In this series of patients with CHB on long-term oral nucleotide analogues, all with negative HBV DNA, those who progressed to cirrhosis had higher levels of Beclin-1.
The progression to cirrhosis in these patients despite antiviral treatment, may indicate that viral suppression by nucleotide analogues is not sufficient in prevention of progression of liver disease. Autophagy may be one of the possible mechanisms driving this progression. Beclin-1, one of the markers of early phase autophagy, was higher in these patients, which may be a piece of evidence for this hypothesis.
It has been shown that HBV uses autophagy as a mechanism for its proliferation within cells. This mechanism may still be active despite viral suppression and lead to fibrosis and cirrhosis, at least in some patients.
Autophagy has been implicated in the development of cirrhosis due to other etiologies. This may act through activation of mesenchymal cells and enhancing collagen production and ultimately fibrosis.
Autophagy is a common mechanism in natural cells for providing required energy and materials, but in some cases, adverse effects of the autophagy system had been observed (34). It could be a double sword enhancing the proliferation of pathogens and abnormal cells, including malignancy. Autophagy has been implicated in the proliferation of HBV (40, 41) and hepatitis C virus infection (42, 43)
Several recent studies have shown enhanced autophagy as a mechanism for developing HCC (35, 36) and fatty liver disease (37–39). Autophagy is also implicated in innate and adaptive immune responses to viral hepatitis, including HBV (21). Studies on HCV pathogenesis showed that this hepatic virus uses cellular autophagy in favor of viral replication and noticeably increases LC3ẞ (44). This may further modulate the course of chronic liver disease.
Focusing on autophagy may introduce a new opportunity to prevent and even reverse fibrosis in patients with chronic liver disease from any cause, especially CHB and CHC. Downregulation of autophagy in HSC has been linked to the attenuation of liver fibrosis (45, 46). We have previously shown that the use of chloroquine as a suppressor of autophagy suppresses HCV replication (47, 48).
Although this study has shown that serum Beclin-1 as a marker of autophagy was higher in patients who developed cirrhosis despite antiviral treatments, our study has several limitations.
Although none of the patients had not cirrhosis based on clinical, endoscopic, and imaging and liver biopsy when available at the time of initiation of anti viral treatment in this series, some may have had subclinical cirrhosis from the beginning. A prospective study is needed to resolve this issue. Tissue studies may further show the events at the molecular level. Our series was a small series from a single center which is another limitation of our study. Further one can argue this is the result rather than the cause of fibrosis. Cirrhosis is a complex and multifactorial state, and several mechanisms may act, which might be different in cirrhosis due to different etiologies. Therefore, further studies are required to investigate the precise role of autophagy in cirrhosis .
In conclusion, our study shows that at least in some patients with CHB, autophagy may have a role in the progression of cirrhosis despite adequate viral suppression. Targeting Beclin-1 and other autophagy mediators may lead to new promising therapies to prevent or even reverse HBV-related liver fibrosis.