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Changing clinical patterns in acute liver failure
Journal of Hepatology 39 (2003) 660–661 www.elsevier.com/locate/jhep
BEYOND THE JOURNAL Associate Editors: Guadalupe Garcia-Tsao and Ronald Oude Elferink Committee: James Boyer, Jean-Franc¸ois Dufour, Hartmut Jaeschke, Luigi Pagliaro, Jorge Rakela, Tania Roskams and Christian Trautwein
Changing clinical patterns in acute liver failure Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, McCashland TM, Shakil AO, Hay JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, Lee WM; U.S. Acute Liver Failure Study Group. Department of Medicine, Gold Coast Hospital, 108 Nerang Street, Southport, QLD 4215, Australia BACKGROUND: Because acute liver failure is rare, related data have been sparse. Studies have suggested that viral hepatitis is the most common underlying cause of this condition. OBJECTIVE: To describe the clinical features, presumed causes, and short-term outcomes of acute liver failure. DESIGN: Prospective cohort study. SETTING: Seventeen tertiary care centers participating in the U.S. Acute Liver Failure Study Group. PATIENTS: Three hundred and eight consecutive patients with acute liver failure, admitted over a 41month period. MEASUREMENTS: Detailed clinical and laboratory data collected during hospitalization, including outcome 3 weeks after study admission. RESULTS: Seventy three percent of patients were women; median age was 38 years. Acetaminophen overdose was the most common apparent cause of acute liver failure, accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of cases, and 17% of cases were of indeterminate cause. Overall patient survival at 3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and 43% survived without transplantation. Short-term transplant-free survival varied greatly from 68% for patients with acetaminophen-related liver failure to 25% and 17% for those with other drug reactions and liver failure of indeterminate cause, respectively. Coma grade at admission appeared to be associated with outcome, but age and symptom duration did not. CONCLUSIONS: Acetaminophen overdose and idiosyncratic drug reactions have
replaced viral hepatitis as the most frequent apparent causes of acute liver failure. Apparent cause and coma grade at admission were associated with outcome. Although transplantation may improve patient survival, it was unavailable or unnecessary for most patients. [Abstract reproduced by permission of Ann Intern Med 2002;137:I24] The US Acute Liver Failure Study Group was set up in 1997 and the paper by Ostapowicz et al. was based on reports from 17 participating liver centers over a 41-month period from January 1998 to May 2001. It provides for the first time substantial information on acute liver failure (ALF) as seen in the US. The overall survival at 3 weeks for the 308 patients in the series was 67%, a much higher figure than the usual textbook quote of 10– 20% for those with severe encephalopathy. With one exception the cases came from transplant centers and likely therefore to represent the more advanced cases. The higher survival is due at least in part to the greater number of cases of acetaminophen hepatotoxicity that are now being encountered—39% of this series. The second largest group was idiosyncratic drug reactions accounting for 13% and fulmi-nant viral hepatitis A and B was implicated in only 12%. The frequency of acetaminophen hepatotoxicity as a cause of ALF is still lower than that encountered in the UK and could well increase even further as acetaminophen is now the most widely used non-prescription analgesic in the US. If so, the US regulatory authorities might well wish to follow the legislative initiatives introduced in the UK on restricting the availability of acetaminophen to the public through limiting pack size particularly in non-prescription outlets. Since 1998 when these regulations were introduced there has been a sharp reduction in the total number of acetaminophen overdoses, the amount of drug taken in overdoses and the number of severe cases of hepatotoxicity referred for liver transplantation [1,2].
0168-8278/$30.00 q 2003 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. doi:10.1016/S0168-8278(03)00405-7
Beyond the Journal
One interesting difference from the UK that has been a feature of reports from the US going back over many years is the high frequency of accidental toxicity. It accounted for 57% in this series with an overdose of acetaminophen tablets being taken repeatedly over a number of days for pain relief. This is to be compared with 37% of cases taking single overdose with suicidal intent. In the UK such cases, sometimes referred to as therapeutic misadventure, are in the minority. Interestingly the survival was similar for both groups and according to other reports from the ALF Study Group the frequency of preceding alcohol abuse, which was said to account for all the hepatotoxicity of acetaminophen toxicity was similar to that in the suicidal intent cases and in accordance with what has been reported over a number of years from the UK [3]. The data of the study group also contains much of interest in relation to the use of liver transplantation in ALF; 84% of the transplanted cases survived showing again the value of this procedure in ALF. Yet only 29% of the cases were transplanted and 43% survived without transplantation. The number transplanted was lowest in the acetaminophen overdose group—6%. This is a reflection on the number of cases in this group excluded from listing because of psychosocial reasons or medical contraindications and also the better spontaneous survival rate in this group. Short term (3-week) survival figures were 50% or greater for acetaminophen overdose, hepatitis A, shock liver and pregnancy related liver failure compared and less than 25% in the other aetiological groups. Despite the high urgency afforded to liver transplantation in the UNOS allocation scheme, some 30% died whilst waiting for a graft. The latter figure highlights the need for an effective liver support device to provide more time for spontaneous recovery to occur or for an organ to be obtained (bridge to liver transplantation). Sadly the one big multi-center trial in ALF to date using the CIRCE device has not provided much encouragement in this area [4]. The authors also point to the need for better prognostic criteria to identify outcome. A proportion of cases not fulfilling accepted criteria for transplantation nevertheless do progress and how to pick out these subjects is an important clinical issue—a plea echoed by the author of this commentary on a number of occasions [5]. Afficionados of ALF will find much more of interest in this paper. The distinction of fulminant from sub-fulminant hepatitis by the French and of hyperacute, acute and subacute by an international group in 1996 was based on the well documented observation that the more rapid the onset of encephalopathy in relation to the first symptoms of illness or appearance of jaundice, the better paradoxically were the chances of spontaneous survival [6]. However, in the series of Ostapowicz when the cases of acetaminophen overdose were excluded, survival results in the hyperacute group were the same as in the acute category. Sub-acute cases had the worst prognosis as in all other series published.
661
Age in this series did not appear to have an important determining factor on outcome but as pointed out by the authors, older patients may have been less likely to have been referred to transplant centers from which this series was derived. Nearly half of the patients (44%) acquired a culture proven infection and in a further analysis of predictors of progression in this series there was a clear relationship between early infection and progression to more severe encephalopathy [7]. This potentially most important observation was first described in a very large series of ALF cases by Rolando and colleagues from the Liver Failure Group at King’s [8], who showed a step wise relationship between the frequency of components of the systemic inflammatory response syndrome (SIRS) and the development of grade IV encephalopathy and cerebral oedema. There seems to be no doubt that infection has a profound influence on the progression of encephalopathy in ALF. Whether this is due to the effects of inflammatory mediators getting across the blood – brain barrier to interact with the processes of ammonia toxicity or to the effects on oxidative and nitrosative stress (including nitric oxide efflux) as described recently be Blei’s group [9], represents one of the most fascinating areas of hepatic encephalopathy research. Roger Williams Institute of Hepatology, 69– 75 Chenies Mews, London, WC1E 6HX, UK
References [1] Wilkinson S, Taylor G, Templeton L, et al. Admissions to Hospital for deliberate self-harm in England 1995–2000: an analysis of Hospital Episode Statistics. J Public Health Med 2002;24:179–183. [2] Deaths related to drug poisoning results for England and Wales, 1993 to 2000. Health Stat Q 2002;13:76-82. http://www.statistics.gov.uk/ downloads.theme_health/HSQ13_v4.pdf [3] Makin A, Williams R. Paracetamol hepatotoxicity and alcohol consumption in deliberate and accidental overdose. Q J Med 2000; 93:341– 349. [4] Stevens AC, Busuttil R, Hans S, et al. An interim analysis of a phase II/ III prospective randomized, multicenter, controlled trial of the Hepatassist(R), bioartificial liver support system for the treatment of fulminant hepatic failure. (Abstract). Hepatology 2001;34:299A. [5] Williams R, Riordan SM. Fulminant hepatic failure. In: Schiff ER, Sorrell MF, Maddrey WC, editors. Schiff’s diseases of the liver, 9th ed. 2002. p. 941–970. [6] Williams R, editor. Fulminant hepatic failure. Seminars for liver disease, 16.; 1996. p. 341–435. [7] Vaquero J, Schiodt F, Chung C, et al. Predictors of progression to deep hepatic encephalopathy in acute liver failure: results of the US Acute Liver Failure Study Group. (Abstract). Hepatology 2002;36:222A. [8] Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000;32:734–739. [9] Song G, Dhodda VK, Blei AT, et al. GeneChip analysis shows altered mRNA expression of transcripts of neurotransmitter and signal transduction pathways in the cerebral cortex of porta-caval shunted rats. J Neurosci Res 2002;68:730–737.
BEYOND THE JOURNAL Associate Editors: Guadalupe Garcia-Tsao and Ronald Oude Elferink Committee: James Boyer, Jean-Franc¸ois Dufour, Hartmut Jaeschke, Luigi Pagliaro, Jorge Rakela, Tania Roskams and Christian Trautwein
Changing clinical patterns in acute liver failure Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, McCashland TM, Shakil AO, Hay JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, Lee WM; U.S. Acute Liver Failure Study Group. Department of Medicine, Gold Coast Hospital, 108 Nerang Street, Southport, QLD 4215, Australia BACKGROUND: Because acute liver failure is rare, related data have been sparse. Studies have suggested that viral hepatitis is the most common underlying cause of this condition. OBJECTIVE: To describe the clinical features, presumed causes, and short-term outcomes of acute liver failure. DESIGN: Prospective cohort study. SETTING: Seventeen tertiary care centers participating in the U.S. Acute Liver Failure Study Group. PATIENTS: Three hundred and eight consecutive patients with acute liver failure, admitted over a 41month period. MEASUREMENTS: Detailed clinical and laboratory data collected during hospitalization, including outcome 3 weeks after study admission. RESULTS: Seventy three percent of patients were women; median age was 38 years. Acetaminophen overdose was the most common apparent cause of acute liver failure, accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of cases, and 17% of cases were of indeterminate cause. Overall patient survival at 3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and 43% survived without transplantation. Short-term transplant-free survival varied greatly from 68% for patients with acetaminophen-related liver failure to 25% and 17% for those with other drug reactions and liver failure of indeterminate cause, respectively. Coma grade at admission appeared to be associated with outcome, but age and symptom duration did not. CONCLUSIONS: Acetaminophen overdose and idiosyncratic drug reactions have
replaced viral hepatitis as the most frequent apparent causes of acute liver failure. Apparent cause and coma grade at admission were associated with outcome. Although transplantation may improve patient survival, it was unavailable or unnecessary for most patients. [Abstract reproduced by permission of Ann Intern Med 2002;137:I24] The US Acute Liver Failure Study Group was set up in 1997 and the paper by Ostapowicz et al. was based on reports from 17 participating liver centers over a 41-month period from January 1998 to May 2001. It provides for the first time substantial information on acute liver failure (ALF) as seen in the US. The overall survival at 3 weeks for the 308 patients in the series was 67%, a much higher figure than the usual textbook quote of 10– 20% for those with severe encephalopathy. With one exception the cases came from transplant centers and likely therefore to represent the more advanced cases. The higher survival is due at least in part to the greater number of cases of acetaminophen hepatotoxicity that are now being encountered—39% of this series. The second largest group was idiosyncratic drug reactions accounting for 13% and fulmi-nant viral hepatitis A and B was implicated in only 12%. The frequency of acetaminophen hepatotoxicity as a cause of ALF is still lower than that encountered in the UK and could well increase even further as acetaminophen is now the most widely used non-prescription analgesic in the US. If so, the US regulatory authorities might well wish to follow the legislative initiatives introduced in the UK on restricting the availability of acetaminophen to the public through limiting pack size particularly in non-prescription outlets. Since 1998 when these regulations were introduced there has been a sharp reduction in the total number of acetaminophen overdoses, the amount of drug taken in overdoses and the number of severe cases of hepatotoxicity referred for liver transplantation [1,2].
0168-8278/$30.00 q 2003 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. doi:10.1016/S0168-8278(03)00405-7
Beyond the Journal
One interesting difference from the UK that has been a feature of reports from the US going back over many years is the high frequency of accidental toxicity. It accounted for 57% in this series with an overdose of acetaminophen tablets being taken repeatedly over a number of days for pain relief. This is to be compared with 37% of cases taking single overdose with suicidal intent. In the UK such cases, sometimes referred to as therapeutic misadventure, are in the minority. Interestingly the survival was similar for both groups and according to other reports from the ALF Study Group the frequency of preceding alcohol abuse, which was said to account for all the hepatotoxicity of acetaminophen toxicity was similar to that in the suicidal intent cases and in accordance with what has been reported over a number of years from the UK [3]. The data of the study group also contains much of interest in relation to the use of liver transplantation in ALF; 84% of the transplanted cases survived showing again the value of this procedure in ALF. Yet only 29% of the cases were transplanted and 43% survived without transplantation. The number transplanted was lowest in the acetaminophen overdose group—6%. This is a reflection on the number of cases in this group excluded from listing because of psychosocial reasons or medical contraindications and also the better spontaneous survival rate in this group. Short term (3-week) survival figures were 50% or greater for acetaminophen overdose, hepatitis A, shock liver and pregnancy related liver failure compared and less than 25% in the other aetiological groups. Despite the high urgency afforded to liver transplantation in the UNOS allocation scheme, some 30% died whilst waiting for a graft. The latter figure highlights the need for an effective liver support device to provide more time for spontaneous recovery to occur or for an organ to be obtained (bridge to liver transplantation). Sadly the one big multi-center trial in ALF to date using the CIRCE device has not provided much encouragement in this area [4]. The authors also point to the need for better prognostic criteria to identify outcome. A proportion of cases not fulfilling accepted criteria for transplantation nevertheless do progress and how to pick out these subjects is an important clinical issue—a plea echoed by the author of this commentary on a number of occasions [5]. Afficionados of ALF will find much more of interest in this paper. The distinction of fulminant from sub-fulminant hepatitis by the French and of hyperacute, acute and subacute by an international group in 1996 was based on the well documented observation that the more rapid the onset of encephalopathy in relation to the first symptoms of illness or appearance of jaundice, the better paradoxically were the chances of spontaneous survival [6]. However, in the series of Ostapowicz when the cases of acetaminophen overdose were excluded, survival results in the hyperacute group were the same as in the acute category. Sub-acute cases had the worst prognosis as in all other series published.
661
Age in this series did not appear to have an important determining factor on outcome but as pointed out by the authors, older patients may have been less likely to have been referred to transplant centers from which this series was derived. Nearly half of the patients (44%) acquired a culture proven infection and in a further analysis of predictors of progression in this series there was a clear relationship between early infection and progression to more severe encephalopathy [7]. This potentially most important observation was first described in a very large series of ALF cases by Rolando and colleagues from the Liver Failure Group at King’s [8], who showed a step wise relationship between the frequency of components of the systemic inflammatory response syndrome (SIRS) and the development of grade IV encephalopathy and cerebral oedema. There seems to be no doubt that infection has a profound influence on the progression of encephalopathy in ALF. Whether this is due to the effects of inflammatory mediators getting across the blood – brain barrier to interact with the processes of ammonia toxicity or to the effects on oxidative and nitrosative stress (including nitric oxide efflux) as described recently be Blei’s group [9], represents one of the most fascinating areas of hepatic encephalopathy research. Roger Williams Institute of Hepatology, 69– 75 Chenies Mews, London, WC1E 6HX, UK
References [1] Wilkinson S, Taylor G, Templeton L, et al. Admissions to Hospital for deliberate self-harm in England 1995–2000: an analysis of Hospital Episode Statistics. J Public Health Med 2002;24:179–183. [2] Deaths related to drug poisoning results for England and Wales, 1993 to 2000. Health Stat Q 2002;13:76-82. http://www.statistics.gov.uk/ downloads.theme_health/HSQ13_v4.pdf [3] Makin A, Williams R. Paracetamol hepatotoxicity and alcohol consumption in deliberate and accidental overdose. Q J Med 2000; 93:341– 349. [4] Stevens AC, Busuttil R, Hans S, et al. An interim analysis of a phase II/ III prospective randomized, multicenter, controlled trial of the Hepatassist(R), bioartificial liver support system for the treatment of fulminant hepatic failure. (Abstract). Hepatology 2001;34:299A. [5] Williams R, Riordan SM. Fulminant hepatic failure. In: Schiff ER, Sorrell MF, Maddrey WC, editors. Schiff’s diseases of the liver, 9th ed. 2002. p. 941–970. [6] Williams R, editor. Fulminant hepatic failure. Seminars for liver disease, 16.; 1996. p. 341–435. [7] Vaquero J, Schiodt F, Chung C, et al. Predictors of progression to deep hepatic encephalopathy in acute liver failure: results of the US Acute Liver Failure Study Group. (Abstract). Hepatology 2002;36:222A. [8] Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000;32:734–739. [9] Song G, Dhodda VK, Blei AT, et al. GeneChip analysis shows altered mRNA expression of transcripts of neurotransmitter and signal transduction pathways in the cerebral cortex of porta-caval shunted rats. J Neurosci Res 2002;68:730–737.