Wednesday, December 22, 2010

Hepatitis B:Screening for Liver Cancer After HBsAg Clearance Age Before Cirrhosis?

Screening for Hepatocellular Carcinoma After HBsAg Clearance Age Before Cirrhosis?: Age Before Cirrhosis?

Journal of Clinical Gastroenterology:
January 2011 - Volume 45 - Issue 1 - p 4–5
doi: 10.1097/MCG.0b013e3181faf0d1

Screening for Hepatocellular Carcinoma After HBsAg Clearance Age Before Cirrhosis?: Age Before Cirrhosis?
Lutchman, Glen A. MD, MHSc; Nguyen, Mindie A. MD, MAS

Article Outline
Author Information
Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA

We have no sources of financial support to declare.

Conflicts of Interest: None.

Reprints: Mindie A. Nguyen, MD, MAS, 750 Welch Road, Ste 210 Palo Alto, CA 94304 (e-mail:

Chronic hepatitis B affects more than 350 million individuals worldwide and is a risk factor for the development of cirrhosis and end-stage liver disease. It is also the most common cause of liver cancer and is responsible for over 50% of cases worldwide. In Asian countries, hepatitis B virus (HBV) is the underlying etiology of liver cancer in 70% to 80% of cases.1 Although the exact mechanism of HBV-related hepatocarcinogenesis is still being investigated, an epidemiologic association between HBV and hepatocellular carcinoma (HCC) is well established. The relative risk of developing liver cancer in HBV-infected patient cohorts ranges from 7 to 98.2 It should be noted that the risk of developing HCC is different for Caucasian compared with Asian populations. Risk factors for the development of HCC for patients with chronic hepatitis B in general include alcohol use, male sex, older age, presence of hepatitis B e antigen (HBeAg), elevated HBV DNA, coinfection with hepatitis C or D virus and cirrhosis.3
The best strategy for decreasing the incidence of liver cancer is to prevent new infections. As such childhood vaccination has not only decreased the hepatitis B surface antigen (HBsAg) carriage rate but has also reduced the annual incidence of childhood liver cancer.4,5 Demonstrating a similar effect in adult populations will require long-term follow-up. Successful antiviral therapy with lamivudine decreases the risk of cancer in well-controlled randomized clinical trials of patients with advanced liver disease. Several lower quality studies suggest that this may also be true for other populations and other antivirals including interferon.6,7 However, vaccination is of no benefit to patients already chronically infected and antiviral therapy is not universally available.

Spontaneous clearance of HBsAg with hepatitis B surface antibody (anti-HBs) production is uncommon (0.5% per year) and there is significant geographical variation in the incidence of this phenomenon. Antiviral therapy has a modest effect on the incidence of HBsAg clearance with annual rates ranging from 1% to 8% with the higher clearance rates being seen with interferon therapy.7 Loss of HBsAg does not result in universal clearance of HBV DNA, which can be detected in up to 14% of patients 10 years later.8

Screening for liver cancer is typically done using liver imaging and/or serum α-fetoprotein. Guidelines by the American Association for the Study of Liver Diseases recommend such screening at 6 to 12 month intervals but data on the utility of this approach are limited.9 One question of interest is how to apply these screening guidelines to patients who have developed HBsAg seroclearance, that is, clearance of HBsAg with or without low persistent level of circulating HBV DNA.

In this issue of the Journal, Dr Kim et al present their experience at a center in South Korea regarding the risk of developing HCC after HBsAg seroclearance.

The latter was defined as the loss of HBsAg on repeated testing for at least a 6-month period. From a cohort of 2870 patients with chronic hepatitis B, 96 patients had seroclearance during a median follow-up of 166.5 months or almost 14 years.

Of these 96 patients, 6 (6.5%) developed HCC following a median follow up of 56 months after HBsAg seroclearance. Aged ≥45 years or clinical evidence of cirrhosis at the time of HBsAg seroclearance was independent risk factors for HCC on univariate analysis with cirrhosis also being significant on multivariate analysis. The authors suggest that screening of HCC should continue in patients who have either of these characteristics at the time of HBsAg seroclearance.10

Although the results of the statistical analysis are limited because of the small patient numbers developing HCC after HBsAg clearance, all studies of this type would suffer a similar restriction given both the low frequency of both HBsAg clearance and HCC incidence in HBsAg carriers. Tong et al11 reported results of a similar analysis on 35 patients who achieved HBsAg seroclearance and found that 4 (11.4%) of these patients developed HCC during follow-up.

They identified low baseline albumin, cirrhosis, family history of HCC, and age ≥50 years as risk factors for developing HCC. The authors recommended continued surveillance indefinitely for the development of HCC. Yuen et al12 evaluated 298 patients with HBsAg seroclearance in which 7 (2.3%) patients developed liver cancer after the median patient follow-up of 108 months. Again age >50 years at the time of seroclearance was associated with a higher rate of liver cancer compared with patients who cleared HBsAg at the age of <50 years.
Thus, advanced age is consistently reported as a risk factor in most of these studies.

This observation may reflect the fact that these patients have a higher chance of having advanced fibrosis or cirrhosis as they may have spent more years with ongoing hepatic inflammation and injury before achieving HBsAg seroclearance. Indeed, if any of these studies were adequately powered to perform multivariate analysis, it is likely that there would be a significant interaction between age at HBsAg seroclearance and the presence of cirrhosis.

Another limitation of studies of this topic is the definition and diagnosis of cirrhosis. In this study from the same issue of the Journal, cirrhosis was based on clinical and biochemical data and in the study by Tong et al, the methodology for determining cirrhosis were not clearly described. Without histologic examination of all patients, many cases of asymptomatic or preclinical cirrhosis would go unnoticed and age at HBsAg seroclearance may serve as a surrogate marker for the presence of more advanced but still silent disease.

Nevertheless, although liver biopsy remains the gold standard for determining the presence of cirrhosis, the practicality, costs, and availability of liver biopsy limits its general application. Should we then ignore the quest for a definite diagnosis of liver cirrhosis in these patients and rely solely on age at seroclearance as a surrogate?

One option that may be considered is the use of commercial panel markers (FibroTest) or noninvasive determination of liver stiffness (FibroScan) which have been validated in patients with chronic HBV infection.13,14 This approach would be particularly useful in cases when HBsAg seroclearance occurs at a younger age either spontaneously or through the use of antiviral therapy.

On the surface, this discussion may seem to be a superfluous discussion as the rate of HBsAg seroclearance is so low that the population impacted by this scenario is a very small minority. However, given the large aging population of individuals with chronic hepatitis B and improvements in antiviral therapy, this topic may become an increasingly important issue. Future studies in patient cohorts who achieve HBsAg seroclearance should attempt to better define and/or diagnose cirrhosis and possibly combine cohorts from several institutions to achieve the patient numbers required to perform robust logistic regression analysis.

In the meantime, in patients who were infected with chronic hepatitis B at a young age and who have successfully achieved HBsAg seroconversion either spontaneously or through antiviral therapy care providers should clearly continue to perform liver cancer surveillance for those already showing signs of liver cirrhosis. It would also be prudent to continue liver cancer surveillance in those without clear signs of liver cirrhosis but underwent HBsAg seroconversion at the age of 40 years to 50 years or later.

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© 2011 Lippincott Williams & Wilkins, Inc.

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