Secondary Logo

Journal Logo

Invited Review

Fulminant Hepatitis in Children: Evidence for an Unidentified Hepatitis Virus

Whitington, P. F.; Alonso, E. M.

Author Information
Journal of Pediatric Gastroenterology and Nutrition: November 2001 - Volume 33 - Issue 5 - p 529-536
  • Free

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.


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.


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.


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.


1. Lee WM. Acute liver failure. N Engl J Med 1993; 329: 1862–72.
2. Whitington PF, Soriano HE, Alonso EM. Fulminant hepatic failure in children. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. Philadelphia: Lippincott Williams & Wilkins; 2001: 63–88.
3. Williams R. Classification, etiology, and considerations of outcome in acute liver failure. Semin Liver Dis 1996; 16: 343–8.
4. Gimson AES, O'Grady J, Ede RJ, et al. Late onset hepatic failure: clinical, serological and histologic features. Hepatology 1986; 6: 288–94.
5. Bernuau J. Fulminant and subfulminant viral hepatitis. Rev Prat 1990; 40: 1652–5.
6. Psacharopoulos HT, Mowat AP, Davies M, et al. Fulminant hepatic failure in childhood: an analysis of 31 cases. Arch Dis Child 1980; 55: 252–8.
7. Saunders SJ, Hickman R, MacDonald R, et al. The treatment of acute liver failure. Prog Liver Dis 1972; 3: 333–44.
8. Bernuau J, Rueff B, Benhamou J-P. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis 1986; 6: 97–106.
9. Mathiesen LR, Skinoj P, Nielson JO, et al. Hepatitis type A, B, and non-A, non-B in fulminant hepatitis. Gut 1980; 21: 72–7.
10. Willner IR, Uhl MD, Howard SC, et al. Serious hepatitis A: an analysis of patients hospitalized during an urban epidemic in the United States. Ann Intern Med 1998; 128: 111–4.
11. Mathiesen LR, Linglof T, Moller AM, et al. Fulminant hepatitis A. Scand J Infect Dis 1979; 11: 303–5.
12. Arora NK, Nanda SK, Gulati S, et al. Acute viral hepatitis types E, A, and B singly and in combination in acute liver failure in children in north India. J Med Virol 1996; 48: 215–21.
13. Gimson AES, White YS, Eddleston WF, et al. Clinical and prognostic differences in fulminant hepatitis type A, B and non-A, non-B. Gut 1983; 24: 1194–8.
14. Debray D, Cullufi P, Devictor D, et al. Liver failure in children with hepatitis A. Hepatology 1997; 26: 1018–22.
15. Chow CB, Lau TTY, Leung NK, et al. Acute viral hepatitis: aetiology and evolution. Arch Dis Child 1989; 64: 211–3.
16. Yohannan AM, Ramia S. Aetiology of icteric hepatitis and fulminant hepatic failure in children and the possible predisposition to hepatic failure by sickle cell disease. Acta Paediatr Scand 1990; 79: 201–5.
17. Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998; 338: 286–90.
18. Wright TL, Mamish D, Combs D, et al. Hepatitis B virus and apparent fulminant non-A, non-B hepatitis. Lancet 1992; 339: 952–5.
19. Chang MH, Lee C-Y, Chen D-S, et al. Fulminant hepatitis in children in Taiwan: the important role of hepatitis B virus. J Pediatr 1986; 3: 34–8.
20. Stevens CE, Toy PT, Tong MJ, et al. Perinatal hepatitis B virus transmission in the United States. JAMA 1985; 253: 1740–5.
21. McNeil M, Hoy JF, Richards MJ, et al. Etiology of fatal viral hepatitis in Melbourne. Med J Aust 1984; 141: 637–40.
22. Liang TJ, Hasegawa K, Rimon N, et al. A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med 1991; 324: 1705–9.
23. Omata M, Ehata T, Yokosuka O, et al. Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. N Engl J Med 1991; 324: 1699–1704.
24. Shafritz DA. Variants of hepatitis B virus associated with fulminant liver disease. N Engl J Med 1991; 324: 1737–8.
25. Terazawa S, Kojima M, Yamanaka T, et al. Hepatitis B virus mutants with precore-region defects in two babies with fulminant hepatitis and their mothers positive for antibody to hepatitis B e antigen. Pediatr Res 1991; 29: 5–9.
26. Farci P, Alter HJ, Shimoda A, et al. Hepatitis C virus-associated fulminant hepatic failure. N Engl J Med 1996; 335: 631–4.
27. Liang TJ, Jeffers L, Reddy RK, et al. Fulminant or subfulminant non-A, non-B viral hepatitis: the role of hepatitis C and E viruses. Gastroenterology 1993; 104: 556–62.
28. Alter HJ, Purcell RH, Shih JW, et al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989; 321: 1494–1500.
29. Feray C, Gigou M, Samuel D, et al. Hepatitis C virus RNA and hepatitis B virus DNA in serum and liver of patients with fulminant hepatitis. Gastroenterology 1993; 104: 549–55.
30. Hibbs JR, Frickhofen N, Rosenfeld SJ, et al. Aplastic anemia and viral hepatitis: non-A, non-B, non-C? JAMA 1992; 267: 2051–4.
31. Fagan EA, Harrison TJ. Exclusion in liver by polymerase chain reaction of hepatitis B and C viruses in acute liver failure attributed to sporadic non-A, non-B hepatitis. J Hepatol 1994; 21: 587–91.
32. Muto Y, Sugihara J, Ohnishi H, et al. Anti-hepatitis C virus antibody prevails in fulminant hepatic failure. Gastroenterol Jpn 1990; 25: 32–5.
33. Liaw YF, Chen TJ, Chu CM, et al. Acute hepatitis delta virus superinfection in patients with liver cirrhosis. J Hepatol 1990; 10: 41–5.
34. Smedile A, Farci P, Verme G, et al. Influence of delta infection on severity of hepatitis B. Lancet 1982; 2: 945–7.
35. Hsu H-Y, Chang M-H, Chen D-S, et al. Hepatitis D virus infection in children with acute or chronic hepatitis B virus infection in Taiwan. J Pediatr 1988; 112: 888–92.
36. Arankalle VA, Spreenivason MA, Popper H, et al. Aetiological association of a virus-like particle with enterically transmitted non-A, non-B hepatitis. Lancet 1988; 1: 550–3.
37. Ramalingaswami V, Purcell RH. Waterborne non-A, non-B hepatitis. Lancet 1988; 1: 571–3.
38. Panda SK, Datta R, Kaur J, et al. Enterically transmitted non-A, non-B hepatitis: recovery of virus-like particles from an epidemic in South Delhi and transmission in Rhesus monkeys. Hepatology 1989; 10: 466–72.
39. Mast EE, Krawczynski K. Hepatitis E: an overview. Annu Rev Med 1996; 47: 257–66.
40. Hussaini SH, Skidmore SJ, Richardson P, et al. Severe hepatitis E infection during pregnancy. J Viral Hepatitis 1997; 4: 51–4.
41. Mphahlele MJ, Lau GK, Carman WF. HGV: the identification, biology and prevalence of an orphan virus. Liver 1998; 18: 143–55.
42. Viazov S, Riffelmann M, Khoudyakov Y, et al. Genetic heterogeneity of hepatitis G virus isolates from different parts of the world. J Gen Virol 1997; 78: 577–81.
43. Alter HJ, Nakatsuji Y, Melpolder J, et al. The incidence of transfusion-associated hepatitis G infection and its relation to liver disease. N Engl J Med 1997; 336: 795–6.
44. Sheng L, Soumillion A, Beckers N, et al. Hepatitis G virus infection in acute fulminant hepatitis: prevalence of HGV infection and sequence analysis of a specific viral strain. J Viral Hepatol 1998; 5: 301–6.
45. Wu JC, Chiang TY, Huang YH, et al. Prevalence, implication, and viral nucleotide sequence analysis of GB virus-C/hepatitis G virus infection in acute fulminant and nonfulminant hepatitis. J Med Virol 1998; 56: 118–22.
46. Frider B, Sookoian S, Castano G, et al. Detection of hepatitis G virus RNA in patients with acute non-A-E hepatitis. J Viral Hepatol 1998; 5: 161–4.
47. Hadziyannis SJ. Fulminant hepatitis and the new G/GBV-C flavivirus. J Viral Hepatol 1998; 5: 15–9.
48. Halasz R, Fischler B, Nemeth A, et al. A high prevalence of serum GB virus C/hepatitis G virus RNA in children with and without liver disease. Clin Infect Dis 1999; 28: 537–40.
49. Iorio R, Pensati P, Botta S, et al. Chronic cryptogenic hepatitis in childhood is unrelated to hepatitis G virus. Pediatr Infect Dis J 1999; 18: 347–51.
50. Perez RG, Zein NN, Freese DK, et al. No evidence of hepatitis G virus in fulminant hepatic failure in children. J Pediatr Gastroenterol Nutr 1999; 28: 400–3.
51. Lin HH, Kao JH, Yeh KY, et al. Mother-to-infant transmission of GB virus C/hepatitis G virus: the role of high-titered maternal viremia and mode of delivery. J Infect Dis 1998; 177: 1202–6.
52. Zuin G, Saccani B, Di Giacomo S, et al. Outcome of mother to infant acquired GBV-C/HGV infection. Arch Dis Child Fetal Neonatal Ed 1999; 80: F72–3.
53. Berg T, Müller AR, Platz KP, et al. Dynamics of GB virus C viremia early after orthotopic liver transplantation indicates extrahepatic tissues as the predominant site of GB virus C replication. Hepatology 1999; 29: 245–9.
54. Pessoa MG, Terrault NA, Detmer J, et al. Quantitation of hepatitis G and C viruses in the liver: evidence that hepatitis G virus is not hepatotropic. Hepatology 1998; 27: 877–80.
55. Kanda T, Yokosuka O, Ikeuchi T, et al. The role of TT virus infection in acute viral hepatitis. Hepatology 1999; 29: 1905–8.
56. Itoh M, Shimomura H, Fujioka S, et al. High prevalence of TT virus in human bile juice samples: importance of secretion through bile into feces. Dig Dis Sci 2001; 46: 457–62.
57. Tawara A, Akahane Y, Takahashi M, et al. Transmission of human TT virus of genotype 1a to chimpanzees with fecal supernatant or serum from patients with acute TTV infection. Biochem Biophys Res Commun 2000; 278: 470–6.
58. Rodriguez-Inigo E, Casqueiro M, Bartolome J, et al. Detection of TT virus DNA in liver biopsies by in situ hybridization. Am J Pathol 2000; 156: 1227–34.
59. Kao JH, Hsiang SC, Chen PJ, et al. Prevalence and implication of TT virus infection: minimal role in patients with non A-E hepatitis in Taiwan. J Med Virol 1999; 59: 307–12.
60. Gimenez-Barcons M, Forns X, Ampurdanes S, et al. Infection with a novel human DNA virus (TTV) has no pathogenic significance in patients with liver disease. J Hepatol 1999; 30: 1028–34.
61. Shibata M, Morizane T, Baba T, et al. TT virus infection in patients with fulminant hepatic failure. Am J Gastroenterol 2000; 95: 3602–6.
62. Connor RW, Lorts G, Gilbert DN. Lethal herpes simplex virus type I hepatitis in a normal adult. Gastroenterology 1979; 76: 590–5.
63. Morishita K, Kodo H, Asana S. Fulminant varicella hepatitis following bone marrow transplantation. JAMA 1985; 253: 511.
64. Rubin MH, Ward DM, Painter CJ. Fulminant hepatic failure caused by genital herpes in a healthy person. JAMA 1985; 253: 1299–1301.
65. Shusterman NH, Frauerhoffer C, Kinsey MD. Fatal massive hepatic necrosis in cytomegalovirus mononucleosis. Ann Intern Med 1978; 80: 810–2.
66. Goyette RE, Donowho EM, Hieger LR, et al. Fulminant herpes virus hominis hepatitis during pregnancy. Obstet Gynecol 1974; 43: 191–6.
67. McMahon JM, Elliott CW, Green RC. Infectious mononucleosis complicated by hepatic coma. Am J Gastroenterol 1969; 51: 200–7.
68. Shaw NJ, Evans JHC. Liver failure and Epstein-Barr virus infection. Arch Dis Child 1988; 63: 432–45.
69. Adkins BJ, Steele RH. Death from massive hepatic necrosis in infectious mononucleosis. N Z Med J 1977; 85: 56–8.
70. Hart GK, Thompson WR, Davis NJ, et al. Fulminant hepatic failure and fatal encephalopathy associated with Epstein-Barr virus infection. Med J Aust 1984; 1984: 112–3.
71. White JG. Fulminating infection with herpes-simplex virus in premature and newborn infants. N Engl J Med 1963; 269: 455.
72. Gillam GL, Stokes KB, McLellan J, et al. Fulminant hepatic failure with intractable ascites due to echovirus 11 infection successfully managed with a peritoneo-venous (LeVeen) shunt. J Pediatr Gastroenterol Nutr 1986; 5: 476–80.
73. Halfon N, Spector SA. Fatal echovirus type II infections. Am J Dis Child 1981; 135: 1017–9.
74. Aradottir E, Alonso EM, Shulman ST. Severe neonatal enteroviral hepatitis treated with pleconaril. Pediatr Infect Dis J 2001; 20: 457–9.
75. Hosier DM, Newton WA. Serious coxsackie infection in infants and children. Am J Dis Child 1958; 96: 251–67.
76. Fagan EA. Acute liver failure of unknown pathogenesis: the hidden agenda. Hepatology 1994; 19: 1307–12.
77. Bortolotti F, Cadrobbi P, Armigliato M, et al. Acute non-A, non-B hepatitis in childhood. J Pediatr Gastroenterol Nutr 1988; 7: 22–6.
78. O'Grady JG, Alexander GJM, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 439–45.
79. Williams R, Wendon J. Indications for orthotopic liver transplantation in fulminant liver failure. Hepatology 1994; 20: S5–10S.
80. Tzakis AG, Arditi M, Whitington PF, et al. Aplastic anemia complicating orthotopic liver transplantation for non-A, non-B hepatitis. N Engl J Med 1988; 319: 393–6.
81. Cattral MS, Langnas AN, Markin RS, et al. Aplastic anemia after liver transplantation for fulminant liver failure. Hepatology 1994; 20: 813–8.
82. Hagglund H, Winiarski J, Ringden O, et al. Successful allogeneic bone marrow transplantation in a 2.5-year-old boy with ongoing cytomegalovirus viremia and severe aplastic anemia after orthotopic liver transplantation for non-A, non-B, non-C hepatitis. Transplantation 1997; 64: 1207–8.
83. Roll C, Ballauff A, Lange R, et al. Heterotopic auxiliary liver transplantation in a 3-year-old boy with acute liver failure and aplastic anemia. Transplantation 1997; 64: 658–60.
84. Kiem HP, Storb R, McDonald GB. Hepatitis-associated aplastic anemia. N Engl J Med 1997; 337: 424–5.
85. Young NS. Acquired aplastic anemia. JAMA 1999; 282: 271–8.
86. Linet MS, Markowitz JA, Sensenbrenner LL, et al. A case-control study of aplastic anemia. Leuk Res 1989; 13: 3–11.
87. McSweeney PA, Carter JM, Green GJ, et al. Fatal aplastic anemia associated with hepatitis B viral infection. Am J Med 1988; 85: 255–6.
88. Busch FW, deVos S, Flehmig B, et al. Inhibition of in vitro hematopoiesis by hepatitis A virus. Exp Hematol 1987; 15: 978–82.
89. Zeldis JB, Mugishima H, Steinberg HN, et al. In vitro hepatitis B infection of human bone marrow cells. J Clin Invest 1986; 78: 411–17.
90. Zeldis JB, Farraye FA, Steinberg HN. In vitro hepatitis B virus suppression of erythropoiesis is dependent on the multiplicity of infection and is reversible with anti-HBs antibodies. Hepatology 1988; 8: 755–9.
91. Brown KE, Tisdale J, Barrett AJ, et al. Hepatitis-associated aplastic anemia. N Engl J Med 1997; 336: 1059–64.
92. Harrison P, Skidmore SJ, Collingham KE, et al. Hepatitis GBV-C and aplastic anaemia. Br J Haematol 1997; 98: 495.
93. Kao JH, Chen PJ, Lai MY, et al. GBV-C/HGV infection and aplastic anaemia. Lancet 1996; 348: 1032–3.
94. Kiem HP, Myerson D, Storb R, et al. Prevalence of hepatitis G virus in patients with aplastic anemia. Blood 1997; 90: 1335–6.
95. Moriyama K, Okamura T, Nakano S. Hepatitis GB virus C genome in the serum of aplastic anaemia patients receiving frequent blood transfusions. Br J Haematol 1997; 96: 864–7.
96. Issaragrisil S, Kaufman D, Thongput A, et al. Association of seropositivity for hepatitis viruses and aplastic anemia in Thailand. Hepatology 1997; 25: 1255–7.
97. Zeldis JB, Dienstag JL, Gale RP. Aplastic anemia and non-A, non-B hepatitis. Am J Med 1983; 74: 64–8.
98. Zeldis JB, Boender PJ, Hellings JA, et al. Inhibition of human hemopoiesis by non-A, non-B hepatitis virus. J Med Virol 1989; 27: 34–8.
99. Paquette RL, Kuramoto K, Tran L, et al. Hepatitis C virus infection in acquired aplastic anemia. Am J Hematol 1998; 58: 122–6.
100. Naides SJ, Karetnyi YV, Cooling LL, et al. Human parvovirus B19 infection and hepatitis. Lancet 1996; 347: 1563–4.
101. Langnas AN, Markin RS, Cattral MS, et al. Parvovirus B19 as a possible causative agent of fulminant liver failure and associated aplastic anemia. Hepatology 1995; 22: 1661–5.
102. Pardi DS, Romero Y, Mertz LE, et al. Hepatitis-associated aplastic anemia and acute parvovirus B19 infection: a report of two cases and a review of the literature. Am J Gastroenterol 1998; 93: 468–70.
103. Fagan E, Williams R. Identification of toga-like virus in fulminant hepatitis attributed to minocycline therapy. BMJ 1989; 299: 1224.
104. Fagan EA, Ellis DS, Tovey GM, et al. Toga-like virus as a cause of fulminant hepatitis attributed to sporadic non-A, non-B. J Med Virol 1989; 28: 150–5.
105. Fagan EA, Ellis DS, Tovey GM, et al. Viruslike particles in liver in sporadic non-A, non-B fulminant hepatitis. J Med Virol 1989; 27: 76–80.
106. Fagan EA, Ellis DS, Tovey GM, et al. Toga virus-like particles in acute liver failure attributed to sporadic non-A, non-B hepatitis and recurrence after liver transplantation. J Med Virol 1992; 38: 71–7.
107. Alonso EM, Sokol RJ, Hart J, et al. Fulminant hepatitis associated with centrilobular necrosis in young children. J Pediatr 1995; 127: 888–94.
108. Gall DG, Cutz E, McClung HJ, et al. Acute liver disease and encephalopathy mimicking Reye syndrome. A report of three cases. J Pediatr 1975; 87: 869–74.
109. Lii YP, Chi SC, Mak SC. [Acute encephalopathy associated with centrilobular necrosis of liver mimicking Reye's syndrome—report of two cases]. [Chinese]. Chung Hua I Hsueh Tsa Chih (Taipei) 1993; 51: 154–7.
110. Shibao K. Non-icteric fulminant hepatitis and Reye's syndrome: comparison of laboratory data. Acta Paediatr Jpn 1990; 32: 399–405.
111. Bakerink JA, Gospe Jr., SM, Dimand RJ, et al. Multiple organ failure after ingestion of pennyroyal oil from herbal tea in two infants. Pediatrics 1996; 98: 944–7.
112. Phillips MJ, Blendis LM, Poucell S, et al. Syncytial giant cell hepatitis: sporadic hepatitis with distinctive pathologic features, a severe clinical course, and paramyxoviral features. N Engl J Med 1991; 324: 455–60.
© 2001 Lippincott Williams & Wilkins, Inc.