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Risk of hepatocellular carcinoma in hepatitis B and prevention through treatment

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ABSTRACT

Risk factors for the development of hepatocellular carcinoma in patients with chronic hepatitis B virus (HBV) infection are being elucidated. An HBV DNA concentration greater than 104 copies/mL is an especially strong predictor of risk in individuals aged 30 years or older, independent of the level of serum alanine aminotransferase (ALT). Other predictors of cancer are HBV genotype, with genotype C imparting an increased risk, and serum ALT values at least two times the upper limit of normal. Viral suppression with continuous lamivudine therapy reduces the risk of complications and delays progression of liver disease as long as response is maintained.

KEY POINTS

  • A high viral load is a significant predictor of the development of hepatocellular carcinoma in patients aged 30 years or older with chronic HBV infection.
  • The risk of developing liver complications from chronic HBV infection increases with increasing concentrations of alanine aminotransferase.
  • Continuous antiviral therapy to suppress viral load dramatically reduces the risk of complications from HBV infection and reduces the rate of disease progression, as long as patients maintain a therapeutic response.


 

References

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.

ASSESSING 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

Figure 1. Hepatocellular carcinoma (HCC) mortality in the Haimen City study by viral load (HBV DNA) category at study entry.2 RR = relative risk of death from HCC

The Haimen City study involved 83,794 subjects aged 25 to 64 years at entry.2,3 The 2,763 subjects who were positive for hepatitis B surface antigen (HBsAg) were tested at baseline for viral load and followed for 11 years. The relative risk of mortality associated with a high viral load (HBV DNA ≥ 105 copies/mL) was 11.2; low viral load (HBV DNA < 105 copies/mL) had no significant association with mortality (Figure 1). Nearly 20% of the study subjects with high viral load died of HCC.

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

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