December 8, 2013

Hepatocellular Carcinoma and Hepatitis B Virus: Family Matters

Clinical Gastroenterology and Hepatology
Volume 11, Issue 12 , Pages 1646-1647, December 2013

Brian J. McMahon, MD, MACP

published online 03 June 2013.

In much of the world, hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, especially in men. In sub-Saharan Africa, most of eastern and southeast Asia, and the Pacific Islands, chronic hepatitis B virus (HBV) is the primary etiology for HCC, where the prevalence of chronic HBV infection ranges from 2% to more than 10% of the population.1 Several demographic, viral, and environmental factors have been found to increase the risk of HCC in HBV infection, which can help to identify those persons who should be targeted for regular surveillance to detect this tumor early, at a more treatable stage. More than 30 years ago, several case-control studies found family history of HCC to be a risk factor in relatives who were infected with HBV,2 but the magnitude of the risk previously was unknown. In this issue ofClinical Gastroenterology and Hepatology3 is an important article that takes advantage of a large population-based cohort study conducted in Taiwan, the REVEAL study, to better define and quantify the risk of family history of HCC. Briefly, the investigators screened more than 22,000 residents of 7 townships in Taiwan for HBV seromarkers and found almost 4000 to be positive for hepatitis B surface antigen (HBsAg). They then followed up those persons positive for HBsAg prospectively for 16 years and have written multiple publications regarding risk factors associated with HCC and cirrhosis that were found in this cohort.4, 5, 6

In this analysis, they examined the effect of a family history of HCC on the incidence of HCC in the entire population who were screened for HBV seromarkers. At baseline, all participants had filled out a questionnaire that included information on alcohol history and family history of HCC. All participants had a unique national health registration number that was used to link them to the National Cancer Registry. This allowed the investigators to identify cases of HCC both in the HBV-infected persons they were following up prospectively and the HBsAg-negative persons who were not tracked routinely after initial enrollment. The authors performed a multivariate analysis of other risk factors they had collected in the HBV-infected cohort including viral load, hepatitis B e antigen (HBeAg) status, and HBV genotype. They used a statistical method called RERI to examine the excessive risk caused by the interaction between HBV infection and family history of HCC, as well as looking at the attributable proportion that was the result of the interaction (AP) and the synergy index, which examines whether a synergistic or antagonistic interaction exists. They found a synergistic interaction between HBsAg positivity and family history, with highest risk of HCC found in those with both factors. When they examined RERI, AP, and synergy index they found evidence of a multiplicative interaction between family history of HCC and HBsAg positivity. The investigators previously showed that high levels of HBV DNA greater than 10,000 copies/mL and the presence of HBeAg at baseline were independent risk factors for HCC.4, 5 Their analysis in this article found that family history was significant and synergistic in HBV-infected patients who were HBeAg positive, HBeAg negative, or had HBV DNA levels greater than or less than the 10,000 copies/mL cut-off value. This means that a family history of HCC is a strong risk factor for the development of HCC in an HBsAg-positive person independent of viral load or HBeAg status. The authors found that the highest risk of all occurred in HBV-infected persons who had a family history of HCC and were HBeAg positive, in whom the cumulative risk of developing HCC during the follow-up period was 40%.

Previously, these investigators had found that basal core promoter and HBV genotype C compared with HBV genotype B (Asia) were independent risk factors for HCC and the precore mutation reduced the risk of HCC.7 Although the findings in this study again found that the basal core promoter and HBV genotype C were independent risk factors for HCC, and again, precore mutation was associated negatively with subsequent risk of HCC, none of the 3 significantly modified the effect of family history on HCC incidence.

The importance of this study is that it was a population-based longitudinal cohort study that showed the influence of family history on risk of HCC. Furthermore, it highlighted the magnitude of the risk of HCC that family history carries. The study provided strong evidence to support the American Association for the Study of Liver Diseases practice guidelines, which recommend regular surveillance for HCC every 6 months, with ultrasound of the liver for HBsAg-positive persons with a family history of HCC regardless of their age.8 Detecting HCC tumors early in HBV-infected persons, when they are smaller than 3 cm, allows for the use of potentially curable treatment with either radiofrequency ablation or surgical resection, which have been shown to prolong both tumor-free and overall survival. Tumors larger than 3 cm but smaller than 6 cm can be resected surgically, or, if Milan Criteria for liver transplant in HCC is met, could be treated by liver transplantation, which also is associated with good tumor-free long-term survival. Thus, active surveillance of those HBsAg-positive persons with a family history of HCC is a must.

The introduction of universal hepatitis B vaccination in children in most countries has shown that immunization against HBV can result in the prevention of HCC caused by this viral infection, as has been shown in population-based studies conducted in children in Taiwan, Thailand, and Alaska.9, 10, 11 However, the incidence of HCC in HBV chronically infected persons is low before infected males reach their late 30s and females reach their late 40s.12 Thus, it will take several decades for a large segment of endemic populations who received HBV vaccine in infancy and early childhood to reach middle age before we may witness a substantial global reduction in the incidence of HCC. In the meantime, a reduction in the rate of death from HCC, decompensated cirrhosis, and liver-related death could be accomplished by treating HBV-infected persons who are found to have cirrhosis, which has been shown in a randomized placebo-controlled trial of patients with compensated cirrhosis caused by HBV that also was conducted in Taiwan.13 Practice guidelines also recommend treating those with active liver inflammation and moderate fibrosis.14 It is not known whether treatment before the development of advanced fibrosis might reduce the future risk of HCC, but it would be unethical to conduct a randomized placebo-controlled trial to answer this question. However, population-based studies could be conducted to examine the effect of treating patients who fulfill criteria for therapy by evidenced-based practice guidelines on the incidence of HCC. These could be performed in population cohorts in whom the incidence of and risk factors for developing HCC have been reported previously and examining the incidence of HCC reported previously compared with that found subsequently after aggressive identification and HBV DNA suppression with antiviral agents of high-risk patients. This study raises the question, because risk of HCC in those with a family history is so high, should antivirals be used in those individuals who do not meet treatment guidelines to completely suppress HBV DNA, in hopes of decreasing the risk? This could be studied using a longitudinal cohort design in populations, such as the REVEAL cohort and the cohort of Alaska native persons with chronic HBV, which have sufficient numbers of HBsAg-positive patients with a family history of HCC.2, 15 A reasonable approach might be to suppress HBV DNA to undetectable levels with 1 of the 2 potent antiviral reverse-transcriptase inhibitors currently available, tenofovir or entecavir, and follow up these persons to see if the incidence would be reduced to less than that reported previously in these populations. Perhaps the subgroup that might yield the fastest answer to this question of earlier therapy might be those with a family history who are also HBeAg positive, in whom the authors found a 40% cumulative risk over a 16-year follow-up period.

In conclusion, the persuasive finding from this study is that persons infected with chronic HBV infection who have a family history of HCC deserve special attention, including regular surveillance for HCC, monitoring for active liver inflammation and fibrosis, and starting antiviral therapy as soon as they have met practice guidelines criteria. In addition, studies to determine if earlier administration of antiviral therapy to completely suppress HBV DNA in those HBV-infected persons with a family history of HCC are urgently needed.

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