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  • Review Article
  • OPEN ACCESS

Clinical Advances in Fibrosis Progression of Chronic Hepatitis B and C

  • Ye-Jiao Wu,
  • Ming-Yi Xu and
  • Lun-Gen Lu*
 Author information  Cite
Journal of Clinical and Translational Hepatology   2014;2(4):222-227

doi: 10.14218/JCTH.2014.00029

Abstract

Chronic liver diseases, such as chronic hepatitis B (CHB) and chronic hepatitis C (CHC), are characterized by the presence of liver fibrosis, which may ultimately lead to cirrhosis. The progression of fibrosis is associated with various factors. Here, we review recent advances in the study of factors related to the progression rate of CHB- and CHC-induced fibrosis. Identification of these factors and establishment of a scoring system for cirrhosis risk are particularly important for predicting cirrhosis development, planning individualized treatment, and preventing fibrosis progression.

Keywords

Chronic hepatitis B, Chronic hepatitis C, Liver fibrosis, Disease progression

Introduction

Liver fibrosis is a common long-term pathological consequence of viral hepatitis, including chronic hepatitis B (CHB) and chronic hepatitis C (CHC).1,2 Due to continuous replacement of normal liver tissue with extracellular matrix (ECM), liver fibrosis results in progressive distortion of the normal hepatic architecture. These changes can evolve into cirrhosis. Severe complications of liver cirrhosis, including portal hypertension, ascites, varices, hepatic encephalopathy, hepatocellular carcinoma, hepatopulmonary syndrome, hepatorenal syndrome, and coagulation disorders, increase the risk of mortality in patients with chronic liver disease.3

The mechanisms underlying fibrogenesis in the liver have not been fully characterized. Accumulating evidence indicates that fibrosis can be triggered by continuous stimulation produced by infection with hepatitis B or C virus (HBV or HCV, respectively) through a three-step cascade.4 According to the current model, the process begins with a preinflammatory stage (Step 1), during which hepatic stellate cells (HSCs) are activated directly through the paracrine action of cytokines released by necrotic hepatocytes. Subsequently (Step 2), preactivated HSCs are further stimulated by infiltrating leukocytes and platelets, as well as by activated Kupffer cells, hepatocytes, and sinusoidal endothelial cells, to transdifferentiate into proliferative, fibrogenic, and contractile myofibroblasts (MFBs). Lastly, in the postinflammatory stage (Step 3), cytokines are released and ECM components are produced by MFBs. During the postinflammatory stage, there is an imbalance of ECM production and degradation, which are controlled by regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), respectively, resulting in an overabundance of ECM accumulation and, ultimately, the development of liver fibrosis (see Fig. 1).5

Synopsis of pathogenetic mechanisms of liver fibrogenesis.
Fig. 1  Synopsis of pathogenetic mechanisms of liver fibrogenesis.

HSCs: hepatic stellate cells; MFBs: myofibroblasts; ECM: extracellular matrix.

A variety of factors have been proposed to contribute to the progression of liver fibrogenesis, including host factors, viral factors, therapeutic strategies, and interactions with comorbid conditions (see Fig. 2). Here, we summarize recent advances in the characterization of factors related to fibrosis progression.

Risk and protective factors of liver fibrosis progression in HBV and HCV infected patients.
Fig. 2  Risk and protective factors of liver fibrosis progression in HBV and HCV infected patients.

HBV: hepatitis B virus; HCV: hepatitis C virus.

Host factors

Demographic features

The putative association between age at infection and fibrosis progression in CHB and CHC patients remains controversial. Age has been identified in a number of studies as an important factor that can predict the progression rate of fibrosis and the development of cirrhosis.6–10 For example, fibrosis progression was found to be relatively slow in CHC patients younger than 20 years old; fibrosis was found to accelerate with increased age, perhaps due to reduced immune defense.6 The natural history of chronic HBV infection also varies with age of infection. Compared with patients younger than 45 years old, the cumulative probability of cirrhosis development was significantly higher in patients older than 45.7 However, there are contradictory results in the literature as well.11 Interestingly, donor age was also reported to be related to fibrosis progression in patients with recurrent HCV infection after liver transplantation.12

Advanced fibrosis is more common among male than female CHB patients.6,10,11 This gender difference might be explained, at least in part, by higher prevalence rates of drinking, smoking, and obesity in males. Additionally, it could be that female gender is protective against progression of liver fibrosis in CHC; it has been suggested that long-term exposure to estrogen may reduce liver fibrosis.13 In addition, pregnancy may have a beneficial influence on the long-term progression of liver fibrosis, whereas menopause appears to be associated with accelerated fibrosis progression in female CHC patients.13

In summary, the current evidence indicates that both age and gender influence the progression of liver fibrosis. Specifically, older age and being male appear to be associated with faster progression of fibrosis.

Host genetic factors

The development of genotyping techniques and candidate gene approaches has enabled researchers to investigate the association between liver fibrosis progression and gene polymorphisms with known or supposed functions in pathways involved in fibrogenesis, inflammatory responses, oxidative stress, apoptosis, and necrosis.14 For example, Richardson et al. examined eight candidate genes and found that six of them, namely HFE, MTP, APOE, CCR5, SOD2, and CTLA4, were related to a more rapidly progressive fibrosis in CHC.15 Additionally, Boursier and Louvet found that the presence of the G/G genotype at a single nucleotide polymorphism (SNP) of interest in the transforming growth factor β1 (TGF-β1) gene was associated significantly with greater severity of fibrosis in CHC patients.16 Thus far, approximately 30 and 10 genes have been identified as being related to fibrosis progression in CHC and CHB, respectively (see Table 1).17

Table 1

Chronic hepatitis C or B-induced fibrosis-associated genes identified by candidate gene studies or genome-wide association studies

Candidate gene studiesGWAS
Chronic hepatitis CAngiotensinogen, ApoE, C5a, CCR5, CPT1A, CTLA4, CYP2D6, DDX5, epoxide hydrolase, HFE, HLA II, IL1E, IL6, IL10, IL12, IFNJ, MCP-1, MMP-1, MMP-3, MMP-9, MTP, MX-1, OAS-1, PAR-1, PKR, SLC11A1, SOD2, TAP2, TGFE1, TNFAP3S2, AQP2, AZIN1, DEGS1, STXBP5L, TLR4, TRPM5
Chronic hepatitis BAngiotensinogen, CD24, COL1A1, CXCL10, GSTP1, IL10, MBL, TNF-, TNF-, vitD-rec/

GWAS: genome-wide association studies.

Although candidate gene techniques allow the genetic architecture of complex traits to be explored, the utility of this technique is limited greatly by its reliance on existing biological knowledge about presumed or known phenotypes.18 Genome-wide scanning, which can proceed without any presuppositions of the significance of specific phenotypes,18 has been widely applied in investigations of associations between genetic factors and multiple disease processes, including liver fibrosis. Huang et al. published a study that included 420 subjects with well-documented CHC and established fibrosis staging and revealed that among 23,823 SNPs, there was a group of seven SNPs that formed a cirrhosis risk score (CRS) signature that could identify Caucasian CHC patients at high risk of cirrhosis (also see table 1).10 The CRS has since been validated in two independent longitudinal trials.11,19

Viral factors

Viral genotypes

Viral genotype has been implicated in the clinical outcome of chronic viral hepatitis. However, the potential association between particular viral genotypes and the progression of liver fibrosis in CHC patients remains controversial. Probst et al. conducted a systematic review and meta-analysis to investigate this issue. When they examined single-biopsy studies, they found a potential association between HCV genotype 3 and rapid progression of fibrosis.20 This putative association, however, did not hold in paired-biopsy studies, suggesting that the single-biopsy analysis may have suffered from indication bias related to a short observation period and small sample size.20

Ten HBV genotypes (labeled A–J) with differing geographical and ethnic distribution patterns have been identified.21 Liu and Kao found that HBV genotypes B and C occur in Asian populations with greater frequency than other genotypes, and that genotype C was associated with an elevated risk of liver cirrhosis.22 In contrast, Yuen et al. observed that patients with HBV genotype C had delayed hepatitis B e antigen (HBeAg) seroconversion, worse liver biochemistry, prolonged active HBV DNA proliferation, and higher hepatitis viral loads across different phases of the disease's natural course relative to genotype B patients. There was no significant difference between genotype C and B patients in their probability of developing cirrhosis-related complications.23,24 It should also be noted that the prevalence rate of the combination of preS deletions and A1762T/G1764A mutations was relatively higher in patients infected with genotype B than genotype C,22,25 which may explain in part the worse clinical outcomes observed among genotype C patients in the study by Liu and Kao. HBV genetic mutations are associated with increased risk of liver cirrhosis. The precore G1896A mutant and the basal core promoter A1762T/G1764A dual mutant have been linked to greater risk of cirrhosis in HBV carriers.26,27 Moreover, the preS deletion mutant appears to be an independent predictor of liver cirrhosis.21,25

Viral load

A Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study was carried out in Taiwan with 3,582 untreated HBV carriers. During the 11-year follow-up period, they found that serum HBV-DNA level correlated positively with the incidence of cirrhosis. Among 365 newly diagnosed cirrhosis patients, the cumulative incidence of cirrhosis in those with serum HBV-DNA levels <300 copies/mL at baseline was significantly lower than that in those with levels >106 copies/mL at baseline.28 Increasing serum HBV-DNA level has been proposed as an independent risk predictor for fibrosis progression and cirrhosis.26 Presumably, high HBV-DNA load might lead to more severe liver damage during the immune clearance phase and, therefore, accelerate the progression of fibrosis.26,28

As for HCV, preexisting evidence of the association between serum HCV RNA levels and liver fibrosis is limited and conflicting. Some studies showed no significant correlation,29–31 while other researchers reported significant relevance of serum HCV RNA level and fibrosis.32–34 Rarely are longitudinal studies regarding fibrosis progression rate are found, and further related studies remain to be conducted.

Therapeutic strategies

Anti-HCV therapy

The standard therapeutic strategy for patients with CHC is combined administration of standard or pegylated interferon-α (IFN-α) with ribavirin. The addition of polyethylene glycol to IFN-α, through a process known as pegylation, prolongs the half-life of IFN-α. The primary goal of anti-HCV therapy is a sustained virological response (SVR), defined as undetectable HCV RNA levels 24 weeks after completion of the treatment.35 A cohort of 150 American patients with SVRs after anti-CHC therapy was followed for 5 years.36 In the fourth year, 82% of patients exhibited a lower fibrosis score than they had prior to initiating therapy.36 Similar results were obtained from other researchers.37 These findings indicated that SVR following IFN-α plus ribavirin therapy could benefit and improve outcome in patients with advanced liver fibrosis. Although IFN-α plus ribavirin therapy has been applied widely, numerous adverse events have been reported. Hence, there is a sustained interest in IFN-free regimens, such as sofosbuvir.38 However, the efficacy of IFN-free regimens for preventing fibrosis progression remains to be elucidated. It is important to note that SVR rate varied by different HCV genotypes. Specifically, the SVR rate was approximately 40–50% in the patients with HCV genotype 1 and 80% in those with genotype 2 and 3.39

Anti-HBV therapy

The main goals of anti-HBV therapy are to prevent disease progression to cirrhotic endpoints and to improve survival by suppressing HBV DNA replication, ideally achieving a sustained reduction of HBV DNA to undetectable levels.40 There are two categories of regimens licensed for the treatment of CHB, namely standard or pegylated IFN-α and five nucleoside/nucleotide analogues (NAs).41 Independent follow-up studies showed that IFN therapy retarded the progression of fibrosis and reduced progression to cirrhosis in HBeAg-positive patients.42,43 A meta-analysis conducted in 2010 indicated that IFN-α treatment can reduce the risks of overall hepatic events and of cirrhotic complications, particularly among treatment responders.44 Meanwhile, long-term NA-based therapy with third-generation NAs (entecavir or tenofovir) has been reported to reverse fibrosis, and even cirrhosis, in several registered clinical trials.45–49

Comorbidities

Human immunodeficiency virus infection

Emerging lines of evidence suggest that human immunodeficiency virus (HIV) infection accelerates fibrosis progression in HCV patients.50 Without successful treatment, more than 20% of HIV/HCV coinfected patients with null or mild fibrosis progressed to advanced fibrosis within 5 years.51 Pegylated IFN-α plus ribavirin therapy has been reported to reduce the incidence of liver complications and death in HIV/HCV coinfected patients.52 The molecular mechanisms involved with rapid fibrosis progression in coinfected patients are complicated, but the most relevant mechanisms involved viral factors, immune system, fibrinogenetic/inflammatory mediators, and metabolic alteration. This topic was recently reviewed in detail by Mastroianni et al.53

Hepatic steatosis

The strong association between HCV-related steatosis and fibrosis progression has been demonstrated in multiple cross-sectional or prospective studies, previously reviewed by Lonardo et al.54 The most convincing evidence among these studies comes from the meta-analysis conducted by Leandro et al.55 The study included 3,068 CHC patients from 10 centers in Europe, Australia, and North America and showed that steatosis was a risk factor for fibrosis progression. In addition, based on the results of its subgroup analyses, the association between steatosis and fibrosis was reasonably inferred to be mediated by hepatic inflammation. However, another meta-analysis indicated that the frequency of hepatic steatosis in CHB patients was similar to that in the general population, suggesting that hepatic steatosis may be related to metabolic factors, rather than fibrosis stage, in CHB patients.56

Insulin resistance

Insulin resistance (IR), a major cause of type 2 diabetes, was shown to drive fibrosis progression in studies conducted by two independent research groups.57,58 Subsequent experimental studies revealed that CHC patients with IR were prone to elevations in serum leptin and TNF- levels, which may promote the activation of HSCs and, consequently, enhance fibrosis progression.59 Another study showed insulin resistance might directly impact HSCs and raise connective tissue growth factor levels, leading to excessive generation of ECM.60 Alternatively, IR-induced hepatic lipid accumulation may increase oxidative stress, thereby promoting fibrosis progression.61 However, IR does not appear to be associated with fibrosis severity in CHB patients.62,63

Other factors

Alcohol intake

The potential association between alcohol consumption and fibrosis progression in HCV-infected patients is still under debate. In a majority of studies, it has been shown that heavy alcohol use (>50 g/day) exerted an adverse effect on fibrosis progression.6,64,65 However, the data regarding light or moderate alcohol use have been conflicting.66 The reason for this discrepancy is unclear, but may be due to patients altering their alcohol habits as a consequence of their disease awareness.

Coffee consumption

Epidemiological studies have shown that coffee drinking was associated with a decreased prevalence of cirrhosis in patients with chronic liver disease.67 Regular coffee consumption is known to have hepatoprotective benefits in CHC patients; advanced fibrosis has been observed less often in patients who drink coffee than in patients who do not.68,69 It has been speculated that coffee might prevent fibrosis progression by regulating insulin sensitivity, leading to alleviation of inflammation and reduction of oxidative stress. Conversely, no significant benefits of regular tea intake were found in CHC patients.69 There has been only one report evaluating the link between coffee consumption and fibrosis in CHB patients, and no benefit was identified as measured by transient elastography.70 Further confirmation of the association is needed.

Recurrent HCV after liver transplantation

CHC is a principal indication for liver transplantation. Approximately 30% of patients who receive a liver transplant go on to develop severe fibrosis within 5 years due to HCV recurrence.71,72 The progression of fibrosis following transplantation appears to be nonlinear over time. Walter et al. observed rapid elevation of fibrosis during the first 3 years after transplantation, followed by less rapid progression in the subsequent 2 years.12 Rapid fibrosis progression in the initial period following transplantation might be related to preoperative antiviral therapy, immunosuppressive regimens, short-term use of hormones, and donor age. Interestingly, a retrospective, single-center study showed that sirolimus-based immunosuppression reduced the risk of fibrosis for HCV infection after liver transplantation.73

Cannabis use

Since daily cannabis smoking may be a predictor of fibrosis progression in CHC patients,74,75 reduction or discontinuation of cannabis use is recommended for HCV-infected patients. The cannabinoid receptors CB1 and CB2 have been implicated in the fibrogenic influence of cannibis. Inactivation of CB1 receptors by genetic or pharmacological approaches prevented fibrogenesis through downregulation of TGF-β1 levels and reduction of fibrogenic cell accumulation.76 In addition, CB2 knockout mice chronically exposed to carbon-tetrachloride demonstrated facilitated apoptosis and reduced proliferation of hepatic MFBs relative to wild-type controls.77

Conclusions

Significant progress has been achieved in the analysis of relevant factors affecting progression of CHB- and CHC-induced fibrosis. Multiple factors, including host factors, viral factors, therapeutic strategies, and comorbidities, are involved in the progression of fibrosis, and the molecular mechanisms underlying these influences have been partially elucidated. Meanwhile, researchers continue to examine how single or multiple factors contribute to the risk of cirrhosis development in patients with chronic viral hepatitis,10,15,26 which, nevertheless, remains to be validated in large samples from different populations. Prospectively, the identification of new predictors and the establishment of a risk score system remain clinical challenges in the assessment of risk of cirrhosis development and the prediction of clinical outcomes in CHB and CHC patients. Continued progress in these areas is critical because individual risk profiles play a critical role in therapeutic strategy determination and prognostic judgment.

Abbreviations

CRS: 

cirrhosis risk score

CHB: 

chronic hepatitis B

CHC: 

chronic hepatitis C

ECM: 

extracellular matrix

HBeAg: 

hepatitis B e antigen

HBV: 

hepatitis B virus

HCV: 

hepatitis C virus

HIV: 

human immunodeficiency virus

HSCs: 

hepatic stellate cells

IR: 

insulin resistance

MFBs: 

myofibroblasts

MMPs: 

metalloproteinases

REVEAL-HBV: 

Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus

TGF-β1: 

transforming growth factor β1

TIMPs: 

metalloproteinases

Declarations

Conflict of interest

None

Authors’ contributions

Writing the manuscript and performing literature searches (YJW). Editing and revising the manuscript (MYX, LGL).

References

  1. Elpek GO. Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update. World J Gastroenterol 2014;20:7260-7276 View Article
  2. Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 2011;6:425-456 View Article
  3. Nusrat S, Khan MS, Fazili J, Madhoun MF. Cirrhosis and its complications: evidence based treatment. World J Gastroenterol 2014;20:5442-5460 View Article
  4. Gressner OA, Gao C. Monitoring fibrogenic progression in the liver. Clin Chim Acta 2014;433:111-122 View Article
  5. Xu R, Zhang Z, Wang FS. Liver fibrosis: mechanisms of immune-mediated liver injury. Cell Mol Immunol 2012;9:296-301 View Article
  6. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-832 View Article
  7. Huo T, Wu JC, Hwang SJ, Lai CR, Lee PC, Tsay SH. Factors predictive of liver cirrhosis in patients with chronic hepatitis B: a multivariate analysis in a longitudinal study. Eur J Gastroenterol Hepatol 2000;12:687-693
  8. Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002;122:1303-1313 View Article
  9. Ghany MG, Kleiner DE, Alter H, Doo E, Khokar F, Promrat K. Progression of fibrosis in chronic hepatitis C. Gastroenterology 2003;124:97-104 View Article
  10. Huang H, Shiffman ML, Friedman S, Venkatesh R, Bzowej N, Abar OT. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 2007;46:297-306 View Article
  11. Marcolongo M, Young B, Dal Pero F, Fattovich G, Peraro L, Guido M. A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C. Hepatology 2009;50:1038-1044 View Article
  12. Walter T, Dumortier J, Guillaud O, Hervieu V, Scoazec JY, Boillot O. Factors influencing the progression of fibrosis in patients with recurrent hepatitis C after liver transplantation under antiviral therapy: a retrospective analysis of 939 liver biopsies in a single center. Liver Transpl 2007;13:294-301 View Article
  13. Di Martino V, Lebray P, Myers RP, Pannier E, Paradis V, Charlotte F. Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure. Hepatology 2004;40:1426-1433 View Article
  14. Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 2003;37:493-503 View Article
  15. Richardson MM, Powell EE, Barrie HD, Clouston AD, Purdie DM, Jonsson JR. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C. J Med Genet 2005;42:e45 View Article
  16. Sanchez-Parada MG, Alvarez-Rodriguez BA, Gomez-Meda BC, Troyo-Sanroman R, Sanchez-Orozco LV, Zamora-Perez AL. Association of genetic polymorphisms with histological grading of necroinflammation, staging of fibrosis, and liver function in Mexicans with chronic hepatitis C virus infection. J Investig Med 2013;61:1088-1096 View Article
  17. Boursier J, Louvet A. Liver fibrogenesis and genetic factors. Clin Res Hepatol Gastroenterol 2011;35:S3-S9 View Article
  18. Zhu M, Zhao S. Candidate gene identification approach: progress and challenges. Int J Biol Sci 2007;3:420-427 View Article
  19. Pradat P, Trepo E, Potthoff A, Bakshi R, Young B, Trepo C. The cirrhosis risk score predicts liver fibrosis progression in patients with initially mild chronic hepatitis C. Hepatology 2010;51:356-357 View Article
  20. Probst A, Dang T, Bochud M, Egger M, Negro F, Bochud PY. Role of hepatitis C virus genotype 3 in liver fibrosis progression–a systematic review and meta-analysis. J Viral Hepat 2011;18:745-759 View Article
  21. Sunbul M. Hepatitis B virus genotypes: global distribution and clinical importance. World J Gastroenterol 2014;20:5427-5434 View Article
  22. Liu CJ, Kao JH. Global perspective on the natural history of chronic hepatitis B: role of hepatitis B virus genotypes A to J. Semin Liver Dis 2013;33:97-102 View Article
  23. Yuen MF, Fung SK, Tanaka Y, Kato T, Mizokami M, Yuen JC. Longitudinal study of hepatitis activity and viral replication before and after HBeAg seroconversion in chronic hepatitis B patients infected with genotypes B and C. J Clin Microbiol 2004;42:5036-5040 View Article
  24. Liu J, Yang HI, Lee MH, Lu SN, Jen CL, Wang LY. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study. Gastroenterology 2010;139:474-482 View Article
  25. Lin CL, Liu CH, Chen W, Huang WL, Chen PJ, Lai MY. Association of pre-S deletion mutant of hepatitis B virus with risk of hepatocellular carcinoma. J Gastroenterol Hepatol 2007;22:1098-1103 View Article
  26. Chen CJ, Yang HI. Natural history of chronic hepatitis B REVEALed. J Gastroenterol Hepatol 2011;26:628-638 View Article
  27. Tseng TC, Liu CJ, Yang HC, Chen CL, Yang WT, Tsai CS. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut 2014 View Article
  28. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678-686 View Article
  29. Fanning L, Kenny E, Sheehan M, Cannon B, Whelton M, O'Connell J. Viral load and clinicopathological features of chronic hepatitis C (1b) in a homogeneous patient population. Hepatology 1999;29:904-907 View Article
  30. Zeuzem S, Scheuermann EH, Waschk D, Lee JH, Blaser C, Franke A. Phylogenetic analysis of hepatitis C virus isolates from hemodialysis patients. Kidney Int 1996;49:896-902 View Article
  31. Kao JH, Lai MY, Chen PJ, Hwang LH, Chen W, Chen DS. Clinical significance of serum hepatitis C virus titers in patients with chronic type C hepatitis. Am J Gastroenterol 1996;91:506-510
  32. Shahid M, Idrees M, Nasir B, Raja AJ, Raza SM, Amin I. Correlation of biochemical markers and HCV RNA titers with fibrosis stages and grades in chronic HCV-3a patients. Eur J Gastroenterol Hepatol 2014;26:788-794 View Article
  33. Adinolfi LE, Utili R, Andreana A, Tripodi MF, Marracino M, Gambardella M. Serum HCV RNA levels correlate with histological liver damage and concur with steatosis in progression of chronic hepatitis C. Dig Dis Sci 2001;46:1677-1683 View Article
  34. Kato N, Yokosuka O, Hosoda K, Ito Y, Ohto M, Omata M. Quantification of hepatitis C virus by competitive reverse transcription-polymerase chain reaction: increase of the virus in advanced liver disease. Hepatology 1993;18:16-20
  35. Formann E, Steindl-Munda P, Hofer H, Jessner W, Bergholz U, Gurguta C. Long-term follow-up of chronic hepatitis C patients with sustained virological response to various forms of interferon-based anti-viral therapy. Aliment Pharmacol Ther 2006;23:507-511 View Article
  36. George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology 2009;49:729-738 View Article
  37. Morisco F, Granata R, Stroffolini T, Guarino M, Donnarumma L, Gaeta L. Sustained virological response: a milestone in the treatment of chronic hepatitis C. World J Gastroenterol 2013;19:2793-2798 View Article
  38. Degasperi E, Aghemo A. Sofosbuvir for the treatment of chronic hepatitis C: between current evidence and future perspectives. Hepat Med 2014;6:25-33 View Article
  39. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54:1433-1444 View Article
  40. van Bommel F, Berg T. Antiviral therapy of chronic hepatitis B. Intervirology 2014;57:171-180 View Article
  41. Santantonio TA, Fasano M. Chronic hepatitis B: Advances in treatment. World J Hepatol 2014;6:284-292
  42. Lin SM, Yu ML, Lee CM, Chien RN, Sheen IS, Chu CM. Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma. J Hepatol 2007;46:45-52 View Article
  43. van Zonneveld M, Honkoop P, Hansen BE, Niesters HG, Darwish Murad S, de Man RA. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology 2004;39:804-810 View Article
  44. Wong GL, Yiu KK, Wong VW, Tsoi KK, Chan HL. Meta-analysis: reduction in hepatic events following interferon-alfa therapy of chronic hepatitis B. Aliment Pharmacol Ther 2010;32:1059-1068 View Article
  45. Chang TT, Lai CL, Kew Yoon S, Lee SS, Coelho HS, Carrilho FJ. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2010;51:422-430 View Article
  46. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008;359:2442-2455 View Article
  47. Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013;381:468-475 View Article
  48. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology 2009;49:1503-1514 View Article
  49. Kitrinos KM, Corsa A, Liu Y, Flaherty J, Snow-Lampart A, Marcellin P. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology 2014;59:434-442 View Article
  50. Hernandez MD, Sherman KE. HIV/hepatitis C coinfection natural history and disease progression. Curr Opin HIV AIDS 2011;6:478-482 View Article
  51. Labarga P, Fernandez-Montero JV, Lopez M, Barreiro P, de Mendoza C, Sierra-Enguita R. Progression to advanced liver fibrosis in HIV/HCV-coinfected patients and prioritization of new hepatitis C therapies. Antivir Ther 2014 View Article
  52. Labarga P, Fernandez-Montero JV, de Mendoza C, Barreiro P, Soriano V. Long-term survival and liver-related events after peginterferon/ribavirin therapy in HIV-infected patients with chronic hepatitis C. Antivir Ther 2014 View Article
  53. Mastroianni CM, Lichtner M, Mascia C, Zuccala P, Vullo V. Molecular mechanisms of liver fibrosis in HIV/HCV coinfection. Int J Mol Sci 2014;15:9184-9208 View Article
  54. Lonardo A, Adinolfi LE, Restivo L, Ballestri S, Romagnoli D, Baldelli E. Pathogenesis and significance of hepatitis C virus steatosis: an update on survival strategy of a successful pathogen. World J Gastroenterol 2014;20:7089-7103 View Article
  55. Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology 2006;130:1636-1642 View Article
  56. Machado MV, Oliveira AG, Cortez-Pinto H. Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients. J Gastroenterol Hepatol 2011;26:1361-1367
  57. Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 2003;125:1695-1704 View Article
  58. Ratziu V, Munteanu M, Charlotte F, Bonyhay L, Poynard T. Fibrogenic impact of high serum glucose in chronic hepatitis C. J Hepatol 2003;39:1049-1055 View Article
  59. Mangia A, Ripoli M. Insulin resistance, steatosis and hepatitis C virus. Hepatol Int 2013;7:782-789 View Article
  60. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001;34:738-744 View Article
  61. Negro F, Sanyal AJ. Hepatitis C virus, steatosis and lipid abnormalities: clinical and pathogenic data. Liver Int 2009;29:26-37 View Article
  62. Petta S, Camma C, Di Marco V, Macaluso FS, Maida M, Pizzolanti G. Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection. Liver Int 2011;31:507-515 View Article
  63. Park SH, Kim DJ, Lee HY. Insulin resistance is not associated with histologic severity in nondiabetic, noncirrhotic patients with chronic hepatitis B virus infection. Am J Gastroenterol 2009;104:1135-1139 View Article
  64. Marcellin F, Roux P, Loko MA, Lions C, Caumont-Prim A, Dabis F. High Levels of Alcohol Consumption Increase the Risk of Advanced Hepatic Fibrosis in HIV/Hepatitis C Virus-Coinfected Patients: a Sex-Based Analysis Using Transient Elastography at Enrollment in the HEPAVIH ANRS CO13 Cohort. Clin Infect Dis 2014;59:1190-1192 View Article
  65. Lim JK, Tate JP, Fultz SL, Goulet JL, Conigliaro J, Bryant KJ. Relationship between alcohol use categories and noninvasive markers of advanced hepatic fibrosis in HIV-infected, chronic hepatitis C virus-infected, and uninfected patients. Clin Infect Dis 2014;58:1449-1458 View Article
  66. Ostapowicz G, Watson KJ, Locarnini SA, Desmond PV. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection. Hepatology 1998;27:1730-1735 View Article
  67. Walton HB, Masterton GS, Hayes PC. An epidemiological study of the association of coffee with chronic liver disease. Scott Med J 2013;58:217-222 View Article
  68. Machado SR, Parise ER, Carvalho L. Coffee has hepatoprotective benefits in Brazilian patients with chronic hepatitis C even in lower daily consumption than in American and European populations. Braz J Infect Dis 2014;18:170-176 View Article
  69. Freedman ND, Everhart JE, Lindsay KL, Ghany MG, Curto TM, Shiffman ML. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology 2009;50:1360-1369 View Article
  70. Ong A, Wong VW, Wong GL, Chan HL. The effect of caffeine and alcohol consumption on liver fibrosis - a study of 1045 Asian hepatitis B patients using transient elastography. Liver Int 2011;31:1047-1053 View Article
  71. Gane E. The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients. Liver Transpl 2003;9:S28-S34 View Article
  72. De Martin E, Senzolo M, Boninsegna S, Guido M, Masier A, Germani G. HCV histological recurrence and survival following liver transplantation in patients with and without hepatocellular carcinoma. Transplant Proc 2008;40:1974-1975 View Article
  73. Kelly MA, Kaplan M, Nydam T, Wachs M, Bak T, Kam I. Sirolimus reduces the risk of significant hepatic fibrosis after liver transplantation for hepatitis C virus: a single-center experience. Transplant Proc 2013;45:3325-3328 View Article
  74. Hezode C, Roudot-Thoraval F, Nguyen S, Grenard P, Julien B, Zafrani ES. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 2005;42:63-71 View Article
  75. Ishida JH, Peters MG, Jin C, Louie K, Tan V, Bacchetti P. Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol 2008;6:69-75 View Article
  76. Teixeira-Clerc F, Julien B, Grenard P, Tran Van Nhieu J, Deveaux V, Li L. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med 2006;12:671-676 View Article
  77. Julien B, Grenard P, Teixeira-Clerc F, Van Nhieu JT, Li L, Karsak M. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 2005;128:742-755 View Article
Copyright © 2014 The Second Affiliated Hospital of Chongqing Medical University. Published by XIA & HE Publishing Ltd. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

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Clinical Advances in Fibrosis Progression of Chronic Hepatitis B and C

Ye-Jiao Wu, Ming-Yi Xu, Lun-Gen Lu
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