Risk of hepatocellular carcinoma in hepatitis B and prevention through treatment

ALT AS PROGNOSTIC DETERMINANT

The risk of developing liver complications from chronic HBV infection increases with increasing concentrations of ALT. Yuen et al⁷ followed 3,233 Chinese patients with chronic HBV infection for approximately 4 years. The risk of developing complications from liver disease increased as ALT concentration increased from less than 0.5 times the upper limit of normal (ULN) to two to six times the ULN; ALT levels one to two times the ULN were associated with the highest risk of development of complications.

Interestingly, an ALT level greater than six times the ULN was associated with a significantly lower risk of liver complications. The speculation is that this phenomenon represents inactivation of disease following HBeAg seroconversion.

VIRAL LOAD SUPPRESSION LIMITS DISEASE PROGRESSION

Disease activity may flare during the natural course of chronic HBV infection, and repeated episodes may lead to progressive fibrosis, cirrhosis, and end-stage liver disease, as well as HCC. Patients whose cirrhosis has progressed to end-stage liver disease are candidates for transplant.

Continuous antiviral therapy with lamivudine has been shown to dramatically reduce the risk of complications and disease progression in patients with chronic HBV infection. In a placebo-controlled trial of 651 patients with chronic HBV infection and advanced fibrosis or cirrhosis, those randomized to lamivudine who remained sensitive to the drug had a 7.8% risk of complications over approximately 3 years, compared with a 17.7% risk in the patients randomized to placebo.⁸ The difference was significant and sizeable enough that the study was terminated after a mean duration of 32.4 months. Patients who developed resistance to lamivudine, caused by a mutation in HBV (YMDD mutation, a sign of lamivudine resistance), lost the protection provided by viral suppression.

The risk of disease progression to cirrhosis or HCC was also significantly lower among HBeAg-positive patients without cirrhosis who were treated with lamivudine for a median of 89.9 months compared with placebo, Yuen et al found.⁹ As in other studies, patients in whom the YMDD mutation developed lost the protection of viral suppression.

In a retrospective study, Di Marco et al¹⁰ also found that a loss of response to lamivudine was associated with higher risk of development of HCC, whereas patients who maintained a response to lamivudine were much less likely to develop progressive disease. The authors found that cirrhosis and loss of antiviral response were independently related to mortality and development of HCC.

SUMMARY

Patients with HBV are at risk for cancer, and the risk factors can be identified. Although not yet fully evaluated, awareness of these factors will make the screening process more efficient and less burdensome than current guidelines recommend. The publication and eventual validation of a risk nomogram will facilitate the determination of risk. An especially strong predictor of adverse outcomes, including HCC, is HBV DNA concentration higher than 10⁴ copies/mL, as shown by two recent large studies; further, investigators observed a correlation between HBV DNA level and incidence of HCC.

Antiviral therapy has dramatically reduced the risk of complications and progression of HBV infection. Those who develop resistance to therapy lose the protection provided by viral suppression.

DISCUSSION

William D. Carey, MD: Does biopsy of nontumorous portions of the liver have value, either by showing dysplasia or perhaps through a staining technique, in predicting the development of liver cancer?

Morris Sherman, MD, PhD: I believe that you’re referring to a recent study in which microarray technology was used to identify patients at risk for the development of a de novo tumor after a resection of the first tumor.¹¹ Liver tissue surrounding the tumor was analyzed by microarray technology, and gene expression profiling accurately predicted the development of a new tumor in another part of the liver more than 2 years later. This discovery suggests the presence of a field defect, or a propensity for the development of new tumors in a damaged organ. Patients who have a field defect identified by the microarray technique are at much higher risk of developing a subsequent cancer. These patients might be candidates for liver transplant despite apparent surgical cure of their HCC. However, because the subsequent liver malignancy occurs some time later and is a new primary tumor, the need for transplant is less urgent than it is for a patient with a progressive hepatoma, for example.

Pierre M. Gholam, MD: Do you consider ethnicity in addition to age, viral load, and other factors in your decision to screen patients for HCC?

Dr. Sherman: We traditionally think of ethnicity as a major factor because HBV is concentrated in Asian and African populations. I’m not entirely sure whether ethnicity or the viral genotypes are more important, because the viral genotypes are distributed along ethnic lines. We know that genotypes B and C, which are common in the Far East, are associated with a high rate of progressive liver disease. Genotype D, observed mainly in Middle Eastern and Greek populations, is associated with a much higher rate of progressive liver disease than genotypes common in Western Europe and most of North America. I believe that genotype should be a factor in decisions to screen.

Robert G. Gish, MD: In your case presentation you described the aspartate aminotransferase (AST) and ALT as being normal. New criteria define an AST/ALT of 20 as being “healthy” for a woman. I like the word “healthy” better than “normal.” How would you have described those test results to the patient?

Dr. Sherman: I would have told her that although her AST and ALT levels were within the laboratory reference range, ideally for a young woman the ALT should be closer to 20 U/L. Her actual levels were at least twice the upper range of ideal, and therefore, I believe a biopsy to determine the extent of injury in the liver would be important.

Tram T. Tran, MD: Are there any new serum markers for liver cancer that have promise?

Dr. Sherman: The problem with serum markers, or biomarkers in general, is the confusion over their intended use, such as for screening, risk stratification, or diagnosis.

I assume that your question refers to their potential use in screening, and so far none of the existing biomarkers is adequate to find small tumors. For screening purposes, you ideally want to find tumors that are 2 cm or smaller, and none of the biomarkers is efficient with those small tumors. A biomarker is not needed to identify tumors that are 5 or 6 cm.