ReviewNatural history of chronic hepatitis B: Special emphasis on disease progression and prognostic factors☆
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.
Section snippets
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,
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
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
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
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].
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
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,
References (143)
- et al.
The contribution of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide
J Hepatol
(2006) Hepatitis B virus infection
Semin Fetal Neonatal Med
(2007)- et al.
The significance of spontaneous hepatitis B e antigen seroconversion in childhood: with special emphasis on the clearance of hepatitis B e antigen before 3 years of age
Hepatology
(1995) - et al.
Clinical relevance of hepatitis B virus genotypes in children with chronic infection and hepatocellular carcinoma
Gastroenterology
(2004) - et al.
Viremia profiles in children with chronic hepatitis B virus infection and spontaneous e antigen seroconversion
Gastroenterology
(2007) - et al.
The development of hepatocellular carcinoma among prospectively followed children with chronic hepatitis B virus infection
J Pediatr
(2004) - et al.
Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period
J Hepatol
(1998) - et al.
Spontaneous regression of hepatitis B virus associated liver cirrhosis developed in childhood
Dig Liver Dis
(2005) - et al.
Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B
Hepatology
(2002) - et al.
Prevalence of HBV precore/core promoter variants in the United States
Hepatology
(2003)
Epidemiological and clinical burden of chronic hepatitis B virus/hepatitis C virus infection. A multicenter Italian study
J Hepatol
Characteristics of patients with chronic hepatitis B in France: predominant frequency of HBe antigen negative cases
J Hepatol
Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study
J Hepatol
Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels
Am J Med
Natural history of chronic HBV carriers in Northern Italy: morbidity and mortality after 30 years
Gastroenterology
Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance
J Hepatol
Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis
Am J Gastroenterol
Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection
Gastroenterology
Epidemiology and natural history of hepatocellular carcinoma
Best Pract Res Clin Gastroenterol
Predicting cirrhosis risk based on the level of circulating hepatitis B viral load
Gastroenterology
Long-term results with interferon therapy in chronic type B hepatitis: a prospective randomized trial
Am J Gastroenterol
Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma
J Hepatol
A long-term follow-up study of asymptomatic hepatitis B surface antigen-positive carriers in Montreal
Gastroenterology
Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population based study
Hepatology
The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B
J Hepatol
Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. A prospective study
Gastroenterology
Incidence of hepatocellular carcinoma in chronic hepatitis B and C: a prospective study of 251 patients
Hepatology
Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation in 2215 patients
J Hepatol
Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis
J Hepatol
Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients
Am J Gastroenterol
Hepatocellular carcinoma in cirrhosis: incidence and risk factors
Gastroenterology
Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal
Hepatology
Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection: association between TGF-β1 polymorphisms and hepatocellular carcinoma
J Hepatol
Integration of the TGF – beta pathway into cellular signalling network
Cell Signal
Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline
J Hepatol
Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C
Gastroenterology
Chronic Hepatitis B
Hepatology
Controversies in the management of pediatric liver disease: Hepatitis B, C and NAFLD; Summary of a Single Topic Conference
Hepatology
Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion
J Viral Hepat
Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origin
J Infect Dis
HBV-DNA related hepatocellular carcinoma occurring in childhood. Report of three cases
Dig Dis Sci
Clinical and histological outcome after hepatitis B e antigen to antibody seroconversion in children with chronic hepatitis B
Hepatology
Chronic hepatitis B in children after e antigen seroclearance: final report of a 29 year longitudinal study
Hepatology
Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients
Hepatology
Natural history and prognosis of hepatitis B
Semin Liver Dis
HBV genotypes: epidemiology and implications regarding natural history
Curr Hepat Rep
Hepatitis B e antigen-negative chronic hepatitis: natural history and treatment
Semin Liver Dis
Serologic and clinical outcomes of 1536 Alaska natives chronically infected with hepatitis B virus
Ann Intern Med
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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