The broadest definition of fulminant hepatic failure (FHF) is the failure of the vital functions of the liver occurring within weeks or a few months of the onset of clinical liver disease (1,2). This definition implies that some agent or combination of agents has caused the sudden death of or severe injury to a large proportion of hepatocytes, leaving less parenchymal function than is needed to sustain life. The currently accepted narrow definition of FHF includes the onset of hepatic encephalopathy (which defines failure of vital function) less than 8 weeks after the beginning of liver disease (i.e., onset of symptoms referable to liver disease) and the absence of pre-existing liver disease of any form (3). Some patients with acute hepatitis have encephalopathy develop more than 8 weeks into the course. Terms such as subacute hepatic failure, subacute hepatic necrosis, and late-onset hepatic failure have been used to describe cases in which encephalopathy develops from 8 to 24 weeks after the onset of liver disease (4,5). In our experience, fulminant and late-onset hepatic failure occur in the pediatric population most frequently in the context of seronegative (non-A–G) hepatitis.
THE ETIOLOGY OF FULMINANT HEPATIC FAILURE
In most published series of pediatric FHF, by far the most common cause is acute viral hepatitis. There is a distinct geographic impact on the frequency of diagnosis, particularly regarding the frequency with which hepatitis A and B infections are implicated. The purpose of this discussion is to examine the large wastebasket of diagnoses we call non-A–G hepatitis, in particular to find evidence for and against the proposition that it is a viral illness.
Viral or presumed viral hepatitis is the cause of most cases of FHF in children of all age groups. In the largest published experiences, viral hepatitis accounted for more than 80% of FHF cases in pediatrics. For example, of 31 children with FHF in London (6), 26 (84%) had acute hepatitis. All 33 children reported from Cape Town, South Africa (7), had viral hepatitis, and 34 of 42 patients in our own experience have had that diagnosis. Excluding neonates and immunocompromised patients, most cases of viral hepatitis resulting in FHF in children are the result of infection with hepatitis virus types A and B, and (putative) sporadic non-A–G hepatitis. A variety of viral agents can cause massive hepatic injury in neonates, and immunodeficient individuals are susceptible to severe injury from the herpes viruses.
THE RECOGNIZED HEPATITIS VIRUSES IN FULMINANT HEPATIC FAILURE
Acute hepatitis A virus (HAV) infection is a relatively frequently diagnosed cause of FHF, but the risk of hepatic failure developing in patients with symptomatic HAV infection is very low, between 0.1% and 0.4%(8–10). The prevalence of HAV among patients of all ages with FHF in larger series has varied from as low as 1.5% to as high as 31%(8–11). Not surprisingly, HAV is a frequent cause of FHF in reports from developing countries where it is endemic (12). It has also been recorded as a frequent cause in developed countries. HAV caused 31% of FHF in a series from King's College Hospital in London (13) and 26% of cases in a recent series from Bicetre, France (14). In the United States, HAV generally causes <5% of FHF. In our own experience with FHF, evidence of HAV infection was found in two patients, both of whom required liver transplantation. The incidence of fulminant failure, that is, the case rate per case of HAV infection, was not determined in any of these studies. It is of interest that 86% of the affected patients in the Bicetre study were from North Africa, an area of high endemicity (14). Even in endemic areas, HAV infection rarely leads to FHF. In one large series of pediatric patients from Hong Kong, 251 of 348 consecutive cases of acute hepatitis seen in one hospital were anti-HAV IgM positive (15). None had hepatic failure, and all recovered. In summary, HAV is a frequent cause of FHF in developing countries and even in Western Europe, but the frequency with which patients acutely infected with HAV have FHF develop is small.
Hepatitis A virus infection can complicate the course of other liver diseases to produce acute liver failure. In a series from Saudi Arabia, 72% of children hospitalized with hepatitis were found to have HAV; three of these had FHF (6.3%) develop, and two died (4.2% case fatality rate) (16). Both patients who died also had sickle cell disease, suggesting that this condition may complicate HAV infection in children, or vice versa. In a recent report from Italy, a large cohort of patients who had either chronic hepatitis B virus or hepatitis C virus and were HAV seronegative were followed for 7 years to determine the events if they became acutely infected with HAV (17). Of 27 patients acquiring HAV, 7 of 17 with chronic HCV had liver failure develop; all but one died as a result. None of the 10 patients with coexistent chronic HBV had failure develop. This again suggests that HAV often produces acute liver failure in patients with chronic liver disease.
The prevalence of acute hepatitis B virus (HBV) infection in large series of FHF ranges from 25% to 75%(8,13), making it the number one cause overall. It may indeed be considerably more common among adult patients than is evidenced by serologic criteria. In work from San Francisco, the polymerase chain reaction (PCR) was used to amplify the surface and core regions of HBV DNA in liver samples obtained at the time of transplantation in 12 patients with FHF, presumably secondary to non-A, non-B (NANB) hepatitis (18). Six of the 12 livers contained HBV DNA despite completely negative serologic evidence and, indeed, the complete absence of HBV DNA in serum. These findings suggest that HBV infection can cause overwhelming hepatic necrosis with perhaps loss of the very machinery necessary to replicate viral particles and export them into serum and also with paralysis of the immune response required for serologic diagnosis. Therefore, patients with FHF at risk for HBV infection should be considered to have that condition even in the absence of serologic evidence. In pediatrics, this group includes infants born to high-risk mothers (who should be investigated for evidence of HBV infection), children from endemic areas (i.e., Asia, Eastern Europe), and teenagers (who may have engaged in high-risk activities).
Documented HBV infection resulting in FHF in children is an unusual occurrence in Western Europe and North America, where HBV is not endemic. In the series from King's College, London, HBV infection could not be identified in any of the 31 children with FHF (6). In our own series, two children have been found to have HBV infection. One of these was a teenage boy with a history of intravenous drug abuse. The other was a 6-week-old girl born to a suburban school teacher, who was subsequently found to have an HBV carrier state (HBsAg positive, anti-HBe positive). In areas of endemic HBV, it plays a much greater role in FHF in children. In work from Taipei (19), of 16 children with presumed viral FHF, 11 were positive for anti-HBc IgM. Five of these had received blood transfusions from HBV-positive donors. The remaining six were born to HBsAg-positive, HBeAg-negative, anti-HBe-positive mothers, a state that in general results in less risk of vertical transmission of HBV but that apparently substantially increases the risk for FHF (20). Two additional patients were positive for HBsAg, but negative for anti-HBc IgM. They may have been HBV carriers in whom another virus caused FHF, or they may have lacked the immune response to an acute HBV infection. None of the patients studied had evidence of HAV infection, and four were presumed to have NANB hepatitis. Thus, in endemic areas, HBV may be the dominant cause for FHF in children.
Despite its prevalence in series of FHF, HBV infection infrequently progresses to this point. The overall rate of FHF in acute HBV infection is estimated to be about 1%. In the large series of patients hospitalized with acute hepatitis in Melbourne (21), the case fatality rate of acute HBV was 0.84% but was substantially greater in patients older than 40 years of age (5.26%) and in individuals acquiring HBV infection as a result of blood transfusions (18.8%). The risk was lower in patients 15 to 29 years old (0.23%) and in intravenous drug abusers (0.063%). Thus, the risk seems to be relatively low in most circumstances that would involve pediatric patients; infants born to anti-HBe-positive HBV carriers and recipients of HBV-positive blood transfusions were the major exceptions.
Recent outbreaks have shown that mutations of HBV pre-core DNA region, which result in the inability to make HBeAg, are associated with a high frequency of FHF (22,23). These reports suggest the usual biology of HBV is to not cause severe hepatic necrosis. The apparent role of HBeAg in moderating hepatic injury lends some understanding to the risk of infants born to anti-HBe-positive HBV carriers and the exacerbation of chronic HBV hepatitis on clearance of HBeAg. Evidently, circulating HBeAg diverts some of the force of the immune response directed against HBV antigens, particularly HBcAg, expressed on the hepatocyte plasma membrane (24). Fulminant HF has been reported in two infants with vertically transmitted HBV infection with pre-core mutations whose mothers were anti-HBe positive (25).
Hepatitis C virus (HCV) is a very unusual cause for FHF (26,27). In large studies of posttransfusion HCV-positive patients, FHF has not been observed (28). Furthermore, in the larger pediatric series of FHF, those cases that apparently resulted from NANB hepatitis distinctly lacked, in most cases, evidence of exposure, which would have placed them at risk for HCV infection. In two recent studies, HCV RNA has not been detected in the serum of patients with sporadic fulminant hepatitis without defined cause (27,29). Moreover, HCV RNA has not been detected in liver specimens from FHF victims using PCR amplification techniques (18,30,31). One study has included specimens from several pediatric patients, including most of those from our own recent series (30). In contrast to this evidence that HCV plays little role in FHF, anti-HCV antibodies were detected in most patients with hepatic failure in one Japanese series (32). However, the specificity of the findings must be questioned in light of the data available to the contrary. HCV RNA has been detected in the serum of 8 of 17 HBsAg-positive patients with FHF, which suggests that coinfection or superinfection with HCV might play a role in producing severe hepatitis in patients with HBV virus infection (29). In summary, HCV infection apparently has little or no role in the cause in FHF in children.
Hepatitis D virus (HDV) infection can be acquired as a coinfection with HBV or as a superinfection in patients previously infected with HBV (33) but requires the presence of HBV infection for virulence. In cases of fulminant HDV infection, the prevalence of coinfection, rather than superinfection, varies from 50% to 75%. HDV coinfection has been found in approximately 30% of patients with acute HBV infection and FHF, so HDV seems to be an important determinant of the severity of acute HBV infection (34). Furthermore, superinfection with HDV can result in FHF in chronic carriers of HBV with or without chronic hepatitis. There is little experience with HDV infection in pediatric patients. In one study from Taiwan, anti-HDV was not detected in any child with FHF related to HBV infection (19), and in another study from Taiwan, three children with anti-HDV antibody did not experience a course different from the usual HBV-infected child, and none had hepatic failure (35). HDV infection probably plays little role in the cause of FHF in children.
Hepatitis E virus (HEV) infection is documented by association with epidemics of water-borne non-A hepatitis and/or by the presence of anti-HEV antibody in serum (36–39). Most experience with HEV comes from the Indian subcontinent. In general, acute HEV infection runs a benign course, similar to HAV infection. However, the case fatality rate from FHF among pregnant women in one study was 10.1%, with women in the third trimester particularly at risk (40). In a study involving 44 children with FHF in north India, 7 had isolated HEV infection, and 16 had mixed HEV and HAV infection (12). There are no reports of HEV involving children from western Europe or the United States.
GB virus-C/hepatitis G virus (GBV-C/HGV) is an RNA virus with similarities to Flaviviridae, including HCV (41,42). Antibodies against the virus and/or viral RNA can be detected in about 2% of US blood donors, and GBV-C/HGV has been investigated as a cause of posttransfusion hepatitis (43). It is frequently found in coinfection with HCV and is thought to have similar routes of transmission. Its role as a primary agent in acute and chronic hepatitis remains controversial. Although it is transmitted by blood transfusion and can lead to persistent infection, the presence of infection does not increase the risk of hepatitis, and there is no consistent relationship between level of viremia and degree of liver damage (43). It has been identified in the serum of a few adult patients with FHF and thereby implicated as a cause of severe, acute liver injury (44–46). However, its relatively high prevalence in the general population has made proving this implication difficult (47). A few studies involving children have failed to demonstrate that GBV-C/HGV is a cause of either acute or chronic liver disease, and it has been specifically excluded in small series of FHF (48–50). Vertical transmission from mother to infant has been demonstrated, but only infants with HCV and HIV coinfection seem to have significant liver disease (51,52). GBV-C/HGV seems to have an extrahepatic site of replication, and it has been implicated as a cause of aplastic anemia (53,54)
The TT virus (TTV) is a recently described circular DNA virus about which little is known (55). TTV has been confirmed as a parenterally acquired agent but may also be transmitted by the fecal-oral route (56,57). The virus has been detected in liver tissue at levels in excess of that found in serum and has been identified by in-situ hybridization in liver biopsy specimens from patients with a variety of liver diseases (58). However, TTV did not seem to worsen the course of chronic viral hepatitis, and the percentage of infected hepatocytes identified by in-situ hybridization did not correlate with histologic disease activity. Several recent Japanese studies have attempted to link TTV infection to FHF with variable results. In one study 45% of patients with fulminant hepatitis were TTV positive compared with 10% of blood donors (59). However, TTV was detected in prehepatitis serum from some of these patients, suggesting these patients had chronic TTV infection that preceded the development of FHF. A Spanish study also identified an increased prevalence of TTV in patients with FHF (39.6%) compared with blood donors (13.7%), yet, the prevalence of TTV in patients with hepatitis B and C and idiopathic hepatitis were similar (60). A case-control study comparing patients with FHF with healthy controls detected a significantly higher rate of TTV infection in patients with seronegative hepatitis. This study controlled for the use of blood products as a risk factor for TTV in the FHF group. Transfusion history did increase the risk of TTV infection, but patients tested before transfusion were still more likely to have TTV infection than patients with acute hepatitis A, B, or C (61). These studies suggest TTV as a possible candidate virus for seronegative viral hepatitis, but the high prevalence of TTV in the general population and the low incidence of FHF will make it difficult to prove a causative relationship.
INFECTION WITH VIRUSES OTHER THAN HEPATITIS VIRUSES
Other viral agents have rarely been reported in association with FHF, except in neonates. The viruses in the herpes family are highly cytopathic and can cause severe hepatic necrosis, often in the absence of significant inflammation. Herpes simplex virus, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus have been reported to cause to FHF, almost always in immunocompromised hosts (62–66), with the Epstein-Barr virus most frequently implicated (67–70). Herpes simplex virus-VI has not been reported to cause FHF. So strong is the association between severe herpes hepatitis and immunodeficiency that the immune system of patients recovering from severe herpes virus hepatitis deserves careful examination. Nothing is known about the incidence or case fatality rates among children with FHF secondary to herpes virus infection. The herpes viruses are not candidate viral agents for producing FHF in general.
Fulminant hepatic failure in the neonate may result from infection with a wide variety of viruses that do not characteristically cause severe hepatitis in older individuals. The reasons for this susceptibility are poorly understood, but they probably include an immature immune system and perhaps overwhelming exposure, either transplacentally or by way of a gut with a poor immune barrier capability. Herpes simplex virus infections are usually associated with systemic features (skin rash, encephalitis) (71). Cytomegalovirus hepatitis usually does not cause FHF in this age group, rather a chronic or chronic-progressive hepatitis, and is usually associated with systemic features (encephalitis, chorioretinitis, nephritis, bone marrow suppression). Epstein-Barr virus has very rarely been identified as the cause of FHF in neonates. Echovirus (principally type 11) has been observed to cause FHF in infants (72,73). Our recent experience suggests pleconaril, a specific antienteroviral agent, may be effective treatment for newborns with FHF secondary to echovirus infection (74). Coxsackievirus has also been recorded as a cause of severe hepatitis in neonates and children (75). Viruses that cause liver failure in newborns are not candidate viral agents for producing FHF in general.
Sporadic non-A–G hepatitis is diagnosed when there is evidence of acute hepatitis in the absence of markers for hepatitis virus infection and in the absence of clinical or serologic evidence of systemic infection with other viral agents. There should also be an absence of history of exposure to drugs or toxins, negative markers of autoimmune disease, and no evidence of infection with nonviral agents capable of causing hepatitis. It is, in other words, a wastebasket diagnosis. The current feeling that it is a viral disease comes from clinical experience (76). Similarities between non-A–G hepatitis FHF and FHF caused by HAV and HBV constitute perhaps the strongest argument that this is a hepatotrophic viral disease. There are distinct differences as well. These similarities and differences will be addressed in detail. Clinical experience with non-A–G hepatitis has come over a number of years, beginning well before hepatitis viruses C-G were discovered. Because these viruses have been reasonably excluded as causing the syndrome, non-A–G hepatitis is equivalent to NANB hepatitis as they relate to pediatric FHF.
One peculiar and puzzling characteristic of non-A–G hepatitis is its propensity to cause severe hepatitis. It is clearly the most important cause of FHF in children in Western developed countries, making up most pediatric FHF cases in series from Western Europe and the United States. In the King's College series, 26 of 31 children with FHF were believed to have NANB hepatitis (6), and in our own series, 26 of 42 children with FHF have diagnosed with non-A–G (or NANB) hepatitis. None in either series had experienced blood exposure, and only four had been exposed to an individual with clinical hepatitis.
Despite it being the leading cause of FHF, non-A–G hepatitis is rarely seen outside of this setting. We have rarely seen acute non-A–G hepatitis except in the context of severe hepatitis or hepatic failure. In a study from Padova, Italy (77), five children fulfilling the diagnostic criteria for NANB hepatitis infection were identified among 93 with acute viral hepatitis. All recovered, but three had severe hepatitis. These data suggest that non-A–G hepatitis is not a common cause of acute hepatitis among children, although it is a relatively common cause of severe acute hepatitis. In our own experience, about half of non-A–G hepatitis results in disease strictly adhering to the diagnosis of FHF and half have had late-onset hepatic failure. Only five of our non-A–G patients failed to have encephalopathy develop before recovering or succumbing to a complication. It is possible that there is a proportion of infected individuals who do not have clinical symptoms or have only mild hepatitis not requiring referral to a tertiary center develop, with hepatic failure cases being the visible tip of the iceberg. Little is known about the epidemiology of this disorder, and, indeed, until an agent or agents can be identified, little will be known.
A high case fatality rate (low rate of spontaneous recovery) is evidently characteristic of FHF secondary to non-A–G hepatitis. The rate of spontaneous recovery in our own series is very low, only 1 of 26 patients (4%), whereas in London, 8 of 26 (30%) children with NANB FHF survived (6). In a series of 73 patients of all ages with FHF in London, 44% had NANB hepatitis, only one with a significant exposure history (13). Survival was only 9.3%, in contrast to HAV infection (43.4%) and HBV infection (16.6%). However, in a series from Copenhagen, NANB infection in adults with FHF was not associated with a worse outcome than HAV or HBV infection (9). The diagnosis of FHF caused by non-A–G hepatitis seems to be particularly ominous in the pediatric patient and should set into immediate motion the mechanism for referral for liver transplantation. This one diagnosis is the reason for young age (<10 years) being the most powerful single determinant for the need for transplantation in the King's College FHF criteria (78,79).
An aspect of non-A–G hepatitis that provides compelling evidence of its viral origin is its association with aplastic anemia. In a series of 32 children and young adults receiving liver transplantation at four major centers for the indication of FHF secondary to NANB hepatitis, nine had aplastic anemia develop after successful transplantation (80). This frequency (28%) is in contrast to 0 incidence among 1463 other patients receiving liver transplantation in the same centers, including 12 patients with FHF secondary to HAV or HBV infection and 18 patients with fulminant drug-induced liver disease. Other centers have reported similar experience (81–83). Furthermore, in recent years, there have been mini-epidemics of FHF/aplastic anemia in several Midwestern states that have not yet been reported in the medical literature. We have recently seen three patients with severe non-A–G hepatitis who spontaneously recovered liver function but had severe aplastic anemia develop. It is apparent from this experience that the non-A–G hepatitis virus infects bone marrow and that aplastic anemia is a second life-threatening event that will confront a significant proportion of children recovering from severe non-A–G hepatitis, with or without liver transplant.
This experience has provided a group of patients on which to focus investigation of possible viral agents involved (30,84,85). There is strong evidence that hepatotrophic viruses are also bone marrow trophic. In a case-controlled study of risk factors in young adults with newly diagnosed aplastic anemia, a recent past history of hepatitis was a strongly positive risk factor with an odds ratio of 9 (95% confidence interval, 0.8–105) (86). HAV and HBV can infect bone marrow, inhibit hematopoiesis, and cause aplastic anemia (87–90), and GBV-C/HGV is thought to replicate in bone marrow and has been considered to be a cause of aplastic anemia (91–95). In a recent study from Thailand, previous exposure to HAV was shown to be an independent risk factor for aplastic anemia developing (odds ratio, 2.9; confidence interval, 1.2–6.7) (96). However, no patient had recent exposure to HAV or had aplastic anemia develop in association with hepatitis. The exposure to HAV was, therefore, thought to be a surrogate marker for another enteric viral agent. The facts that hepatitis viruses can infect bone marrow, that new-onset aplastic anemia in young adults is strongly associated with hepatitis, and that other noninfectious liver diseases are not associated with aplastic anemia have led to the belief that non-A–G hepatitis is a viral disease. Moreover, serum from patients with acute NANB hepatitis has been shown to inhibit human hematopoiesis (97,98).
There is evidence to the contrary. The known hepatitis viruses, including HCV, have been conclusively excluded as etiologic agents in the FHF/aplastic anemia syndrome (30). Patients with FHF from HAV and HBV have not had aplastic anemia after liver transplantation, and it has proven difficult to unequivocally link GBV-C/HGV to bone marrow dysfunction. Furthermore, exhaustive searches for a viral agent in patients with FHF and aplastic anemia have so far been fruitless.
Hepatitis C virus, the major cause of NANB posttransfusion hepatitis, has been associated with acquired aplastic anemia (99). In the study by Paquette et al., 17 of 90 patients with acquired aplastic anemia were found to be HCV viremic. All of these patients had been transfused before routine blood screening for HCV, and most had received more than 20 units of blood. HCV is, at most, a very rare cause of FHF. Furthermore, examination of liver and marrow tissue from patients with FHF/aplastic anemia has failed to reveal HCV RNA. HCV is, therefore, an unlikely candidate viral agent for the syndrome.
Parvovirus B19 infection has been the subject of study in FHF/aplastic anemia. This virus routinely infects children, causing one of the common childhood exanthems. It can rarely cause severe bone marrow depression and has been associated with mild hepatitis as evidenced by elevated aminotransferases. In one study involving six patients with FHF who had aplastic anemia develop in the peritransplant period, parvovirus B19 DNA was identified in the liver of four, and all six had IgG antibodies against the virus (100,101). Parvovirus B19 has been identified in some cases of aplastic anemia associated with mild non-A-B-C hepatitis (102). This virus has been looked for and not found in other studies involving larger numbers of FHF/aplastic anemia patients. The importance of parvovirus B19 in the syndrome is unclear at this point. It may exhibit latency, and its presence in liver tissue may only reflect prior exposure, as would IgG antibodies. It may occasionally cause FHF/aplastic anemia and should be looked for in all cases. However, it seems to be an unlikely candidate viral agent for the syndrome in general.
Another possible agent in NANB FHF has been identified in London (103–106). Toga virus–like particles were demonstrated by electron microscopy in hepatectomy specimens from 7 of 18 patients undergoing orthotopic liver transplantation for the indication of FHF from apparent NANB hepatitis. Three of the patients were children, ages 3, 13, and 16 years, whereas the rest were young adults. This group of patients experienced a high frequency of graft failure within a week of transplantation (5 of 7 patients) because of reinfection of the graft. No epidemiologic factors were identified that separated the group with infection from those with no identifiable viral agent. Further studies will be required to establish the importance of this viral agent, but it seems to be an unlikely candidate agent for the syndrome in general.
Recently, a series of children was reported with FHF and the absence of evidence of typable viral disease, but with minimal jaundice (107). Other features distinguish these patients from those with typical non-A–G hepatitis. Histopathologic findings are characterized by variable degrees of centrilobular necrosis, and the prognosis for recovery is better, with more than 50% of patients recovering. Exposure to acetaminophen in all patients in association with central necrosis, the lesion typically seen in acetaminophen overdose, suggested the possible role of this hepatotoxin in the disease. Similar “epidemics” of nonicteric FHF have been recorded in Vancouver (108), Taiwan (109,110), and central California (111). In the California cases, a potential hepatotoxin, pennyroyal oil, was ingested in the form of folk remedies, again suggesting an interaction of a viral agent with a toxin. To date, no patient with nonicteric hepatic failure has had aplastic anemia develop. It seems that this may be a separate and distinct form of non-A–G FHF.
Yet another form of FHF has been reported from Toronto. Syncytial giant cell hepatitis with FHF was associated with paramyxovirus infection (112). This infection is more likely to result in chronic-progressive hepatitis or late-onset hepatic failure than FHF but should be considered in all three circumstances. The frequency, epidemiology, and prevalence in FHF of this infection are not known. It has not been reported in any other series and seems to be an unlikely candidate viral agent in FHF in general.
Most FHF in children is caused by hepatitis without an identifiable specific viral agent. These patients have a very high fatality rate, and a significant proportion of them will require liver transplantation. A significant proportion will experience aplastic anemia. There is strong circumstantial evidence that non-A–G FHF is a viral disease, but to date no viral agent has been identified.
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