Review Article

Visc Med 2016;32:80–85 Published online: April 7, 2016

DOI: 10.1159/000444915

Liver Failure due to Acute Viral Hepatitis (A–E)

Paul Manka a, b, c Jens Verheyen d Guido Gerken a Ali Canbay a
a
Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany;
b
Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK;
c Division of Transplantation Immunology and Mucosal Biology, King’s College, London, UK;
d Institute of Virology, University Hospital, University Duisburg-Essen, Essen, Germany

Keywords Introduction
Viral hepatitis · Acute liver failure · Hepatitis E virus ·
Hepatitis B virus reactivation Acute liver failure (ALF) is a devastating clinical syndrome as-
sociated with high mortality in the absence of immediate state-of-
Summary the-art intensive care, specific treatment, or liver transplantation. It
Background: Viral hepatitis is still one of the key causes is partly accompanied by the onset of hepatic encephalopathy
of acute liver failure (ALF) in the world. Methods: A se- within 8 weeks of the first symptoms [1]. The American Associa-
lective literature search of the PubMed database was tion for the Study of Liver Disease (AASLD) position paper recom-
conducted, including current studies, reviews, meta- mends that all patients with clinical or laboratory evidence of acute
analyses, and guidelines. We obtained an overview of hepatitis should have immediate measurement of prothrombin
ALF due to viral hepatitis in terms of epidemiology, time and careful evaluation for subtle alterations in mentation [2].
course, and treatment options. Results: Most fulminant The most widely accepted definition proposed by the AASLD in-
viral courses are reported after infection with hepatitis A, cludes evidence of coagulopathy (international normalized ratio ˰
B, and B/D, but not with hepatitis C. Hepatitis E is also 1.5) and presence of an altered sensorium (encephalopathy) with-
known to cause ALF but has not gained much attention out pre-existing cirrhosis and with duration of symptoms of less
in recent years. However, more and more autochtho- than 26 weeks [3]. For patients meeting this definition, hospital ad-
nous hepatitis E virus infections have been recently ob- mission, ideally to a transplant center, is mandatory [2].
served in Europe. Reactivation of hepatitis B virus (HBV) ALF can occur as a result of various etiologies (overdosing with
under immunosuppressive conditions, such as after in- acetaminophen or other drugs, viral hepatitis, ischemia, and other
tensive chemotherapy, is also an increasing problem. causes). When ALF is not fatal, the liver has a unique capacity to
For most viral-induced cases of ALF, liver transplantation recover completely, although reliably predicting mortality remains
represented the only therapeutic option in the past. challenging [4, 5].
Today, immediate treatment of HBV-induced ALF with
nucleotide or nucleoside analogs is well tolerated and
beneficially affects the course of the disease. Conclusion: Causes and Epidemiology
Although numbers in Western European countries are
decreasing rapidly, reliable diagnostic screening for hep- ALF is a rare disease especially in the developed world [3]. The
atitis A–E is necessary to identify the etiology and to de- causes of ALF are heterogeneous and may vary from country to
termine those most at risk of developing ALF. country. Traditionally, hepatitis B was regarded as the most com-
© 2016 S. Karger GmbH, Freiburg mon cause of ALF [6]. Over the last decade, statistics suggest a
change in ALF etiology in developed countries. According to the
United States ALF Group Registry statistics, drug-induced liver in-
jury (DILI), including acetaminophen and idiosyncratic related eti-
ologies, is responsible for more than 50% of cases, followed by in-

© 2016 S. Karger GmbH, Freiburg Prof. Dr. med. Ali Canbay

2297–4725/16/0322–0080$39.50/0 Klinik für Gastroenterologie und Hepatologie
Fax +49 761 4 52 07 14 Universitätsklinik Essen
[email protected] Accessible online at: Hufelandstraße 55, 45122 Essen, Germany
www.karger.com www.karger.com/vis ali.canbay @ uni-due.de
Fig. 1. Causes of ALF worldwide. *Others include non-A–E viral hepatitis; **no discrimination between acetaminophen and idiosyncratic drug injury [3, 11, 17,
71–76].

determinate causes (14%), hepatitis B (7.7%), and autoimmune primary ALF. In contrast to findings in the USA and the UK, idio-
hepatitis (5.9%), followed by less common causes including is- syncratic drug injuries, rather than acetaminophen, are most com-
chemia, Wilson’s disease, Budd-Chiari syndrome, and pregnancy- monly related to DILI. Additionally, hepatitis B, with 18% of all
related liver failure (e.g. HELLP syndrome) [7, 8]. Statistics from cases, still plays a major role in etiology. The substantial proportion
Northern European countries and the UK stand in line with statis- of unknown cases and the fact that the diagnosis of idiosyncratic
tics from the USA [3, 9]. Reasons for the decline in viral-related liver injury is based on the exclusion of other diagnoses leaves the
cases of ALF range from successful vaccination programs over im- question open whether other etiologies might be overlooked [17].
proved control of blood products to a more health-educated soci- Indeed, we could prove recently that a reasonable number of pa-
ety [10]. However, statistics from Southern Europe are contrary tients with ALF might be related to unappreciated hepatitis E infec-
where viral hepatitis still is a main cause of ALF [11, 12]. Therefore tions. Figure 1 provides an overview of the causes of ALF world-
we can assume a north-south gradient within Europe. Predictions wide [18].
for Eastern Europe will become more sophisticated as statistics
with reasonable numbers of patients are reported. As most of those
infected with hepatitis B virus (HBV) in the European region live Hepatotropic Viruses
in Eastern European countries [13, 14], a severe impact in the role
of ALF is likely. Hepatitis A
Bernal and Wendon [3] assume that, globally, hepatitis E and A Hepatitis A virus (HAV) can cause liver disease that ranges
infections are probably responsible for the majority of ALF cases. from mild to severe illness but does not cause chronic liver disease.
This can be related to high incidence in some Asian countries. In It is usually transmitted through ingestion of contaminated food
India, for example, one study reported that 44% of ALF cases were and water or through direct contact with infectious persons. Thus,
related to hepatitis E virus (HEV) infection. Similar results were the risk is higher in areas with a lack of safe water and poor sanita-
obtained in Bangladesh [15, 16]. tion. Transmission by blood transfusion is rare; however, polymer-
In Germany, findings can be categorized alongside recent devel- ase chain reaction (PCR) testing for blood donors is recommended.
opments in Europe. Drug toxicity appears to be the major cause of Measures to improve these issues as well as vaccination are known

Liver Failure due to Acute Viral Hepatitis (A–E) Visc Med 2016;32:80–85 81
to be most effective to combat the disease. Usually most patients Table 1. Initial laboratory tests to perform in the initial evaluation of ALF
make a full recovery from hepatitis A [19]. Unfortunately, a small (HAV, HBV, HEV) [2, 18]
proportion of infected patients develop a fulminant hepatitis with a HAV IgM antibody to HAV (IgM anti-HAV)
high mortality rate. The World Health Organization (WHO) cal- HBV hepatitis B surface antigen (HBsAg)
culates that 1.4 million people become infected with HAV each IgM antibody to hepatitis B core (IgM anti-HBc)
year [20, 21]. HBV DNA PCR
HEV IgG and IgM antibody to HEV (IgG/IgM anti-HEV)
In Germany, 681 cases of hepatitis A were reported to the Rob- HEV RNA PCR
ert Koch Institute (RKI) in 2014. This is the lowest rate since 2001,
and the prevalence dropped to 0.8/100,000 inhabitants. Most of the
patients acquired their infection within Germany (63%) [22].
Less than 1% of acute HAV infections result in ALF [20]. Young drugs; medical, surgical, and dental procedures; tattooing; and the
children generally belong to the group of patients with unapparent use of razors and similar objects that are contaminated with in-
or subclinical hepatitis and have no symptoms or jaundice [23]. In fected blood [32, 33].
contrast, the infection is more severe in adults, with symptoms oc- In Germany, the hepatitis B surface antigen (HBsAg) prevalence
curring in 70%. Generally, hepatitis A-related ALF has a spontane- is less than 1%. In 2014, the RKI reported 755 new infections (0.9
ous survival rate of 69%; the remaining 31% require emergency cases per 100,000 inhabitants). A rise in infection rates has been es-
liver transplant (ELT) or die [24]. Furthermore, patients with pre- pecially observed in metropolitan regions. However, rates in some
existing liver damage such as non-alcoholic fatty liver disease Asian, African, and Eastern European parts are much higher [22].
(NAFLD) or alcoholic steatohepatitis (ASH) are more susceptible In adults, hepatitis B infection is usually asymptomatic. Young
to develop an acute-on-chronic liver failure in cases of HAV infec- children are most likely to develop a chronic infection whereas in
tion [25]. adults, less than 5% of otherwise healthy persons who get infected
The reasons why HAV infection may progress infrequently to will develop chronic infection [34]. According to the WHO, one
ALF are poorly understood. Underlying host factors such as age quarter of the world’s population (2 billion) is estimated to have
and even minor pre-existing liver damage may play a role [26, 27]. experienced HBV infection and 3% (240 million) are chronically
Moreover, viral factors including low viral load and a higher rate of infected with hepatitis B [35]. About 1% of persons with acute hep-
substitutions in the 5' untranslated region of the viral genome are atitis develop ALF, which can be regarded as a more atypical course
also thought to increase the likelihood of a fulminant course [28, of acute hepatitis [36]. However, in a fulminant course, HBV DNA
29]. Investigations to find a clear difference in genomic sequences and HBsAg levels often fall rapidly as liver failure develops; thus,
between patients with fulminant courses of HAV and those with a some patients are HBsAg-negative by the time of onset of hepatic
minor course did not lead to clear results [30]. In contrast, there is coma [37]. Therefore, a transfer to a specialized unit and accurate
some evidence that cytolytic T cells may play an important role in testing are crucial (table 1). Reasons why some patients develop a
the pathogenesis of HAV infection and in determining the course fulminant course in comparison to others are not well investigated.
[31]. The declining incidence of HAV infection in developed coun- Simultaneous intake of alcohol, acetaminophen, or methampheta-
tries makes it unlikely that great efforts will be taken to target this mines may play a role [38]. In addition, HBV genotype might affect
problem in the near future. the outcome. In one study comparing the genotypes of chronic
Specific diagnosis can be made by the detection of HAV-specific HBV patients to cases with HBV-related ALF, the latter showed a
immunoglobulin (Ig) M and IgG antibodies in serum. Additional higher prevalence of genotype D [39].
tests may include reverse transcription PCR (RT-PCR) to detect The mechanisms whereby HBV induces ALF are not well
the viral RNA. There is currently no specific treatment. With acute known. There are several studies showing that HBV core promoter
hepatitis A, as with many other etiologies of ALF, care is mainly mutations have been implicated in the pathogenesis of fulminant
supportive (according to the AASLD guidelines), and if recovery is hepatitis B. A common hallmark of these mutations is a phenotype
unlikely, liver transplantation should be considered [2]. Data for of enhanced viral replication. It is common in patients with a more
outcomes after transplantation is not available. aggressive course such as fulminant hepatitis but also in chronic
hepatitis. Enhanced viral replication may result in a stronger im-
Hepatitis B mune response and extended infection. Consequently, this could
Hepatitis B is a viral infection caused by the HBV and can lead be an important factor in driving the disease towards a fulminant
to both acute and chronic liver disease. HBV is a DNA virus and a course. Moreover, there is also evidence that at least some mutated
member of the Hepadnaviridae family that is transmitted through variants may induce apoptosis in hepatocytes [40, 41]. Further-
contact with blood or other body fluids of an infected person. In more, it is worthwhile mentioning that patients with underlying
highly endemic areas, hepatitis B is most commonly spread from chronic liver disease are more susceptible to develop acute-on-
mother to child at birth (perinatal transmission). In industrialized chronic liver failure if infected with certain mutants [42]. However,
countries, hepatitis B is mostly spread by sexual transmission. since patients with fulminant hepatitis exhibit different phenotypes
Other modes of transmission include the reuse of needles and sy- so that a highly replicative phenotype is not exclusive, additional
ringes either in healthcare settings or among persons who inject mechanisms must be involved.

82 Visc Med 2016;32:80–85 Manka/Verheyen/Gerken/Canbay

 Another possible factor with major impact in HBV-related ALF Hepatitis D
could be the overwhelming activation of humoral immunity. A Hepatitis D virus (HDV) can be regarded as an altered RNA
massive accumulation of plasma cells secreting IgG and IgM and virus as it is dependent on the coexistence of HBV. The virus con-
complement components were found in necrotic areas in livers of sists of only one protein, a circular RNA strand, i.e. the actual hep-
HBV-related ALF. Furthermore, these antibodies were found to atitis D antigen. It requires the HBsAg for the encapsidation of its
target hepatitis B core antigen (HBcAg) [43]. How relevant these own genome. It is further dependent on the sharing of envelope
results are for HBV-related ALF and underlying mechanisms needs proteins to facilitate the assembly of the HDV genome into new
further investigation, as this particular study has been performed virus particles. Apart from that, the replication of the circular RNA
with only 2 patients. is independent of HBV [51, 52].
The incidence of reactivation of previously stable subclinical in- In Germany, 17 cases of hepatitis D were reported to the RKI in
fection with HBV without a manifestation of chronic disease char- 2014 [22]. Hepatitis D coinfection may occur in conjunction with
acteristics is steadily rising. This is related to patients with treat- acute hepatitis B. In this case, the rate of hepatitis B to progress to
ment-induced immunosuppression during or after cancer therapy. ALF approaches 20%. In addition, HDV superinfection of a
Therefore, identification of patients at high risk as well as the use of chronic HBV patient can also result in ALF [53]. Although there is
prophylaxis is crucial [44]. High disease activity usually leads to no specific therapy for hepatitis D infection, diagnosis is impor-
clinical and serological resolution. However, even after serological tant, as the disease follows a characteristic biphasic pattern in
resolution, small amounts of covalently closed circular DNA (ccc- which initial recovery is followed by clinical deterioration.
DNA) persist in the liver for years, decades, and possibly for the
lifetime. T cell immunity suppresses viral replication from these ccc- Hepatitis E
DNA copies to very low levels [45]. Mutations in the HBV genome, Approximately 20–40% of ALF cases are caused by HEV infec-
immunosuppressive therapy, and viral- or drug-induced injury are tions in developing countries. However, in western countries, liver
common causes of reactivation. Fulminant hepatic failure in the failure caused by hepatitis E has only been recently regarded as an
setting of HBV reactivation has a much higher morbidity and imported infection. In line with this opinion, data from surveys
mortality rate than de novo fulminant hepatitis [46]. The AASLD based on population from the USA showed hepatitis E as a rare
recommends that patients found to be positive for HBsAg who are cause of ALF [54]. However, recent studies showed HEV seroprev-
to begin such a therapy should be treated prophylactically with a alence rates between 16 and 20% among adults in industrialized
nucleoside analog and that it should be continued for 6 months countries [55–57]. Nevertheless, these numbers should be inter-
after completion of immunosuppressive therapy. Moreover, the preted with caution as results may be influenced by serological
American Gastroenterological Association recommends in their assay discrepancies. Despite these inter-assay variations, there is
guidelines to offer HBsAg-negative but anti-HBc-positive patients some evidence of autochthonous HEV, particularly genotype 3,
a prophylactic therapy if treated with B-cell-depleting agents being endemic to Europe [58, 59].
(eg. rituximab) [47]. In contrast to ALF, a study by Davern et al. [60] from 2013
The prognosis of HBV-related ALF is generally limited without showed that in a US multicenter study 9 (3%) patients of 318 cases
liver transplantation. Transplant-free survival rates range from 26 of suspected DILI were misdiagnosed. After reassessment these
to 53% [48]. Hepatitis serological testing should be done for identi- cases were considered more likely to be hepatitis E-related [60].
fication of acute viral infection. This should also be performed in This study is supported by another study, which showed that 22.2%
case another putative etiology has been identified [2]. of patients diagnosed with autochthonous hepatitis E were initially
To date, there is not enough evidence that artificial liver support thought to have DILI prior to HEV testing. Moreover, the investi-
devices can enhance the patient’s survival. In contrast, there is first gators could demonstrate that 21.4% of patients with criterion-ref-
evidence that initial antiviral therapy could be beneficial. Jochum erenced DILI had autochthonous hepatitis E after the reassessment
et al. [49] could show that immediate treatment of HBV-induced of stored serum with HEV testing [61]. These studies underline
ALF with drugs such as entecavir is well tolerated and beneficially that a structured assessment of medical history can be difficult.
affects the course of the disease. Therefore, the AASLD recom- Therefore, it is necessary for western clinicians to take HEV into
mends to take nucleos(t)ide analogs into consideration as a possi- account as a cause of liver disease when making their treatment
ble treatment option for hepatitis B ALF as well as for the preven- assessments.
tion of post-transplant recurrence [2]. Indeed, this should also be the case in the setting of ALF. Con-
trary to results from the USA, one retrospective study from Ger-
Hepatitis C many suggests that hepatitis E contributes to a substantial propor-
Although controversial, currently there is no evidence that hep- tion of acute liver injury cases in developed countries [60, 62]. In a
atitis C alone appears to cause ALF. However, an acute hepatitis C retrospective analysis of 80 ALF cases, 8 of these cases have been
is able to induce hepatic damage and a severe increase of transami- detected to be potentially hepatitis E-related, suggesting that HEV
nases. Nevertheless, this does happen without altered synthesis testing is necessary in every case of ALF. Moreover, this study sug-
function [50]. gests that it is necessary to perform both serological testing and
RNA testing as well [18].

Liver Failure due to Acute Viral Hepatitis (A–E) Visc Med 2016;32:80–85 83
 In immunocompetent patients, HEV infection usually takes an Considering all of the above, the question arises whether antivi-
asymptomatic course [63]. In contrast to descriptions of a higher ral therapies might be effective against HEV-related ALF. There is
incidence of chronic hepatitis E in immunocompromised patients, only little evidence for the use of pegylated interferon alpha and
two case reports of acute hepatitis E claim that steroids may pre- ribavirin to treat chronic HEV infection [67–69]. Ribavirin also
vent the progress of acute hepatitis E during ALF [64, 65]. Further seems to be a possible treatment option in acute hepatitis [67]. De-
studies are needed to evaluate whether steroid treatment has a sup- scriptions of treatment in ALF are rare although there are occa-
portive role in hepatitis E-related acute liver injury. However, pa- sional reports of successful treatment in acute-on-chronic liver
tients with underlying liver disease as well as the elderly are more failure [70]. Further trials must be conducted to clarify the need
likely to show a more dramatic ALF course [62]. and benefit of any antiviral treatment.
There is little known about the impact of acute infections and
the likelihood of exacerbation to fulminant liver injury in the set-
ting of immunosuppression and hematopoietic stem cell trans- Disclosure Statement
plantation (HSCT). Recently, a fatal outcome of autochthonous
The authors have nothing to disclose.
hepatitis E in a patient with B-cell lymphoma in France has been
reported [66]. However, contrary to HBV, descriptions of fulmi-
nant courses in hematological malignancies are rare.

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