Indeterminate acute liver failure: A riddle wrapped in a mystery inside an enigma


  • Potential conflict of interest: Nothing to report.


Fulminant hepatitis of unknown origin remains a significant cause of mortality, for which liver transplantation is often considered as the only therapeutic option. In retrospective studies, human herpesvirus 6 (HHV-6) infections have been associated with such diseases, but the diagnosis of HHV-6 infection of the liver is rarely established during the acute phase of liver failure. Using real-time polymerase chain reaction (PCR), we diagnosed two cases of severe acute liver failure (ALF) related to HHV-6 occurring in immunocompetent young adults. Both cases had a favourable outcome, one after valganciclovir therapy and one after liver transplantation associated with ganciclovir. Viral origin was evidenced in each case by the detection of high amounts of HHV-6 DNA in liver tissue by the PCR assay. The decrease of intrahepatic viral load after therapeutic intervention was also monitored by quantitative PCR and paralleled in the two cases the clinical improvement. Diagnosis of HHV-6 infection must be systematically evoked in case of unexplained ALF, since it might lead to specific therapeutic interventions, in addition to liver transplantation.

Cacheux W, Carbonell N, Rosmorduc O, Wendum D, Paye F, Poupon R, Chazouilleres O, Gozlan J. HHV-6-related acute liver failure in two immunocompetent adults: favourable outcome after liver transplantation and/or ganciclovir therapy. J Intern Med. 2005;258:573-8. (Reprinted with permission from Blackwell Publishing Ltd.


Like Winston Churchill's classic description of early communist Russia, the syndrome of acute liver failure (ALF) is often enigmatic. For example, the etiology of ALF is mysterious in approximately 20% of adult patients in the US, and an even larger fraction of studies done elsewhere.1 This group of so-called indeterminate ALF probably reflects a panoply of underlying etiologies including infection with seronegative and novel viruses, exposure to environmental toxins, unrecognized idiosyncratic drug reactions, occult metabolic and genetic problems, and ill-defined autoimmune processes (Fig. 1). Indeed, essentially any of the well-established etiologies for ALF, if occult, could conceivably lead to a diagnosis of indeterminate ALF.

Figure 1.

The same categories of etiological agents that are responsible for ALF of known cause likely contribute to indeterminate ALF: viral infection, drug and toxin-induced injury, metabolic and genetic defects, vascular compromise, and autoimmune insults.

Over the last several years, there has been a burgeoning interest in idiosyncratic drug-induced liver injury (DILI) in the United States evidenced by the establishment of an NIH-funded network [the Drug-Induced Liver Injury Network (DILIN)] dedicated to this area of investigation.2 With this increasing attention on DILI necessarily comes an emergent interest in accurately defining the incidence and etiologies of indeterminate ALF because a diagnosis of DILI is essentially always one of exclusion. Indeed, the possibility of indeterminate ALF lurks in the background of every diagnosis of severe DILI; the careful clinician must routinely ask the question: Is this really a case of ALF from DILI or is it actually a patient with indeterminate ALF who coincidentally is taking a drug? Furthermore, there is growing hope that defining the etiology of indeterminate ALF may provide clues to successful medical treatment. As a group, indeterminate ALF carries a dismal prognosis, with a spontaneous (without liver transplant) survival of approximately 20% or less, so such therapies are desperately needed.1

A recent study from the U.S. Acute Liver Failure Study Group (ALFSG) suggests that acetaminophen toxicity, the major cause of ALF in the United States and most of Europe, may at least occasionally be occult and might be responsible for almost 20% of indeterminate ALF in the United States.3, 4 This study utilized a novel HPLC-based assay to measure protein adducts in the serum formed when a highly reactive metabolite of acetaminophen, N-acetylparabenzoquinoneimine (NAPQI), binds covalently to intracellular proteins within hepatocytes that are released into the serum with hepatocyte necrosis. Because this assay, representing the fruit of years of research dedicated to understanding acetaminophen toxicity, measures serum adducts, it strongly suggests that a patient with detectable adduct levels has consumed excessive acetaminophen and that this is at least in part responsible for the development of severe liver injury and liver failure.3 Detection of serum adducts requires not only that sufficient NAPQI be generated to exhaust intracellular glutathione, but that the NAPQI covalently binds to proteins within hepatocytes and that the hepatocytes undergo some form of cell death with release of the protein adducts into serum. As such, detection of serum adducts appears to represent the gold standard for the diagnosis of acetaminophen hepatotoxicity. However, cases of surreptitious acetaminophen overdose identified by the adducts assay typically had a clinical signature, including a rapid course associated with high serum aminotransferases and a relatively low bilirubin level, distinct from most cases of indeterminate ALF that is classically characterized by a subacute course with fluctuating aminotransferases and a often a viral prodrome.

Numerous publications have implicated infections from a diverse assortment of unusual viruses in patients with otherwise occult ALF. Togaviruses, paramyoviruses, herpes simplex virus, SEN virus, and many others have been associated with ALF.5–7 However, after an initial report or two, most of these observations have generally not been reproduced.8 Some authors have even questioned the likelihood of a viral etiology of indeterminate ALF given that most patients have no parenteral risk factors, there have been no source outbreaks, and convincing descriptions of post-transplant recurrence are quite rare.9 On the other hand, aplastic anemia, which may occur following otherwise successful liver transplant for indeterminate ALF, represents a relatively unique feature associated with indeterminate ALF, particularly in young patients, and raises suspicion of a viral etiology.10

Against this controversial backdrop, the study by Cacheux et al. describes two young women with ALF that the investigators attribute to infection with human herpes virus 6 (HHV-6). Both women underwent an impressively thorough evaluation for other causes of liver disease, including testing for conventional hepatitis (A to E) viruses as well as Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV), serologies for autoimmune hepatitis, and testing for Wilson disease, all of which was unrevealing. Neither patient took medications, herbal products, used alcohol or illicit drugs. Clinically, both women also had a slowly evolving viral syndrome, in one case associated with persistent fever, prior to the diagnosis of liver injury. Both patients had serological evidence of HHV-6 infection, a virus linked to indeterminate ALF in prior reports, and one even appeared to have acute seroconversion. Liver but not serum in each patient also had detectable HHV-6 DNA. One patient required an urgent liver transplant, while the other appeared to clinically respond, albeit slowly, to valgancyclovir treatment which is potentially active against HHV-6 infection.

HHV-6 is a member of the β-herpesviruses that has two distinct variants, A and B. Although it can infect epithelial and other cell types, HHV-6 is T-lymphotropic. HHV-6B appears to cause exanthem subitum (roseola infantum or sixth disease), a febrile illness of early childhood characterized by rash and occasionally seizures.11 The seroprevalence of HHV-6 is very high, approaching 100% even in children, and following initial infection, HHV-6 persists for life and is shed in saliva. Interestingly, HHV-6 appears to be capable of site-specific chromosomal integration and may thus be inherited.12 Although HHV-6 infection is usually asymptomatic, HHV-6 has been associated with a wide variety of diseases, including encephalitis, multiple sclerosis, chronic fatigue, and hepatitis, but establishing causality is challenging because of the very high prevalence of infection in the population.13

Liver disease attributed to HHV-6 infection has been intermittently reported since the late 1980s, soon after discovery of the virus.14–16 However, since HHV-6 can be detected in the blood of approximately 70% of hospitalized patients with a variety of debilitating conditions, these reports have appropriately been viewed with skepticism.17 More recently, Harma et al. found HHV-6 antigens in the explant livers of 12 of 15 (80%) of the patients transplanted at their center with indeterminate ALF, but they also detected these antigens in a significant number [4 of 17 (24%)] of patients with ALF of known cause.18 Furthermore, HHV-6 antigens were detected primarily in lymphocytes and other inflammatory cells rather than hepatocytes in most of these patients. Nonetheless, the authors subsequently reported that half of the patients with pretransplant HHV-6 infection in their initial study developed some evidence of posttransplant infection with hepatic histology consistent with viral infection in most cases.19

The hunt for novel viruses that may cause indeterminate ALF will undoubtedly benefit from microarray technology that has already been a boon to viral discovery in other fields, including bioterrorism detection. One recently developed microarray, the so-called “Virochip”, contains more than 20,000 conserved gene sequences (oligonucleotides) from all known human, animal, plant, and microbial viruses.20, 21 This microarray has recently been used to identify a virus associated with prostate cancer tissue as well as to assist in the identification of the novel virus that causes severe acute respiratory syndrome (SARS) from respiratory secretions.22, 23 Such a platform should facilitate an unbiased search for both seronegative but known viruses as well as novel viruses associated with ALF of indeterminate cause. Of course, once a virus is identified, establishing a causal link between the virus and the disease is the next and often more difficult step, as the situation with HHV-6 and indeterminate ALF illustrates.

The report by Cacheux et al., as well as prior reports, have clearly established an association between HHV-6 and indeterminate ALF, but have they established causation? Establishing such a causal link is very difficult because of the ubiquitous nature of HHV-6 infection; in the vast majority of infected individuals, HHV-6 appears to be a harmless commensal. If HHV-6 infection causes severe liver injury, why don't more infected patients develop ALF? It is likely that most hepatologists will take a deeply jaundiced view of any claims alleging that such a ubiquitous viral infection causes the very rare syndrome of indeterminate ALF. Perhaps we should view HHV-6–associated ALF as we do idiosyncratic drug reactions; only very rare individuals develop severe liver injury in association viral infection because of uncommon and currently poorly understood characteristics, both genetic and environmental, that are unique to the individual. However, if this analogy is correct, establishing causality between HHV-6 infection and the development of ALF will be very challenging.

Clearly, more studies are needed to define the role of HHV-6 in the pathogenesis of ALF. I completely concur with the authors that a rigorous search for HHV-6 in cases of indeterminate ALF, particularly if clinical features of viral infection are present, is appropriate in the context of research studies such as the multicenter ALFSG. Indeed, only through carefully controlled studies on blood and liver tissue with appropriate molecular techniques will we define the etiologies underlying indeterminate ALF, lift the shroud of mystery surrounding this enigmatic syndrome, and hopefully develop rational and effective medical therapies in the future.


The author thanks Sadie O. McFarlane for drawing Fig. 1.