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Gastroenterology. 2008 Oct;135(4):1192-9. Epub 2008 Jul 16.
HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma.
Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, Lau K, Yuen JC, Lai CL.
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong. [email protected]
Comment in:
Gastroenterology. 2009 Apr;136(4):1459-60; author reply 1460-1.
Gastroenterology. 2009 May;136(5):1842-3; author reply 1843-4.
BACKGROUND & AIMS: Our aims were to study the virologic, histologic, and clinical outcome in chronic hepatitis B (CHB) patients with hepatitis B surface antigen (HBsAg) seroclearance. METHODS: We determined the age of HBsAg seroclearance that is associated with a lower risk for hepatocellular carcinoma (HCC) in 298 CHB patients (median follow-up, 108 months). The following virologic and histologic features were also determined: liver stiffness (n = 229), liver histology, serum HBV DNA levels over time (n = 265), intrahepatic HBV DNA with covalently closed circular DNA (cccDNA) levels, and messenger RNA (mRNA) expression. RESULTS: The median age of HBsAg seroclearance was 49.6 years. Seven (2.4%) patients developed HCC. Cumulative risk for HCC was higher in patients with HBsAg seroclearance at ages >or=50 years compared with those with HBsAg seroclearance at ages <50 (P = .004) years. Of these 2 groups of patients, 29.5% and 7.9%, respectively, had significant fibrosis by liver stiffness measurement (P = .001), and 15.4% of patients had mild histologic fibrosis. Intrahepatic total HBV DNA and cccDNA were detected in 100% and 79.3% of patients, respectively. All patients had undetectable surface and precore/pregenomic RNA transcripts. One (9.1%) patient had X mRNA expression. Serum HBV DNA were detectable in 13.4%, 6.1%, and 3.7% of patients within 1 year and 5-10 and >10 years after HBsAg seroclearance, respectively, and 82.1% patients had persistently normal alanine aminotransferase levels. CONCLUSIONS: HBV persisted at low replicative and transcriptional levels after HBsAg seroclearance. HBsAg seroclearance at age <50 years was associated with a lower risk for the development of HCC.
HBsAg Seroclearance: The More and Earlier, the Better , 19 March 2009
Tai–Chung Tseng, Jia–Horng Kao
Gastroenterology
May 2009 (Vol. 136, Issue 5, Pages 1842-1843)
Dear Sir:
We read with great interest the article entitled “HBsAg Seroclearance in Chronic Hepatitis B in Asian Patients: Replicative Level and Risk of Hepatocellular Carcinoma”by Yuen et al in the October 2008 issue of GASTROENTEROLOGY. 1 Although effective vaccines have been available for >2 decades,2 chronic hepatitis B virus (HBV) infection remains a leading cause of end-stage liver disease and hepatocellular carcinoma (HCC) worldwide. In clinical practice, seroclearance of hepatitis B surface antigen (HBsAg) has been recognized as an important endpoint in both natural history of HBV infection and treatment of chronic hepatitis B.3,4 However, because of the rarity of spontaneous or treatment-induced HBsAg seroclearance, the incidence and long-term outcomes of HBV carriers experiencing this event remain disputed.5,6 Yuen et al analyzed 298 patients who achieved HBsAg seroclearance between 1980 and 2006. Among them, the risks of significant hepatic fibrosis and HCC were significantly lower in patients with HBsAg seroconversion at ages <50 years than at >50.1 Their findings suggested that earlier HBsAg seroconversion with sustained suppression
of HBV DNA and remission of liver damage can bring out a better prognosis over time. Although these data are important to practicing gastroenterologists and hepatologists, some of their results deserve further discussion.
In a long-term follow-up cohort in Taiwan, a total 245 patients achieving spontaneous HBsAg seroclearance were identified.7 The annual HBsAg seroclearance was estimated to be 1.15% on the basis of 21,267 person-years follow-up (1965 anti-HBe–positive HBsAg carriers with 10.8 +- 5.4 years of follow-up). In the current study, the number of patients achieving HBsAg seroclearance was even greater than that in the Taiwanese study. Unfortunately, the number of HBV carriers and total person-years of the entire cohort were not offered. If the authors would provide relevant data, we could understand more about the annual incidence of spontaneous HBsAg seroclearance in Asian HBV carriers.
Two possible flaws were also noted in this study. First, the surveillance for HCC was to perform ultrasound of the liver in patients with elevated -fetoprotein levels. This measure is misleading and obviously violates the recommendations of current guidelines of HCC management, 3 and may lead to a later diagnosis of HCC in their patients. Second, intrahepatic HBV-related mRNAs were analyzed and none but X-mRNA was identified in 1 of the 11 HBsAg seroconverters. This observation is contradictory to our understanding of HBV lifecycle. It is known that all 4 HBV-related mRNAs overlapped at the open reading frame of X gene8; therefore, only X-mRNA could be found by using region-specific primers seems unusual. One possibility is that the visible band on the gel might not be X-mRNA alone, but the summation of all m-RNAs. Further studies are needed to clarify this interesting observation.
In summary, existing lines of evidence indicate that spontaneous or treatment-induced HBsAg seroclearance, albeit rare, does occur in chronic hepatitis B patients. The better prognosis of earlier HBsAg seroclearance is likely caused by less HBV replication as well as less liver damage. To provoke more and earlier HBsAg seroclearance in HBV carriers, a better understanding of the mechanisms involved in HBsAg seroclearance is required.
TAI–CHUNG TSENG
Division of Hepatogastroenterology
Department of Internal Medicine
Buddhist Tzu Chi General Hospital Taipei Branch
Taipei, Taiwan
JIA–HORNG KAO
Division of Gastroenterology
Department of Internal Medicine and
Graduate Institute of Clinical Medicine and
Hepatitis Research Center, and
Department of Medical Research
National Taiwan University College of Medicine and
National Taiwan University Hospital
Taipei, Taiwan
1. Yuen MF, Wong DK, Fung J, et al. HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology 2008;135:1192–1199.
2. Kao JH, Chen DS. Universal hepatitis B vaccination: killing 2 birds with 1 stone. Am J Med 2008;121:1029–1031.
3. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507–539.
4. Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect Dis 2002;2:395–403.
5. Liaw YF, Sheen IS, Chen TJ, et al. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study. Hepatology 1991;13: 627–631.
6. Hsu HY, Chang MH, Lee CY, et al. Spontaneous loss of HBsAg in children with chronic hepatitis B virus infection. Hepatology 1992; 15:382–386.
7. Chu CM, Liaw YF. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up. Hepatology 2007;45:1187–1192.
8. Block TM, Guo H, Guo JT. Molecular virology of hepatitis B virus for clinicians. Clin Liver Dis 2007;11:685–706.
Reply. We would like to thank Tseng and Kao for their interest in our study.1 The following are our responses to their comments. Our study was primarily aimed at examining various virologic and histologic aspects as well as clinical events for chronic hepatitis B patients with hepatitis B surface antigen (HBsAg) seroclearance. Therefore, we did not mention the size of the study population to estimate the incidence of this event. This supplementary information was mentioned in our reply to another letter to editor submitted by Chu and Liaw.2 In brief, the total number of patients followed during the study period of 26 years is 8690. The estimated annual incidence for HBsAg seroclearance is 0.13%. This is comparable with previous published data.3,4
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