Journal of Hepatology 48 (2008) 335352

www.elsevier.com/locate/jhep

Review

Natural history of chronic hepatitis B: Special emphasis

on disease progression and prognostic factorsq
Giovanna Fattovich1,*, Flavia Bortolotti2, Francesco Donato3
1
Department of Surgical and Gastroenterological Sciences, University of Verona, Piazzale L.A. Scuro, 10, Verona 37134, Italy
2
Fifth Medical Clinic, University of Padova, Padova, Italy
3
Institute of Hygiene, Epidemiology and Public Health, University of Brescia, Brescia, Italy

The natural history of chronic hepatitis B virus (HBV) infection and disease is complex and highly variable. We review
the natural history of chronic hepatitis B with emphasis on the rates of disease progression and factors inuencing the
course of the liver disease. Chronic hepatitis B is characterized by an early replicative phase (HBeAg positive chronic hep-
atitis) and a late low or non-replication phase with HBeAg seroconversion and liver disease remission (inactive carrier
state). Most patients become inactive carriers after spontaneous HBeAg seroconversion with good prognosis, but progres-
sion to HBeAg negative chronic hepatitis due to HBV variants not expressing HBeAg occurs at a rate of 13 per 100 per-
son years following HBeAg seroconversion. The incidence of cirrhosis appears to be about 2-fold higher in HBeAg negative
compared to HBeAg positive chronic hepatitis. In the cirrhotic patient the 5-year cumulative risk of developing hepatocel-
lular carcinoma is 17% in East Asia and 10% in the Western Europe and the United States and the 5-year liver related
death rate is 15% in Europe and 14% in East Asia. There is a growing understanding of viral, host and environmental
factors inuencing disease progression, which ultimately could improve the management of chronic hepatitis B.
2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Keywords: Chronic hepatitis B; Natural history; Prognostic factors

1. Introduction disease progression is important in the management of

Chronic infection with hepatitis B virus (HBV) cur-
rently aects about 400 million people, particularly in
developing countries, and it is estimated that worldwide
over 200,000 and 300,000 chronic HBV carriers die each
year from cirrhosis and hepatocellular carcinoma
(HCC), respectively [1,2]. The natural history of chronic
HBV infection and disease is variable and complex and
has still not been completely dened. A careful under-
standing of the clinical outcomes and factors aecting
Associate Editor: R.P. Perrillo
q
The authors declare that they do not have anything to disclose
regarding funding from industries or conict of interest with respect to
this manuscript
*
Corresponding author. Tel./fax: +39 045 8124205.
E-mail address: giovanna.fattovich@univr.it (G. Fattovich).
chronic hepatitis B. This article reviews the natural his-
tory of chronic hepatitis B, with emphasis on summariz-
ing the available data to estimate the rates of disease
progression according to the stage of the disease and
factors inuencing its course.
2. Phases of chronic HBV infection
The likelihood of developing chronic HBV infection is
higher in individuals infected perinatally (90%) or during
childhood (2030%), when the immune system is thought
to be immature, compared with immunocompetent sub-
jects infected during adulthood (<1%). The phases of
chronic HBV infection described herein refer to patients
infected early in life. The natural course of chronic HBV
infection can be divided into four phases based on the

0168-8278/$32.00 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jhep.2007.11.011
336 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352
virushost interaction: immune tolerance, immune clear-
ance, low or non-replication, and reactivation [1,3].
2.1. Immune tolerance
The initial immunotolerant phase is characterized by
the presence of hepatitis B e antigen (HBeAg), high
serum levels of HBV-DNA, but normal or minimally
elevated serum alanine aminotransferase (ALT) and
normal liver or only minimal histological activity and
scant brosis. Most carriers with perinatally acquired
HBV infection present in the immunotolerant phase
with HBeAg positive chronic hepatitis with normal
ALT (mostly Asian children). The immunotolerant
phase may persist for 1030 years in perinatally infected
subjects, whereas it is generally short-lived or absent in
childhood or adult-acquired HBV infection.
2.2. Immune clearance
After a variable period of HBeAg positivity, depending
on the age at acquisition of HBV infection, immune toler-
ance to the virus is lost and the immune system mounts an
attack on infected hepatocytes. This second immunoac-
tive phase is characterized by uctuating, but progres-
sively decreasing, HBV-DNA levels, elevated ALT and
hepatic necroinammation. Patients with late childhood,
adolescence or adult-acquired chronic HBV infection
usually present in the immunoactive phase with HBeAg
positive chronic hepatitis with elevated serum ALT and
moderate or severe necroinammation with variable
amounts of brosis on liver biopsy. Serum HBV-DNA
levels generally exceed 20,000 IU/ml (105 copies/ml)
among patients with HBeAg positive chronic hepatitis.
2.3. Low or non-replication phase: inactive carrier state
An important outcome of the immunoactive phase is
seroconversion from HBeAg to anti-HBe, marking the
transition to the third low or non-replication phase
(inactive HBsAg carrier state) which is characterized
by HBeAg negativity and anti-HBe positivity, undetect-
able or low levels of HBV-DNA [suggested levels less
than 2000 IU/ml (104 copies/ml)], persistently normal
ALT levels and inactive liver histology with a usually
minimal amount of brosis.
2.4. Reactivation phase
As viral supercoiled DNA persists in the liver, a num-
ber of inactive HBsAg carriers may eventually develop
HBV reactivation with recrudescence of liver disease
either spontaneously or triggered by active immunosup-
pression. Reactivation of viral replication may occur
due to reactivation with the wild type virus with rever-
sion back to the HBeAg positive state, or much more
frequently with replication-competent HBV variants
that prevent HBeAg expression. The fourth reactivation
phase is characterized by HBeAg negativity with anti-
HBe positivity, detectable serum HBV-DNA levels
[200020 million IU/ml (104 108 copies/ml)], ALT ele-
vation and moderate or severe necroinammation with
variable amounts of brosis on liver biopsy (HBeAg
negative chronic hepatitis).
Inactive HBsAg carriers may eventually lose HBsAg
with development of neutralizing HBs antibodies (anti-
HBs), but low levels of HBV-DNA may still be detect-
able by PCR in serum and liver biopsy specimens.
Immunosuppression in such patients, as occurs with
cancer chemotherapy or after organ transplantation,
can lead to reactivation of hepatitis B.
Based on a knowledge of the natural history of
chronic HBV infection, patients can be classied accord-
ing to their serologic status as shown in Table 1.
3. Chronic hepatitis B in children
Chronic hepatitis B in childhood has some unique fea-
tures which largely depend on age at primary HBV infec-
tion and route of transmission [4,5]. HBV can be
transmitted to the child either perinatally or horizontally.
Perinatal infection of infants from highly infectious
HBeAg positive mothers is frequent in Asia, whereas in
Africa, the Mediterranean basin and Eastern Europe,
where the proportion of HBeAg positive mothers is much
lower, infection is mainly transmitted horizontally during
infancy or childhood by HBsAg positive family members
and playmates or by unsafe therapeutic injections. In Tai-
wan, prior to mass vaccination, perinatal transmission of
HBV was estimated to account for 4050% of the HBsAg
carriers and horizontal transmission early in life for the
remaining cases [5,6]. Clinical data indicate that there
are dierences in the natural course of chronic hepatitis
B in children according to perinatal or postnatal acquisi-
tion of HBV infection.
3.1. Natural history of perinatally acquired chronic
hepatitis B
Many Asian children infected in the perinatal period
present with HBeAg positive chronic hepatitis with nor-
mal ALT and minimal liver damage (immunotolerant
phase) and are usually asymptomatic. The rate of spon-
taneous HBeAg seroconversion is low, less than 2% per
year among children aged 3 years or less, and 45% per
year in older children [5,7], so that by the age of 1015
years around 90% of children remain HBeAg positive
[6]. A higher rate of HBeAg seroconversion has been
reported in a cohort of 70 Asian-born children living in
Canada, recruited at an average age of 2 years, as 75%
of cases underwent spontaneous HBeAg seroconversion
 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352
Table 1
Serological proles of chronic hepatitis B virus infection
Phase Serum ALT HBeAg
Immune tolerance Normal or minimally Positive
elevated
HBeAg positive Persistently elevated Positive
chronic hepatitis
HBeAg negative Elevated and often Negative
chronic hepatitis uctuating
Inactive carrier Normal Negative
by 13 years after diagnosis [8]. Many of these patients
were adopted and it is suggested that taking care of
the nutritional status of such children and of concomi-
tant viral infections could strengthen the immune
response accelerating HBeAg seroconversion [8]. When
children enter the HBeAg seroconversion phase the
ALT levels become elevated and HBV DNA values
decline [5]. In Taiwan genotype B is most common
(>70%) in children with chronic HBV infection and
HBeAg seroconversion is delayed in those with genotype
C [9]. Longitudinal studies showed that HBeAg serocon-
version leads to the inactive HBsAg carrier state in most
children [7,10]. Spontaneous HBsAg clearance is rare
(estimated rate of 0.6%/year).
3.1.1. Disease progression
Cirrhosis is uncommon during childhood. In a cohort
study from Taiwan cirrhosis developed in 5% of 58
HBsAg carrier children who received histologic examina-
tion [7]. HCC has been described in both Asian [4,5,11]
and Caucasian children [12] with perinatal infection. In
a prospective cohort study of 426 children with chronic
hepatitis B from Taiwan the HCC incidence was 32 per
100,000 person years [11]. HCC occurs mainly in children
over the age of 6, with male predominance [5,11,12]. Most
childhood cases of HCC (around 80%) are anti-HBe posi-
tive and accompanied by cirrhosis. HCC has been
described in children who had undergone early HBeAg
seroconversion and/or rapid progression to cirrhosis
[11,12], suggesting that severe necroinammation may
occur during the process of HBeAg seroconversion lead-
ing to cirrhosis, which is a risk factor for HCC.
3.2. Natural history of postnatally acquired chronic
hepatitis B
Most children infected postnatally come to observa-
tion during the immunoclearance phase with HBeAg
positive chronic hepatitis with elevated ALT and active
liver disease. About 10% have a history of acute onset
and 2030% complain of non-specic symptoms. Spon-
taneous HBeAg seroconversion occurs frequently at an
average rate of 1416% per year during the rst 10 years
of follow-up [13,14]. ALT ares are often observed prior
to HBeAg seroconversion. The predictive role of HBV
337
Anti-HBe HBV-DNA
Copies/ml IU/ml
Negative Very high levels 1081011 20 million20 billion
Negative High levels 1061010 200,0002 billion
Positive Moderate levels, often uctuating 104 108 200020 million
Positive Low or no detectable levels <104 <2000
genotypes in relation to HBeAg seroconversion or dis-
ease severity is of limited value in areas such as Italy
where genotype D accounts for the vast majority of pae-
diatric infections [14]. A 29-year longitudinal study of 91
Italian children with HBeAg positive chronic hepatitis
showed that 81 (95%) out of 85 children without cirrho-
sis at enrolment who underwent spontaneous HBeAg
serococonversion became inactive HBsAg carriers
before reaching adulthood [14]. HBsAg clearance occurs
at a rate of approximately 1% per year [14].
3.2.1. Disease progression
Progression to HBeAg negative chronic hepatitis B or
HBeAg seroreversion are uncommon events occurring
in 5% of children during a mean follow-up of 15 years
after HBeAg serocoversion [14]. Potential cofactors such
as drug addiction or pregnancy have been associated
with HBV reactivation in adulthood [14].
Cirrhosis is infrequent, being observed in 34% of
cases at baseline in cohort studies of Italian and Spanish
children with chronic hepatitis B [1315]. Cirrhosis
appears to be an early complication, being observed
mainly (70% of cases) before the age of 4 years. In addi-
tion, cirrhosis has been described only in male children,
frequently associated with a history of acute hepatitis or
severe disease activity, with early HBeAg seroconversion
and/or with concurrent viral infections [15]. In longitu-
dinal studies progression of chronic hepatitis B to cir-
rhosis was not observed over a period up to 29 years
[1315]. Reversion of cirrhosis to signicant brosis
[13] or even to near normal liver in adulthood [16] has
been reported in few cases with well-compensated liver
disease. HCC is also a rare complication aecting cir-
rhotic males. In the long term follow-up study from
Italy HCC has been reported a few to several years after
the diagnosis of cirrhosis in 2% of children with chronic
HBV infection over a period of 20 years [14].
4. Chronic hepatitis B in adults
4.1. HBeAg positive chronic hepatitis
Adult patients with HBeAg positive chronic hepatitis
usually present with the disease in the third or fourth
338 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352
decade of life and are more frequently males. Typical
HBeAg positive chronic hepatitis in adult patients is
marked by high levels of HBV-DNA, which may be as
high as 2 billion IU/ml (1010 copies/ml), with variable
elevation of ALT and histological activity.
The duration of typical HBeAg positive chronic hep-
atitis is variable, and it can be prolonged and result in
disease deterioration to cirrhosis, but approximately
65% of patients eventually undergo seroconversion from
HBeAg to anti-HBe associated with reduction of HBV-
DNA replication, biochemical remission and a dimin-
ished risk of disease progression [17,18]. A study
reported that in addition to HBeAg seroconversion sus-
tained disease remission dened as normal ALT and
HBV-DNA levels less than 104 copies/ml is required in
order to achieve regression of brosis and hepatic
inammation [19]. HBeAg seroconversion occurs at an
annual rate of 1015% in adults with elevated ALT
[20]. A recent longitudinal study has reported that up
to 90% of Caucasian adults with chronic hepatitis B
clear HBeAg within 10 years of follow-up, with an inci-
dence rate of 18 per 100 person years [18]. Factors asso-
ciated with higher rates of spontaneous HBeAg
seroconversion include older age, higher ALT levels,
HBV genotypes B (versus C) and A (versus D) and eth-
nicity other than Asian [3,20,21].
4.2. HBeAg negative chronic hepatitis
Persistent HBV replication despite HBeAg serocon-
version or HBV reactivation following a period of
remission after HBeAg seroconversion leads to HBeAg
negative chronic hepatitis. Other concomitant or super-
imposed causes of liver disease should be excluded
[3,22]. The most common mutation that prevents
HBeAg production is a guanine (G) to adenine (A)
change at nucleotide 1896 (G1896A) creating a stop
codon (at pre-core codon 28) that prematurely termi-
nates synthesis of HBeAg [22]. Other pre-core changes
as well as mutations in the basic core promoter (BCP)
region which down-regulate HBeAg synthesis at the
transcriptional level have been described [22]. Selection
of these mutants is inuenced by viral genotype. HBeAg
negative chronic hepatitis is therefore more common in
Southern Europe, where genotype D predominates, and
in Asia, where both genotypes B and C are common.
Available data indicate an increased prevalence of
HBeAg negative chronic hepatitis worldwide, probably
reecting the aging of existing HBsAg carriers [22,23].
Recent studies have reported that 7090% of unselected
adult chronic HBV carriers from Italy and France are
HBeAg negative and anti-HBe positive at diagnosis
[24,25].
Patients with HBeAg negative chronic hepatitis are
usually older than patients with HBeAg positive chronic
hepatitis and are more likely to have cirrhosis at the time
of their rst presentation [17,22,25]. Patients with
HBeAg negative chronic hepatitis have lower levels of
serum HBV-DNA [200020 million IU/ml (104108 cop-
ies/ml)] than patients with HBeAg positive chronic hep-
atitis [200,0002 billion IU/ml (1061010 copies/ml)].
However, many patients with HBeAg negative chronic
hepatitis have wide uctuations in both HBV-DNA
and serum ALT levels [26]. Spontaneous sustained
remissions of disease activity are rare.
4.3. Inactive HBsAg carrier
A patient with chronic HBV infection, HBeAg nega-
tivity and anti-HBe positivity, undetectable or low
serum HBV-DNA levels (<2000 IU/ml) and normal
serum ALT levels in one occasion should not be classi-
ed as an inactive carrier without an appropriate fol-
low-up. Indeed patients with HBeAg negative chronic
hepatitis have wide uctuations in serum ALT and 20
30% of these patients with histological documented
chronic hepatitis have normal ALT at the time of pre-
sentation [22].
Long term longitudinal studies (up to 23 years) of
adult inactive carriers have reported that 1524% devel-
oped HBeAg negative chronic hepatitis and 117% had
sustained reversion back to HBeAg positivity
[17,18,27,28]. It is estimated that the incidence of
HBeAg negative chronic hepatitis from inactive carriers
ranges from 1 to 3 per 100 person years [17,18,28].
4.4. Spontaneous HBsAg clearance
During the inactive carrier state spontaneous HBsAg
loss may occur at a rate of 12% per year in Caucasian
carriers in low endemic areas, but even lower (0.05
0.8%) in high endemic areas where infection is usually
acquired perinatally or in early childhood [3,20]. How-
ever, a recent study has reported a 40% cumulative rate
of spontaneous HBsAg seroclearance in asymptomatic
adult Chinese after 25 years of follow-up, suggesting
that the low HBsAg seroclearance rate in previous stud-
ies from high endemic areas might be due to the relative
short follow-up [29]. Factors signicantly associated
with spontaneous HBsAg seroclearance include older
age at diagnosis and sustained remission of hepatitis
during follow-up [19,27,30]. HBsAg seroclearance is
generally accompanied by improved liver histology in
spite of HBV-DNA persistence in the liver [31,32].
Longitudinal studies have demonstrated that HBsAg
seroclearance usually confers excellent long-term prog-
nosis, provided that HBsAg loss occurred at a younger
age, in the absence of concurrent viral infections, and
preceeded the development of cirrhosis. Indeed, as
shown in the studies presented in Table 2, clinical out-
comes of disease progression such as decompensation,
HCC or death may occur in these patients, particularly
 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352 339

Table 2
Occurrence of hepatocellular carcinoma, decompensation and liver related death/OLT after HBsAg seroclearance in patients with chronic hepatitis B or
cirrhosis
Clinical status at Author Geographic No. Mean age at % Mean No. No. No.
HBsAg loss (Reference) area patients entry (yr) males follow-up (y) HCC decompensation death/ OLT
Chronic hepatitis Chen [34] Taiwan 189 (43) 43 79 5.1 2 (2) 0 1 (1)
Ahn [32] Korea 32a 50 73 1.6 1 na na
Arase [35] Japan 164a 51 80 5 0 0 0
Chronic hepatitis Yuen [31] China 92a 43 71 4.2 5b 0 na
or cirrhosis
Cirrhosis Fattovich [33] Europe 32 (na) 45 90 4.6 1 (1) 2 2 (1)
Chen [34] Taiwan 29 (12) 54 79 5.1 1 (1) 4 (2) 1 (1)
Ahn [32] Korea 17a 50 73 1.6 4 na na
Arase [35] Japan 67a 51 80 6.1 2 0 0
HCC, hepatocellular carcinoma; OLT, orthotopic liver transplantation. Number in parentheses refer to number of patients with concurrent hepatitis
C virus or hepatitis delta virus infection; na, not available.
a
None of the patients had concurrent infection with hepatitis C virus or hepatitis delta virus.
b
Four of the ve patients had cirrhosis.

those with cirrhosis or in patients with concurrent hep-
atitis C virus (HCV) or hepatitis delta virus (HDV)
infection at the time of HBsAg clearance [3135].
5. Incidence rates of disease progression
5.1. Methods
Although several studies on the risk of cirrhosis,
HCC, decompensation and liver-related mortality in
patients with chronic HBV infection have been pub-
lished, a summary of their results is hampered by the dif-
ferent study designs (case-control, cross-sectional,
longitudinal) and the heterogeneity of the study popula-
tions relative to the clinical status (asymptomatic car-
rier, inactive carrier, chronic hepatitis, cirrhosis),
geographical area and ethnicity.
We performed a systematic review to estimate sum-
mary measures of the incidence rates of cirrhosis,
HCC, decompensation and liver-related mortality in
subjects with chronic HBV infection. We selected studies
according to the following criteria: (1) longitudinal
(cohort) study design; (2) diagnosis of chronic hepatitis
or cirrhosis based on biopsy or well-dened clinical cri-
teria; (3) patients untreated for HBV infection; (4) avail-
ability of data suitable for computing approximate
estimates of the incidence rates: number of subjects at
risk, number of patients with the clinical event consid-
ered as the outcome (cirrhosis, HCC, decompensation
or liver-related mortality) and mean duration of fol-
low-up.
We performed a PubMed search and only articles
written in English were examined. We searched for all
papers published until June 2007. If multiple publica-
tions on identical study population were found, only
the main study or that with the longest follow-up was
included. If one study presented results for dierent
independent populations, for example people with
chronic hepatitis or cirrhosis, data from dierent strata
were included in the analysis separately.
All the studies were examined independently by two
researchers (F.D. and G.F.). Study characteristics and
results of individual studies were extracted from
included papers and were entered into a database. For
some studies, additional information was retrieved by
the authors.
Then a summary measure was computed by pooling
together all the data, summing up person-years on the
one hand and outcome variables on the other. We calcu-
lated separate summary measures according to two broad
geographic areas, Western countries on the one hand and
East Asia on the other hand, since dierences have been
found in both liver disease incidence and HBV infection
prevalence and its role in liver disease pattern between
these areas of the world [36]. We therefore lumped the
studies into two broad geographical areas, one including
North America and West and South Europe, the other
one including East Asian countries, i.e. Taiwan, China,
Singapore, Korea and Japan. No studies from other
countries were suitable for the analysis.
The incidence rate estimates were computed per 100
person years. We compared the incidence rates found
in Eastern and Western areas by computing the inci-
dence rate ratios (IRRs) by Poisson regression analysis
when a sucient number of studies were available [37].
Since age and gender inuence the risk of liver disease
progression [38], we computed the IRRs as the ratios
incidence rates in Eastern with respect to Western areas
adjusting for mean age at diagnosis and proportion of
males, when information on age and gender was avail-
able in a sucient number of studies.We also computed
a summary measure of the 5-year cumulative incidence
derived from the incidence rate estimate.
340 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352

The statistical tests were performed using the com-
mon cut-o of p = 0.05 for refusing the null hypothesis.
All the analyses were conducted by using the statistical
software package Stata (version 10.0, Stata Corpora-
tion, College Station, Texas).
5.2. Results
5.2.1. Incidence of cirrhosis
Summary measure of cirrhosis incidence rates accord-
ing to clinical status and geographic area is shown in
Table 3 [17,28,30,3948]. Inactive Asian and Caucasian
carriers have a very low risk of cirrhosis development,
below 0.1 per 100 person years [17,30].
In patients with HBeAg positive chronic hepatitis, the
summary cirrhosis incidence rates were 1.6 and 3.8 per
100 person years in East Asian countries and European
countries, respectively; the corresponding 5-year cumu-
lative incidences of cirrhosis were 8% and 17%. An
IRR (95% CI) of 0.41 (0.230.75; p = 0.004) was found
for studies carried out in East Asia with respect to Eur-
ope; the corresponding IRR when adjusting for mean
age and proportion of males was 0.17 (0.050.56;
p < 0.003).
In patients with HBeAg negative chronic hepatitis,
the summary cirrhosis incidence rates were 2.8 and 9.7
per 100 person years in East Asian and European coun-
tries, respectively; the corresponding 5-year cumulative
incidences of cirrhosis were 13% and 38%.
5.2.2. Incidence of hepatocellular carcinoma
Summary measures of HCC incidence rates in
patients with chronic HBV infection are reported in
Table 4 [17,26,28,30,39,42,45,4982]. In studies con-
ducted in East Asian countries, the summary HCC inci-
dence rate ranged from 0.2 per 100 person years among
inactive carriers to 0.6 in persons with chronic hepatitis
B but without cirrhosis and 3.7 in subjects with compen-
sated cirrhosis; the corresponding 5-year HCC cumula-
tive incidences were 1%, 3% and 17%. In studies
performed in Europe and the United States, the sum-
mary HCC incidence rate was 0.02 per 100 person years
in inactive carriers, 0.3 in subjects with chronic hepatitis
B without cirrhosis, and 2.2 in subjects with compen-
sated cirrhosis; the corresponding 5-year HCC cumula-
tive incidences were 0.1%, 1% and 10%. The mean age
at HCC diagnosis was 59 and 63 years in studies from
China [68] and Europe [84], respectively.
Among patients with chronic hepatitis the IRR (95%
CI) for studies carried out in East Asia with respect to
Europe and North America was 2.3 (1.34.1;
p = 0.003). Among patients with compensated cirrhosis
the IRR (95% CI) for studies carried out in East Asia
with respect to Europe and North America was 1.7
(1.32.1; p < 0.001); the corresponding IRR when
adjusting for mean age and proportion of males was
2.1 (1.43.2; p < 0.001).
5.2.3. Incidence of hepatic decompensation
The incidence of hepatic decompensation and/or gas-
troesophageal varices bleeding was 34 per 100 person
years in patients with early stages of cirrhosis in both
European and Asian studies, with a 5-year cumulative
incidence of liver decompensation of 15% [66,7577].
The mean age at the time of development of hepatic
decompensation ranged from 55 to 60 years [68,75].
5.2.4. Liver-related mortality rates
Table 5 shows liver-related mortality rates according
to clinical status and geographic area [30,49,5153,58
60,66,73,75,76,81,82,84]. The summary liver related
death rate was 0.03 per 100 person years among inactive

Table 3
Overall cirrhosis incidence rates in longitudinal studies of patients with chronic hepatitis B infection according to clinical status and geographic area
Referencesa Clinical Geographic No. No. Mean age % Mean Cirrhosis 95% Condence
status area Studies patients at entry (yr) Male follow-up (years) incidenceb Interval
[39,40] Asymptomatic carriers Taiwan 2c 5077 43 72 9.1 0.9 0.80.97
[30] Inactive carrierd Europe 1 296 36 68 29 0.01 00.03
[17] Taiwan 1 184 32 79 8 0.07 00.2
Chronic hepatitise
[41,42] HBeAg positive Europe 2 77 35 69 4.5 3.8 1.655.96
[28,4346] HBeAg positive Taiwan, Korea 5 1198 30 80 7.6 1.6 1.31.9
[47,48] HBeAg negativef Europe 2 30 34g 85g 3 9.7 2.9716.36
[17] HBeAg negativef Taiwan 1 62 32 79 8 2.8 1.344.3
a
References are listed in chronologic order within the same geographical area.
b
Incidence per 100 person years.
c
One population based study.
d
Repeatedly normal alanine aminotransferase levels and absence of hepatitis B e antigen (HBeAg) with presence of anti-HBe.
e
Patients treated with interferon were excluded from the analysis.
f
HBeAg negative, anti-HBe positive, detectable serum HBV-DNA by hybridization assays, ALT elevation and exclusion of other concomitant or
superimposed causes of liver disease.
g
Data available for one study (reference [47]).
 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352 341

Table 4
Overall hepatocellular carcinoma incidence rates in longitudinal studies of patients with chronic hepatitis B infection according to clinical status and
geographic area
Referencesa,b Clinical Geographic No. No. Mean age % Mean HCC 95% Condence
status area studies patients at entry (y) males follow-up (y) incidencec interval
[4952] Asymptomatic Europe, North 4d 6089 29 73 19 0.04 0.030.5
carrier America
[39,5358] Taiwan, China, 7e 27807 39f 88 9 0.5 0.490.55
Korea, Japan
[30,59] Inactive Europe 2 364 35 79 19.6 0.02 00.05
carrierg
[17] Taiwan 1 189 32 79 8 0.2 00.42
[26,42,6064] Chronic Europe, 7 732 36i 77i 6 0.3 0.120.41
hepatitish United States
[28,45,6571] Taiwan, China, 9 5661 36 70 6.6 0.6 0.530.72
Korea, Japan
[61,63,64,7275] Compensated Europe, 7 540 47 82 6 2.2 1.712.71
cirrhosisl United States
[45,53,56,66,7682] Taiwan, 11m 1160 45 83 6 3.7 3.24.14
Singapore, Japan
HCC, hepatocellular carcinoma.
a
References are listed in chronologic order within the same geographical area.
b
References [26,52,60,61,63] and [81] were update by the authors.
c
Incidence per 100 person years.
d
Three population based studies.
e
Four population based studies.
f
Data available for one study (reference [39]).
g
Repeatedly normal alanine aminotransferase levels and absence of hepatitis B e antigen with presence of anti-HBe.
h
Patients with cirrhosis at entry and patients treated with interferon were excluded from the analysis.
i
Data available for two studies (references [42] and [60]).
l
Patients treated with interferon were excluded.
m
Two population based studies.

HBsAg carriers and <0.1 in persons with chronic hepa- In patients with compensated cirrhosis B, the sum-
titis without cirrhosis when considering together an Ital- mary liver-related death rates were 3.3 and 2.9 per 100
ian and a Chinese study. person years in Europe and East Asia, respectively,

Table 5
Overall liver-related death rates in longitudinal studies of patients with chronic hepatitis B infection according to clinical status and geographic area
Referencesa Clinical Geographic No. No. Mean age % Mean Liver-related 95% Condence
status area studies patients at entry (y) males follow-up (y) death rateb Interval
[49,51,52] Asymptomatic Europe, 3c 6181 31 73 19.7 0.09 0.080.11
carrier North America
[53,58,84] Taiwan, 3d 6690 42e 84 8.7 0.8 0.720.85
China, Japan
[30,59] Inactive Europe 2 387 35 79 19.9 0.03 00.07
carrierf
[60] Chronic Europe 1 105 30 76 5.5 0 0
hepatitisg
[66] China 1 246 34 84 13.5 0.6 0.310.83
[73,75] Compensated Europe 2 179 48 89 6.2 3.3 2.284.4
cirrhosish
[53,66,76,81,82] Taiwan, China, Japan 5i 410 43 84 8 2.9 2.343.52
a
References are listed in chronologic order within the same geographical area.
b
Incidence per 100 person years.
c
Two population based studies.
d
Population based studies.
e
Data available for one study (reference [84]).
f
Repeatedly normal alanine aminotransferase levels and absence of hepatitis B e antigen with presence of anti-HBe.
g
Patients with cirrhosis at entry were excluded from the analysis.
h
Patients treated with interferon were excluded.
i
One population based study.
342 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352
and the 5-year liver-related death rate was 15% in Eur-
ope and 14% in East Asia. An IRR (95% CI) of 0.8
(0.61.3), not statistically signicant, was found for
studies carried out in East Asia with respect to Europe,
which did not vary when controlling for mean age and
proportion of males.
Once hepatic decompensation occurs, mortality rate
increases remarkably ranging from 70% to 85% at 5-year
follow-up in dierent studies [20,75,85]. The highest
mortality occurs in patients presenting with more than
one complication, and the lowest in those with ascites
alone [75].
5.3. Comments
Substantial dierences were found in the incidence of
cirrhosis (Table 3) and HCC (Table 4) between Eastern
and Western areas.
Among patients with HBeAg positive chronic hepati-
tis, a lower overall risk of cirrhosis was observed in
Asian studies compared with Western studies. A
detailed analysis of the ve studies from East Asia
showed the lowest incidence of cirrhosis (0.5 per 100
person years) in a study of HBeAg positive patients
(mean age 27 yrs) with normal ALT (immunotolerant
phase) [28] and the highest incidence (3 per 100 person
years), similar to the incidence in western studies, in
another study of HBeAg positive patients with elevated
ALT and active hepatitis demonstrated by liver biopsy
at enrollment [45]. Of note, a recent Chinese prospective
longitudinal study with follow-up liver biopsies showed
that immune tolerant patients have minimal or no bro-
sis progression over 5 years, but once these patients pro-
gress into the immune clearance phase the rate of
brosis progression increases [86]. Thus, the lower over-
all incidence rates of cirrhosis in Asian compared to
Western studies may be due to the inclusion in the for-
mer of a substantial proportion of HBeAg positive car-
riers presenting in the early immune tolerant phase of
chronic HBV infection.
Among patients with HBeAg negative chronic hep-
atitis, the higher incidence of cirrhosis found in the
two European studies [47,48] compared to the study
from Taiwan [17] could be due to the inclusion in
the former of a large proportion of patients with his-
tologically documented moderate or severe chronic
active hepatitis at diagnosis. Overall a roughly 2-fold
increased risk of progression to cirrhosis was found
in patients with HBeAg negative chronic hepatitis
compared with those with HBeAg positive chronic
hepatitis in both broad geographical areas. These data
are in agreement with the view that HBeAg negative
chronic hepatitis represents a late phase in the natural
history of chronic HBV infection and that patients
with HBeAg negative chronic hepatitis have a longer
duration of liver disease.
A total of 42 publications of independent cohort
studies reported incidence rates of HCC in patients with
chronic HBV infection. The HCC incidence rate varies
substantially according to geographic area and the
underlying stage of liver disease at diagnosis. The risk
of acquiring HCC is higher in patients with, than those
without, cirrhosis in both Eastern and Western studies.
Indeed cirrhosis per se is a well-recognized risk factor
for HCC regardless of its etiology [83]. The risk of
HCC is higher in persons with HBV infection from Asia
than from Western countries, possibly because of earlier
acquisition of the virus infection and of longer duration
of disease.
6. Factors predicting disease progression
6.1. Host related factors
Host factors that appear to have an impact on the
progression of chronic hepatitis B to cirrhosis and its
complications include older age, male gender and dis-
ease expression. Several studies found that Asian
patients aged 40 years and over are at higher risk of cir-
rhosis and HCC than are younger individuals
[39,40,43,44,56,69]. Western studies also demonstrated
that the incidence of cirrhosis and HCC increased signif-
icantly with increasing age at entry [26,41,60,83]. Older
age appears to be an important determinant of progres-
sion to cirrhosis and HCC probably because it is a proxy
for a longer duration of HBV infection and liver disease.
Male gender has been identied as an independent
risk factor of cirrhosis [40,44]. The molecular mecha-
nisms by which sex aects brosis progression are
unknown. The antibrogenic eect of oestrogen has
been proposed, possibly through the inhibition of stel-
late cells [87]. Overall, the risk of HCC in chronic
HBV carriers is three to six times higher in men than
in women [56,69].
The severity of brosis stage at presentation corre-
lates with the risk of cirrhosis, which was 4-fold higher
for stage F3 as compared to stage F1 or F2 [69,71].
Repeated severe acute exacerbations with failure to sup-
press HBV replication have been shown to predict
higher rates of cirrhosis [28,43]. A study has reported
that the probabilities of development of cirrhosis,
decompensation and HCC were signicantly higher in
patients whose ALT levels were persistently elevated
without ares or ared-up without normalization than
in patients whose ALT ared-up with normalization or
were persistently normal [69]. In patients with compen-
sated HBV-cirrhosis baseline biochemical characteristics
indicative of longer duration of liver disease (albumin,
bilirubin, platelets) are also signicant predictors of
HCC, decompensation occurrence and liver-related
mortality [75].
 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352
The risk of HCC is higher in persons with a family
history of HCC, suggesting a role of genetic susceptibil-
ity [88].
The role of certain genetic variants in modulating the
progression of hepatic brosis and in increasing HCC
risk is under investigation [89,90]. Angiotensin II, the
main peptide of the renin-angiotensin system, is
involved in hepatic brosis through activation of hepatic
stellate cells [89,91] and polymorphisms in the promoter
region of the angiotensinogen gene have been shown to
be associated with liver cirrhosis in patients with chronic
hepatitis B [92].
Single nucleotide polymorphisms at various foci of
the TGF-b gene with a higher TGF-b production and
a lower risk of HBV-related HCC have been described
[93,94], thus supporting the concept of the tumour sup-
pressor activity of TGF at the early stage of tumourigen-
esis [95]. However, the diculty in using genetic marker
for HCC is the dierence in the background prevalence
of dierent single nucleotide polymorphisms in dierent
ethnic populations.
6.2. Viral related factors
6.2.1. Viral load
Several lines of evidence support the association
between sustained high levels of HBV replication with
accompanying hepatitis and risk of cirrhosis and its
complications.
Ongoing HBV replication, dened by serum HBV-
DNA detectable by hybridization assays (>105106 cop-
ies per ml) or HBeAg, may accelerate the progression of
chronic hepatitis B to cirrhosis [17,26,40,43,60]. Delayed
HBeAg seroconversion (over 40 years of age) and
HBeAg seroreversion after spontaneous HBeAg sero-
conversion, indicating a prolonged period of viral repli-
cation and necroinammation, were associated with
increased risk of cirrhosis [17,28].
Among European studies, a 25-year longitudinal
study of Italian patients with HBeAg positive chronic
hepatitis B at diagnosis showed that the risk for liver
related death was increased 33-fold in patients who
remained HBeAg positive and 38-fold in those with
HBeAg negative chronic hepatitis or HBeAg reversion
relative to inactive carriers [18]. Other studies showed
that patients with compensated cirrhosis B and HBeAg
positivity and/or serum HBV-DNA detectable by
hybridization assays are at increased risk of decompen-
sation and liver related death [75].
Among studies conducted in Asian patients, a popu-
lation-based study on 11,893 Taiwanese men found that
the risk of HCC increased 10-fold among men positive
for HBsAg alone and 60-fold for those who were posi-
tive for both HBsAg and HBeAg at diagnosis compared
to those negative for both markers [96]. The increased
HCC risk in individuals seropositive for HBeAg
343
remained signicant regardless of serum level of ALT
and status of liver cirrhosis [97].
Another population-based cohort study of more than
3500 untreated HBsAg carriers (45 years of age at enrol-
ment, 85% HBeAg negative, 94% with normal ALT) in
Taiwan found that the risk of cirrhosis and HCC
increased signicantly with increasing baseline serum
HBV-DNA levels detected by sensitive polymerase
chain reaction (PCR) assays [40,56]. The adjusted rela-
tive risks (RRs) of cirrhosis were 2.5, 5.6 and 6.5 when
baseline HBV-DNA levels were equal to or greater than
104, 105 and 106 copies/ml, respectively [40]. The risk of
HCC increased signicantly at the level of 104 copies/ml
and was highest for patients with the highest baseline
HBV-DNA level (>106 copies/ml) with hazard risk
(HR) values of 2.3 and 6.1, respectively [56]. HBV-
DNA level remained an independent predictor of cirrho-
sis or HCC after adjustment for risk factors of age, sex,
smoking, alcohol and HBeAg status and serum ALT
levels at enrolment [40,56]. The authors suggested that
HBV-DNA levels of 104 copies/ml or more are the
strongest predictor of future cirrhosis or HCC risk,
regardless of HBeAg status and serum ALT levels at
baseline [40,56].
A prospective Chinese cohort study of 2763 HBsAg
positive adults reported that high viral load at baseline
(>105 copies/ml) was associated with increased mortal-
ity from HCC and chronic liver disease over a 11-year
period [84].
Overall, these studies support the concept that the
higher the level of HBV replication, the greater the risk
of cirrhosis, HCC, decompensation and liver related
mortality. However, the above ndings from popula-
tion-based cohort studies in Taiwan of a direct associa-
tion between serum HBV DNA levels above 104 copies/
ml and cirrhosis or HCC risk should be considered with
caution because only baseline measures of HBV-DNA
level were tested, which are poorly related with the levels
of HBV replication and disease activity during the whole
follow-up of an individual [40,56]. In addition, these
ndings in Chinese subjects in their 40s with perinatally
or early childhood acquired HBV infection cannot be
directly referred to Caucasian patients with adolescence
or adult acquired HBV infection and a shorter duration
of infection.
Persistent reduction of HBV replication during fol-
low-up predicts a favourable outcome. Long term fol-
low-up studies of adult inactive HBsAg carriers have
shown that these patients rarely progress to cirrhosis
or HCC (Tables 3 and 4) [17,30]. Cirrhotic patients
who clear HBeAg with sustained reduction of HBV-
DNA, ALT normalization, and eventually, HBsAg loss
have a very low risk of developing HCC and decompen-
sation and increased survival compared to cirrhotics
with persistently high levels of HBV replication [20].
In addition it has been reported that survival can be
344 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352
prolonged in HBsAg positive decompensated cirrhotics
who subsequently lose HBsAg [20].
6.2.2. HBV genotypes
HBV is currently classied into 8 genotypes, A to H.
HBV genotypes can be further segregated into subgeno-
types based on a more than 4% (but less than 8%) dier-
ence in the entire nucleotide sequence with distinct
ethnic or geographic origin [21]. Increasing evidence
supports the view that dierent HBV genotypes have a
role in determining the clinical outcome of liver disease.
This has been shown with genotypes B and C, and geno-
types A and D. Genotypes B and C are seen mostly in
Asia, genotype A in Northwest Europe, North America,
India and Africa and genotype D in Southern Europe,
the Middle East and India. Various cross sectional stud-
ies found that patients with genotype C have more
severe liver disease, including cirrhosis or HCC, than
those with genotype B, as recently reviewed [21,98]. In
a longitudinal study of 202 patients with HBeAg posi-
tive chronic hepatitis from Taiwan, genotype C was pre-
dictive of cirrhosis development [99]. A lower rate of
spontaneous HBeAg seroconversion, and a longer dura-
tion of high levels of HBV replication associated with
more severe hepatitis activities may contribute to a
higher risk of progression to cirrhosis among genotype
C patients compared to those with genotype B infection
[100]. In cohort studies of 426 chronic hepatitis B
patients from Hong Kong [67] and of 4841 HBsAg posi-
tive men from Taiwan [55] genotype C was associated
with a 3- and 5-fold increased HCC risk, respectively,
compared with other HBV genotypes. The main discrep-
ant nding comes from a study in Taiwan reporting that
genotype B is associated with an increased risk of HCC
in young adult patients mostly non-cirrhotic [101]. Sim-
ilarly, in Taiwan the majority of children with HCC and
chronic HBV infection have genotype B [9].
As for other genotypes, a cross-sectional study from
India [102] and a longitudinal report from Spain [103]
found that genotype D was associated with more pro-
gressive liver disease compared to genotype A. A study
in Vietnamese patients has reported that genotype D
correlated positively with the presence of liver cirrhosis
and genotype C and D were signicantly associated with
HCC [104]. However, a case control study in sub-Saha-
ran Africans showed a 4.5-fold increased risk for HCC
in HBV carriers infected with genotype A compared
with those infected with non-A genotypes and this
increased risk was entirely attributable to subgenotype
A1 [105]. Another study found a signicant association
between genotype F and the development of HCC
among native Alaskans with chronic HBV infection
[106]. Overall these data suggest that genotype D infec-
tion is associated with more active liver disease and
advanced liver brosis compared with genotype A infec-
tion, whereas the association with HCC is controversial.
6.2.3. HBV mutations
Because of the spontaneous error rate of viral reverse
transcriptase, HBV mutants often emerge during the
course of infection. The most common naturally occur-
ring HBV mutations are the pre-core G1896A mutation
and the dual basal core promoter (BCP) A1762T/
G1764A mutation.
Cross-sectional studies have reported that core pro-
moter mutations are associated with more severe liver
damage [107109]. Genotype C tends to have a higher
proportion of BCP T1762/A1764 mutation than does
genotype B [107,108] and this fact may partly explain
the association between genotype C and poor histology
[109].
Studies have indicated that BCP T1762/A1764 muta-
tion is associated with an increased risk of developing
HCC independently of HCV genotype [108,110,111]
and of serum viral load [111,112]. BCP T1762/A1764
mutation might contribute to HCC risk because it is
associated with changes in the overlapping X gene and
therefore in the X protein, a transactivator of cellular
gene including oncogene [113].
A case-control study found a higher prevalence of
pre-S deletion, BCP T1762/A1764 mutation and pre-
core G1896A mutation in patients with progressive liver
disease, including patients with HCC, as compared to
age-matched chronic HBV carriers with persistently nor-
mal ALT [110]. The same study also found that combi-
nation of mutations rather than single mutation was
associated with progressive liver disease and HCC, espe-
cially in combination with pre-S deletion [110].
6.2.4. Concurrent infection
Concurrent infection with HCV is present in 1015%
of patients with chronic HBV infection, particularly in
area where both HBV and HCV are endemic [24]. The
eect of concurrent HCV or HDV infections on the risk
of progression of liver disease in patients with HBV
infection deserves to be better dened, in spite of a large
number of cross-sectional and case-control studies per-
formed so far. Two meta-analyses of case-control stud-
ies showed a synergism between HBV and HCV
infections for HCC risk [114,115], but cohort studies
were not taken into account as they were too sparse
and with low power to investigate the eect of concur-
rent infection.
Thus, we evaluated the interaction between HBV and
HCV or HDV infection in the liver disease progression
by examining publications of cohort studies which
reported separate results according to the presence of
HCV or HDV concurrent infection in people with
chronic HBV infection. We computed the RRs as the
ratios of cirrhosis or HCC incidence rates among sub-
jects with and without HCV or HDV concurrent infec-
tion. We performed a meta-analysis of these studies to
estimate a summary RR. We computed summary RRs
 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352 345

as the weighted means of the RRs of each study using
weights equal to the inverse of the variances, when a suf-
cient number of studies without substantial heteroge-
neity among them were available [116]. We evaluated
heterogeneity using the Cochran Q test and we quanti-
ed the extent of heterogeneity using I2, the percentage
of total variation across studies attributable to heteroge-
neity between studies [117].
Among cohort studies which estimated the inci-
dence rate of cirrhosis among chronic HBV carriers,
we retrieved only three studies investigating the pres-
ence of HCV infection, and four studies regarding
the presence of HDV infection (Table 6) [44,71,118
120]. As regards the inuence of concurrent HCV
infection, only one study found a signicant increased
risk of cirrhosis development, with a RR of 3.3, in
patients with dual HBV and HCV infection as com-
pared to a sex and age matched control group of
patients with HBV infection alone [118]. Of note, this
is the only study that eliminated the inuence of age
and gender factors on disease progression by selection
of a well-matched control group of active chronic hep-
atitis B [118]. An increase in the risk of cirrhosis
occurrence due to HDV infection was observed in
all the four studies we retrieved, however it was statis-
tically signicant in two of them, with RRs of 2.6 and
2.8 [119,120]. HDV genotype II is dominant in Tai-
wan [121] and may explain the less aggressive course
of HDV infection reported in studies from Taiwan
[44,118] compared with those in dierent geographic
areas [119,120]. In addition, the complex viral inter-
play in cases of dual HBV and HCV or HBV and
HDV infection [122], the limited power of some stud-
ies, due to the small number of patients included and/
or the short follow-up, and the dierent study design
may provide an explanation for these discrepancies.
Due to the high, statistically signicant heterogeneity
among studies, we did not compute a summary RR
for both HCV and HDV concurrent infection.
Eight cohort studies were retrieved on the risk of
HCC among patients with HBV-related cirrhosis
according to the presence of HCV infection, most of
them having been carried out in Europe and US (Table
7) [74,79,123128]. A roughly 2-fold increased risk of
developing HCC was found in patients with dual HBV
and HCV infection compared with those with HBV
infection only both in Western and East Asian studies.
No signicant heterogeneity was found (Cochran Q test:
p = 0.8; I2 = 0%). The summary RR when including
both Western and Asian studies was 1.98 (1.392.82).
Only two cohort studies evaluated the incidence of
HCC according to the presence of HDV infection:
patients with concurrent HDV infection had a roughly
3-fold increased risk for HCC, both in subjects with
chronic HBV infection [120] and in patients with cirrho-
sis type B compared to those with HBV infection only
[129] (data not shown in Table).
The prevalence of HBV infection among human
immunodeciency virus (HIV) positive subjects varies
markedly, from 510% in Western Europe and the Uni-
ted States to 2030% in Asia and parts of sub-Saharan
Africa [130]. Studies conducted before the introduction
of the highly active anti-retroviral therapy (HAART)
have shown that HIV-related immune deciency modi-
es the natural history of chronic HBV infection with
higher levels of HBV replication and a lower rate of

Table 6
Relative risk of cirrhosis occurrence in cohort studies of patients with chronic HBV infection according to HBV infection alone or with concurrent HBV
and HCV or HBV and HDV infection
Author Geographic Clinical No. Mean age % Mean Cirrhosis cases Relative 95% Condence
(reference) area status patients at entry (y) males follow-up risk Interval
HBV/HCV
Huo [44] Taiwan No 377 na na 5.7 47 1
Yes 49 na na 5.7 9 1.5 0.633.04
Ikeda [71] Japan No 610 34 78 4.1 62 1
Yes 52 43 82 4.1 4 0.75 0.202.03
Liaw [118] Taiwan No 64 na na 12.3 11 1
Yes 64 na na 6.8 20 3.3 1.507.60
HBV/HDV
Fattovich [119] Italy No 69 36 76 4.7 19 1
Yes 13 26 72 5 10 2.6 1.095.93
Tamura [120] Japan No 1058 na na 10 43 1
Yes 69 na na 10 8 2.8 1.166.14
Huo [44] Taiwan No 377 na na 5.7 47 1
Yes 90 na na 5.7 15 1.3 0.692.43
Liaw [118] Taiwan No 64 na na 12.3 11 1
Yes 64 na na 8.2 12 1.6 0.664.09

HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis delta virus.
346 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352

Table 7
Relative risk of hepatocellular carcinoma occurrence in patients with cirrhosis according to HBV infection alone or HBV and HCV concurrent infection
Referencesa,b Geographic No. HBV/HCV No. Mean age % Mean HCC Relative 95% Condence
area studies coinfection patientsc at entry (y) males follow-up (y) cases risk interval
[74,123127] Europe, 6 No 274 46d 74d 6.29 34 1
United States
Yes 108 47 81 6.66 29 2.04 1.223.42
[79,128] Taiwan, 2 No 321 50 75 3.8 78 1
Japan
Yes 50 55 70 2.9 19 1.92 1.193.10
HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma.
a
References are listed in chronologic order within the same geographical area.
b
References [124] and [125] were updated by the authors.
c
Patients with cirrhosis in Child-Pugh class A, B or C were included.
d
Data available for two studies.

spontaneous HBeAg seroconversion, leading to a more
rapid progression towards cirrhosis [131,132].
A higher rate of cirrhosis decompensation, but not of
HCC, was reported in HIV/HBV co-infected individuals
with cirrhosis before the introduction of HAART
[131,132]. In addition individuals co-infected with HIV
and HBV are at greater risk of liver-related mortality
than those with HIV or HBV alone [133]. A retrospec-
tive analysis of 2041 HIV/HBV coinfected patients has
shown that the use of lamivudine as part of combination
antiretroviral therapy is associated with a reduced risk
of liver related death over 4 years of follow-up [134].
6.3. Other factors
nese investigation found that heavy alcohol intake can
increase the risk of progression to cirrhosis 6-fold rela-
tive to alcohol abstinence among patients chronically
infected with HBV [71]. Of the two longitudinal studies
on HCC risk which reported the amount of alcohol
intake, a Japanese study among patients with compen-
sated HBV-related cirrhosis showed that heavy alcohol
intake was associated with a 3-fold increased risk for
HCC [80]. A population based cohort study from Korea
found that in the subgroup of chronic HBV carriers the
HCC risk started to increase signicantly with an alco-
hol intake of 50 g/day or more with a RR (95% CI) of
1.2 (1.01.5) for 5099 g/day and of 1.5 (1.22.0) for
>100 g/day [136].

6.3.1. Alcohol 6.3.2. Metabolic factors

An Italian case control study found a 2-fold higher
risk of HCC for combined HBV infection and drinking
>60 g/day of alcohol for at least 10 years compared to
HBV infection alone [135]. However, very few cohort
studies investigated the interaction between HBV infec-
tion and alcohol drinking with quantication of the
amount of alcohol usually drunk by patients. A Japa-
The prevalence of steatosis ranges from 20% to 70%
in liver biopsies of patients with chronic hepatitis B
[137140]. Superimposed non-alcoholic fatty liver dis-
ease and non-alcoholic steatohepatitis in patients with
chronic hepatitis B seem to be related to the components
of the metabolic syndrome (obesity, dyslipidemia,
hypertension and insulin resistance) and not to the virus

50 50
% Taiwan and Korea % Europe
40 HBeAg negative 40 HBeAg negative
HBeAg positive HBeAg positive
30 30

20 20

10 10

0 0
0 1 2 3 4 5 0 1 2 3 4 5
years years

Fig. 1. Combined data from published studies of the cumulative incidence of cirrhosis in patients with hepatitis B e antigen (HBeAg) positive or negative
chronic hepatitis according to geographical area. In East Asia the 5-year cumulative incidence was 8% in HBeAg positive chronic hepatitis and 13% in
HBeAg negative chronic hepatitis. In Europe the 5-year cumulative incidence was 17% in HBeAg positive chronic hepatitis and 38% in HBeAg negative
chronic hepatitis.
 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352
20 20
% Taiwan, China, Singapore, Korea
%
and Japan
15 15
cirrhosis
10 chronic hepatitis 10
inactive carrier
5 5
1 1
0 0
0 1 2 3 4 5
years
Fig. 2. Combined data from published studies of the cumulative incidence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection
according to geographical area and clinical status. In East Asia the 5-year cumulative incidence was 1% in inactive carriers, 3% in chronic hepatitis
without cirrhosis and 17% in cirrhosis. In Europe and the United States the 5-year cumulative incidence was 0.1% in inactive carriers, 1% in chronic
hepatitis without cirrhosis and 10% in cirrhosis.
itself [137139]. There is no conclusive evidence concern-
ing a possible association between hepatic steatosis and
brosis progression in chronic hepatitis B. Two cross
sectional studies found that hepatic steatosis was not
correlated with severity of brosis [137,138], whereas a
longitudinal study of Italian patients with chronic hepa-
titis B reported that steatosis (present in approximately
40% of patients) was associated with a 2-fold increased
risk of progression to clinical cirrhosis [26].
Data on the impact of diabetes or obesity on progres-
sion to cirrhosis and HCC of HBV infected patients are
scanty. One longitudinal study on Asian patients with
chronic hepatitis B found that diabetes was associated
with a signicant 5-fold increased risk for cirrhosis
[44]. A systematic review of case-control and cohort
studies found that diabetes was associated with a 2.5-
fold increased risk for HCC, when taking account of
the major risk factors for the disease [141]. The signi-
cant association between diabetes and HCC was inde-
pendent of HBV infection in the only study that
examined this factor [142].
In a recent study, the presence of central obesity
seems to inuence the development of brosis in patients ease manifest in adulthood, whereas the majority of
with chronic hepatitis B, probably related to the strong
association between central obesity, insulin resistance
and probrogenic adipokines [139]. Some data support
a role of obesity as a single agent or rather as a cofactor
in causing HCC, but most studies did not take into
account confounding risk factors, such as diabetes, alco-
hol consumption or viral infections, as recently reviewed
[135].
6.3.3. Environmental factors
Environmental hepatotoxins including tobacco
smoke and aatoxins may increase the risk of HCC.
Few and discordant data are available on the associa-
tion of cigarette smoking with HCC in patients with
chronic HBV infection [56,96]. In the study of 11,893
347
Europe and USA
cirrhosis
chronic hepatitis
inactive carrier
0 1 2 3 4 5
years
Taiwanese men the risk of HCC increased 1.5-fold
among cigarette smokers compared to non-smokers
[96], whereas in the population-based cohort study of
more than 3500 HBsAg carriers from Taiwan smoking
did not aect the HCC risk [HR (95% CI): 1.0 (0.7
1.4)] [56], after adjustment for the known risk factors
for HCC. It has been reported that exposure to even
modest levels of aatoxin, a mycotoxin which contami-
nates food in humid conditions, triples HCC risk in
HBV infected men [143].
7. Conclusions
The following conclusions can be drawn: (1) The
course of perinatally acquired chronic hepatitis B is dif-
ferent from that of postnatally-acquired chronic hepa-
titis B in that children in the former group have
minimal, if any, hepatitis activities despite the presence
of high levels of HBV replication for 13 decades, are
at low near-term risk of developing signicant morbid-
ity and mortality and most complications of liver dis-
children in the latter group become inactive HBsAg
carriers before adulthood. However HCC may occur
during childhood especially in children with cirrhosis.
(2) Long term studies of HBeAg positive chronic hep-
atitis in adults show that most become inactive carriers
after spontaneous HBeAg seroconversion. Progression
to HBeAg negative chronic hepatitis occurs at a rate
of 13 per 100 person years following HBeAg serocon-
version. (3) Figs. 1 and 2 illustrate the 5-year cumula-
tive incidence of cirrhosis and HCC, respectively,
according to clinical status and geographical area.
The incidence of cirrhosis appears to be about 2-fold
higher in HBeAg negative compared to HBeAg posi-
tive chronic hepatitis both in Europe (5-year cumula-
tive incidence 38% and 17%, respectively) and in East
348 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352

Asia (5-year cumulative incidence 13% and 8%, respec- Table 9

tively). Irrespective of the severity of the underlying Factors associated with increased risk of HCC occurrence
liver disease, the risk of HCC in persons with HBV Factors Comment
infection is higher in East Asian countries than in Wes- Host related
tern countries, possibly because of earlier acquisition of Older age (>40 years) Important
HBV infection, longer duration of disease and/or expo- Male gender Important
Presence of cirrhosis Important
sure to environmental factors. The cirrhotic patient has Family history of HCC Important
an increased risk of HCC compared with patients with Race (Asian, African) Important
chronic hepatitis B without cirrhosis or inactive carriers Genetic diversity More research needed
both in East Asia (5-year cumulative risk 17%, 3% and Viral related
1%, respectively) and in the West (5-year cumulative High levels of HBV replication Important
risk 10%, 1% and 0,1%, respectively). 4. Factors inu- during follow-up
encing progression to cirrhosis and HCC in patients HBV genotype (C > B) Increasing evidence
HBV variant (core promoter; pre-S) Increasing evidence
with chronic hepatitis B are shown in Tables 8 and 9,
HDV concurrent infection Importanta
respectively. High levels of HBV-DNA replication HCV concurrent infection Importantb
and disease activity at enrolment and during follow- HIV concurrent infection More research needed
up are the best predictors of adverse clinical outcomes
Other factors
(cirrhosis, HCC, decompensation and liver related Heavy alcohol consumption Important
mortality). Sustained reduction of HBV replication Aatoxin Important in HBV
before the onset of cirrhosis confers a favourable prog- endemic regions
nosis, with similar survival compared to uninfected Smoking More research needed
Diabetes More research needed
individuals. Sustained reduction of viral replication in
Obesity More research needed
cirrhotic patients lowers the risk of HCC and improves a
Few cohort studies.
survival. Older age, male gender, multiple ALT ares, b
Cohort studies conducted among patients with cirrhosis.
severity of brosis stage at presentation, severity of
compensated cirrhosis at presentation, concurrent
infections (HBV/HCV and/or HBV/HDV) and alcohol types, genotype mixtures), mutants and viral load)
abuse are additional predictors of disease progression. and to investigate other viral factors (HIV coinfection
Further studies are needed to clarify the interplay of during the HAART era) and preventable or treatable
each known viral factor (HBV genotypes (subgeno- comorbidities (obesity, diabetes) in the prognosis of
chronic hepatitis B. (5) Recent improvements in the
Table 8
knowledge of the natural history of chronic hepatitis
Factors associated with increased risk of progression to cirrhosis B and a detailed understanding of predictors of disease
Factors Comment
progression will help in the management of children
and adults with chronic hepatitis B and in deciding
Host related
Older age (>40 years) Important
whom to treat. Counselling on cofactors of liver dam-
Male gender Important age, such as alcohol, is important, as they can change
Severity of brosis stage at Important the prognosis at any time. Dierences in long term out-
presentation (F3) comes between patients infected perinatally or early in
Recurrent ares of hepatitis Important life and those infected during adulthood should be
Genetic diversity More research needed
taken into account in current recommendation for
Viral related treatment of chronic hepatitis B.
High levels of HBV replication Important
during follow-up
HBV genotype (C > B; D > A) Increasing evidence Acknowledgements
HBV variant (core promoter; pre-S) Increasing evidence
HDV concurrent infection Importanta We wish to thank Dr. Giovanni Maifredi for his
HCV concurrent infection Importanta invaluable help in statistical data analysis. The following
HIV concurrent infection Importantb
researchers kindly provided unpublished information
Other factors regarding the results of their studies: Dr. L. Benvegnu`,
Heavy alcohol consumption Important University of Padova, Padova, Italy; Professor V. Di
Steatosis More research needed
Diabetes More research needed
Marco, University of Palermo, Palermo, Italy; Dr.
Obesity More research needed M.R. Brunetto, Azienda Ospedaliera Universitaria
a Pisana, Pisa, Italy; Dr. M. Kobayashi, Toranomon Hos-
Many cross-sectional and case-control studies, but few cohort
studies. pital, Tokyo, Japan; Dr. S.M. Lin, Chang Gung Memo-
b
Studies conducted before the introduction of highly active antiret- rial Hospital, Taipei, Taiwan; Dr. G.V. Papatheodoritis,
roviral therapy. Hippokration General Hospital, Athens, Greece; Dr. J.
 G. Fattovich et al. / Journal of Hepatology 48 (2008) 335352
Ribes, Hospitalet del Llobregat, Spain; Professor M
Colombo and Dr. A. Sangiovanni, IRCSS Maggiore
Hospital and University of Milan, Milan, Italy.
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