Journal of Hepatology 39 (2003) S160–S163

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Chronic hepatitis B e antigen (HBeAg) negative, anti-HBe positive

hepatitis B: an overview
Ferruccio Bonino1, Maurizia Rossana Brunetto2,*
1
Direzione Scientifica, Ospedale Maggiore di Milano, Policlinico, IRCCS, Via Francesco Sforza, 28, 20122 Milan, Italy
2
U.O. Gastroenterologia ed Epatologia, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy

1. Introduction profile of these patients [8]. In 1989 two independent studies

performed in anti-HBe positive patients of the Mediterra-
In the eighties, after the hepatitis Delta virus (HDV) nean area showed that the most frequent cause of the
epidemics occurred in the Mediterranean area, hepatologists discrepancy between the presence of HBV DNA and the
began to look for unknown Non-A, Non-B, Non-D hepatitis absence of HBeAg was the infection with HBV variants
agents in anti-HDV negative, hepatitis B e antigen (HBeAg) unable to secrete the soluble form of the HBV nucleocapsi-
negative, anti-HBe positive hepatitis B surface antigen dic protein (HBeAg minus mutant, [9 –10]). The mutation is
(HBsAg) carriers with chronic liver disease [1,2]. The a G to A switch at position 1896 of the pre-core region of the
intrahepatic detection of hepatitis B core antigen (HBcAg) HBV genome that leads to a translational stop codon in the
was the gold standard for etiologic diagnosis of chronic leader sequence of HBeAg protein resulting in the inhibition
hepatitis B [1,2] and serum HBeAg correlated with the of the protein synthesis [8 – 10]. Subsequently many other
nuclear staining of HBcAg in a large number of hepatocytes groups confirmed this observation and identified other
[1 –3]. However, intrahepatic HBcAg with both nuclear and mutations resulting in HBeAg defective viruses [11,12]. So
cytoplasmic staining was detected also (but in a lower far two major groups of mutations have been described:
number of hepatocytes) in a few of anti-HDV negative, anti- those occurring in the basic core promoter, that modulate
HBe positive patients [2]. HBeAg secretion at the transcriptional level and those
In 1980 by molecular hybridization techniques detection occurring in the pre-core region, which block HBeAg
of hepatitis B virus (HBV) DNA in the serum became an production at the translational level [11,12]. Core promoter
alternative to demonstrate HBV replication because it was and stop codon mutants appear to be frequently associated,
shown that serum HBV DNA was associated with leading to the interesting question whether one category of
intrahepatic HBcAg in both HBeAg positive and negative mutants precedes or influences the prevalence of the other.
patients [2 –6]. The great majority of HBeAg and anti-HDV The prevalence of the1896 stop codon mutation appears
negative, anti-HBe positive patients with chronic liver to be significantly associated with HBV genotypes harbor-
disease from the Mediterranean area tested positive for ing a T nucleotide at position 1858 (genotypes B, D, E and
serum HBV DNA [2 – 6]. In the following years, in a cohort part of genotypes C and F) because the generation of the G
study the clinical and pathological profile of ‘chronic anti- to A mutation at nucleotide 1896 would stabilize the
HBe positive hepatitis B’ was characterized as significantly secondary structure of the encapsidation signal loop [13].
different from that of chronic HBeAg positive hepatitis B
By contrast, in genotype A and part of genotype C and F the
[7]. Mean HBV DNA serum levels were lower, the
presence of C at nucleotide 1858 would significantly reduce
intracytoplasmic staining of HBcAg was more frequent
the possibility for G to A 1896 variants to be selected,
and liver disease was more severe [7].
because of their lower replication fitness [13]. The
At the same time the molecular biology of HBV allowed
geographic distribution of HBV genotypes would therefore
to hypothesize the molecular basis of the atypical serologic
influence the worldwide distribution of 1896 stop codon
* Corresponding author. [14]. Therefore molecular virology could be responsible for
E-mail addresses: Brunetto@med-club.com (M.R. Brunetto); bonino@ the different geographic prevalence of HBeAg negative/
med-club.com (F. Bonino). anti-HBe positive chronic hepatitis B, which appears to be
0168-8278/03/$30.00 q 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
doi:10.1016/S0168-8278(03)00319-2
 F. Bonino, M.R. Brunetto / Journal of Hepatology 39 (2003) S160–S163 S161

the most common form of chronic hepatitis B in Southern the low rates of parenteral exposure and history of acute
Europe and Asia, where 30– 80% of patients with chronic hepatitis and HBeAg carrier status [21]. The disease caused
hepatitis B are HBeAg negative as compared with Northern by HBeAg minus HBV runs usually asymptomatic for three
Europe and the United States where only 10 –40% lack to four decades and reaches the stage of histologic cirrhosis
HBeAg [11 – 14]. at a median age of about 45 years [21]. Thereafter cirrhosis
Preliminary data using oligonucleotide hybridization progresses to end stage complications in about 25% of
technique showed that wild-type and HBeAg minus HBV patients in about 10 years; recurrent hepatitis B exacer-
may coexist in a HBV carrier and their relative ratio vary bations accelerate disease progression [21]. The virologic
over time [15 – 18]. Furthermore, follow-up studies and biochemical patterns of chronic anti-HBe positive
suggested the important association between different ratios hepatitis B vary from intermittently to persistently detect-
of circulating wild-type and HBeAg minus HBVs and able viremia and elevated ALT levels and three major
pathogenetic events during the course of chronic hepatitis B patterns can be identified [11,21] (Fig. 1):
[17,18]. Considering the paramount role of HBeAg in the
equilibrium between HBV and the immune system it will be 1. recurrent hepatitis B exacerbations with periods of
extremely important to shed new light on the molecular biochemical and virological remission;
mechanisms that affect the ratio between wild-type and 2. unremitting chronic hepatitis B;
HBeAg minus HBV. 3. unremitting chronic hepatitis B with acute
exacerbations.
2. Natural history of liver disease
In spite of an intermitting disease profile associated with
The clinical characterization of anti-HBe positive frequent and some times long lasting remissions spon-
chronic hepatitis B and the study of its course were taneous recovery from anti-HBe positive chronic hepatitis B
performed in patients from the Mediterranean area is very rare [11,14,19– 21]. Persistent viral replication is a
[7,14,19– 21]. Therefore the possibility that differences at major cause of chronic liver damage and development of
virologic and genetic levels may influence both disease cirrhosis: in a cohort study after a mean follow-up of 10
profile and outcome had to be taken into account when years about 50% of the patients with chronic hepatitis at
considering HBeAg negative/anti-HBe positive chronic baseline developed cirrhosis and persistently detectable
hepatitis B from other geographic areas. HBV DNA was a factor independently associated with
In most of anti-HBe positive patients from the Medi- disease progression [21]. Further, cirrhosis development as
terranean area HBV infection occurs in the childhood as an end point complication was associated with recurrent
suggested by the high rate of intrafamilial HBV infection, hepatitis exacerbations [21].

Fig. 1. Biochemical patterns in 164 untreated anti-HBe positive patients with chronic hepatitis B. Disease profiles were identified by monthly
monitoring for 23 months (range 12– 36: ref. [21]).
S162 F. Bonino, M.R. Brunetto / Journal of Hepatology 39 (2003) S160–S163

3. Diagnosis the following features:

Chronic hepatitis B runs a long asymptomatic course and † chronic HBV infection;
is diagnosed in . 90% of patients by occasional blood † chronic hepatitis at the histologic, biochemical and
testing. In studies applying uniform and stringent monitor- ultrasound level;
ing criteria major fluctuations of viremia and ALT levels † persistent (at least 1 year) anti-HBe positive serology in
were found in . 50% of patients [21]. HBV DNA levels fell absence of HBeAg;
below the sensitivity limits of the hybridization assay † serum HBV DNA . than 104 – 105 1 genome equivalents
(, 2.8 £ 106 genomes/ml) more than once yearly in about or copies per ml (at least intermittently) and/or anti-HBc
90% and six or more times in 60% of patients [21]. IgM levels . 4 Paul Ehrlich Institute Units;
Similarly, ALT levels showed recurrent flares in 65% of † absence of HDV markers (2);
patients and in 70% ALT fell to normal values between † absence of HCV markers (2).
flares. These findings clearly demonstrate that disease
progression can be studied only by follow-up of using The most frequent molecular cause for the absence of
virologic and biochemical patterns and not by simple HBeAg is infection with a HBV variant or mutant that is
baseline ALT and HBV DNA assays thus avoiding biases unable to secrete HBeAg, HBeAg minus HBV.
caused by single time-point observations. In addition, the
rapid fluctuations of both ALT and HBV DNA may hamper
an accurate monitoring of the pathogenetic events occurring
in patients unless a monthly monitoring is performed. References
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1
4. Conclusions The cut-off has to be defined by prospective studies.
2
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disease can be diagnosed only if HBV-DNA is .104 genome equivalents or
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