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Review
. 2016 Nov;20(4):667-679.
doi: 10.1016/j.cld.2016.06.003.

Liver Fibrosis Reversion After Suppression of Hepatitis B Virus

Don C Rockey  1
Affiliations
Review

Liver Fibrosis Reversion After Suppression of Hepatitis B Virus

Don C Rockey. Clin Liver Dis. 2016 Nov.

Abstract

Great strides have been made in hepatitis B virus (HBV)-related fibrosis and cirrhosis. Available evidence indicates that HBV viral suppression causes regression of advanced fibrosis and even cirrhosis, and therefore should be attempted in all patients with advanced fibrosis and cirrhosis. The preferred agents in patients with cirrhosis are entecavir and tenofovir, primarily because the risk of breakthrough is low. HBV viral suppression leads to improved clinical outcomes even in patients with cirrhosis and complications. The risk of hepatocellular carcinoma is reduced, but not eliminated. Thus, patients with HBV cirrhosis should continue to have routine screening for hepatocellular carcinoma, even after viral suppression.

Keywords: Cirrhosis; HIV; Hepatocellular carcinoma; Portal hypertension; Regression; Stellate cell; Viral suppression.

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Figures

Figure 1.
Figure 1.
Histological reversal of fibrosis. An example of reversal of HBV cirrhosis is shown. In (a) and (b) is shown a liver biopsy prior to lamivudine treatment. In (c), after treatment with lamivudine, liver biopsy was repeated, and reveals almost complete dissolution of fibrosis. Data similar to this have been found in patients with autoimmune liver disease, alcoholic hepatitis, hepatitis C, and others. From Wanless IR, Nakashima E, Sherman M. Arch Pathol Lab Med 124:1599–1607, 2000, with permission.
Figure 2.
Figure 2.
Reversal of organ fibrosis. Fibrosis is remarkably plastic. In many, though not all, instances, tissue fibrosis can be reversed as extracellular matrix proteins are degraded. Often, removal of the inciting stimulus is sufficient, and in a few instances, therapeutic interventions _targeting the underlying disease process contribute, as well. From Don C Rockey, P Darwin Bell, and Joseph A Hill. Fibrosis – A Common Pathway to Organ Injury and Failure. N Engl J Med 372:1138–1149, 2015, with permission.
Figure 3.
Figure 3.
Stellate cell activation. A key pathogenic feature underlying liver fibrosis and cirrhosis is activation of hepatic stellate cells (note that activation of other effector cells is likely to parallel that of stellate cells). The activation process is complex, both in terms of the events that induce activation and the effects of activation. Multiple and varied stimuli participate in the induction and maintenance of activation, including, but not limited to cytokines, peptides, and the extracellular matrix itself. Phenotypic features of activation include production of extracellular matrix, loss of retinoids, proliferation, of upregulation of smooth muscle proteins, secretion of peptides and cytokines (with autocrine effects on stellate cells and paracrine effects on other cells such as leukocytes and malignant cells – see Figure 4), and upregulation of various cytokine and peptide receptors. Additionally, evidence indicates that stellate cells exhibit several cell fates that are likely to play a critical role in fibrosis regression, highlighted at the bottom of the figure. From Rockey DC. Hepatic Fibrosis. In Yamada’s Textbook of Gastroenterology, Wiley and Sons, Ltd. West Sussex, UK. 2016, with permission.
Figure 4.
Figure 4.
The cellular response to wound healing. Most forms of liver injury result in hepatocyte injury, followed by inflammation, leading to activation of HSCs. Inflammatory effectors are multiple and include T cells, NK and NKT cells as well as Kupffer cells. These cells produce growth factors, cytokines, and chemokines that play an important role in stellate cell activation. Additionally, injury leads to disruption of the normal cellular environment, and also to stellate cell activation. Once activated, stellate cells themselves produce a variety of compounds, including growth factors, cytokines, chemokines, and vasoactive peptides. These substances have pleotrophic effects in the local environment, including autocrine effects on stellate cells themselves. ECM synthesis, as well as production of matrix degrading enzymes are major consequences of stellate cell activation. From Rockey DC. Hepatic Fibrosis. In Yamada’s Textbook of Gastroenterology, Wiley and Sons, Ltd. West Sussex, UK. 2016, with permission.
Figure 5.
Figure 5.
The cellular mechanism of fibrosis reversion is linked to stellate cell phenotype. Activated hepatic stellate cells are removed from the fibrogenic milieu during fibrosis regression. The mechanism for their removal appears to be via their complete elimination (i.e. via apoptosis) or via reversion from an activated to a quiescent phenotype. From Rockey DC. Hepatic Fibrosis. In Yamada’s Textbook of Gastroenterology, Wiley and Sons, Ltd. West Sussex, UK. 2016, with permission.
Figure 6.
Figure 6.
Kaplan–Meier estimate of time to disease progression. Patients were randomized to treatment with placebo or lamivudine, and followed for 36 months. Disease progression was defined as the development of hepatocellular carcinoma, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or had death related to liver disease. From Yun-Fan Liaw, Joseph J.Y. Sung, Wan Cheng Chow, et al. Lamivudine for Patients with Chronic Hepatitis B and Advanced Liver Disease. N Engl J Med 351:1521–1531, 2004, with permission.
Figure 7.
Figure 7.
Histology results over 5-year treatment phase. The Ishak stage (0 to 6) of fibrosis in paired liver biopsy specimens from 348 patients at baseline, at 1 year, and at 5 years of treatment with tenofovir is shown (344 patients had specimens at all 3 time points). From Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. The Lancet 381: 468–75, 2013, with permission.
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References

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