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Liver International ISSN 1478-3223

REVIEW ARTICLE

Management of acute hepatitis B and reactivation of hepatitis B


Ankur Jindal, Manoj Kumar and Shiv K. Sarin
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India

Keywords
Acute hepatitis B Chronic hepatitis B
Hepatitis B reactivation Antiviral drugs
Fulminant hepatitis Hepatitis are
Abbreviations
ACLR, acute-on-chronic liver failure; ALF,
acute liver failure; AVH-B, acute hepatitis B;
CHB, chronic hepatitis B; ESR1, oestrogen
receptor alpha; GCSF, granulocyte-colony
stimulating factor; HAV, hepatitis A virus;
HBV, hepatitis B virus; HCV, hepatitis C virus;
HDV, hepatitis delta virus; HEV, hepatitis E
virus; HIV, human immunodeciency virus;
NNRTI, non-nucleoside reverse transcriptase
inhibitors; WHV woodchuck hepatitis virus.
Correspondence
Dr S K Sarin, MD, DM, Senior Professor,
Hepatology, Institute of Liver & Biliary
Sciences (ILBS), New Delhi, India
Tel: +91 11 4630 0000
Fax: +91 11 2612 3504
e-mail: shivsarin@gmail.com

Abstract
The natural course of hepatitis B virus infection and the resulting hepatic
injury is determined by the degree of virus replication and the intensity of
host immune response. Upon exposure to hepatitis B virus (HBV), individuals with a vigorous and broad immune response develop acute self-limited
infection, which may result in acute hepatitis. However, with stringent testing for HBV and universal precautions, acute HBV is rather rare. Reactivation of HBV most often presents as acute hepatitis B (AVH-B) and clinically,
it is difcult to differentiate AVH-B from reactivation of chronic hepatitis B
(CHB) and it requires a high index of suspicion. In the presence of high
HBV DNA (>2 9 104 IU/ml) underlying liver disease should be investigated
by liver biopsy, endoscopy and/or imaging. The degree of liver failure often
depends on the severity of acute insult and the stage of underlying chronic
liver disease. Mutations in the HBV genome, immunosuppressive therapy
and viral or drug induced injury are common causes of reactivation. As most
patients with AVH-B resolve the infection spontaneously, antiviral therapy is
not indicated in them. However, the use of a potent oral nucleoside(tide)
analogue is necessary as soon as possible in patients with CHB reactivation.
Liver transplantation should be considered in patients who develop liver failure secondary to severe acute exacerbation. If this is not feasible, supportive
therapy with the addition of granulocyte colony stimulating factor (GCSF)
therapy could be benecial.

DOI:10.1111/liv.12081

Hepatitis B virus (HBV) infection is the tenth leading


cause of death worldwide (1). Almost 30% of the world
population has been exposed to HBV and an estimated
400 million of these are chronically infected (2). The
natural course of HBV infection is determined by the
interplay between viral replication and the host
immune response. Upon exposure to HBV, individuals
with a vigorous and broad immune response to the
virus develop an acute self-limited infection, which
may result in acute hepatitis. An aberrant response can
lead to fulminant hepatitis. Individuals who do not
have a broad and vigorous immune response do not
clear the virus, but develop persistent chronic hepatitis
B virus. The virus persists in the body even after serological recovery from acute hepatitis B; therefore, individuals who have been exposed to HBV are at risk for
reactivation [are or exacerbation] of hepatitis when
an immune imbalance occurs (3). The severity of the
are depends on the state of underlying liver disease.
As patients with severe acute exacerbation of chronic
hepatitis B may not have underlying cirrhosis, they
may recover to relatively normal liver function in contrast to those with end-stage cirrhosis. It is therefore

164

important to recognize this clinical presentation of


chronic hepatitis B.
Although there is no consensus denition of reactivation [are or exacerbation] of hepatitis B is characterized by sudden elevation of serum ALT levels. It usually
refers to an abrupt increase in serum ALT to >5
10 times the upper limit of normal or >3 times the
baseline level (4). Reactivation of hepatitis in chronic
HBV-infected patients is common and may be caused
by a number of factors (Table 1). Reactivation of hepatitis B virus (HBV) replication is a sudden increase or
reappearance of serum HBV DNA in a patient with
chronic or past HBV infection (5).
This review will focus on management of acute hepatitis B and reactivation of hepatitis B (are or exacerbation) spontaneous or that owing to superimposed
hepatotropic viruses.
Acute hepatitis B

During acute hepatitis B, manifestations range from


subclinical or anicteric hepatitis to icteric and, in some
cases, fulminant hepatitis.

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Table 1. Causes of reactivation [are or exacerabation] of hepatitis
in chronic hepatitis B virus infected patients
Reactivation (are or exacerbation) of hepatitis B
Caused by immunosuppressive medications
Cancer chemotherapy
Antirejection drugs
Corticosteroids
Caused by antiviral therapy
Interferon
Nucleoside analogues
Corticosteroid withdrawal
Caused by superimposed infections with other hepatotropic viruses
Hepatitis A/E virus
Hepatitis C virus
Hepatitis delta virus
Caused by interaction with HIV infection
Reactivated hepatitis
Effect of immune reconstitution therapy

Approximately 70% of patients with acute hepatitis B


have subclinical or anicteric hepatitis. The average incubation period is 75 days (range 40140 days). The onset
of hepatitis B is typically insidious, with nonspecic
symptoms of malaise, poor appetite, nausea and pain in
the right upper quadrant. During the icteric phase, fatigue and anorexia usually worsen. Jaundice can last from
a few days to several months, but usually 23 weeks.
Itching and pale stools may occur. The convalescent
phase begins with the resolution of jaundice.
The physical signs of typical acute hepatitis B may
include variable degrees of jaundice, mild and slightly
tender hepatomegaly and mild enlargement of spleen
and lymph nodes.
Pathogenesis

An incubation phase lasting weeks or months with


increasing and nally very high viraemia, but without
clinical or biochemical signs of liver damage shows that
replication and persistance of HBV is not cytopathic per se.
Analysis of the hepatocellular expression patterns in
acutely HBV-infected chimpanzees showed that no host
response to viral replication occurred during the incubation phase. HBV infection is a stealth virus infection
that does not stimulate the innate immune system,
which recognizes pathogen-associated molecular patterns (6). In contrast, later during infection, most of the
effector molecules associated with the adaptive cellular
immune response are induced, followed by HBV antibodies. HBV elimination starts several weeks before the
onset of the disease with T-cell-dependent noncytolytic
mechanisms, but later cytolytic immune responses follow and generate the symptoms of acute hepatitis (7).
During acute disease, high numbers of cytolytic CD8
(+) cells are present in the liver and they react with a
multitude of HBV epitopes and eliminate the virus by
destroying infected cells. The increased level of arginase
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Acute hepatitis B

in patients with acute hepatitis B suppresses the functions of activated CD8 (+) T cells. This mechanism
might limit the amount of liver damage caused by activated CD8 (+) T cells in patients with acute HBV infection (8).
A recent study compared the intrahepatic transcriptional proles of neonatal woodchucks with self-limiting
woodchuck hepatitis virus (WHV) infection to woodchucks progressing to persistent WHV infection. Instead
of early-acute stage (8 weeks) gene expression, a midacute phase (14 weeks) expression was seen and resolution was associated with induction of a prominent
cytotoxic T cell signature (9).
The CD4(+) Foxp3(+) regulatory T cells (Tregs) mitigate immunomediated liver damage by down-regulating the antiviral activity of effector T cells but do not
inuence development of HBV-specic CD8 T cells or
development of memory T cells. They may contribute to
conservation of tissue integrity and organ function at
the cost of prolonging virus clearance (10).
We have shown that CD4 + Tregs were more abundant and there was a higher expression of CCR1, CCR3,
CCR4, CCR5 and CCR8 in patients with AVH-B. Effector T cells with a potential role in necro-inammation
accumulate during the acute infeciton and subsequent
down-regulation occurs by T regulatory cells, favouring
viral persistence during chronic infection (11).
High disease activity usually leads to clinical and
serological resolution. However, even after serological
resolution, small amounts of cccDNA persist in the liver
for years, decades and possibly for life. T-cell immunity
suppresses viral replication originating from these
cccDNA copies to very low levels (12). Anti-HBs is
formed during convalescence and later stage may
enhance opsonization of HBsAg and block de novo
infection of hepatocytes by released HBV. In contrast to
the other HBV antibodies, anti-HBc induction is partially T-cell independent. This explains the presence of
anti-HBc even in those patients who do not build up an
efcient immune response. Serological resolution is
dened by disappearance of HBsAg, which may take
months after onset.
Diagnosis

The main differential diagnosis of HBsAg-positive acute


hepatitis is reactivation of hepatitis in CHB virus
patients.
Laboratory testing during the acute phase of acute
hepatitis B reveals elevated alanine and aspartate aminotransferase levels (ALT and AST). Values up to 1000
2000 IU/l are seen during the acute phase with ALT
higher than AST. Serum alkaline phosphatase and lactic
dehydrogenase are usually only mildly elevated (less
than three-fold). Bilirubin is variably increased, in both
direct and indirect fractions. Serum bilirubin concentrations may be normal in patients with anicteric hepatitis.
Serum albumin decreases especially in protracted severe

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Jindal et al.

Acute hepatitis B

hepatitis. The prothrombin time can increase and is the


most reliable marker of severity and prognosis. In
patients who recover, normalization of serum aminotransferases usually occurs within 14 months. Persistently elevated serum ALT for more than 6 months may
indicate progression to chronic hepatitis. Various autoantibodies can appear during acute hepatitis B, most
smooth muscle.
The diagnosis of acute hepatitis B is based on the
detection of HBsAg and IgM anti-HBc. During the initial phase, markers of HBV replication, HBeAg and
HBV DNA, are present. Resolution of infection is
accompanied by the disappearance of HBV DNA,
HBeAg to anti-HBe seroconversion and then HBsAg to
anti-HBs seroconversion. As acute hepatitis B resolves,
anti-HBe appears after anti-HBc, but before anti-HBs. It
usually disappears earlier than anti-HBs.
Patients rarely present during the window period
when HBsAg has become negative, but anti-HBs is not
yet positive. In this setting, which is more common in
patients with fulminant hepatitis B with rapid clearance,
IgM anti-HBc is the sole marker of acute HBV infection.
During acute infection, HBsAg concentrations rise
exponentially for weeks to months from undetectable to
typical nal concentrations of 10 000100 000 ng/ml
with 24 days of doubling time (13). If acute HBV is
resolved, HBsAg decreases with an initial half-life of
8 days until it has been disappeared completely from
serum after weeks to months. In about 25% of cases of
acute resolving hepatitis B, HBsAg disappears much faster, so that samples taken in the late acute phase may be
HBsAg negative (14). A decrease in HBsAg concentrations by more than 50% within the rst 4 weeks indicates
resolving acute infection in >95% of cases (15). Hence,
quantitative analysis of highly concentrated HBsAg is an
excellent prognostic marker, indicating progression to
chronicity if the values remain stable or increase.
Anti-HBc immunoglobulin [IgM anti-HBc] may be
useful in two situations: (a) to distinguish acute hepatitis caused by HBV from a hepatitis of different aetiology
in a patient with chronic HBV infection; and (b) to
identify acute hepatitis in some hepatitis B patients, particularly those with fulminant hepatitis B or HDV coinfection, where HBsAg may have been eliminated very
rapidly. Predominant TH1 immune response in AVH-B
favours cell-mediating viral clearance, whereas TH2
mediated immune response in CHB favours antibody
production. HBV antigens elicit immune mediated liver
injury in a dose-dependent manner; therefore, low viral
antigen load and subsequent resolution of infection in
AVH-B compared to persistent viral antigenaemia in
CHB leads to signicantly increased production of
HBV-specic antibodies (anti-HBe and anti-HBc) in
CHB or exacerbation compared to AVH-B (16, 17).
Tests should be quantitative because anti-HBc IgM is
also positive in chronic hepatitis B and during convalescence. Levels >600 PaulEhrlich units/mL or IgM antiHBc (>1:1000) suggest an acute HBV infection with

166

high inammatory activity (18, 19). In all other situations, concentrations are lower or undetectable. In one
Greek study (20), low molecular weight (78S) IgM
anti-HBc was observed more frequently in HDV superinfection and was related to low mortality. On the other
hand, 19S IgM anti-HBc was observed more frequently
in spontaneous reactivation of chronic hepatitis B and
was related to a high mortality.
Outcome of acute hepatitis B

Fulminant hepatitis B is an atypical course for acute hepatitis B infection, occurring in less than 1% of icteric cases.
Typically, in fulminant disease, HBV DNA and HBeAg
become undetectable as hepatic failure supervenes. The
reasons that HBV has a fulminant course in some patients
are not well-understood. A case-control trial evaluated risk
factors for a fulminant course in an outbreak among injection drug users. Compared with control patients, case
patients were more likely to have used acetaminophen
during their illness (P = 0.08), used more alcohol and
methamphetamine, and lost more weight in the six
months before illness. Furthermore, all nine isolates were
genotype D (21).
A more comprehensive study by the US Acute Liver
Failure Study Group comparing 34 patients with HBVrelated acute liver failure with a cohort of 530 patients
with chronic HBV infection showed a higher prevalence
of genotype D in the acute liver failure group (32% vs.
16%) even after matching for race and HBeAg status
(22). These results indicate that HBV genotypes may
play a role in the outcome of acute infection.
Prole and pattern of HBV mutations and their relevance

Precore and core promoter variants have been described


in association with fulminant hepatitis (23, 24). It has
been suggested that these variants result in a fulminant
course because of enhanced HBV replication or a more
aggressive immune response (25). The mechanism by
which precore variants cause fulminant hepatitis in the
new host, but an inactive liver disease in the original
host remains unclear.
In a recent report from Japan, higher HBV DNA levels, subgenotypes B1/Bj, A1762T/G1764A, G1896A,
G1899A and A2339G mutations were signicantly more
frequent in fulminant hepatitis B than in nonfulminant
AVH-B. In multivariate analysis, G1896A mutations,
serum HBV DNA (>5.23 log copies/ml) and total bilirubin (>10.35 mg/ml) were independently associated with
a fulminant outcome by AVH-B (26). Subgenotypes B1/
Bj HBV(HBV/B1) are known to frequently cause ALF in
Japan. T1961V/C1962D mutations, which lead to S21
substitution in the core protein were found frequently
in fulminant hepatitis B and may play important roles
in the development of fulminant hepatitis B (27).
Because of the increased use of lamivudine (28),
AVH-B caused by lamivudine-resistant strains is being
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described. In one study from China, lamivudine-resistant mutations identied using direct PCR sequencing
were found in 11 of the 234 (4.7%) AVH-B patients.
Two patients infected with viruses with lamivudineresistant mutations developed severe acute hepatitis,
whereas one patient developed CHB (29).
Traces of HBV are often detectable in the blood using
PCR for many years after a clinical recovery of acute
hepatitis, despite the presence of serum antibodies and
HBV-specic cytotoxic T cells, which can be present at
high levels. Persistent histological abnormalities (including brosis and mild inammation) were present as
many as 10 years in another series in nine patients with
a complete serological recovery after acute infection
(30). These observations suggest that eradication of HBV
rarely occurs after recovery from acute HBV infection
and that latent infection can maintain the T cell response
for decades following clinical recovery, thus keeping
the virus under control. Immunosuppression in these
patients can lead to reactivation of the virus.
The rate of progression from acute to chronic hepatitis B is mainly determined by the age at infection. The
rate is approximately 90 per cent for a perinatally
acquired infection, 2050 per cent for infections
between the age of 1 and 5 years old and less than 5 per
cent for an adult-acquired infection.
Treatment

Treatment for acute HBV is mainly supportive. In addition, appropriate measures should be taken to prevent
infection in exposed contacts. The decision to hospitalize patients should be individualized. Patients who have
coagulopathy, are deeply jaundiced, or are encephalopathic should be hospitalized. Hospitalization may also
be considered in patients who are older, have signicant
co-morbidities, or cannot tolerate oral intake.
There is no consensus on whether patients should be
treated with non-nucleoside reverse transcriptase inhibitors (NNRTI) therapy because few studies have
addressed the benets of antiviral therapy during acute
infection (3135) (Table 2). As virus-specic antibodyproducing B cells are enriched early after acute viral
infection, the host immune system needs to be exposed
to viral antigen during the early phase to induce production of neutralizing antibodies. Therefore, giving
antiviral therapy early may inhibit the production of
neutralizing antibodies to some extent. Nevertheless, it
has also been reported that anti-HBs does not develop
in 10% of untreated patients with AVH-B and longterm follow-up of these patients would help dene the
risk of reactivation of hepatitis B virus (HBV) in
patients treated with antiviral therapy (36).
Thus, antiviral therapy is not indicated in the most
patients with acute hepatitis B, but may be indicated in
certain subgroups of patients: (i) Patients with fulminant hepatitis B; (ii) Severe AVH-B: Individuals who full any two of the following criteria: (a) hepatic
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Acute hepatitis B

encephalopathy; (b) serum bilirubin >10.0 mg/dl; and


(c) international normalized ratio (INR) >1.6, especially
if it is increasing; (iii) A protracted course (such as
persistent symptoms or marked jaundice (bilirubin
>10 mg/dl) for more than 4 weeks after presentation);
and (iv) Those who are immunocompromised, have
concomitant infection with hepatitis C or D virus, or
have pre-existing liver disease.
These indications outline the limitations of differentiating AVH-B from reactivation of CHB. Interferon
should be avoided because of the increased risk of hepatic necro-inammation. Tenofovir, telbivudine and
entecavir are acceptable options given as monotherapy
because the treatment duration may be short. Treatment
can be stopped when the patients clinical condition
improves and HBsAg has been cleared.
Spontaneous reactivation (are or exacerbation) of
hepatitis B

The natural history of chronic hepatitis B is punctuated


by spontaneous reactivation of the disease. The natural
course of perinatally acquired chronic HBV infection
has four phases, the rst phase (immune tolerance) is
characterized by the presence of HBeAg, high levels of
serum HBV DNA, normal serum aminotransferases and
minimal or no liver inammation on histology. In
patients with childhood-or adult-acquired HBV infection, the immune-tolerant phase is short-lived or
absent.
After two to three decades of chronic infection,
patients enter the second phase of immune-clearance. In
these patients, HBV replication intensies, serum HBV
DNA levels increase and biochemical deterioration
occurs. Frequently, ares of hepatitis precede clearance
of the virus and HBeAg-to-anti-HBe seroconversion.
However, ares may also occur without subsequent loss
of HBeAg (37). These episodes can be viewed as an
abortive attempt at seroconversion. Some patients
undergo multiple episodes in which ares precede
HBeAg seroconversion only to have a second are
months later. Multiple episodes of reactivation and
remission have been shown to accelerate the progression
of chronic hepatitis B (38).
The next phase after immune-clearance is the low
replicative phase, characterized by the absence of
HBeAg, presence of anti-HBe, relatively normal AT levels and relatively low serum HBV DNA. Liver biopsy
generally shows mild hepatitis and brosis, but signicant liver injury or even cirrhosis in patients who have
had severe liver injury during the preceding immuneclearance phase. This phase may persist indenitely,
especially if this state is reached early. However, some
patients have reactivation of HBV replication either
spontaneously or as a result of immunosuppression.
Most clinically recognizable reactivations occurs in
patients who are in the low replicative phase of infection. During these episodes, serum aminotransferase

167

Jindal et al.

Acute hepatitis B
Table 2. Major studies on antivirals in acute viral hepatitis B.
Author, year,
Country

Patients
[n]

Severe
AVH-B
[n]

Bilirubin

INR

Treatment
duration

Mortality/LT
(%)

18 6.8

4.5 6.4

36 mo

14.4

14.44 7.77

4.15 2.19

Till HBsAg

17.6

19.18 12.04
10.9 5.7

3.91 1.59
2 0.86

negative
3 mo

80
0

1
10

12.3 6.7
8.7

1.89 0.41

0
30

23
40

23
0

10.7
14.56 3.42

1.5 0.10

Till HBsAg

73.9
7.5

40

13.5 3.65

1.48 0.12

negative

Type of study

Treatment

Schmilowitz Weiss
et al. 2004
Israel (31)
Tillman HL et al.
2006
Germany (32)

Cases series

Lamivudine
100 mg/ days

15

15

Historical
cohort

17

17

RCT

20
31

20
22

Kumar et al.
2007 India (33)
Miyake et al.
2008 Japan (34)

Retrospective
cohort

40
10

25
10

Yu et al.
2010 China (35)

RCT

Lamivudine
100150
mg/ days
No antivirals
Lamivudine
100 mg/ days
Placebo
Lamivudine
100150
mg/ days
No antivirals
Lamivudine
100 mg/days
Placebo

23
40
40

Table 3. Differences between acute viral hepatitis B and spontaneous reactivation of hepatitis B [Modied From: (90)]

Parameters
Serum bilirubin
median (range);
mg/dl
ALT levels median
(range); IU/ml
PT prolongation
median (range); s
Serum albumin
median
(range);g/dl
Albumin/globulin
ratio median
(range)
Anti-HBe-positive,
n (%)
IgM anti-HBc
>1:1000
HBV DNA
<0.5 pg/ml

Acute viral
hepatitis B
[n = 49]

Spontaneous
reactivation
of hepatitis B
[n = 30]

P value

8.2 (2.772.9)

9.8 (3.037.2)

0.264

1085 (4006920)

923 (4002900)

0.103

4.4 (016

0.689

3.0 (032)
3.70 (2.94.6)

3.75 (2.74.5)

0.887

1.20 (0.941.85)

1.09 (0.772.00)

0.070

10 (20.4)

25 (83.3)

<0.001

38 (77.5)

9 (30)

<0.001

47 (95.9)

4 (13.3)

<0.001

levels increase in response to the sudden re-emergence


of viral replication.
Thus, reactivation of hepatitis can occur in both
HBeAg-positive and -negative patients (39, 40). A proportion of patients develop jaundice and hepatic
decompensation during the hepatitis reactivation,
namely, severe acute exacerbation, and may progress to
acute-on-chronic hepatic failure (41, 42).

168

ALF [n]

25
P = 0.034

Reactivation of chronic HBV infection can occur in


the immune-clearance phase affecting 4050% of hepatitis B e antigen (HBeAg)-positive patients, and can be
prolonged when there is repeated unsuccessful clearance
of HBeAg (43). Reactivation of CHB at the HBeAg-negative phase, seen in 1530% of HBeAg-negative patients,
can also result in acute decompensation, and is occasionally associated with HBeAg seroreversion (44).
In Far Eastern regions, 2338% of patients have been
reported to develop jaundice and hepatic decompensation during biochemical exacerbation of CHB (44,45).
These exacerbations are often associated with signicant
mortality. Inuence of HBV Genotypes on reactivation
has also been assessed. In casecontrol studies from
Hong Kong (46, 47) and Japan (48) genotype B was
found to be the predominant HBV strain among
patients suffering from severe acute exacerbation as
compared to control patients with various severities of
liver diseases. Genotype B HBV may associate with more
vigorous immune response that leads to a higher chance
of successful immune clearance but also a higher risk of
hepatic decompensation during the hepatitis are.
Several HBV mutant strains, including mutations in
precore, core promoter and deletion mutation in pre-S/
S genes have been reported (49). Viral populations in
the immune tolerance phase mostly consist of exclusively wild-type virus or HBeAg-positive strains with
little or no precore/core promoter mutants or HBeAgnegative strains (50). Acute ares in chronic hepatitis B
may also occur in response to HBV genotypic variation.
Chronic infection with precore mutant is often associated with multiple ares interspersed with periods of
asymptomatic infection (51, 52). A function of the
HBeAg is to induce immunological tolerance. It is
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possible that the absence of HBeAg in patients harbouring precore mutant HBV may permit a more vigorous
immunological response to core peptides expressed on
the surface of hepatocytes. Episodic ares have been
attributed to increases in the concentration of precore
mutants and changes in the proportion of precore to
wild-type HBV (53). It has been suggested that disease
exacerbations remain uncommon during the earliest
phase of chronic HBV at a time when wild-type HBV
predominates and that ares become common with the
gradual emergence of the precore variant. These ares
have been thought to subside with time as the genetic
heterogeneity disappears and patients become exclusively infected with precore HBV (53). Mutations at the
basal core promoter region are associated with
decreased HBeAg synthesis, active liver histology and
increased viral replication. Sometimes these exacerbations have been fatal, presenting as fulminant liver
failure (54).
Pathogenesis of spontaneous reactivation of hepatitis B
virus infection

Spontaneous reactivation (are or exacerbation) of


hepatitis B virus infection are likely explained by
changes in the immunological control of viral replication. Reactivation seems to occur more commonly in
male homosexuals, patients who are infected with
human immunodeciency virus (HIV), concurrent with
bacterial infections or surgery and when there is emotional or physical stress (55). Pregnancy and postpartum
may also be a risk factor (56). Liver injury during these
spontaneous ares appears to be mediated by expanded
numbers of T cells that are reactive to hepatitis B e antigen (HBeAg) and HBcAg that are crossreactive at the Tcell level (57). Increased T-cell responses occur in the
early phase of acute ares and subside after recovery
from acute exacerbation and HBeAg seroconversion
(57). T-cell responses do not diminish if the patient
does not enter a clinical remission and low-level
responses to S gene products are noted throughout all
phases of the are, indicating that HBcAg/HBeAg-specic T cells play an important role in acute exacerbations. Immunopathological studies during acute
exacerbations have shown that the cellular inltrates at
the site of necroinammatory reaction are mainly CD81
cytotoxic T lymphocytes (CTL), which are generally
considered to be directed to HBcAg peptides that reside
on the surface of hepatocytes (58).
Once acute-on-chronic liver failure (ACLF) develops,
the immunological changes seen in the inammatory
process are very similar to that of severe sepsis (59).
There is reduced monocyte activation, which is associated with an exacerbated production of anti-inammatory cytokines, including interleukin (IL)-6, IL-10, IL-12
and interferon-gamma. Cytokine production is associated with activation of toll-like receptors (TLR), an
important component of the innate immune system in
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Acute hepatitis B

recognizing specic pathogen-associated molecular


patterns. TLR2/3/4/5/7/9/10 shows an increased expression during ACLF because of reactivation of HBV (60,
61). IL-17-producing CD4 + T (Th17) cells have also
been shown to be involved in liver injury in CHB
patients with ACLF (62). However, Th-17 is not specically involved in ACLF because of reactivation of CHB,
but is also involved in ACLF of different aetiologies. B
cells may also be involved, as shown in a study demonstrating a massive accumulation of plasma cells secreting
immunoglobulin (Ig)M and IgG targeting the hepatitis
B core antigen in liver tissues of CHB patients who
required liver transplantation because of ACLF (63).
Peripheral glucocorticoid receptor expression is also
increased in CHB patients with ACLF (64). As the ACLF
progresses, the resulting inammatory responses in the
liver and its associated cellular immune dysfunction can
result in multiorgan failure.
Diagnosis

The typical presentation of severe reactivation is a


short onset of jaundice and very high ALT level,
sometimes preceded by prodromal constitutional
symptoms, in a patient with chronic hepatitis B. If
signs of chronic liver disease are present, the diagnosis could be easy, however, most patients presenting
with severe acute reactivation of chronic hepatitis B
may not have been earlier diagnosed as chronic HBV
infection. In countries with intermediate and high
endemicity, the possibility of reactivation of chronic
HBV infection is high, which may be the rst presentation of chronic hepatitis B or compensated cirrhosis, which was asymptomatic before exacerbation.
Hence, a possibility exists that the large proportion of
patients with suspected acute hepatitis B might actually be suffering from chronic hepatitis B and manifesting clinically for the rst time during a period of
severe reactivation (are or exacerbation) (19). In
areas of intermediate to high HBV endemicity, endemic for CHB, reactivation (are or exacerbation)
accounts for 2770% of presumed acute hepatitis B
(19, 65). The symptoms and biochemical parameters
of severe acute reactivation of chronic hepatitis B can
be very similar to those of acute hepatitis B (19).
Hence, severe acute reactivation of chronic hepatitis
B might be misdiagnosed as acute hepatitis B in
some cases. Patients with severe acute reactivation of
CHB can have positive IgM anti-HBc, which may
again be confused with the diagnosis of acute hepatitis B. Levels >600 PaulEhrlich units/ml or IgM
anti-HBc (>1:1000) suggest an acute HBV infection
with high inammatory activity. In all other situations,
concentrations are lower or undetectable (18,19)
(Table 3).
An Indian study suggests that a low titer of IgM antiHBc (<1:1000) and high HBV DNA level (>0.5 pg/ml,
which equals ~141 500 copies/ml) are useful to identify

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Jindal et al.

Acute hepatitis B

severe acute reactivation of CHB from acute hepatitis B


(19). However, HBV DNA may sometimes become
undetectable at the peak of the biochemical exacerbation because of vigorous immune-clearance. The presence of basal core promoter mutation and precore stop
codon mutations have been suggested to differentiate
severe acute exacerbation of chronic hepatitis B from
acute hepatitis B in Japanese series, but its use in clinical
practice needs further validation (66).
A previous history of chronic hepatitis B or a positive
family history of chronic hepatitis B may suggest reactivation; whereas recent history of at risk blood, percutaneous or sexual exposure may suggest AVH-B. Liver
biopsy showing evidence of chronicity may suggest
chronic infection.
In uncertain cases of acute hepatitis B vs. severe reactivation of CHB, one should manage these patients as
severe reactivation and hepatitis B surface antigen
should be retested after 6 months. In over 95% of AVHB acquired in adulthood, HBsAg will be cleared on the
follow-up testing; however, a small percentage of
patients with acute reactivation of CHB may also clear
HBsAg.
As CHB infected patients can still acquire other viral
infections that cause acute hepatitis, other sources of
viral hepatitis (A, C, D and E) must be excluded by serological assays. If suspected, other aetiologies should also
be excluded before a diagnosis of severe acute exacerbation of chronic hepatitis B is made.
Outcome

The clinical presentation of acute reactivation of chronic


hepatitis B infection depends on the underlying severity
of liver disease and other factors.
In a Chinese study on the evaluation of prognostic
factors in severe reactivation (are or exacerbation) of
CHB, the following parameters were independently
associated with adverse outcome at admission: preexisting cirrhosis, high Child-Pugh score, low albumin
level, high bilirubin level, prolonged prothrombin time
(PT) and low platelet count (47). For the subsequent
stay in the hospital, these factors were as follows: high
peak bilirubin level, long peak prothrombin time, long
duration to reach the peak prothrombin time, development of encephalopathy and presence of ascites (47).
In a study from Hong Kong reporting 46 chronic
hepatitis B patients who developed severe reactivation,
but without hepatic encephalopathy at presentation,
24% patients died or received liver transplantation during hospital admission. The only independent factors
that could predict in-hospital mortality were low platelet count and high serum bilirubin. The mortality of
patients who had both risk factors (low platelet and high
bilirubin) was 69%. On the other hand, the mortality of
patients who had either thrombocytopenia or elevated
bilirubin alone was much lower (11% and 13%, respectively), and the mortality of patients who had none of

170

the two risk factors was zero in this series (67). Because
of the limited hepatic reserve, patients with cirrhosis
recover more slowly and are more prone to complications, including sepsis, gastrointestinal bleeding and
acute renal failure.
Many other studies from Hong Kong, Taiwan and
Japan, have found that patients with pre-existing cirrhosis and more serious hepatic dysfunction (prolonged
prothrombin time, elevated serum bilirubin and high
ChildPugh score) have a higher risk of mortality (68,
69, 70).
In one study from Taiwan on HBeAg-positive noncirrhotic patients with acute exacerbation, 5.1% of the
exacerbation episodes resulted in hepatic decompensation, and serum HBV DNA level was the only signicant
risk factor (P = .003). A serum HBV DNA cut-off value
of 1.55 9 10 (9) copies/ml predicted decompensation
with a sensitivity of 85.7%, a specicity of 85.5%, a negative predictive value of 99.1% and positive predictive
value of 24.0% (71). Once the disease reaches the stage
of ACLF, the prognosis is extremely poor, with 3-month
mortality rates without liver transplantation around
50% (72). Different predictive models have been used in
predicting acute-on-chronic liver failure in chronic hepatitis B. MELD score has been found in many studies to
be more objective score compared to ChildPugh score
in predicting survival in CHB patients with ACLF (73,
74).
One regression model, using the presence of hepatorenal syndrome, cirrhosis, positive HBeAg, low albumin
and prolonged PT, was found to be better than the
MELD score in predicting 3-month mortality (72).
Another model based on the presence of hepatic encephalopathy, hepatorenal syndrome, positive HBeAg, cirrhosis and prolonged PT was also found to be better than
both the MELD and ChildPugh score (75). Additional
studies to externally validate these models are needed.
Treatment

Patients need intensive supportive care including close


monitoring and treatment of complications.
In severe reactivation of chronic hepatitis B when
immune activity is already excessive, IFN-based treatment may aggravate the hepatic decompensation and is
thus contraindicated. Oral nucleos(t)ide analogues are
the treatment of choice.
In one initial case series from Japan, three patients
with cirrhosis who presented with severe acute exacerbation and hepatic encephalopathy responded dramatically
to lamivudine treatment (76). However, many later case
series or case-control studies did not demonstrate any
benet in survival of lamivudine treatment (67, 69, 77).
The high mortality rate of these patients despite lamivudine treatment was probably related to the delayed
beginning of lamivudine and viral suppression. In
patients with liver failure, the main determinant for
recovery is liver regeneration and rapid cessation of
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Jindal et al.

ongoing necro-inammation. Neither factors are


directly dependent on HBV replication. Thus, complications including sepsis and multiorgan dysfunction
develop in patients in whom treatment is delayed (78).
A study from Taiwan suggests that the benecial effect
of antiviral therapy on short-term survival depends on
the timing of treatment. In a group of consecutive CHB
patients with severe acute exacerbation treated with
lamivudine, all 25 patients who had baseline bilirubin
below 20 mg/dl survived. In patients with low (<20 mg/
dl) baseline serum bilirubin levels, lamivudine treatment
denitely improves survival compared to historic controls who did not receive lamivudine (5/20 patients
died, 20%, P = 0.013). On the other hand, the mortality
rate of patients who received lamivudine when bilirubin
was above 20 mg/dl (23/35, 67%) was similar to that in
untreated historical controls (9/11, 82%) (68). A more
recent study found improved survival in lamivudinetreated patients compared to controls in patients with a
MELD score of 30 or less. However, those treated with
lamivudine still had a 3-month mortality of 50.7%. A
low pretreatment HBV DNA and a rapid decline in viral
load were predictors of good outcome (79).
Recently, studies have been performed with more
potent antivirals. A study from China compared entecavir (n = 33), lamivudine (n = 34), or no nucleoside
analogues (n = 37). Both nucleoside analogues achieved
signicant viral suppression after 3 months, but there
was no improvement in survival; 3-month survival rates
were 48.5, 50.0 and 40.5% respectively (80). In one Japanese study, 34 patients with acute exacerbation were
consecutively treated with lamivudine or entecavir and
all patients in both groups survived. Twelve months
after treatment, 41.6% of 24 lamivudine patients developed lamivudine-resistant mutations. On the other
hand, patients receiving entecavir did not need to
change drugs (81). Another study from Hong Kong
found entecavir (n = 36) to be associated with increased
short-term mortality compared to lamivudine
(n = 117), perhaps caused by lactic acidosis (82, 83).
This nding must be conrmed.
A randomized trial from India (84) found improved
3-month survival with tenofovir (57%) compared to
placebo (15%) in patients with acute exacerbation of
CHB presenting as acute-on-chronic liver failure. A
reduction in more than 2 log in HBV DNA levels at
2 weeks was found to be an independent predictor of
survival.
The denitive treatment for severe reactivation (are
or exacerbation) with ACLF is liver transplantation. A
study from Hong Kong retrospectively analysed 149
patients presenting with ACLF who received liver transplantation including 50 with severe exacerbation of
CHB. The 5-year survival rates exceeded 90% (85).
A lot of research is being undertaken to improve the
poor outcome of ACLF due to CHB reactivation. One
randomized placebo-controlled trial found the administration of granulocyte-colony stimulating factor
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Acute hepatitis B

improved survival after 2 months (86). Use of bioarticial liver support systems is controversial and the results
of a randomized controlled multicentre study in ACLF
patients failed to identify any benet in survival (87).
Corticosteroids, based on their anti-inammatory activity, have been used in CHB with ACLF. In a recent
study, intravenous dexamethasone 10 mg daily was
given for 5 days with continuous lamivudine in 56
patients. Dexamethasone was an independent factor
inuencing survival compared to controls, and a rapid
decline in serum bilirubin in the rst 5 days was predictive of survival (88).

Reactivation (are or exacerbation) of hepatitis B


caused by infection with other viruses

Patients with chronic HBV infection may exhibit reactivation (are or exacerbation) of hepatitis when superinfected with other hepatotropic viruses, such as hepatitis
A virus (HAV), hepatitis E virus (HEV), hepatitis C
virus (HCV) and hepatitis delta virus (HDV). The severity
of hepatitis are depends on the severity of the underlying hepatitis B.
Excess mortality has been reported by several investigators when hepatitis A is superimposed on chronic
hepatitis B (89). HEV has also been described as a cause
of acute exacerbation of CHB. In one Indian study,
HEV super-infection contributed to 20% of acute exacerbation episodes and, in particular, 36% of episodes in
initially HBeAg ( ) patients (90). Severe hepatitis are
frequently occurs when delta virus super-infection is
superimposed on chronic hepatitis B (91). Should infection with delta virus become chronically established, as
is often the case, this frequently leads to an increase in
disease activity and accelerated progression to cirrhosis,
during which time multiple uctuations in serum aminotransferase levels are common (91).
Acute hepatitis C may also lead to severe hepatitis
ares in patients with chronic hepatitis B (92).Similar to
delta infection, infection with HCV frequently becomes
chronic, and the subsequent course may be characterized by frequent uctuations in ALT and AST values
(93).
Super-infection with another virus on chronic HBV
infection is not uncommon. In one study, in 55% of the
patients, acute ares in serum aminotransferase levels in
antiHBe-positive patients had delta superinfection,and
only 24% were considered to have reactivation of HBV
(94). In an Indian study (90), only 9.5% of exacerbations
in the HBeAg-positive patients were owing to superinfection with other hepatitis viruses, whereas 90.5%
had spontaneous exacerbation of HBV per se; whereas in
the HBeAg-negative patients, superinfection, and acute
exacerbation of HBV both were equally common.
Patients with chronic hepatitis B who become
infected with other hepatotropic viruses may be found
to be HBeAgnegative and serum HBV DNA negative

171

Acute hepatitis B

by molecular hybridization tests due to a process of viral


interference (95). In some instances, these super-infections
may result in HBeAg and HBsAg seroconversion (96).
Conclusions

The presentation of acute hepatitis caused by reactivation of chronic hepatitis B is quite common and is often
difcult to clinically and biochemically differentiate
from AVH-B. The presence of high serum HBV DNA
and evidence of underlying chronic liver disease by
imaging techniques, liver biopsy, endoscopy or raised
hepatic venous pressure gradient are helpful in differentiating the two conditions. As most patients with acute
HBV resolve this infection spontaneously, treatment
with an oral anti-HBV agent is not necessary. However,
the use of an oral anti-HBV agent may be indicated in
certain subgroups of patients. Spontaneous reactivation
(are or exacerbation) of hepatitis during the course of
chronic HBV infection is a common phenomena in
areas where HBV infection is moderately or highly
endemic. Reactivation may sometimes be confused with
acute viral hepatitis B. The severity of the reactivation
depends on the severity of underlying liver disease, but
can progress to liver failure and death. Antivirals should
be started as early as possible and should be continued.
Liver transplantation should be considered in patients
with severe disease.
Disclosure

The authors have no disclosure.


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