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Clin Mol Hepatol > Volume 25(1); 2019 > Article
Kim: Can hepatic steatosis really promote hepatitis B viral hepatocarcinogenesis? The jury is out on.
See Article on Page 52
There is accumulating evidence that metabolic risk factors such as high body mass index, insulin resistance, and concurrent fatty liver can boost the risk of hepatocelluar carcinoma (HCC) in patients infected with hepatitis B virus (HBV) [1-3]. The exact mechanism by which hepatic steatosis can promote HBV-related hepatocarcinogenesis is still unknown; however, fatty liver represents a proinflammatory state and a condition of profound insulin resistance. Thus, insulin and insulin-like growth factors may partly promote the development of HCC through their proliferative and anti-apoptotic effects [4].
HBV is not likely steatogenic unlike hepatitis C virus; rather, HBV infection seems to decrease the risk of nonalcoholic fatty liver disease (NAFLD) according to recent epidemiological studies [5,6]. In a similar manner, hepatic steatosis seems to affect HBV replication adversely with a higher chance of HBV seroclearance in an immunocompetent mouse model of HBV replication, although HBV X protein (HBx) is shown to favor lipid accumulation in cell culture systems [7,8]. Eventually, the humanized mouse model of HBV would be required to solve the HBV-steatosis conundrum.
It has been suggested that hepatic steatosis can result in either cytoplasmic hepatitis B surface antigen distribution or hepatocellular death, thereby leading to HBV seroclearance [9]. It is already well established that steatosis is related to alterations in gut microbiota, dysbiosis, and hepatic inflammation. Gut microbiota can also activate innate immunity leading to HBV seroclearance [10]. Thus, gut dysbiosis caused by hepatic steatosis may play a role in viral clearance, which still needs to be validated. Paradoxically, hepatic steatosis limits the replication of HBV, while steatosis offers contributory environment for pathogenic liver conditions that can culminate in HCC.
In the current issue, the authors demonstrated that histologically confirmed NAFLD significantly increased the risk of HCC development in patients with chronic hepatitis B, although propensity score matching showed no significant association between fatty liver and HCC development [11]. Based on these results, they finally concluded that NAFLD as a hepatic manifestation of metabolic syndrome but not hepatic steatosis per se, may be a harbinger of HCC that portends worse clinical outcomes in patients with HBV infection. Nonetheless, several points merit further scrutiny.
First, due to the retrospective design, it was unclear whether HBV-related hepatocarcinogenesis predated hepatic steatosis or hepatic steatosis increased the risk of HCC in patients with HBV infection. Indeed, HBx-induced lipogenesis is mediated by liver X receptor during HBV-related hepatocarcinogenesis [12]. Second, we are not sure of what is the main culprit of HBV-related hepatocarcinogenesis, since insulin resistance might confound or mediate the effect of hepatic steatosis on hepatocarcinogenesis. Finally, it might be overlooked that nonalcoholic steatohepatitis or severe fibrosis could precipitate de novo oncogenesis from HBV infection, since they did not provide detailed information on the histological severity of NAFLD. In future, further research regarding the effect of HBV-steatosis concurrence on the minichromosome (covalently closed circular DNA) formation is strongly warranted to reveal the molecular pathways of steatosis-induced, HBV-related hepatocarcinogenesis.

Footnotes

Conflict of Interest
The authors have no conflicts to disclose.

Abbreviations

HBV
hepatitis B virus
HBx
hepatitis B virus X protein
HCC
hepatocellular carcinoma
NAFLD
nonalcoholic fatty liver disease

REFERENCES

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11. Lee YB, Ha YJ, Chon YE, Kim MN, Lee JH, Park HN, et al. Association between hepatic steatosis and the development of hepatocellular carcinoma in patients with chronic hepatitis B. Clin Mol Hepatol 2019;25:52-64.

12. Na TY, Shin YK, Roh KJ, Kang SA, Hong I, Oh SJ, et al. Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2009;49:1122-1131.
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