Fulminant hepatitis (FH) is a rare and devastating syndrome caused by a variety of hepatic insults. It characterized by severe metabolic derangements, neurologic complications and ultimately, multiorgan failure. Liver transplantation is the gold standard therapy for patients with irreversible FH. The major areas of current research in this field include the development of: hepatic support devices, strategies to accelerate hepatic regeneration and criteria for accurate prognostic classification of patients. This review aims to focus on the definitions, aetiologies and management strategies for FH.
KeywordsFulminant HepatitisLiver TransplantLiver SupportIntensive Care
Schiodt, F.V., Atillasoy, E., Shakil, A.O., Schiff, E.R., Caldwell, C., Kowdley, K.V., Stribling, R., Crippin, J.S., Flamm, S., Somberg, K.A., et al. (1999) Etiology and Outcome for 295 Patients with Acute Liver Failure in the United States. Liver Transplantation and Surgery: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 5, 29-34. http://dx.doi.org/10.1002/lt.500050102
Ostapowicz, G., Fontana, R.J., Schiodt, F.V., Larson, A., Davern, T.J., Han, S.H., McCashland, T.M., Shakil, A.O., Hay, J.E., Hynan, L., et al. (2002) Results of a Prospective Study of Acute Liver Failure at 17 Tertiary Care Centers in the United States. Annals of Internal Medicine, 137, 947-954. http://dx.doi.org/10.7326/0003-4819-137-12-200212170-00007
Szabo, G., Mandrekar, P. and Dolganiuc, A. (2007) Innate Immune Response and Hepatic Inflammation. Seminars in Liver Disease, 27, 339-350. http://dx.doi.org/10.1055/s-2007-991511
Novelli, G., Rossi, M., Ferretti, G., Pugliese, F., Ruberto, F., Lai, Q., Novelli, S., Piemonte, V., Turchetti, L., Morabito, V., et al. (2009) Predictive Criteria for the Outcome of Patients with Acute Liver Failure Treated with the Albumin Dialysis Molecular Adsorbent Recirculating System. Therapeutic Apheresis and Dialysis: Official Peer-Reviewed Journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy, 13, 404-412.
Trey, C. and Davidson, C.S. (1970) The Management of Fulminant Hepatic Failure. Progress in Liver Diseases, 3, 282-298.
O’Grady, J.G., Schalm, S.W. and Williams, R. (1993) Acute Liver Failure: Redefining the Syndromes. Lancet, 342, 273-275. http://dx.doi.org/10.1016/0140-6736(93)91736-6
Bernuau, J. and Benhamou, J.P. (1993) Classifying Acute Liver Failure. Lancet, 342, 252-253. http://dx.doi.org/10.1016/0140-6736(93)91809-Z
Acharya, S.K., Dasarathy, S. and Tandon, B.N. (1993) Should We Redefine Acute Liver Failure? Lancet, 342, 1421-1422. http://dx.doi.org/10.1016/0140-6736(93)92778-R
Polson, J. and Lee, W.M. (2005) American Association for the Study of Liver D: AASLD Position Paper: The Management of Acute Liver Failure. Hepatology, 41, 1179-1197. http://dx.doi.org/10.1002/hep.20703
Ichai, P. and Saliba, F. (2009) Fulminant and Subfulminant Hepatitis: Causes and Treatment. Presse Medicale, 38, 1290-1298.
Farci, P., Alter, H.J., Shimoda, A., Govindarajan, S., Cheung, L.C., Melpolder, J.C., Sacher, R.A., Shih, J.W. and Purcell, R.H. (1996) Hepatitis C Virus-Associated Fulminant Hepatic Failure. The New England Journal of Medicine, 335, 631-634. http://dx.doi.org/10.1056/NEJM199608293350904
Ichai, P. and Samuel, D. (2008) Etiology and Prognosis of Fulminant Hepatitis in Adults. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 14, S67-S79. http://dx.doi.org/10.1002/lt.21612
Lee, W.M., Squires Jr., R.H., Nyberg, S.L., Doo, E. and Hoofnagle, J.H. (2008) Acute Liver Failure: Summary of a Workshop. Hepatology, 47, 1401-1415. http://dx.doi.org/10.1002/hep.22177
O’Grady, J.G., Alexander, G.J., Hayllar, K.M. and Williams, R. (1989) Early Indicators of Prognosis in Fulminant Hepatic Failure. Gastroenterology, 97, 439-445.
Brandsaeter, B., Hockerstedt, K., Friman, S., Ericzon, B.G., Kirkegaard, P., Isoniemi, H., Olausson, M., Broome, U., Schmidt, L., Foss, A. and Bjøro, K. (2002) Fulminant Hepatic Failure: Outcome after Listing for Highly Urgent Liver Transplantation-12 Years Experience in the Nordic Countries. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 8, 1055-1062.
Auzinger, G. and Wendon, J. (2008) Intensive Care Management of Acute Liver Failure. Current Opinion in Critical Care, 14, 179-188. http://dx.doi.org/10.1097/MCC.0b013e3282f6a450
Lidofsky, S.D., Bass, N.M., Prager, M.C., Washington, D.E., Read, A.E., Wright, T.L., Ascher, N.L., Roberts, J.P., Scharschmidt, B.F. and Lake, J.R. (1992) Intracranial Pressure Monitoring and Liver Transplantation for Fulminant Hepatic Failure. Hepatology, 16, 1-7. http://dx.doi.org/10.1002/hep.1840160102
Davies, M.H., Mutimer, D., Lowes, J., Elias, E. and Neuberger, J. (1994) Recovery Despite Impaired Cerebral Perfusion in Fulminant Hepatic Failure. Lancet, 343, 1329-1330. http://dx.doi.org/10.1016/S0140-6736(94)92471-6
Bernal, W. and Wendon, J. (2013) Acute Liver Failure. The New England Journal of Medicine, 369, 2525-2534. http://dx.doi.org/10.1056/NEJMra1208937
Karvellas, C.J., Pink, F., McPhail, M., Cross, T., Auzinger, G., Bernal, W., Sizer, E., Kutsogiannis, D.J., Eltringham, I. and Wendon, J.A. (2009) Predictors of Bacteraemia and Mortality in Patients with Acute Liver Failure. Intensive Care Medicine, 35, 1390-1396. http://dx.doi.org/10.1007/s00134-009-1472-x
Trewby, P.N. and Williams, R. (1977) Pathophysiology of Hypotension in Patients with Fulminant Hepatic Failure. Gut, 18, 1021-1026. http://dx.doi.org/10.1136/gut.18.12.1021
Deasy, N.P., Wendon, J., Meire, H.B. and Sidhu, P.S. (1999) The Value of Serial Doppler Ultrasound as a Predictor of Clinical Outcome and the Need for Transplantation in Fulminant and Severe Acute Liver Failure. The British Journal of Radiology, 72, 134-143.
Eefsen, M., Dethloff, T., Frederiksen, H.J., Hauerberg, J., Hansen, B.A. and Larsen, F.S. (2007) Comparison of Terlipressin and Noradrenalin on Cerebral Perfusion, Intracranial Pressure and Cerebral Extracellular Concentrations of Lactate and Pyruvate in Patients with Acute Liver Failure in Need of Inotropic Support. Journal of Hepatology, 47, 381-386. http://dx.doi.org/10.1016/j.jhep.2007.04.015
Shawcross, D.L., Davies, N.A., Mookerjee, R.P., Hayes, P.C., Williams, R., Lee, A. and Jalan, R. (2004) Worsening of Cerebral Hyperemia by the Administration of Terlipressin in Acute Liver Failure with Severe Encephalopathy. Hepatology, 39, 471-475. http://dx.doi.org/10.1002/hep.20044
Fisher, N.C. and Mutimer, D.J. (1999) Central Venous Cannulation in Patients with Liver Disease and Coagulopathy— A Prospective Audit. Intensive Care Medicine, 25, 481-485. http://dx.doi.org/10.1007/s001340050884
Chuansumrit, A., Chantarojanasiri, T., Isarangkura, P., Teeraratkul, S., Hongeng, S. and Hathirat, P. (2000) Recombinant Activated Factor VII in Children with Acute Bleeding Resulting from Liver Failure and Disseminated Intravascular Coagulation. Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis, 11, S101-S105.
Cochran, J.B. and Losek, J.D. (2007) Acute Liver Failure in Children. Pediatric Emergency Care, 23, 129-135. http://dx.doi.org/10.1097/PEC.0b013e3180308f4b
Mehta, R., Reilly, J.J. and Olson, R.E. (1991) Vitamin K Therapy in Severe Liver Disease. JPEN Journal of Parenteral and Enteral Nutrition, 15, 350-353. http://dx.doi.org/10.1177/0148607191015003350
Rahman, T. and Hodgson, H. (2001) Clinical Management of Acute Hepatic Failure. Intensive Care Medicine, 27, 467-476. http://dx.doi.org/10.1007/s001340100873
Hoffman, R., Mahajana, A., Agmon, P., Baruch, Y. and Brenner, B. (2002) Successful Use of Recombinant Activated Factor VII (Novoseven) in Controlling Severe Intra-Abdominal Bleeding after Liver Needle Biopsy. Thrombosis and Haemostasis, 87, 346-347.
Pugliese, F., Ruberto, F., Summonti, D., Perrella, S., Cappannoli, A., Tosi, A., D’Alio, A., Bruno, K., Martelli, S., Celli, P., et al. (2007) Activated Recombinant Factor VII in Orthotopic Liver Transplantation. Transplantation Proceedings, 39, 1883-1885. http://dx.doi.org/10.1016/j.transproceed.2007.05.062
Chung, R.T., Stravitz, R.T., Fontana, R.J., Schiodt, F.V., Mehal, W.Z., Reddy, K.R. and Lee, W.M. (2012) Pathogenesis of Liver Injury in Acute Liver Failure. Gastroenterology, 143, e1-e7. http://dx.doi.org/10.1053/j.gastro.2012.07.011
Rolando, N., Wade, J., Davalos, M., Wendon, J., Philpott-Howard, J. and Williams, R. (2000) The Systemic Inflammatory Response Syndrome in Acute Liver Failure. Hepatology, 32, 734-739. http://dx.doi.org/10.1053/jhep.2000.17687
Vaquero, J., Polson, J., Chung, C., Helenowski, I., Schiodt, F.V., Reisch, J., Lee, W.M. and Blei, A.T. (2003) Infection and the Progression of Hepatic Encephalopathy in Acute Liver Failure. Gastroenterology, 125, 755-764. http://dx.doi.org/10.1016/S0016-5085(03)01051-5
Gotthardt, D., Riediger, C., Weiss, K.H., Encke, J., Schemmer, P., Schmidt, J. and Sauer, P. (2007) Fulminant Hepatic Failure: Etiology and Indications for Liver Transplantation. Nephrology Dialysis Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal Association, 22, viii5-viii8.
Berg, C.L., Gillespie, B.W., Merion, R.M., Brown Jr., R.S., Abecassis, M.M., Trotter, J.F., Fisher, R.A., Freise, C.E., Ghobrial, R.M., Shaked, A., Fair, J.H. and Everhart, J.E. (2007) Improvement in Survival Associated with Adult-to-Adult Living Donor Liver Transplantation. Gastroenterology, 133, 1806-1813. http://dx.doi.org/10.1053/j.gastro.2007.09.004
Campsen, J., Blei, A.T., Emond, J.C., Everhart, J.E., Freise, C.E., Lok, A.S., Saab, S., Wisniewski, K.A., Trotter, J.F. and Adult-to-Adult Living Donor Liver Transplantation Cohort Study Group (2008) Outcomes of Living Donor Liver Transplantation for Acute Liver Failure: The Adult-to-Adult Living Donor Liver Transplantation Cohort Study. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 14, 1273-1280.
Liu, C.L., Fan, S.T., Lo, C.M., Yong, B.H., Fung, A.S. and Wong, J. (2002) Right-Lobe Live Donor Liver Transplantation Improves Survival of Patients with Acute Liver Failure. The British Journal of Surgery, 89, 317-322. http://dx.doi.org/10.1046/j.0007-1323.2001.02035.x
Nishizaki, T., Hiroshige, S., Ikegami, T., Uchiyama, H., Hashimoto, K., Soejima, Y. and Shimada, M. (2002) Living-Donor Liver Transplantation for Fulminant Hepatic Failure in Adult Patients with a Left-Lobe Graft. Surgery, 131, S182-S189. http://dx.doi.org/10.1067/msy.2002.119574
Uemoto, S., Inomata, Y., Sakurai, T., Egawa, H., Fujita, S., Kiuchi, T., Hayashi, M., Yasutomi, M., Yamabe, H. and Tanaka, K. (2000) Living Donor Liver Transplantation for Fulminant Hepatic Failure. Transplantation, 70, 152-157.
Brown Jr., R.S., Russo, M.W., Lai, M., Shiffman, M.L., Richardson, M.C., Everhart, J.E. and Hoofnagle, J.H. (2003) A Survey of Liver Transplantation from Living Adult Donors in the United States. The New England Journal of Medicine, 348, 818-825. http://dx.doi.org/10.1056/NEJMsa021345
Ghobrial, R.M., Freise, C.E., Trotter, J.F., Tong, L., Ojo, A.O., Fair, J.H., Fisher, R.A., Emond, J.C., Koffron, A.J., Pruett, T.L. and Olthoff, K.M. (2008) Donor Morbidity after Living Donation for Liver Transplantation. Gastroenterology, 135, 468-476. http://dx.doi.org/10.1053/j.gastro.2008.04.018
Yasutomi, M., Uemoto, S., Inomata, Y. and Tanaka, K. (2000) Liver Failure Following Living Donor Liver Transplantation for Fulminant Hepatic Failure. Transplantation Proceedings, 32, 2133. http://dx.doi.org/10.1016/S0041-1345(00)01602-X
Renner, E.L. (2007) How to Decide When to List a Patient with Acute Liver Failure for Liver Transplantation? Clichy or King’s College Criteria, or Something Else? Journal of Hepatology, 46, 554-557. http://dx.doi.org/10.1016/j.jhep.2007.01.009
Escorsell, A., Mas, A. and de la Mata, M. (2007) Spanish Group for the Study of Acute Liver F: Acute Liver Failure in Spain: Analysis of 267 Cases. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 13, 1389-1395.
Bernal, W., Donaldson, N., Wyncoll, D. and Wendon, J. (2002) Blood Lactate as an Early Predictor of Outcome in Paracetamol-Induced Acute Liver Failure: A Cohort Study. Lancet, 359, 558-563. http://dx.doi.org/10.1016/S0140-6736(02)07743-7
Baquerizo, A., Anselmo, D., Shackleton, C., Chen, T.W., Cao, C., Weaver, M., Gornbein, J., Geevarghese, S., Nissen, N., Farmer, D., Demetriou, A. and Busuttil, R.W. (2003) Phosphorus Ans an Early Predictive Factor in Patients with Acute Liver Failure. Transplantation, 75, 2007-2014. http://dx.doi.org/10.1097/01.TP.0000063219.21313.32
Chung, P.Y., Sitrin, M.D. and Te, H.S. (2003) Serum Phosphorus Levels Predict Clinical Outcome in Fulminant Hepatic Failure. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 9, 248-253.
Schmidt, L.E. and Dalhoff, K. (2005) Alpha-Fetoprotein Is a Predictor of Outcome in Acetaminophen-Induced Liver Injury. Hepatology, 41, 26-31. http://dx.doi.org/10.1002/hep.20511
Taylor, R.M., Davern, T., Munoz, S., Han, S.H., McGuire, B., Larson, A.M., Hynan, L., Lee, W.M., Fontana, R.J. and Group USALFS (2006) Fulminant Hepatitis A Virus Infection in the United States: Incidence, Prognosis, and Outcomes. Hepatology, 44, 1589-1597. http://dx.doi.org/10.1002/hep.21439
Miyake, Y., Iwasaki, Y., Makino, Y., Kobashi, H., Takaguchi, K., Ando, M., Sakaguchi, K. and Shiratori, Y. (2007) Prognostic Factors for Fatal Outcomes Prior to Receiving Liver Transplantation in Patients with Non-Acetaminophen-Related Fulminant Hepatic Failure. Journal of Gastroenterology and Hepatology, 22, 855-861. http://dx.doi.org/10.1111/j.1440-1746.2007.04874.x
Escudie, L., Francoz, C., Vinel, J.P., Moucari, R., Cournot, M., Paradis, V., Sauvanet, A., Belghiti, J., Valla, D., Bernuau, J. and Durand, F. (2007) Amanita phalloides Poisoning: Reassessment of Prognostic Factors and Indications for Emergency Liver Transplantation. Journal of Hepatology, 46, 466-473. http://dx.doi.org/10.1016/j.jhep.2006.10.013
Ganzert, M., Felgenhauer, N. and Zilker, T. (2005) Indication of Liver Transplantation Following Amatoxin Intoxication. Journal of Hepatology, 42, 202-209. http://dx.doi.org/10.1016/j.jhep.2004.10.023
Freeman Jr., R.B., Steffick, D.E., Guidinger, M.K., Farmer, D.G., Berg, C.L. and Merion, R.M. (2008) Liver and Intestine Transplantation in the United States, 1997-2006. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 8, 958-976.
Germani, G., Theocharidou, E., Adam, R., Karam, V., Wendon, J., O’Grady, J., Burra, P., Senzolo, M., Mirza, D., Castaing, D., et al. (2012) Liver Transplantation for Acute Liver Failure in Europe: Outcomes over 20 Years from the ELTR Database. Journal of Hepatology, 57, 288-296. http://dx.doi.org/10.1016/j.jhep.2012.03.017
O’Grady, J. (2013) Timing and Benefit of Liver Transplantation in Acute Liver Failure. Journal of Hepatology, 60, 663-670.
Barshes, N.R., Lee, T.C., Balkrishnan, R., Karpen, S.J., Carter, B.A. and Goss, J.A. (2006) Risk Stratification of Adult Patients Undergoing Orthotopic Liver Transplantation for Fulminant Hepatic Failure. Transplantation, 81, 195-201. http://dx.doi.org/10.1097/01.tp.0000188149.90975.63
Bernal, W., Cross, T.J., Auzinger, G., Sizer, E., Heneghan, M.A., Bowles, M., Muiesan, P., Rela, M., Heaton, N., Wendon, J. and O’Grady, J.G. (2009) Outcome after Wait-Listing for Emergency Liver Transplantation in Acute Liver Failure: A Single Centre Experience. Journal of Hepatology, 50, 306-313. http://dx.doi.org/10.1016/j.jhep.2008.09.012
Hassanein, T.I., Tofteng, F., Brown Jr., R.S., McGuire, B., Lynch, P., Mehta, R., Larsen, F.S., Gornbein, J., Stange, J. and Blei, A.T. (2007) Randomized Controlled Study of Extracorporeal Albumin Dialysis for Hepatic Encephalopathy in Advanced Cirrhosis. Hepatology, 46, 1853-1862. http://dx.doi.org/10.1002/hep.21930
Heemann, U., Treichel, U., Loock, J., Philipp, T., Gerken, G., Malago, M., Klammt, S., Loehr, M., Liebe, S., Mitzner, S., Schmidt, R. and Stange, J. (2002) Albumin Dialysis in Cirrhosis with Superimposed Acute Liver Injury: A Prospective, Controlled Study. Hepatology, 36, 949-958.
Mitzner, S.R., Stange, J., Klammt, S., Risler, T., Erley, C.M., Bader, B.D., Berger, E.D., Lauchart, W., Peszynski, P., Freytag, J., et al. (2000) Improvement of Hepatorenal Syndrome with Extracorporeal Albumin Dialysis MARS: Results of a Prospective, Randomized, Controlled Clinical Trial. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 6, 277-286.
Sen, S., Davies, N.A., Mookerjee, R.P., Cheshire, L.M., Hodges, S.J., Williams, R. and Jalan, R. (2004) Pathophysiological Effects of Albumin Dialysis in Acute-on-Chronic Liver Failure: A Randomized Controlled Study. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 10, 1109-1119.
Kjaergard, L.L., Liu, J., Als-Nielsen, B. and Gluud, C. (2003) Artificial and Bioartificial Support Systems for Acute and Acute-on-Chronic Liver Failure: A Systematic Review. JAMA: The Journal of the American Medical Association, 289, 217-222. http://dx.doi.org/10.1001/jama.289.2.217
Stutchfield, B.M., Simpson, K. and Wigmore, S.J. (2011) Systematic Review and Meta-Analysis of Survival Following Extracorporeal Liver Support. The British Journal of Surgery, 98, 623-631. http://dx.doi.org/10.1002/bjs.7418
Saliba, F., Camus, C., Durand, F., Mathurin, P., Letierce, A., Delafosse, B., Barange, K., Perrigault, P.F., Belnard, M., Ichai, P. and Samuel, D. (2013) Albumin Dialysis with a Noncell Artificial Liver Support Device in Patients with Acute Liver Failure: A Randomized, Controlled Trial. Annals of Internal Medicine, 159, 522-531. http://dx.doi.org/10.7326/0003-4819-159-8-201310150-00005