Journal of Hepatology
Volume 48, Issue 2 , Pages 335-352, February 2008

Natural history of chronic hepatitis B: Special emphasis on disease progression and prognostic factors☆

  • Giovanna Fattovich

      Affiliations

    • Department of Surgical and Gastroenterological Sciences, University of Verona, Piazzale L.A. Scuro, 10, Verona 37134, Italy
    • Corresponding Author InformationCorresponding author. Tel./fax: +39 045 8124205.
    • ,
  • Flavia Bortolotti

      Affiliations

    • Fifth Medical Clinic, University of Padova, Padova, Italy
    • ,
  • Francesco Donato

      Affiliations

    • Institute of Hygiene, Epidemiology and Public Health, University of Brescia, Brescia, Italy

published online 04 December 2007.

Associate Editor: R.P. Perrillo

Article Outline

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 influencing the course of the liver disease. Chronic hepatitis B is characterized by an early replicative phase (HBeAg positive chronic hepatitis) 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 progression to HBeAg negative chronic hepatitis due to HBV variants not expressing HBeAg occurs at a rate of 1–3 per 100 person 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 hepatocellular 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 influencing disease progression, which ultimately could improve the management of chronic hepatitis B.

Keywords: Chronic hepatitis B, Natural history, Prognostic factors

 

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1. Introduction 

Chronic infection with hepatitis B virus (HBV) currently affects 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 defined. A careful understanding of the clinical outcomes and factors affecting disease progression is important in the management of chronic hepatitis B. This article reviews the natural history of chronic hepatitis B, with emphasis on summarizing the available data to estimate the rates of disease progression according to the stage of the disease and factors influencing its course.

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2. Phases of chronic HBV infection 

The likelihood of developing chronic HBV infection is higher in individuals infected perinatally (90%) or during childhood (20–30%), when the immune system is thought to be immature, compared with immunocompetent subjects 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 virus–host interaction: immune tolerance, immune clearance, 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 fibrosis. 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 10–30 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 tolerance to the virus is lost and the immune system mounts an attack on infected hepatocytes. This second immunoactive phase is characterized by fluctuating, but progressively decreasing, HBV-DNA levels, elevated ALT and hepatic necroinflammation. 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 necroinflammation with variable amounts of fibrosis on liver biopsy. Serum HBV-DNA levels generally exceed 20,000IU/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, undetectable or low levels of HBV-DNA [suggested levels less than 2000IU/ml (104 copies/ml)], persistently normal ALT levels and inactive liver histology with a usually minimal amount of fibrosis.

2.4. Reactivation phase 

As viral supercoiled DNA persists in the liver, a number of inactive HBsAg carriers may eventually develop HBV reactivation with recrudescence of liver disease either spontaneously or triggered by active immunosuppression. Reactivation of viral replication may occur due to reactivation with the wild type virus with reversion 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 [2000–20 million IU/ml (104– 108 copies/ml)], ALT elevation and moderate or severe necroinflammation with variable amounts of fibrosis 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 detectable 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 classified according to their serologic status as shown in Table 1.

Table 1. Serological profiles of chronic hepatitis B virus infection
PhaseSerum ALTHBeAgAnti-HBeHBV-DNA
Copies/mlIU/ml
Immune toleranceNormal or minimally elevatedPositiveNegativeVery high levels108–101120 million–20 billion
HBeAg positive chronic hepatitisPersistently elevatedPositiveNegativeHigh levels106–1010200,000–2 billion
HBeAg negative chronic hepatitisElevated and often fluctuatingNegativePositiveModerate levels, often fluctuating104– 1082000–20 million
Inactive carrierNormalNegativePositiveLow or no detectable levels<104<2000

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3. Chronic hepatitis B in children 

Chronic hepatitis B in childhood has some unique features which largely depend on age at primary HBV infection 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 Taiwan, prior to mass vaccination, perinatal transmission of HBV was estimated to account for 40–50% of the HBsAg carriers and horizontal transmission early in life for the remaining cases [5], [6]. Clinical data indicate that there are differences in the natural course of chronic hepatitis B in children according to perinatal or postnatal acquisition 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 normal ALT and minimal liver damage (immunotolerant phase) and are usually asymptomatic. The rate of spontaneous HBeAg seroconversion is low, less than 2% per year among children aged 3 years or less, and 4–5% per year in older children [5], [7], so that by the age of 10–15 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 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 concomitant 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 seroconversion 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 examination [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 positive 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 necroinflammation may occur during the process of HBeAg seroconversion leading 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 observation 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 20–30% complain of non-specific symptoms. Spontaneous HBeAg seroconversion occurs frequently at an average rate of 14–16% per year during the first 10 years of follow-up [13], [14]. ALT flares are often observed prior to HBeAg seroconversion. The predictive role of HBV genotypes in relation to HBeAg seroconversion or disease severity is of limited value in areas such as Italy where genotype D accounts for the vast majority of paediatric 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 cirrhosis 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 3–4% of cases at baseline in cohort studies of Italian and Spanish children with chronic hepatitis B [13], [14], [15]. Cirrhosis appears to be an early complication, being observed mainly (70% of cases) before the age of 4 years. In addition, 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 longitudinal studies progression of chronic hepatitis B to cirrhosis was not observed over a period up to 29 years [13], [14], [15]. Reversion of cirrhosis to significant fibrosis [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 affecting cirrhotic 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].

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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 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 hepatitis 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 diminished risk of disease progression [17], [18]. A study reported that in addition to HBeAg seroconversion sustained disease remission defined as normal ALT and HBV-DNA levels less than 104 copies/ml is required in order to achieve regression of fibrosis and hepatic inflammation [19]. HBeAg seroconversion occurs at an annual rate of 10–15% 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 incidence rate of 18 per 100 person years [18]. Factors associated with higher rates of spontaneous HBeAg seroconversion include older age, higher ALT levels, HBV genotypes B (versus C) and A (versus D) and ethnicity other than Asian [3], [20], [21].

4.2. HBeAg negative chronic hepatitis 

Persistent HBV replication despite HBeAg seroconversion or HBV reactivation following a period of remission after HBeAg seroconversion leads to HBeAg negative chronic hepatitis. Other concomitant or superimposed 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 terminates 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 influenced 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 reflecting the aging of existing HBsAg carriers [22], [23]. Recent studies have reported that 70–90% 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 first presentation [17], [22], [25]. Patients with HBeAg negative chronic hepatitis have lower levels of serum HBV-DNA [2000–20 million IU/ml (104–108 copies/ml)] than patients with HBeAg positive chronic hepatitis [200,000–2 billion IU/ml (106–1010 copies/ml)]. However, many patients with HBeAg negative chronic hepatitis have wide fluctuations 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 negativity and anti-HBe positivity, undetectable or low serum HBV-DNA levels (<2000IU/ml) and normal serum ALT levels in one occasion should not be classified as an inactive carrier without an appropriate follow-up. Indeed patients with HBeAg negative chronic hepatitis have wide fluctuations in serum ALT and 20–30% of these patients with histological documented chronic hepatitis have normal ALT at the time of presentation [22].

Long term longitudinal studies (up to 23 years) of adult inactive carriers have reported that 15–24% developed HBeAg negative chronic hepatitis and 1–17% 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 1–2% 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]. However, 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 studies from high endemic areas might be due to the relative short follow-up [29]. Factors significantly 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 prognosis, 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 outcomes of disease progression such as decompensation, HCC or death may occur in these patients, particularly those with cirrhosis or in patients with concurrent hepatitis C virus (HCV) or hepatitis delta virus (HDV) infection at the time of HBsAg clearance [31], [32], [33], [34], [35].

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 HBsAg lossAuthor (Reference)Geographic areaNo. patientsMean age at entry (yr)% malesMean follow-up (y)No. HCCNo. decompensationNo. death/ OLT
Chronic hepatitisChen [34]Taiwan189 (43)43795.12 (2)01 (1)
Ahn [32]Korea32a50731.61nana
Arase [35]Japan164a51805000
Chronic hepatitis or cirrhosisYuen [31]China92a43714.25b0na
CirrhosisFattovich [33]Europe32 (na)45904.61 (1)22 (1)
Chen [34]Taiwan29 (12)54795.11 (1)4 (2)1 (1)
Ahn [32]Korea17a50731.64nana
Arase [35]Japan67a51806.1200

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.

aNone of the patients had concurrent infection with hepatitis C virus or hepatitis delta virus.

bFour of the five patients had cirrhosis.

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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 published, a summary of their results is hampered by the different study designs (case-control, cross-sectional, longitudinal) and the heterogeneity of the study populations relative to the clinical status (asymptomatic carrier, inactive carrier, chronic hepatitis, cirrhosis), geographical area and ethnicity.

We performed a systematic review to estimate summary 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-defined clinical criteria; (3) patients untreated for HBV infection; (4) availability of data suitable for computing approximate estimates of the incidence rates: number of subjects at risk, number of patients with the clinical event considered as the outcome (cirrhosis, HCC, decompensation or liver-related mortality) and mean duration of follow-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 publications 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 different independent populations, for example people with chronic hepatitis or cirrhosis, data from different 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 calculated separate summary measures according to two broad geographic areas, Western countries on the one hand and East Asia on the other hand, since differences 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 incidence rate ratios (IRRs) by Poisson regression analysis when a sufficient number of studies were available [37]. Since age and gender influence 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 available in a sufficient number of studies.We also computed a summary measure of the 5-year cumulative incidence derived from the incidence rate estimate.

The statistical tests were performed using the common cut-off 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 Corporation, College Station, Texas).

5.2. Results 

5.2.1. Incidence of cirrhosis 

Summary measure of cirrhosis incidence rates according to clinical status and geographic area is shown in Table 3 [17], [28], [30], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48]. Inactive Asian and Caucasian carriers have a very low risk of cirrhosis development, below 0.1 per 100 person years [17], [30].

Table 3. Overall cirrhosis incidence rates in longitudinal studies of patients with chronic hepatitis B infection according to clinical status and geographic area
ReferencesaClinical statusGeographic areaNo. StudiesNo. patientsMean age at entry (yr)% MaleMean follow-up (years)Cirrhosis incidenceb95% Confidence Interval
[39], [40]Asymptomatic carriersTaiwan2c507743729.10.90.8–0.97
[30]Inactive carrierdEurope12963668290.010–0.03
[17] Taiwan1184327980.070–0.2
Chronic hepatitise
[41], [42]HBeAg positiveEurope27735694.53.81.65–5.96
[28], [43], [44], [45], [46]HBeAg positiveTaiwan, Korea5119830807.61.61.3–1.9
[47], [48]HBeAg negativefEurope23034g85g39.72.97–16.36
[17]HBeAg negativefTaiwan162327982.81.34–4.3

aReferences are listed in chronologic order within the same geographical area.

bIncidence per 100 person years.

cOne population based study.

dRepeatedly normal alanine aminotransferase levels and absence of hepatitis B e antigen (HBeAg) with presence of anti-HBe.

ePatients treated with interferon were excluded from the analysis.

fHBeAg negative, anti-HBe positive, detectable serum HBV-DNA by hybridization assays, ALT elevation and exclusion of other concomitant or superimposed causes of liver disease.

gData available for one study (reference [47]).

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 cumulative incidences of cirrhosis were 8% and 17%. An IRR (95% CI) of 0.41 (0.23–0.75; p=0.004) was found for studies carried out in East Asia with respect to Europe; the corresponding IRR when adjusting for mean age and proportion of males was 0.17 (0.05–0.56; 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 countries, 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], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82]. In studies conducted in East Asian countries, the summary HCC incidence 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 compensated cirrhosis; the corresponding 5-year HCC cumulative incidences were 1%, 3% and 17%. In studies performed in Europe and the United States, the summary 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 compensated cirrhosis; the corresponding 5-year HCC cumulative 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.

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,bClinical statusGeographic areaNo. studiesNo. patientsMean age at entry (y)% malesMean follow-up (y)HCC incidencec95% Confidence interval
[49], [50], [51], [52]Asymptomatic carrierEurope, North America4d60892973190.040.03–0.5
[39], [53], [54], [55], [56], [57], [58] Taiwan, China, Korea, Japan7e2780739f8890.50.49–0.55
[30], [59]Inactive carriergEurope2364357919.60.020–0.05
[17] Taiwan1189327980.20–0.42
[26], [42], [60], [61], [62], [63], [64]Chronic hepatitishEurope, United States773236i77i60.30.12–0.41
[28], [45], [65], [66], [67], [68], [69], [70], [71] Taiwan, China, Korea, Japan9566136706.60.60.53–0.72
[61], [63], [64], [72], [73], [74], [75]Compensated cirrhosislEurope, United States7540478262.21.71–2.71
[45], [53], [56], [66], [76], [77], [78], [79], [80], [81], [82] Taiwan, Singapore, Japan11m1160458363.73.2–4.14

HCC, hepatocellular carcinoma.

aReferences are listed in chronologic order within the same geographical area.

bReferences [26], [52], [60], [61], [63] and [81] were update by the authors.

cIncidence per 100 person years.

dThree population based studies.

eFour population based studies.

fData available for one study (reference [39]).

gRepeatedly normal alanine aminotransferase levels and absence of hepatitis B e antigen with presence of anti-HBe.

hPatients with cirrhosis at entry and patients treated with interferon were excluded from the analysis.

iData available for two studies (references [42] and [60]).

lPatients treated with interferon were excluded.

mTwo population based studies.

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 (1.3–4.1; 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 (1.3–2.1; p<0.001); the corresponding IRR when adjusting for mean age and proportion of males was 2.1 (1.4–3.2; p<0.001).

5.2.3. Incidence of hepatic decompensation 

The incidence of hepatic decompensation and/or gastroesophageal varices bleeding was 3–4 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], [75], [76], [77]. 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], [51], [52], [53], [58], [59], [60], [66], [73], [75], [76], [81], [82], [84]. The summary liver related death rate was 0.03 per 100 person years among inactive HBsAg carriers and <0.1 in persons with chronic hepatitis without cirrhosis when considering together an Italian and a Chinese study.

Table 5. Overall liver-related death rates in longitudinal studies of patients with chronic hepatitis B infection according to clinical status and geographic area
ReferencesaClinical statusGeographic areaNo. studiesNo. patientsMean age at entry (y)% malesMean follow-up (y)Liver-related death rateb95% Confidence Interval
[49], [51], [52]Asymptomatic carrierEurope, North America3c6181317319.70.090.08–0.11
[53], [58], [84] Taiwan, China, Japan3d669042e848.70.80.72–0.85
[30], [59]Inactive carrierfEurope2387357919.90.030–0.07
[60]Chronic hepatitisgEurope110530765.500
[66] China1246348413.50.60.31–0.83
[73], [75]Compensated cirrhosishEurope217948896.23.32.28–4.4
[53], [66], [76], [81], [82] Taiwan, China, Japan5i410438482.92.34–3.52

aReferences are listed in chronologic order within the same geographical area.

bIncidence per 100 person years.

cTwo population based studies.

dPopulation based studies.

eData available for one study (reference [84]).

fRepeatedly normal alanine aminotransferase levels and absence of hepatitis B e antigen with presence of anti-HBe.

gPatients with cirrhosis at entry were excluded from the analysis.

hPatients treated with interferon were excluded.

iOne population based study.

In patients with compensated cirrhosis B, the summary liver-related death rates were 3.3 and 2.9 per 100 person years in Europe and East Asia, respectively, and the 5-year liver-related death rate was 15% in Europe and 14% in East Asia. An IRR (95% CI) of 0.8 (0.6–1.3), not statistically significant, 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 different 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 differences were found in the incidence of cirrhosis (Table 3) and HCC (Table 4) between Eastern and Western areas.

Among patients with HBeAg positive chronic hepatitis, a lower overall risk of cirrhosis was observed in Asian studies compared with Western studies. A detailed analysis of the five 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 fibrosis progression over 5 years, but once these patients progress into the immune clearance phase the rate of fibrosis progression increases [86]. Thus, the lower overall incidence rates of cirrhosis in Asian compared to Western studies may be due to the inclusion in the former of a substantial proportion of HBeAg positive carriers presenting in the early immune tolerant phase of chronic HBV infection.

Among patients with HBeAg negative chronic hepatitis, 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 histologically 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.

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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 disease expression. Several studies found that Asian patients aged 40 years and over are at higher risk of cirrhosis and HCC than are younger individuals [39], [40], [43], [44], [56], [69]. Western studies also demonstrated that the incidence of cirrhosis and HCC increased significantly with increasing age at entry [26], [41], [60], [83]. Older age appears to be an important determinant of progression to cirrhosis and HCC probably because it is a proxy for a longer duration of HBV infection and liver disease.

Male gender has been identified as an independent risk factor of cirrhosis [40], [44]. The molecular mechanisms by which sex affects fibrosis progression are unknown. The antifibrogenic effect of oestrogen has been proposed, possibly through the inhibition of stellate 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 fibrosis stage at presentation correlates 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 suppress 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 significantly higher in patients whose ALT levels were persistently elevated without flares or flared-up without normalization than in patients whose ALT flared-up with normalization or were persistently normal [69]. In patients with compensated HBV-cirrhosis baseline biochemical characteristics indicative of longer duration of liver disease (albumin, bilirubin, platelets) are also significant predictors of HCC, decompensation occurrence and liver-related mortality [75].

The risk of HCC is higher in persons with a family history of HCC, suggesting a role of genetic susceptibility [88].

The role of certain genetic variants in modulating the progression of hepatic fibrosis and in increasing HCC risk is under investigation [89], [90]. Angiotensin II, the main peptide of the renin-angiotensin system, is involved in hepatic fibrosis 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-β gene with a higher TGF-β production and a lower risk of HBV-related HCC have been described [93], [94], thus supporting the concept of the tumour suppressor activity of TGF at the early stage of tumourigenesis [95]. However, the difficulty in using genetic marker for HCC is the difference in the background prevalence of different single nucleotide polymorphisms in different 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, defined by serum HBV-DNA detectable by hybridization assays (>105–106 copies 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 seroconversion, indicating a prolonged period of viral replication and necroinflammation, 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 decompensation and liver related death [75].

Among studies conducted in Asian patients, a population-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 positive for both HBsAg and HBeAg at diagnosis compared to those negative for both markers [96]. The increased HCC risk in individuals seropositive for HBeAg remained significant 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 enrolment, 85% HBeAg negative, 94% with normal ALT) in Taiwan found that the risk of cirrhosis and HCC increased significantly with increasing baseline serum HBV-DNA levels detected by sensitive polymerase chain reaction (PCR) assays [40], [56]. The adjusted relative 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 significantly 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 cirrhosis 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 mortality 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 findings from population-based cohort studies in Taiwan of a direct association 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 findings 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 follow-up predicts a favourable outcome. Long term follow-up studies of adult inactive HBsAg carriers have shown that these patients rarely progress to cirrhosis or HCC (Table 3, Table 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 decompensation and increased survival compared to cirrhotics with persistently high levels of HBV replication [20]. In addition it has been reported that survival can be prolonged in HBsAg positive decompensated cirrhotics who subsequently lose HBsAg [20].

6.2.2. HBV genotypes 

HBV is currently classified into 8 genotypes, A to H. HBV genotypes can be further segregated into subgenotypes based on a more than 4% (but less than 8%) difference in the entire nucleotide sequence with distinct ethnic or geographic origin [21]. Increasing evidence supports the view that different HBV genotypes have a role in determining the clinical outcome of liver disease. This has been shown with genotypes B and C, and genotypes 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 studies 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 positive chronic hepatitis from Taiwan, genotype C was predictive of cirrhosis development [99]. A lower rate of spontaneous HBeAg seroconversion, and a longer duration 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 positive 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 discrepant finding 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]. Similarly, 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 progressive 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 significantly associated with HCC [104]. However, a case control study in sub-Saharan 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 significant association between genotype F and the development of HCC among native Alaskans with chronic HBV infection [106]. Overall these data suggest that genotype D infection is associated with more active liver disease and advanced liver fibrosis compared with genotype A infection, 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 occurring 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 promoter mutations are associated with more severe liver damage [107], [108], [109]. 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 mutation 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 normal ALT [110]. The same study also found that combination of mutations rather than single mutation was associated with progressive liver disease and HCC, especially in combination with pre-S deletion [110].

6.2.4. Concurrent infection 

Concurrent infection with HCV is present in 10–15% of patients with chronic HBV infection, particularly in area where both HBV and HCV are endemic [24]. The effect of concurrent HCV or HDV infections on the risk of progression of liver disease in patients with HBV infection deserves to be better defined, in spite of a large number of cross-sectional and case-control studies performed so far. Two meta-analyses of case-control studies 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 effect of concurrent 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 subjects with and without HCV or HDV concurrent infection. We performed a meta-analysis of these studies to estimate a summary RR. We computed summary RRs as the weighted means of the RRs of each study using weights equal to the inverse of the variances, when a sufficient number of studies without substantial heterogeneity among them were available [116]. We evaluated heterogeneity using the Cochran Q test and we quantified the extent of heterogeneity using I2, the percentage of total variation across studies attributable to heterogeneity between studies [117].

Among cohort studies which estimated the incidence rate of cirrhosis among chronic HBV carriers, we retrieved only three studies investigating the presence of HCV infection, and four studies regarding the presence of HDV infection (Table 6) [44], [71], [118], [119], [120]. As regards the influence of concurrent HCV infection, only one study found a significant increased risk of cirrhosis development, with a RR of 3.3, in patients with dual HBV and HCV infection as compared 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 influence of age and gender factors on disease progression by selection of a well-matched control group of active chronic hepatitis 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 statistically significant in two of them, with RRs of 2.6 and 2.8 [119], [120]. HDV genotype II is dominant in Taiwan [121] and may explain the less aggressive course of HDV infection reported in studies from Taiwan [44], [118] compared with those in different geographic areas [119], [120]. In addition, the complex viral interplay in cases of dual HBV and HCV or HBV and HDV infection [122], the limited power of some studies, due to the small number of patients included and/or the short follow-up, and the different study design may provide an explanation for these discrepancies. Due to the high, statistically significant heterogeneity among studies, we did not compute a summary RR for both HCV and HDV concurrent infection.

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 (reference)Geographic areaClinical statusNo. patientsMean age at entry (y)% malesMean follow-upCirrhosis casesRelative risk95% Confidence Interval
HBV/HCV
Huo [44]TaiwanNo377nana5.7471
Yes49nana5.791.50.63–3.04
Ikeda [71]JapanNo61034784.1621
Yes5243824.140.750.20–2.03
Liaw [118]TaiwanNo64nana12.3111
Yes64nana6.8203.31.50–7.60
HBV/HDV
Fattovich [119]ItalyNo6936764.7191
Yes1326725102.61.09–5.93
Tamura [120]JapanNo1058nana10431
Yes69nana1082.81.16–6.14
Huo [44]TaiwanNo377nana5.7471
Yes90nana5.7151.30.69–2.43
Liaw [118]TaiwanNo64nana12.3111
Yes64nana8.2121.60.66–4.09

HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis delta virus.

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], [123], [124], [125], [126], [127], [128]. 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 significant heterogeneity was found (Cochran Q test: p=0.8; I2=0%). The summary RR when including both Western and Asian studies was 1.98 (1.39–2.82).

Table 7. Relative risk of hepatocellular carcinoma occurrence in patients with cirrhosis according to HBV infection alone or HBV and HCV concurrent infection
Referencesa,bGeographic areaNo. studiesHBV/HCV coinfectionNo. patientscMean age at entry (y)% malesMean follow-up (y)HCC casesRelative risk95% Confidence interval
[74], [123], [124], [125], [126], [127]Europe, United States6No27446d74d6.29341
Yes10847816.66292.041.22–3.42
[79], [128]Taiwan, Japan2No32150753.8781
Yes5055702.9191.921.19–3.10

HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma.

aReferences are listed in chronologic order within the same geographical area.

bReferences [124] and [125] were updated by the authors.

cPatients with cirrhosis in Child-Pugh class A, B or C were included.

dData available for two studies.

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 cirrhosis type B compared to those with HBV infection only [129] (data not shown in Table).

The prevalence of HBV infection among human immunodeficiency virus (HIV) positive subjects varies markedly, from 5–10% in Western Europe and the United States to 20–30% 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 deficiency modifies the natural history of chronic HBV infection with higher levels of HBV replication and a lower rate of 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 retrospective 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 

6.3.1. Alcohol 

An Italian case control study found a 2-fold higher risk of HCC for combined HBV infection and drinking >60g/day of alcohol for at least 10 years compared to HBV infection alone [135]. However, very few cohort studies investigated the interaction between HBV infection and alcohol drinking with quantification of the amount of alcohol usually drunk by patients. A Japanese investigation found that heavy alcohol intake can increase the risk of progression to cirrhosis 6-fold relative 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 compensated 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 significantly with an alcohol intake of 50g/day or more with a RR (95% CI) of 1.2 (1.0–1.5) for 50–99g/day and of 1.5 (1.2–2.0) for >100g/day [136].

6.3.2. Metabolic factors 

The prevalence of steatosis ranges from 20% to 70% in liver biopsies of patients with chronic hepatitis B [137], [138], [139], [140]. Superimposed non-alcoholic fatty liver disease 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 itself [137], [138], [139]. There is no conclusive evidence concerning a possible association between hepatic steatosis and fibrosis progression in chronic hepatitis B. Two cross sectional studies found that hepatic steatosis was not correlated with severity of fibrosis [137], [138], whereas a longitudinal study of Italian patients with chronic hepatitis 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 progression 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 significant 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 significant association between diabetes and HCC was independent of HBV infection in the only study that examined this factor [142].

In a recent study, the presence of central obesity seems to influence the development of fibrosis in patients with chronic hepatitis B, probably related to the strong association between central obesity, insulin resistance and profibrogenic 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, alcohol consumption or viral infections, as recently reviewed [135].

6.3.3. Environmental factors 

Environmental hepatotoxins including tobacco smoke and aflatoxins may increase the risk of HCC. Few and discordant data are available on the association of cigarette smoking with HCC in patients with chronic HBV infection [56], [96]. In the study of 11,893 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 affect 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 aflatoxin, a mycotoxin which contaminates food in humid conditions, triples HCC risk in HBV infected men [143].

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7. Conclusions 

The following conclusions can be drawn: (1) The course of perinatally acquired chronic hepatitis B is different from that of postnatally-acquired chronic hepatitis B in that children in the former group have minimal, if any, hepatitis activities despite the presence of high levels of HBV replication for 1–3 decades, are at low near-term risk of developing significant morbidity and mortality and most complications of liver disease manifest in adulthood, whereas the majority of 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 hepatitis in adults show that most become inactive carriers after spontaneous HBeAg seroconversion. Progression to HBeAg negative chronic hepatitis occurs at a rate of 1–3 per 100 person years following HBeAg seroconversion. (3) Fig. 1, Fig. 2 illustrate the 5-year cumulative 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 positive chronic hepatitis both in Europe (5-year cumulative incidence 38% and 17%, respectively) and in East Asia (5-year cumulative incidence 13% and 8%, respectively). Irrespective of the severity of the underlying liver disease, the risk of HCC in persons with HBV infection is higher in East Asian countries than in Western countries, possibly because of earlier acquisition of HBV infection, longer duration of disease and/or exposure to environmental factors. The cirrhotic patient has an increased risk of HCC compared with patients with chronic hepatitis B without cirrhosis or inactive carriers both in East Asia (5-year cumulative risk 17%, 3% and 1%, respectively) and in the West (5-year cumulative risk 10%, 1% and 0,1%, respectively). 4. Factors influencing progression to cirrhosis and HCC in patients with chronic hepatitis B are shown in Table 8, Table 9, respectively. High levels of HBV-DNA replication and disease activity at enrolment and during follow-up are the best predictors of adverse clinical outcomes (cirrhosis, HCC, decompensation and liver related mortality). Sustained reduction of HBV replication before the onset of cirrhosis confers a favourable prognosis, with similar survival compared to uninfected individuals. Sustained reduction of viral replication in cirrhotic patients lowers the risk of HCC and improves survival. Older age, male gender, multiple ALT flares, severity of fibrosis stage at presentation, severity of compensated cirrhosis at presentation, concurrent infections (HBV/HCV and/or HBV/HDV) and alcohol abuse are additional predictors of disease progression. Further studies are needed to clarify the interplay of each known viral factor (HBV genotypes (subgenotypes, genotype mixtures), mutants and viral load) and to investigate other viral factors (HIV coinfection during the HAART era) and preventable or treatable comorbidities (obesity, diabetes) in the prognosis of chronic hepatitis B. (5) Recent improvements in the knowledge of the natural history of chronic hepatitis B and a detailed understanding of predictors of disease progression will help in the management of children and adults with chronic hepatitis B and in deciding whom to treat. Counselling on cofactors of liver damage, such as alcohol, is important, as they can change the prognosis at any time. Differences in long term outcomes between patients infected perinatally or early in life and those infected during adulthood should be taken into account in current recommendation for treatment of chronic hepatitis B.

  • View full-size image.
  • 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.

  • View full-size image.
  • 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.

Table 8. Factors associated with increased risk of progression to cirrhosis
FactorsComment
Host related
Older age (>40 years)Important
Male genderImportant
Severity of fibrosis stage at presentation (F3)Important
Recurrent flares of hepatitisImportant
Genetic diversityMore research needed
Viral related
High levels of HBV replication during follow-upImportant
HBV genotype (C>B; D>A)Increasing evidence
HBV variant (core promoter; pre-S)Increasing evidence
HDV concurrent infectionImportanta
HCV concurrent infectionImportanta
HIV concurrent infectionImportantb
Other factors
Heavy alcohol consumptionImportant
SteatosisMore research needed
DiabetesMore research needed
ObesityMore research needed

aMany cross-sectional and case-control studies, but few cohort studies.

bStudies conducted before the introduction of highly active antiretroviral therapy.

Table 9. Factors associated with increased risk of HCC occurrence
FactorsComment
Host related
Older age (>40 years)Important
Male genderImportant
Presence of cirrhosisImportant
Family history of HCCImportant
Race (Asian, African)Important
Genetic diversityMore research needed
Viral related
High levels of HBV replication during follow-upImportant
HBV genotype (C>B)Increasing evidence
HBV variant (core promoter; pre-S)Increasing evidence
HDV concurrent infectionImportanta
HCV concurrent infectionImportantb
HIV concurrent infectionMore research needed
Other factors
Heavy alcohol consumptionImportant
AflatoxinImportant in HBV endemic regions
SmokingMore research needed
DiabetesMore research needed
ObesityMore research needed

aFew cohort studies.

bCohort studies conducted among patients with cirrhosis.

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Acknowledgements 

We wish to thank Dr. Giovanni Maifredi for his invaluable help in statistical data analysis. The following researchers kindly provided unpublished information regarding the results of their studies: Dr. L. Benvegnù, University of Padova, Padova, Italy; Professor V. Di Marco, University of Palermo, Palermo, Italy; Dr. M.R. Brunetto, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy; Dr. M. Kobayashi, Toranomon Hospital, Tokyo, Japan; Dr. S.M. Lin, Chang Gung Memorial Hospital, Taipei, Taiwan; Dr. G.V. Papatheodoritis, Hippokration General Hospital, Athens, Greece; Dr. J. 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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☆ The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript

PII: S0168-8278(07)00637-X

doi:10.1016/j.jhep.2007.11.011

Journal of Hepatology
Volume 48, Issue 2 , Pages 335-352, February 2008

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