Hepatoma in hepatitis B: Infectious disease or liver disease?
Authors: David K. Wong
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. See Article on Page 1757 Chronic hepatitis B (HBV) infection is still a very common infection worldwide. Although most with chronic infection are asymptomatic and may never even know that they were infected, some develop complications of cirrhosis, liver failure, and liver cancer. The link between hepatitis B infection and hepatoma was convincingly shown by Palmer Beasley's report of a prospective study of 22,707 Taiwanese men in 1981.1 Since then, hepatoma has been linked to many other causes of chronic liver disease (CLD) in the setting of established cirrhosis. Hepatitis B is unique in that hepatoma can occur even in those without cirrhosis.2 A reexamination of a cohort of 3,653 Taiwanese adult men from 1991 to 1992 using modern sensitive methods to quantify HBV DNA suggested that the HBV viral load had a major impact on the risk of hepatoma.3 This finding has led many to conclude that everyone with chronic HBV infection should be treated with a goal complete viral suppression. Essentially, chronic hepatitis B (CHB) is viewed as an infectious disease that needs treatment. Treatment of CHB infection is now quite simple. Oral nucleoside/nucleotide analogs can effectively block HBV viral replication. However, treatment is not curative. Furthermore, HBV viral suppression reduces, but does not eliminate, the risk of hepatoma.4 Current treatment guidelines do not advocate treatment for all infected individuals. Rather, clinical parameters are assessed to determine those who might be at risk and who might therefore benefit from treatment. Essentially, guidelines acknowledge that CHB is a liver disease where treatment is warranted for those at risk. Identifying which patients are at risk has been tricky. The natural history of hepatitis B is convoluted with phases of liver injury and phases where liver injury seems to abate.5 The inactive carrier state seems to be low risk for hepatoma where the HBV‐DNA levels are low. However, the immune tolerant state found in most young individuals with extremely high HBV‐DNA levels is also a low risk for hepatoma. It has been recognized that male sex, older age, higher HBV‐DNA level, and presence of cirrhosis are the biggest risks for hepatoma in those with chronic HBV infection. Of these variables, the assessment of liver fibrosis and cirrhosis has historically been problematic because of the need for liver biopsy. Liver biopsy is impractical for large cohort studies. Without liver biopsy, cirrhosis was diagnosed based on imaging and clinical characteristics—methods that are very insensitive for cirrhosis in its earlier stages. Currently, liver biopsy is rarely done for chronic HBV infection for fibrosis assessment because of the availability of noninvasive methods, such as vibration‐controlled transient elastography, which estimates liver stiffness. Liver stiffness measurements (LSMs) have considerable advantage over liver biopsy not only because it is noninvasive, but also the dynamic range is much greater in those with cirrhosis. For liver biopsy, the worst score is cirrhosis. For LSMs, cirrhosis is diagnosed at 13‐14 kilopascals (kPa), but the dynamic range for cirrhosis is 13‐75 kPa. This large range in LSMs likely corresponds with the large range in cirrhosis: from early cirrhosis, where the liver still looks normal on imaging despite cirrhotic nodules on biopsy, to late‐stage cirrhosis, where dense cirrhotic nodules with large areas of extinction and parenchymal collapse result in a small, dense, nodular liver where the diagnosis of cirrhosis is so obvious clinically that a liver biopsy is not needed. There is likely a big difference in hepatoma risk between those with cirrhosis and liver stiffness 14 kPa, compared to those with liver stiffness of 20 or 40 kPa. HBV‐DNA levels as a risk predictor of hepatoma is also problematic. For those on antiviral therapy, HBV DNA should be very low, if not undetectable. Nevertheless, these individuals remain at risk for hepatoma. Jung et al.7 report on a study comparing the performance of five prediction models when applied to 1,308 Korean patients (Fig. 1). CU‐HCC8 and GAG‐HCC9 are models that put most of the weight on whether or not cirrhosis is present. However, cirrhosis was mostly defined by radiographic or clinical parameters without biopsy. The heavy weighting to age and low albumin levels are also likely surrogate markers for cirrhosis. The REACH‐B10 model had a heavy weighting for age (surrogate marker for fibrosis—cirrhosis not used in the model) and HBV‐DNA levels. Finally, the LSM‐HCC11 model was the first to use elastography to estimate fibrosis. This model gave heavy weighting to LSM and age—HBV DNA weighted less. Jung et al. go one step further by modifying REACH‐B, where HBV DNA was eliminated and replaced by LSM. Not surprisingly, they found their model to be very accurate, especially for those on antiviral therapy where HBV DNA is suppressed. It is telling that in the subgroup of 460 not on antiviral therapy, mREACH‐B (model that does not use HBV DNA) performed as well as, if not better than, the models that did use HBV DNA in their models. In all of this, we must remember that these models were derived from populations where the extremes of age were either under‐represented or not present at all.Figure 1: Models of hepatoma risk. Many factors have been identified as risks for hepatoma. The common features are the factors that lead to cirrhosis (longer duration of infection with increasing age, higher HBV‐DNA levels at older ages) and markers of advanced cirrhosis (clinical or radiographic evidence of cirrhosis, features of liver failure with low albumin levels or high bilirubin). This implies that hepatitis B is predominantly a liver disease where the infection at high viral loads over time leads to liver injury, cirrhosis, and is then complicated by hepatoma, rather than a high viral load alone leading to cancer. Abbreviations: ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen.The above observations suggest that for hepatitis B, it is the liver disease more so than the infectious disease that is the important risk for hepatoma. The persistence of high HBV‐DNA levels at older age puts individuals at higher risk of liver injury leading to cirrhosis and then hepatoma. If this model is true, it suggests that until a cure for hepatitis B is found, HBV suppression is reasonable for those with risks for fibrosis progression. Hepatoma screening is best targeted at those with advanced liver fibrosis. Going forward, we have to decide how to use our available tests and models in the management of patients with chronic HBV infection. Liver biopsy is unlikely to make a comeback, whereas LSM is likely to become more readily available. It will hopefully become less likely that clinicians will only make a diagnosis of cirrhosis based on clinical liver failure or liver morphology on imaging. Furthermore, it is unlikely that LSM will be a test that we apply only once at initial assessment—it will be used to follow patients over time. Changes in LSM over time might be a better predictor of hepatoma risk where those with persistently high LSM measurements have the highest risk, whereas those with improvements in LSM over time have intermediate risk and those with persistently low LSM measurements have the lowest risk.6 In the end, following liver fibrosis may be easier and more practical than having to calculate scores based on different models, even in this age of smartphones and apps.