The role of hepatitis B virus (HBV) as a risk factor for the development of hepatocellular carcinoma (HCC) is well established. Not every patient with HBV infection develops HCC; yet, the current guidelines issued by the American Association for the Study of Liver Diseases1 recommend screening all patients who have HBV infection when they reach certain ages associated with increased risk. Improved identification of risk factors specifically associated with the likelihood of developing HCC may spare some patients the burden of unnecessary testing. This article reviews up-to-date information that will help identify patients who are at risk of HCC based on factors with more specificity than age, and considers whether treatment can alter their risk.
Several factors are associated with increased risk of developing HCC (see “Case: Hepatocellular carcinoma in a young woman”):
- An elevated serum alanine aminotransferase (ALT) level signifies the presence of active disease and increases risk, particularly if the ALT is persistently or intermittently elevated over years.
- Persistently elevated alpha-fetoprotein level is a reflection of enhanced regenerative state in the liver; the increased rate of cell division increases the risk of mutation, leading to increased risk of HCC.
- A low platelet count suggests the presence of cirrhosis, which itself increases the risk of HCC.
- Histologic risk factors revealed at biopsy include dysplasia, geographic morphologic changes that suggest clonal populations of cells, and a positive stain for proliferating cell nuclear antigen.
- Viral load (HBV DNA) is a significant predictor of HCC; two recent large, prospective studies—the Haimen City study2,3 and the REVEAL-HBV (Risk Evaluation of Viral Load Evaluation and Associated Liver Disease/Cancer-Hepatitis B Virus) study4—support the importance of this risk factor.
Haimen City study
The REVEAL-HBV study
The REVEAL-HBV study was a multicenter observational cohort study of 23,820 Taiwanese individuals aged 30 to 65 years old who were free of HCC at baseline.4 Of these, 3,653 were seropositive for HBsAg and seronegative for antibodies to hepatitis C virus.
Some 1,619 men and women had serum HBV DNA levels greater than or equal to 104 copies/mL at study entry.4 A direct correlation was observed between baseline HBV DNA levels and the incidence of HCC.During a mean follow-up period of 11.4 years, there were 164 new cases of HCC. In a model that integrated baseline and follow-up HBV DNA levels, the cumulative incidence of HCC ranged from 1.3% of those with undetectable levels of HBV DNA to 14.9% of those with HBV DNA levels of 106 copies/mL or greater. The same association between viral load and incidence of HCC was evident in patients who upon study entry had normal ALT levels and were hepatitis B e antigen (HBeAg) negative, a group previously considered to be inactive carriers of HBV.
The incidence of HCC was higher in the subjects with persistent viremia than in those whose viral load decreased over time, representing a biologic gradient of risk. Compared with the reference group (baseline HBV DNA < 104 copies/mL), the adjusted relative risk was nine times greater in those who maintained HBV DNA levels of 105 copies/mL or greater.
Genotype further defines risk
In addition to viral load, genotype may further define the risk of HCC in HBV carriers aged 30 years or older. In a nested case-control study, genotype C was associated with fivefold increased risk of HCC compared with other genotypes.5 Consistent with other studies, the risk of HCC increased with increasing viral load.
Caveats to the viral load–HCC link
The association between viral load and the development of HCC applies to patients aged 30 years or older, the subjects of the aforementioned studies. Younger patients who present with a high viral load and are HBeAg positive are likely to be in an immune-tolerant phase of HBV infection. Among patients aged 30 years or older, the association between viral load and HCC applies to HBeAg-positive as well as HBeAg-negative status. The longer the HBeAg-positive state is maintained, the greater the risk of developing cirrhosis and HCC, which is a reflection of active disease over a prolonged period. The association applies equally to patients with normal or elevated ALT levels. A risk nomogram is being developed that will help identify patients at highest risk of HCC.6