New Therapeutic Aspects in Fulminant Hepatic Failure* Michael R Manns, M.D.
F
ulminant hepatic failure as defined by Trey and Davidson 1 is the development of encephalopathy within 8 wk of the onset ofhepatic symptoms in the absence ofunderlying chronic liver disease. Fulminant hepatic failure is commonly classified into four grades (I-IV). ~TIOLOGY, PATHOGENESIS, PROGNOSIS
Mortality rates for fulminant hepatic failure range between 50% and 90%. Several independent factors influence survival: age, etiology, 4epth and duration of the encephalopathy, and prevention of complications. The main causes of fulminant hepatic failure are hepatotropic viruses, adverse drug effects, and toxins (Table 1). All major hepatotropic viruses can induce fulminant hepatic failure. ~ distinguish hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis D (delta) virus (HDV), hepatitis C virus (HCV), non-A, non-B viruses, and hepatitis E virus (HEV); However, the risk for the development of fulminant hepatic failure varies with the different viruses (Table 2). The prevalence offulminan~ hepatic failure after acute HAV infection is relatively lo~ about 0.2%, whereas as many as 20% of patients coinfected with HBV and HDV reportedly develop fulminant hepatic failure. The prevalence of fulminant hepatic failure is also high in pregnant women infected by the recently discovered HE~I This virus has recently been identified in tropical countries, 6rst in India and Kashmir, and later in the Soviet Union. The clinical and epidemiologic characteristics of HEV infection are similar to those of HAV infection; HEV infection is therefore sometimes known as waterborne hepatitis. Clinical and experimental evidence indicates that HBV itself is not cytopathogenic, and that the host's immunologic response to virus-infected liver cells is responsible for the organ damage. An overwhelming immune system response is regarded as the main pathogenetic mechanism leading to fulminant hepatic failure in acute HBV infection. Therefore, hepatitis B surface-antigen (HBsAG) and the complete virus may already have been cleared from serum by the time the signs of fulminant hepatic failure appear. Immunoglobulin (Ig) M antibody to hepatitis B core antigen (anti-HBc) may be the only serologic marker for acute HBV infection in these cases. The mechanisms by wh~ch HAV and non-A, non-B viruses induce fulminant hepatic failure are unclear. However, the presence of IgM antibody to HAV (anti-HAV) is diagnostic of fulminant hepatic failure due to HA~ The presence of IgM anti-delta antibodies is diagnostic of HDV-induced fulminant hepatic failure, and the simultaneous detection of IgM anti-HBc is diagnostic of a coinfection with HBV and ·From the Department of Medicine I, University of Mainz, Mainz, Germany.
HD~ a condition associated with a poor prognosis. For a long time, the search for the etiologic agents of sporadic and posttransfusional non-A, non-B hepatitis was unsuccessful. In 1989 Houghton and colleaguesJ described the isolation of a cDNA derived from the serum of infected chimpanzees that showed sequence homology with Baviviruses. Moreover, 70%-80% of patients with chronic posttransfusional non-A, non-B hepatitis seroconverted for antibodies against the cloned protein derived from this cDNA, termed anti-HeY antibodies.· The diagnostic value of the anti-HCV antibody test is now being evaluated worldwide. Future work may lead to the development of IgM anti-HCV tests for the diagnosis of fulminant hepatic failure due to acute HCV infection. Although HEV has been isolated from stools, no serologic tests are presently available to diagnose HEV infection. An HEV infection must be considered when persons residing in tropical countries, as well as Europeans and North Americans who have traveled to these countries, develop acute hepatitis in the absence of markers for other hepatitis viruses. In such cases, the clinician must keep in mind the high risk for fulminant hepatic failure in pregnant women with HEV infection.
Drug I ntorication Several drugs may cause fulminant hepatic failure (Table 1). Paracetamol intoxication directly correlates with drug dose; the
Table I-Cause. a/Fulminant Hepatic Failure Etiology
Prevalence (%)
Hepatitis viruses (A, B, C, D, E, and non-A, non-B) Drugs (halothane, paracetamol, isoniazid) Toxins (CCI3 , amanitotoxin) Ischemia, hypoxia (Budd-Chiari syndrome, lymphoma, heat shock, shock) Miscellaneous (Wilson's disease, fatty liver)
30-80 30-50
5 5
5-10
Table 2-Preoolence ofFulmintmt Hepatic Failure ira Viral Hepatitia, by Infection Type Virus(es)
Prevalence (%)
HAV HBV HBVIHDV Non-A, non-B viruses (Hev) HEV
CHEST I 100 I 3 I SEPTEMBER. 1991 I Supplement
0.2 1 2-20 1 22
1935
lethal dose is around 10 g. Up to 20% of patients undergoing halothane anesthesia develop moderately elevated serum transaminase levels thereafter. In a very small percentage of cases, patients given halothane for anesthesia develop "halothane hepatitis" and are at high risk for fulminant hepatic failure. Evidently, fulminant hepatic failure due to halothane anesthesia is directly associated with previous exposures. Neuberger and WilliamsS reported that 94% of their patients with halothane hepatitits had had at least one previous halothane exposure. The severity of halothane hepatitis correlates with a short time interval since the previous halothane anesthesia. Predisposing factors for halothane-induced fulminant liver injury in man are genetic and constitutional and environmental factors. Further risk factors are obesityt hypoxia during anesthesia, and simultaneous treatment with enzyme-inducing agents, such as phenobarbital and isoniazid. Our understanding of the molecular basis of halothane-induced t immunologically mediated fulminant hepatic failure has progressed considerably in the past decade. In 1980 the King·s College group from London8 reported that sera from patients with halothane hepatitis were positive for antibodies reacting with the surface of hepatocytes isolated from rabbits pretreated with halothane. These sera did not react with hepatocytes from nontreated rabbits. This observation suggested the existence of halothane-induced neoantigens. ~stern blot analysis subsequently revealed that humans exposed to halothane express liver neoantigens that are analogous to halothane metabolite protein neoantigens in halothane-exposed animals. 7 The metabolism of halothane is well established, and involves cytochrome P450 enzymes. 8 An oxidative and a reductive metabolite pathway are distinguished. Hypoxia under anesthesia may lead to predominance of the reductive pathway. Kenna and c0workers" have shown that antibodies in sera from patients with halothane-induced hepatitis recognize liver antigens containing the trifluoroacetyl (TFA) group derived from halothane. Several antigens with a molecular weight between 54 and 100 kd have been identified as neoantigens, all consisting of the TFA group plus the protein carriers. 7 In 1989 8atoh et al lO identified a microsomal 59-kd halothane-induced neoantigen and reported that it is carboxylesterase covalently modified by the TFA halide metabolite ofhalothane. Although the molecular mechanisms leading to halothane-induced fulminant hepatic failure have become clarified, no specific treatment is available. However, purified halothane-induced neoantigens are available for diagnostic tests. This is important, since halothane-induced fulminant hepatic failure has a very poor prognosis. Therefore, liver transplantation must be considered early in these patients. THERAPY
Specific
~atment
Apart from general therapeutic procedures, such as mannitol
infusion for the treatment of cerebral edema, speciRc treatment for fulminant hepatic failure is rarely available. Only in paracetamolinduced fulminant hepatic failure and liver failure due to Amanita phalloides intoxication is a specific drug treatment effective. Acetylcysteine is given for paracetamol intoxication, while penicillin G or silimarin is given for A phalloides intoxication. Penicillin G and Silimarin block the uptake of the fungus toxin into hepatocytes. Artificial Uver Support Survival from fulminant hepatic failure seems to have improved in recent years, likely owing to improvements in intensive care medicine. Many therapeutic procedures, such as corticosteroid administration, exchange transfusion, extracorporeal pig liver perfusion, plasmapheresis, hemodialysis, heparin, and charcoal hemoperfusion, have shown promise in pilot studies in small numbers of patients (Table 3). Frequently, however, the results of pilot studies were compared with historical survival data, and none of these
1948
procedures-also known as arti6cial liver support-has increased survival from fulminant hepatic failure in controlled trials. 11 GABA/Benzodiazepine Receptor Antagonists in the Treatment of Hepatic Encephalopathy
The pathogenesis of hepatic encephalopathy is multifactorial, and it is unknown to what extent individual mechanisms contribute to the encephalopathy. In encephalopathy due to chronic liver failure, amino acid imbalances favor increased blood levels of aromatic amino acids. This led to the hypothesis that aromatic amino acids penetrate into the central nervous system, where they are metabolized to substrates like octopamine, which may function as false neurotransmitters. Furthermore, a change in the expression ofreceptors for GADA, the main inhibitory neurotransmitter of the brain, has heen reported in hepatic encephalopath~ Lately, the anatomic and functional relationship between the GABA receptor and the benzodiazepine binding site has been elucidated. Other recently reported data support the hypothesis that endogenous benzodiazepine receptor agonists contribute to hepatic encephalopath~12 For many years, clinicians had observed that benzodiazepines or related drugs sometimes induced the manifestations of hepatic encephalopath~ A logical pharmacologic approach was the development of synthetic benzodiazepine receptor antagonists. In 1988 Grimm et al 13 from Vienna reported their first data on the treatment of hepatic encephalopathy with the benzodiazepine receptor antagonist 8umazenil. In their series, the encephalopathy stage improved in 12 of 20 patients within 3-60 min after ftumazenil injection. However, 8 of the 12 responders worsened shortly thereafter. Since 5 of the 8 nonresponders also had cerebral edema, the authors concluded that flumazenil may be beneficial in the treatment of hepatic encephalopath~ A drawback of this treatment is the short half-life of flumazenil. Furthermore, such a treatment can in8uence only encephalopathy, not the underlying disease process or liver regeneration. However, benzodiazepine receptor antagonists may become standard therapeutic agen~ in the management of hepatic encephalopathy and thus fulminant hepatic failure. Uver transplantation
As indicated by data published by the European Liver Transplant Registry,14 the number of patients undergoing liver transplantation for fulminant hepatic failure is steadily increasing. In addition, with progress in surgical techniques, intensive care medicine, patient selection, and immunosup-
Table 3- Treatment of Fulminant Hepatic Failure Artificial liver support Exchange transfusion Extracorporealliver perfusion Hemodialysis, hemo61tration Charcoal hemoperfusion Plasma separation Plasma perfuSion, plasmapheresis New therapeutic developments -y-Aminobutyric acid (GABA)lbenzodiazepine receptor antagonists Liver transplantation Liver-specific growth factors
New Therapeutic Aspects in ftJInWlant Hepatic Failure (Michael F. Manns)
Table 5-GrotDth FGCtorI ira lMJer Regeneration
pressive treatment, the results of liver transplantation have
also improved. Therefore, the percentage of patients under-
Non-liver-specific
going emergency liver transplantation for fulminant hepatic
failure is increasing. However, it is not known whether liver
transplantation increases survival in fulminant hepatic failure. Although the perioperative mortality is high for emergency liver transplantation, long-term results are generally good once the liver transplantation has been survived. As we learned from the evaluation of artificial liver support procedures, promising results in pilot studies may not be confirmed in controlled trials with larger numbers of patients. Certainly selected patients who would have died with conservative medical treatment may survive after liver transplantation. We have to take into account that liver transplantation is expensive and time-consuming. Patients undergoing liver transplantation must receive lifelong immunosuppressive therapy, whereas patients surviving hepatic failure without transplantation experience full recovery. A number of nonrandomized comparisons for survival have been reported after liver transplantation in patients with fulminant hepatic failure (Table 4). ~ The I-yr survival rate after liver transplantation for fulminant hepatic failure is around 50%, whereas it is about 80% after elective liver transplantation. Conservative medical treatment is associated with a survival rate of around 30%. Since the numbers reported for each liver transplant center are relatively small, a comparison with historical survival data is inappropriate. It is well established that fulminant hepatic failure is associated with a high mortality if the neurologic status deteriorates rapidl~ if coagulation factor V levels are below 20%, if the patient is more than 40 or less than 11 yr old, if the patient suffers from late-onset hepatic failure, and if serum bilirobin levels are above 300 mmoVL. Furthermore, survival data from different centers are comparable only if the etiologies of the fulminant liver failure are comparable. The closest approach to a controlled trial has been reported by Vickers et al le from Birmingham. In this series, 9 of 16 patients survived after transplantation, while 4 (40%) of 10 patients for whom a donor liver did not become available survived without transplantation. This comparison is not large, it is not statistically significant, and it does not provide evidence that transplantation is beneficial. At present, clinicians selecting patients with fulminant liver failure for emergency liver transplantation should focus on patients with rapid deterioration of neurologic status, Table 4-Nonrandorraiz.ed ComptJriIona ofSurviool after Uver 1'nmBplantation for Fulminant Hepatic Failure· Transplant
No transplant
Study, Year
No.
(%)
No.
Hannover, 1986 Villejuif, 1987 Pittsburgh, 1987 Birmingham, 1988 King's College, London, 1987 Chicago, 1989
319 17/23 7/13 9/16 11119 11119
(33) (74) (54) (56) (58) (58)
NA NA
3116 4110
(19)
313
(100)
Total
58199
(59)
10/29
(34)
(%)
(40)
NA
*From Chapman ~ et ale Lancet 1990; i:32-35. Reproduced by permission.
Portal
Insulin IGF Glucagon
Nonportal Hormones Polypeptides (ie, EGF)
Liver-specific
Serum Hepatopoietin A Hepatopoietin 8 Thrombocytes HGF Liver Hepatic-stimulatory substance
IGF = insulin growth factor; EGF = epidermal growth factor; HGF = hepatocyte growth factor
rapidly falling coagulation factor V levels, late-onset hepatic failure, high bilirubin levels, and etiologies associated with a known high mortality such as halothane-induced hepatitis, HBV and HDV coinfection, and possibly HEV infection. Brunner and LOsgen from Hannover recommend direct monitoring of brain pressure. 17 Rapidly increasing brain pressure is indicative of the development of irreversible brain damage. However, multicenter controlled trials are needed to establish the role of liver transplantation in fulminant hepatic failure. Growth Factors in Uver Regeneration
The liver has an impressive ability to regenerate. All therapeutic regimens in fulminant hepatic failure apart from liver transplantation aim at temporary support of liver cell function or temporary treatment of symptoms secondary to liver failure until endogenous liver regeneration takes over. From animal experiments primarily done by surgeons, we know that after 70% partial hepatectomy in rats, the liver regenerates to normal size within a month. Starzl and Terblanche 18 have shown that insulin and glucagon are major hepatotropic growth factors in portal blood. At present, liver regeneration is studied on a more molecular level. Several growth factors involved in liver regeneration have been described, both liver-specific and liver-nonspecific (Table 5). Nonportal growth factors like hormones and polypeptides significantly contribute to liver regeneration. One of them is epidennal growth factor (EGF).18 Recently, liver-specific growth factors, called hepatopoietin A and B, have been identified in the serum ofanimals after partial hepatectomy. m Such factors have also been identified in the serum of patients with fulminant hepatic failure. 2J In addition, a hepatocyte growth factor from thrombocytes has been described. 1I Possibly the most important growth factor for liver regeneration is produced in the regenerating liver itseU: Thus, the regenerating liver is producing its own specific growth factor, such as hepatic stimulatory substance (HSS).D-Z Presumably the regenerating liver is not producing only growth factors. Once the organ has reached original size, growth inhibitors seem to terminate liver regeneration. These growth inhibitors await molecular identiBcation. Oncogens are expressed early in the regenerating liver. The role of oncogen expression in the regenerating liver is unclear. The expression of oncogens occurs before DNA synthesis has started.- A possible major role of oncogen expression in liver regeneration may be sensitization of CHEST I 100 I 3 I SEPTEMBER, 1991 I Supplement
1958
hepatocytes to extrahepatic growth factors like EGF or direct stimulation of DNA synthesis. Future research on liver regeneration will likely lead to the identification, isolation, and characterization of Iive~ specific growth factors that, with the aid of recombinant DNA technolo~ will become available as new therapeutic agents. Early data on the molecular cloning and expression of a human hepatocyte growth factor were published in 1989. i7 These new drugs may improve our treatment regimens for fulminant hepatic failure. CONCLUSIONS
At present, with the exception of paracetamol-induced liver injury and liver failure due to A phalloides, no specific treatment for fulminant hepatic failure is available; liver transplantation for this condition awaits controiled trials. Apart from treatment of symptoms like hepatic encephalopathy, support of liver regeneration is the most appropriate approach, since it helps the liver recover without the lifelong immunosuppression that is necessary after liver transplantation. Animal experiments have already shown that survival after experimentally induced fulminant hepatic failure can be improved by growth factors like insulin, glucagon, and 088.-'30 REFERENCES 1 Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis 1970; 3:282-90 2 Khumo MS. Study of an epidemic non-A, non-B hepatitis: possibility of another human hepatitis virus distinct from posttransfusion non-A, non-B type. Am J Med 1980; 68:818-24 3 Choo Q-L, Kuo G, Weiner AJ, Overby LR, Bradley D~ Houghton M. Isolation of cDNA clone derived from a bloodborne non-A, non-B viral hepatitis genome. Science 1989; 244:359-62 4 Kuo G, Choo Q-L, Alter.HJ, Gitnick GL, Redeker AG, Purcell RH, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244:36264
5 Neuberger J, Williams R. Halothane anaesthesia and liver damage. Br Med J 1984; 289:1136-39 6 Vergani D, Mieli-Vergani G, Alberti A, et aI. Antibodies to the surface of halothane altered rabbit hepatocytes in patients with severe halothane associated hepatitis. N Engi J Med 1980; 303:66-69
7 KennaJG, Neuberger J, Williams R. Evidence for the expression in human liver of halothane-induced neoantigens recognized by antibodies in sera from patients with halothane hepatitis. Hepatology 1988; 8:1635-41 8 Farrell GC. Mechanism of halothane-induced liver injury: is it immune or metabolic idiosyncrasy? J Gastroenterol Hepatol 1988; 3:465-82 9 Kenna JG, Satoh H, Christ DD, Pohl LR. Metabolic basis for a drug hypersensitivity: antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the triOuoroacetyl group derived from halothane. J Pharmacol Exp Ther 1988; 245: 1103-09 10 Satoh H, Martin BM, Schulick AH, Christ DD, KennaJG, Pohl LR. Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a
1988
triHuoroacetylated carboxylesterase. Proc Natl Acad Sci USA 1989; 86:322-26 11 O'Grady JG, Gimson AES, O'Brian CJ, et ale Controlled trials of charcoal baemperfusion and prognostic factors in fulminant hepatitis. Gastroenterology 1988; 94:1186-92 12 Mullen KD, Martin ~ Mendelson WB, Bassett ML, Jones EA. Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy? Lancet 1988; i:457-59 13 Grimm G, Ferenci ~ Katzenschlager R, Madl C, Schneeweiss B, Laggner AN, et ale Improvement of hepatic encephalopathy treated with ftumazenil. Lancet 1988; ii:1392-94 14 Bismuth ;II, Caistang D, Ericzon BG, et ale Hepatic transplantation in Europe. Lancet 1987; 2:674-76 15 Chapman ~ Forman D, Peto R, Smallwood R. Liver transplantation for acute hepatic failure? Lancet 1990; i:32-35 16 Vickers C, Neuberger J, Buckels J, McMaster ~ Elias E. Transplantation ofthe liver in adults and children with fulminant hepatic failure. J Hepatoll988; 7:143-50 17 Brunner G, LOsgen J. Artificial liver support. Leber Magen Darm 1985; 15:186 18 Stanl TE, Terblanche J. Hepatotropic substances. Prog Liver Dis 1979; 6:135-51 19 St. Hilaire RJ, Jones AL. Epidermal growth factor: its biologic and metabolic effects with emphasis on the hepatocyte. Hepatology 1982; 2:601-13 20 Michalopoulos G, Houck K, Dolan M, Luetteke N. Control of hepatocyte replication by two serum factors. Cancer Res 1984; 44:601-13 21 Gohda E, Tsubouchi H, Nakayama H, Hirono S, Takahashi K, Koura M, et ale Human hepatocyte growth factor in plasma from patients with fulminant hepatic failure. Exp Cell Res 1986; 166:139-50 22 Nakamura T, Teramoto H, Ichihara A. Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary cultures. Proc Natl Acad Sci 1986; 83:6489-92 23 Francavilla A, DiLeo A, Polimeno L, Gavaler J, Pellicci R, Todo S, et ale The effect of hepatic stimulatory substance, isolated from regenerating hepatic cytosol, and 50000 and 300000 subfractions in enhancing survival in experimental acute hepatic failure in rats treated with D-galactosamine. Hepatology 1986; 6:1346-51 24 Fausto N, Shank E Oncogene expression in liver regeneration and hepatocarcinogenesis. Hepatology 1983; 6: 1016-23 25 Fleig ~ Lehmann H, Wagner H, Hoss G, Ditschuneit H. Hepatic regenerative stimulator substance in the rabbit: relation to liver regeneration after partial hepatectomy. J Hepatoll988; 3:19-26 26 Makino R, Hayashi K, Sugimura T. C-myc transcript is induced in rat liver at a very early stage of regeneration or by cycloheximide treatment. Nature 1984; 310:697-98 27 Nakamura A, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, et ale Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342:400-43 28 Farivar M, Wands J, Isselbacher K, Bucher N. Effect of insulin and glucagon on fulminant murine hepatitis. N Engl J Moo 1976; 27:1517-19 29 Ohkawa M, Hayashi H, Chaudry I, Clemens M, Baue A. Effects of regenerating liver cytosol on drug-induced hepatic failure. Surgery 1985; 97:455-62 30 Miyazaki M, Makowka'L, Falk R, Falk ~ Venturi D. Reversal of lethal chemotherapeutically induced acute hepatic necrosis in rats by regenerating liver cytosol. Surgery 1983; 94:142-50
New Therapeutic Aspects in Fulminant Hepatic Failure (Michael F. Manns)
F
ulminant hepatic failure as defined by Trey and Davidson 1 is the development of encephalopathy within 8 wk of the onset ofhepatic symptoms in the absence ofunderlying chronic liver disease. Fulminant hepatic failure is commonly classified into four grades (I-IV). ~TIOLOGY, PATHOGENESIS, PROGNOSIS
Mortality rates for fulminant hepatic failure range between 50% and 90%. Several independent factors influence survival: age, etiology, 4epth and duration of the encephalopathy, and prevention of complications. The main causes of fulminant hepatic failure are hepatotropic viruses, adverse drug effects, and toxins (Table 1). All major hepatotropic viruses can induce fulminant hepatic failure. ~ distinguish hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis D (delta) virus (HDV), hepatitis C virus (HCV), non-A, non-B viruses, and hepatitis E virus (HEV); However, the risk for the development of fulminant hepatic failure varies with the different viruses (Table 2). The prevalence offulminan~ hepatic failure after acute HAV infection is relatively lo~ about 0.2%, whereas as many as 20% of patients coinfected with HBV and HDV reportedly develop fulminant hepatic failure. The prevalence of fulminant hepatic failure is also high in pregnant women infected by the recently discovered HE~I This virus has recently been identified in tropical countries, 6rst in India and Kashmir, and later in the Soviet Union. The clinical and epidemiologic characteristics of HEV infection are similar to those of HAV infection; HEV infection is therefore sometimes known as waterborne hepatitis. Clinical and experimental evidence indicates that HBV itself is not cytopathogenic, and that the host's immunologic response to virus-infected liver cells is responsible for the organ damage. An overwhelming immune system response is regarded as the main pathogenetic mechanism leading to fulminant hepatic failure in acute HBV infection. Therefore, hepatitis B surface-antigen (HBsAG) and the complete virus may already have been cleared from serum by the time the signs of fulminant hepatic failure appear. Immunoglobulin (Ig) M antibody to hepatitis B core antigen (anti-HBc) may be the only serologic marker for acute HBV infection in these cases. The mechanisms by wh~ch HAV and non-A, non-B viruses induce fulminant hepatic failure are unclear. However, the presence of IgM antibody to HAV (anti-HAV) is diagnostic of fulminant hepatic failure due to HA~ The presence of IgM anti-delta antibodies is diagnostic of HDV-induced fulminant hepatic failure, and the simultaneous detection of IgM anti-HBc is diagnostic of a coinfection with HBV and ·From the Department of Medicine I, University of Mainz, Mainz, Germany.
HD~ a condition associated with a poor prognosis. For a long time, the search for the etiologic agents of sporadic and posttransfusional non-A, non-B hepatitis was unsuccessful. In 1989 Houghton and colleaguesJ described the isolation of a cDNA derived from the serum of infected chimpanzees that showed sequence homology with Baviviruses. Moreover, 70%-80% of patients with chronic posttransfusional non-A, non-B hepatitis seroconverted for antibodies against the cloned protein derived from this cDNA, termed anti-HeY antibodies.· The diagnostic value of the anti-HCV antibody test is now being evaluated worldwide. Future work may lead to the development of IgM anti-HCV tests for the diagnosis of fulminant hepatic failure due to acute HCV infection. Although HEV has been isolated from stools, no serologic tests are presently available to diagnose HEV infection. An HEV infection must be considered when persons residing in tropical countries, as well as Europeans and North Americans who have traveled to these countries, develop acute hepatitis in the absence of markers for other hepatitis viruses. In such cases, the clinician must keep in mind the high risk for fulminant hepatic failure in pregnant women with HEV infection.
Drug I ntorication Several drugs may cause fulminant hepatic failure (Table 1). Paracetamol intoxication directly correlates with drug dose; the
Table I-Cause. a/Fulminant Hepatic Failure Etiology
Prevalence (%)
Hepatitis viruses (A, B, C, D, E, and non-A, non-B) Drugs (halothane, paracetamol, isoniazid) Toxins (CCI3 , amanitotoxin) Ischemia, hypoxia (Budd-Chiari syndrome, lymphoma, heat shock, shock) Miscellaneous (Wilson's disease, fatty liver)
30-80 30-50
5 5
5-10
Table 2-Preoolence ofFulmintmt Hepatic Failure ira Viral Hepatitia, by Infection Type Virus(es)
Prevalence (%)
HAV HBV HBVIHDV Non-A, non-B viruses (Hev) HEV
CHEST I 100 I 3 I SEPTEMBER. 1991 I Supplement
0.2 1 2-20 1 22
1935
lethal dose is around 10 g. Up to 20% of patients undergoing halothane anesthesia develop moderately elevated serum transaminase levels thereafter. In a very small percentage of cases, patients given halothane for anesthesia develop "halothane hepatitis" and are at high risk for fulminant hepatic failure. Evidently, fulminant hepatic failure due to halothane anesthesia is directly associated with previous exposures. Neuberger and WilliamsS reported that 94% of their patients with halothane hepatitits had had at least one previous halothane exposure. The severity of halothane hepatitis correlates with a short time interval since the previous halothane anesthesia. Predisposing factors for halothane-induced fulminant liver injury in man are genetic and constitutional and environmental factors. Further risk factors are obesityt hypoxia during anesthesia, and simultaneous treatment with enzyme-inducing agents, such as phenobarbital and isoniazid. Our understanding of the molecular basis of halothane-induced t immunologically mediated fulminant hepatic failure has progressed considerably in the past decade. In 1980 the King·s College group from London8 reported that sera from patients with halothane hepatitis were positive for antibodies reacting with the surface of hepatocytes isolated from rabbits pretreated with halothane. These sera did not react with hepatocytes from nontreated rabbits. This observation suggested the existence of halothane-induced neoantigens. ~stern blot analysis subsequently revealed that humans exposed to halothane express liver neoantigens that are analogous to halothane metabolite protein neoantigens in halothane-exposed animals. 7 The metabolism of halothane is well established, and involves cytochrome P450 enzymes. 8 An oxidative and a reductive metabolite pathway are distinguished. Hypoxia under anesthesia may lead to predominance of the reductive pathway. Kenna and c0workers" have shown that antibodies in sera from patients with halothane-induced hepatitis recognize liver antigens containing the trifluoroacetyl (TFA) group derived from halothane. Several antigens with a molecular weight between 54 and 100 kd have been identified as neoantigens, all consisting of the TFA group plus the protein carriers. 7 In 1989 8atoh et al lO identified a microsomal 59-kd halothane-induced neoantigen and reported that it is carboxylesterase covalently modified by the TFA halide metabolite ofhalothane. Although the molecular mechanisms leading to halothane-induced fulminant hepatic failure have become clarified, no specific treatment is available. However, purified halothane-induced neoantigens are available for diagnostic tests. This is important, since halothane-induced fulminant hepatic failure has a very poor prognosis. Therefore, liver transplantation must be considered early in these patients. THERAPY
Specific
~atment
Apart from general therapeutic procedures, such as mannitol
infusion for the treatment of cerebral edema, speciRc treatment for fulminant hepatic failure is rarely available. Only in paracetamolinduced fulminant hepatic failure and liver failure due to Amanita phalloides intoxication is a specific drug treatment effective. Acetylcysteine is given for paracetamol intoxication, while penicillin G or silimarin is given for A phalloides intoxication. Penicillin G and Silimarin block the uptake of the fungus toxin into hepatocytes. Artificial Uver Support Survival from fulminant hepatic failure seems to have improved in recent years, likely owing to improvements in intensive care medicine. Many therapeutic procedures, such as corticosteroid administration, exchange transfusion, extracorporeal pig liver perfusion, plasmapheresis, hemodialysis, heparin, and charcoal hemoperfusion, have shown promise in pilot studies in small numbers of patients (Table 3). Frequently, however, the results of pilot studies were compared with historical survival data, and none of these
1948
procedures-also known as arti6cial liver support-has increased survival from fulminant hepatic failure in controlled trials. 11 GABA/Benzodiazepine Receptor Antagonists in the Treatment of Hepatic Encephalopathy
The pathogenesis of hepatic encephalopathy is multifactorial, and it is unknown to what extent individual mechanisms contribute to the encephalopathy. In encephalopathy due to chronic liver failure, amino acid imbalances favor increased blood levels of aromatic amino acids. This led to the hypothesis that aromatic amino acids penetrate into the central nervous system, where they are metabolized to substrates like octopamine, which may function as false neurotransmitters. Furthermore, a change in the expression ofreceptors for GADA, the main inhibitory neurotransmitter of the brain, has heen reported in hepatic encephalopath~ Lately, the anatomic and functional relationship between the GABA receptor and the benzodiazepine binding site has been elucidated. Other recently reported data support the hypothesis that endogenous benzodiazepine receptor agonists contribute to hepatic encephalopath~12 For many years, clinicians had observed that benzodiazepines or related drugs sometimes induced the manifestations of hepatic encephalopath~ A logical pharmacologic approach was the development of synthetic benzodiazepine receptor antagonists. In 1988 Grimm et al 13 from Vienna reported their first data on the treatment of hepatic encephalopathy with the benzodiazepine receptor antagonist 8umazenil. In their series, the encephalopathy stage improved in 12 of 20 patients within 3-60 min after ftumazenil injection. However, 8 of the 12 responders worsened shortly thereafter. Since 5 of the 8 nonresponders also had cerebral edema, the authors concluded that flumazenil may be beneficial in the treatment of hepatic encephalopath~ A drawback of this treatment is the short half-life of flumazenil. Furthermore, such a treatment can in8uence only encephalopathy, not the underlying disease process or liver regeneration. However, benzodiazepine receptor antagonists may become standard therapeutic agen~ in the management of hepatic encephalopathy and thus fulminant hepatic failure. Uver transplantation
As indicated by data published by the European Liver Transplant Registry,14 the number of patients undergoing liver transplantation for fulminant hepatic failure is steadily increasing. In addition, with progress in surgical techniques, intensive care medicine, patient selection, and immunosup-
Table 3- Treatment of Fulminant Hepatic Failure Artificial liver support Exchange transfusion Extracorporealliver perfusion Hemodialysis, hemo61tration Charcoal hemoperfusion Plasma separation Plasma perfuSion, plasmapheresis New therapeutic developments -y-Aminobutyric acid (GABA)lbenzodiazepine receptor antagonists Liver transplantation Liver-specific growth factors
New Therapeutic Aspects in ftJInWlant Hepatic Failure (Michael F. Manns)
Table 5-GrotDth FGCtorI ira lMJer Regeneration
pressive treatment, the results of liver transplantation have
also improved. Therefore, the percentage of patients under-
Non-liver-specific
going emergency liver transplantation for fulminant hepatic
failure is increasing. However, it is not known whether liver
transplantation increases survival in fulminant hepatic failure. Although the perioperative mortality is high for emergency liver transplantation, long-term results are generally good once the liver transplantation has been survived. As we learned from the evaluation of artificial liver support procedures, promising results in pilot studies may not be confirmed in controlled trials with larger numbers of patients. Certainly selected patients who would have died with conservative medical treatment may survive after liver transplantation. We have to take into account that liver transplantation is expensive and time-consuming. Patients undergoing liver transplantation must receive lifelong immunosuppressive therapy, whereas patients surviving hepatic failure without transplantation experience full recovery. A number of nonrandomized comparisons for survival have been reported after liver transplantation in patients with fulminant hepatic failure (Table 4). ~ The I-yr survival rate after liver transplantation for fulminant hepatic failure is around 50%, whereas it is about 80% after elective liver transplantation. Conservative medical treatment is associated with a survival rate of around 30%. Since the numbers reported for each liver transplant center are relatively small, a comparison with historical survival data is inappropriate. It is well established that fulminant hepatic failure is associated with a high mortality if the neurologic status deteriorates rapidl~ if coagulation factor V levels are below 20%, if the patient is more than 40 or less than 11 yr old, if the patient suffers from late-onset hepatic failure, and if serum bilirobin levels are above 300 mmoVL. Furthermore, survival data from different centers are comparable only if the etiologies of the fulminant liver failure are comparable. The closest approach to a controlled trial has been reported by Vickers et al le from Birmingham. In this series, 9 of 16 patients survived after transplantation, while 4 (40%) of 10 patients for whom a donor liver did not become available survived without transplantation. This comparison is not large, it is not statistically significant, and it does not provide evidence that transplantation is beneficial. At present, clinicians selecting patients with fulminant liver failure for emergency liver transplantation should focus on patients with rapid deterioration of neurologic status, Table 4-Nonrandorraiz.ed ComptJriIona ofSurviool after Uver 1'nmBplantation for Fulminant Hepatic Failure· Transplant
No transplant
Study, Year
No.
(%)
No.
Hannover, 1986 Villejuif, 1987 Pittsburgh, 1987 Birmingham, 1988 King's College, London, 1987 Chicago, 1989
319 17/23 7/13 9/16 11119 11119
(33) (74) (54) (56) (58) (58)
NA NA
3116 4110
(19)
313
(100)
Total
58199
(59)
10/29
(34)
(%)
(40)
NA
*From Chapman ~ et ale Lancet 1990; i:32-35. Reproduced by permission.
Portal
Insulin IGF Glucagon
Nonportal Hormones Polypeptides (ie, EGF)
Liver-specific
Serum Hepatopoietin A Hepatopoietin 8 Thrombocytes HGF Liver Hepatic-stimulatory substance
IGF = insulin growth factor; EGF = epidermal growth factor; HGF = hepatocyte growth factor
rapidly falling coagulation factor V levels, late-onset hepatic failure, high bilirubin levels, and etiologies associated with a known high mortality such as halothane-induced hepatitis, HBV and HDV coinfection, and possibly HEV infection. Brunner and LOsgen from Hannover recommend direct monitoring of brain pressure. 17 Rapidly increasing brain pressure is indicative of the development of irreversible brain damage. However, multicenter controlled trials are needed to establish the role of liver transplantation in fulminant hepatic failure. Growth Factors in Uver Regeneration
The liver has an impressive ability to regenerate. All therapeutic regimens in fulminant hepatic failure apart from liver transplantation aim at temporary support of liver cell function or temporary treatment of symptoms secondary to liver failure until endogenous liver regeneration takes over. From animal experiments primarily done by surgeons, we know that after 70% partial hepatectomy in rats, the liver regenerates to normal size within a month. Starzl and Terblanche 18 have shown that insulin and glucagon are major hepatotropic growth factors in portal blood. At present, liver regeneration is studied on a more molecular level. Several growth factors involved in liver regeneration have been described, both liver-specific and liver-nonspecific (Table 5). Nonportal growth factors like hormones and polypeptides significantly contribute to liver regeneration. One of them is epidennal growth factor (EGF).18 Recently, liver-specific growth factors, called hepatopoietin A and B, have been identified in the serum ofanimals after partial hepatectomy. m Such factors have also been identified in the serum of patients with fulminant hepatic failure. 2J In addition, a hepatocyte growth factor from thrombocytes has been described. 1I Possibly the most important growth factor for liver regeneration is produced in the regenerating liver itseU: Thus, the regenerating liver is producing its own specific growth factor, such as hepatic stimulatory substance (HSS).D-Z Presumably the regenerating liver is not producing only growth factors. Once the organ has reached original size, growth inhibitors seem to terminate liver regeneration. These growth inhibitors await molecular identiBcation. Oncogens are expressed early in the regenerating liver. The role of oncogen expression in the regenerating liver is unclear. The expression of oncogens occurs before DNA synthesis has started.- A possible major role of oncogen expression in liver regeneration may be sensitization of CHEST I 100 I 3 I SEPTEMBER, 1991 I Supplement
1958
hepatocytes to extrahepatic growth factors like EGF or direct stimulation of DNA synthesis. Future research on liver regeneration will likely lead to the identification, isolation, and characterization of Iive~ specific growth factors that, with the aid of recombinant DNA technolo~ will become available as new therapeutic agents. Early data on the molecular cloning and expression of a human hepatocyte growth factor were published in 1989. i7 These new drugs may improve our treatment regimens for fulminant hepatic failure. CONCLUSIONS
At present, with the exception of paracetamol-induced liver injury and liver failure due to A phalloides, no specific treatment for fulminant hepatic failure is available; liver transplantation for this condition awaits controiled trials. Apart from treatment of symptoms like hepatic encephalopathy, support of liver regeneration is the most appropriate approach, since it helps the liver recover without the lifelong immunosuppression that is necessary after liver transplantation. Animal experiments have already shown that survival after experimentally induced fulminant hepatic failure can be improved by growth factors like insulin, glucagon, and 088.-'30 REFERENCES 1 Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis 1970; 3:282-90 2 Khumo MS. Study of an epidemic non-A, non-B hepatitis: possibility of another human hepatitis virus distinct from posttransfusion non-A, non-B type. Am J Med 1980; 68:818-24 3 Choo Q-L, Kuo G, Weiner AJ, Overby LR, Bradley D~ Houghton M. Isolation of cDNA clone derived from a bloodborne non-A, non-B viral hepatitis genome. Science 1989; 244:359-62 4 Kuo G, Choo Q-L, Alter.HJ, Gitnick GL, Redeker AG, Purcell RH, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244:36264
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New Therapeutic Aspects in Fulminant Hepatic Failure (Michael F. Manns)
