring system are the King's College Hospital criteria (KCC) [20]. The model was developed in a series of 588 patients with acute liver failure who were managed without transplantation between 1973 and 1985 [20]. These criteria discriminate between acetaminophen induced liver failure and other etiologies (see Table 3). In acetaminophen-induced FHF, there are two important criteria for indication to liver transplantation: an arterial pH of less than 7.3, irrespective of grade of encephalopathy; or a prothrombin time (PT) greater than 100 seconds and a serum creatinine concentration greater than 3.4 mg/dL (301 µmol/L) in patients who have grade III or IV encephalopathy. In other causes of FHF, liver transplantation is indicated in patients who have either a PT greater than 100 seconds, irrespective of the grade of encephalopathy, or any three of following variables: age less than 10 or greater than 40, non-A, non-B hepatitis, idiosyncratic drug reactions, duration of jaundice before development of encephalopathy greater than seven days, PT greater than 50 seconds, or serum bilirubin greater than 18 mg/dL. The accuracy of the King's College Criteria has been evaluated in separate cohorts. Although, relatively low negative predictive values have been shown for these criteria no other scores have been shown to be superior [30,31].


View this table:
[in this window]
[in a new window]

  		Table 3. King's College Hospital criteria for liver transplantation in fulminant hepatic failure

 
Summary
Fulminant hepatic failure is characterized by the rapid development of severe liver injury with impaired synthetic function and encephalopathy. Most common, FHF is caused by toxin-induced or viral hepatitis, but can result from a wide variety of causes. The mainstay of therapy is orthotopic liver transplantation. Therefore, patients with liver failure should be transferred as soon as possible to a transplant center, to ensure management of complications. The decision for transplantation depends on the probability of hepatic recovery, which is difficult to predict. The most important factors, which in part are included in the King's College Criteria, for predicting the outcome in FHF are the degree of encephalopathy, the patient's age, and the underlying cause of fulminant hepatic failure.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Main Text
 References
 

  1. Trey C, Davidson C. The management of fulminant hepatic failure. In: Progress in Liver Disease—Popper H, Schaffner F, eds. (1970) New York: Grune and Stratton.
  2. Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis (1986) 6:97–106.[Web of Science][Medline]
  3. Lidofsky SD. 2Liver transplantation for fulminant hepatic failure. Gastroenterol Clin North Am (1993) 22:257–269.[Web of Science][Medline]
  4. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med (2002) 137:947–954.[Abstract/Free Full Text]
  5. Services USDoHaH. (2005) 2005 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1995–2004. Rockville, MD: Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation.
  6. Indikationen für eine Lebertransplantation 2005. In: Deutsche Stiftung Organtransplantation Emil von Behring-Passage 63263 (2006) Neu-Isenburg.
  7. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology (2005) 41:1179–1197.[CrossRef][Web of Science][Medline]
  8. Andrade RJ, Lucena MI, Fernandez MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology (2005) 129:512–521.[CrossRef][Web of Science][Medline]
  9. O'Grady JG, Portmann B, Williams R. Fulminant hepatic failure. In: Diseases of the liver—Schiff L, Schiff R, eds. (1993) Philadelphia: JB Lippincott.
  10. Tillmann HL, Hadem J, Leifeld L, et al. Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat (2006) 13:256–263.[CrossRef][Web of Science][Medline]
  11. Schiodt FV, Davern TJ, Shakil AO, McGuire B, Samuel G, Lee WM. Viral hepatitis-related acute liver failure. Am J Gastroenterol (2003) 98:448–453.[Web of Science][Medline]
  12. Khuroo MS, Rustgi VK, Dawson GJ, et al. Spectrum of hepatitis E virus infection in India. J Med Virol (1994) 43:281–286.[Web of Science][Medline]
  13. Khuroo MS, Kamili S, Yattoo GN. Hepatitis E virus infection may be transmitted through blood transfusions in an endemic area. J Gastroenterol Hepatol (2004) 19:778–784.[CrossRef][Web of Science][Medline]
  14. Murad SD, Valla DC, de Groen PC, et al. Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome. Hepatology (2004) 39:500–508.[CrossRef][Web of Science][Medline]
  15. Murad SD, Valla DC, de Groen PC, et al. Pathogenesis and treatment of Budd-Chiari syndrome combined with portal vein thrombosis. Am J Gastroenterol (2006) 101:83–90.[CrossRef][Web of Science][Medline]
  16. Mas A, Rodes J. Fulminant hepatic failure. Lancet (1997) 349:1081–1085.[CrossRef][Web of Science][Medline]
  17. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology (1995) 22:767–773.[CrossRef][Web of Science][Medline]
  18. Eisenbach C, Sauer P, Mehrabi A, Stremmel W, Encke J. Prevention of hepatitis B virus recurrence after liver transplantation. Clin Transplant (2006) 20(Suppl 17):111–116.[CrossRef][Web of Science][Medline]
  19. Kjaergard LL, Liu J, Als-Nielsen B, Gluud C. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review. Jama (2003) 289:217–222.[Abstract/Free Full Text]
  20. O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology (1989) 97:439–445.[Web of Science][Medline]
  21. White H. Evaluation and management of liver failure. In: Intensive Care Medicine—Rippe J, ed. (1996) Boston: Little Brown.
  22. Hoofnagle JH, Carithers RL Jr., Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop. Hepatology (1995) 21:240–252.[CrossRef][Web of Science][Medline]
  23. Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology (2002) 36:659–665.[CrossRef][Web of Science][Medline]
  24. 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) 29:648–653.[CrossRef][Web of Science][Medline]
  25. Hanau C, Munoz SJ, Rubin R. Histopathological heterogeneity in fulminant hepatic failure. Hepatology (1995) 21:345–351.[Web of Science][Medline]
  26. Dhiman RK, Seth AK, Jain S, Chawla YK, Dilawari JB. Prognostic evaluation of early indicators in fulminant hepatic failure by multivariate analysis. Dig Dis Sci (1998) 43:1311–1316.[CrossRef][Web of Science][Medline]
  27. Huo TI, Wu JC, Sheng WY, et al. Prognostic factor analysis of fulminant and subfulminant hepatic failure in an area endemic for hepatitis B. J Gastroenterol Hepatol (1996) 11:560–565.[Web of Science][Medline]
  28. Takahashi Y, Kumada H, Shimizu M, et al. A multicenter study on the prognosis of fulminant viral hepatitis: early prediction for liver transplantation. Hepatology (1994) 19:1065–1071.[Web of Science][Medline]
  29. Lake JR, Sussman NL. Determining prognosis in patients with fulminant hepatic failure: when you absolutely, positively have to know the answer. Hepatology (1995) 21:879–882.[Web of Science][Medline]
  30. Mitchell I, Bihari D, Chang R, Wendon J, Williams R. Earlier identification of patients at risk from acetaminophen-induced acute liver failure. Crit Care Med (1998) 26:279–284.[CrossRef][Web of Science][Medline]
  31. 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) 6:163–169.[Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gotthardt, D.
Right arrow Articles by Sauer, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gotthardt, D.
Right arrow Articles by Sauer, P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?