Prediction of fibrosis progression in hepatitis C infection: Are genetics ready for clinical use?
Authors: Hermann E. Wasmuth, Christian Trautwein
Journal: Journal of Hepatology (2011)

Role of a cirrhosis risk score for the early prediction of fibrosis progression in hepatitis C patients with minimal liver diseaseJournal of HepatologyVol. 55Issue 1PreviewFibrosis progression in patients with chronic hepatitis C (CHC) is highly variable. A Cirrhosis Risk Score (CRS) based on seven genetic variants has been recently developed for identifying patients at risk for cirrhosis. The objective of this study was to assess the role of the CRS for the early prediction of fibrosis progression in CHC patients with mild liver fibrosis. In addition, we evaluated the potential benefit, for prediction accuracy, of a recently described non-invasive fibrosis staging assay, the Enhanced Liver Fibrosis (ELF) test. Full-Text PDF Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease worldwide and results in complications, such as decompensated cirrhosis and hepatocellular carcinoma. However, large epidemiological studies have suggested that only about half of all HCV infected patients show significant fibrosis and only a fraction of these are at risk of developing end-stage liver disease [[1]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: 825-832Abstract Full Text Full Text PDF PubMed Scopus (2768) Google Scholar]. These large inter-individual differences in the progression of HCV infection are partly due to exogenous factors (e.g. alcohol intake, co-infections, diabetes) [[2]Mallat A. Hezode C. Lotersztajn S. Environmental factors as disease accelerators during chronic hepatitis C.J Hepatol. 2008; 48: 657-665Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar]. Nevertheless, recent studies have demonstrated that fibrosis development significantly depends on host genetic factors. In this respect, liver fibrosis is considered to be a complex genetic trait, in which multiple genes and their interactions contribute to the severity of liver fibrosis. This hypothesis has been supported by multiple cross-sectional case-control studies which were based on the a priori hypothesis that the distribution of polymorphic alleles is different between subjects with mild versus patients with severe fibrosis. A major limitation of these studies was their lack of reproducibility and the limited number of polymorphisms investigated within the respective cohorts [[3]Weber S.N. Wasmuth H.E. Liver fibrosis: from animal models to mapping of human risk variants.Best Pract Res Clin Gastroenterol. 2010; 24: 635-646Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]. The elucidation of the genetic basis for liver fibrosis was taken a step further by the first large-scale genetic screen in patients with HCV induced liver fibrosis in 2007 [[4]Huang H. Shiffman M.L. Friedman S. Venkatesh R. Bzowej N. Abar O.T. et al.A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C.Hepatology. 2007; 46: 297-306Crossref PubMed Scopus (254) Google Scholar]. In this analysis more than 20,000 single polymorphisms were analyzed in two independent cohorts of patients of Caucasian ethnicity in a genome-wide scan. The genetic data were subsequently analyzed in depth and a genetic score was calculated which predicted the presence of severe fibrosis in the investigated patients [[4]Huang H. Shiffman M.L. Friedman S. Venkatesh R. Bzowej N. Abar O.T. et al.A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C.Hepatology. 2007; 46: 297-306Crossref PubMed Scopus (254) Google Scholar]. This gene signature was termed the “cirrhosis risk score” (CRS) and consisted of single nucleotide polymorphisms in seven different genes (AP3S2, AQP2, AZIN1, DEGS1, STXBP5L, TLR4, and TRPM5). Such a combination of SNPs into a score has also been applied in studies on the genetic basis of cholesterol levels and prostate cancer [[5]Manolio T.A. Genomic association studies and assessment of the risk of disease.N Engl J Med. 2010; 363: 166-176Crossref PubMed Scopus (1110) Google Scholar]. The validity and potential clinical applicability of the CRS was subsequently validated in a cohort from Italy [[6]Marcolongo M. Young B. Dal Pero F. Fattovich G. Peraro L. Guido M. et al.A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C.Hepatology. 2009; 50: 1038-1044Crossref PubMed Scopus (87) Google Scholar]. All of the patients in this study had mild fibrosis at initial biopsy but did not undergo antiviral therapy due to various clinical reasons. After a median follow-up of 60 months the subjects underwent a second liver biopsy. Overall, 24.4% showed no histologic progression, while 75.6% progressed by at least one stage. In this group 45.0% progressed by at least two stages, and 10.3% by more than two stages. When the CRS was applied to this cohort, the mean CRS values were significantly higher in patients with fibrosis progression compared with those without progression [[6]Marcolongo M. Young B. Dal Pero F. Fattovich G. Peraro L. Guido M. et al.A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C.Hepatology. 2009; 50: 1038-1044Crossref PubMed Scopus (87) Google Scholar]. In the current issue of the Journal of Hepatology, the clinical value of the CRS in predicting fibrosis progression has now been prospectively validated in two further cohorts of HCV infected patients with minimal liver fibrosis at baseline [[7]Trepo E. Potthoff A. Pradat P. Bakshi R. Young B. Lagier R. Moreno C. Verset L. Cross R. Degre D. Lemmers A. Gustot T. Berthillon P. Rosenberg W.M. Trepo C. Sninsky J. Alder M. Wedemeyer H. Role of a cirrhosis risk score for the early prediction of the fibrosis progression in hepatitis C patients with minimal liver disease.J Hepatol. 2011; 55: 38-44Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Although both cohorts were significantly smaller than the number of patients investigated by Marcolongo et al. [[6]Marcolongo M. Young B. Dal Pero F. Fattovich G. Peraro L. Guido M. et al.A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C.Hepatology. 2009; 50: 1038-1044Crossref PubMed Scopus (87) Google Scholar], the CRS was again significantly associated with fibrosis progression in untreated patients for a follow-up period of at least five years. These results suggest that the CRS remains a prognostic marker even in relatively low powered studies. An additional strength of the study by Trepo et al. is that the CRS was also analyzed together with a recent non-invasive fibrosis staging score, the enhanced liver fibrosis (ELF) test [[8]Rosenberg W.M. Voelker M. Thiel R. Becka M. Burt A. Schuppan D. et al.Serum markers detect the presence of liver fibrosis: a cohort study.Gastroenterology. 2004; 127: 1704-1713Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar]. This biomarker based score includes the serum levels of hyaluronic acid, amino-terminal propeptide of type III collagen (PNIIIP), and tissue inhibitor of matrix metalloproteinase 1 (TIMP1) and has been validated as a non-invasive marker of liver fibrosis in cross-sectional studies of different liver disease etiologies. Notably, this score has now been identified to predict histologic fibrosis progression in the study by Trepo et al. [[7]Trepo E. Potthoff A. Pradat P. Bakshi R. Young B. Lagier R. Moreno C. Verset L. Cross R. Degre D. Lemmers A. Gustot T. Berthillon P. Rosenberg W.M. Trepo C. Sninsky J. Alder M. Wedemeyer H. Role of a cirrhosis risk score for the early prediction of the fibrosis progression in hepatitis C patients with minimal liver disease.J Hepatol. 2011; 55: 38-44Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Since the ELF score is a combination of matrix components and functional inhibitors of their degradation, this new and interesting observation again underscores that fibrosis is a dynamic process involving different aspects of matrix biology. Clinically, the association of the ELF score with fibrosis progression in HCV infection needs confirmation in larger cohorts, but might lead to new predictive parameters in the future. In a regression model, the CRS was associated with an OR of 2.23 for fibrosis progression, an effect size which is low for combined SNP scores but in the range of large-scale SNP analysis in complex diseases [[9]Hardy J. Singleton A. Genomewide association studies and human disease.N Engl J Med. 2009; 360: 1759-1768Crossref PubMed Scopus (574) Google Scholar]. In ROC analysis the combination of the CRS with the ELF test together with readily available clinical parameters (gender, alcohol consumption and presence of diabetes) yielded an area under the curve of 0.87, which is better than the predictive value of clinical parameters (AUC 0.74) or the CRS (AUC 0.85) score alone [[7]Trepo E. Potthoff A. Pradat P. Bakshi R. Young B. Lagier R. Moreno C. Verset L. Cross R. Degre D. Lemmers A. Gustot T. Berthillon P. Rosenberg W.M. Trepo C. Sninsky J. Alder M. Wedemeyer H. Role of a cirrhosis risk score for the early prediction of the fibrosis progression in hepatitis C patients with minimal liver disease.J Hepatol. 2011; 55: 38-44Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. These analyses indeed suggest that the specificity and sensitivity of the combined markers are sufficient for predicting fibrosis progression in clinical practice. The findings by Trepo et al. stress the question whether there is a clinical need for predicting fibrosis progression in patients with chronic HCV infection since some current guidelines [[10]Sarrazin C. Berg T. Ross R.S. Schirmacher P. Wedemeyer H. Neumann U. et al.Prophylaxis, diagnosis and therapy of hepatitis C virus (HCV) infection: the German guidelines on the management of HCV infection.Z Gastroenterol. 2010; 48: 289-351Crossref PubMed Scopus (161) Google Scholar] recommend the treatment of almost all HCV-RNA positive patients. Indeed, prediction of fibrosis progression might be reserved for subjects with relative contraindications to interferon and ribavirin treatment (e.g. psychiatric disorders, hemoglobin abnormalities, concurrent autoimmune diseases), patients who failed to achieve a sustained virological response to current regimens or who are candidates for clinical studies which assess the utility of anti-fibrotic treatments. However, these populations represent a significant number of individuals seen at specialised centers and the CRS might help to personalise clinical care of these individuals. Personalised decision making might even be supplemented by genetic determination of the likelihood of treatment response by genotyping the IL28B locus [[11]Suppiah V. Moldovan M. Ahlenstiel G. Berg T. Weltman M. Abate M.L. et al.IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.Nat Genet. 2009; 41: 1100-1104Crossref PubMed Scopus (1703) Google Scholar] and by estimation of the risk for ribavirin induced anemia by ITPA variants [[12]Fellay J. Thompson A.J. Ge D. Gumbs C.E. Urban T.J. Shianna K.V. et al.ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C.Nature. 2010; 464: 405-408Crossref PubMed Scopus (409) Google Scholar]. However, with such genetic parameters on the horizon, the question arises about how to deal with persons who carry the at-risk alleles for fibrosis progression, treatment failure, or anemia. These aspects need to be thoroughly discussed with the affected patients prior to starting antiviral therapy and a clinical consensus needs to be established in the hepatologists community. What other lessons can be drawn from the validated association of the CRS with fibrosis progression in HCV infection? Despite the fact that all genes included into the score have now been identified, only one (TLR4) has yet been functionally associated with liver fibrosis in vitro and in vivo [[13]Seki E. De Minicis S. Osterreicher C.H. Kluwe J. Osawa Y. Brenner D.A. et al.TLR4 enhances TGF-beta signaling and hepatic fibrosis.Nat Med. 2007; 13: 1324-1332Crossref PubMed Scopus (1458) Google Scholar]. However, the other genes of the CRS might also point to interesting molecular pathways of fibrogenesis, such as aquaporins which seem to be implicated in chronic kidney injury [[14]Bedford J.J. Leader J.P. Walker R.J. Aquaporin expression in normal human kidney and in renal disease.J Am Soc Nephrol. 2003; 14: 2581-2587Crossref PubMed Scopus (90) Google Scholar]. According to this hypothesis, we have learned from large-scale genetic association studies in age-related macular degeneration and Crohn’s disease that strong and reliable associations might lead to new molecular driven concepts for these diseases. This has already led to the first clinical trials in age-related macular degeneration by blocking the complement pathway [[15]Wagner E. Frank M.M. Therapeutic potential of complement modulation.Nat Rev Drug Discov. 2010; 9: 43-56Crossref PubMed Scopus (175) Google Scholar], although a few years ago the involvement of this inflammatory pathway in the disease had not even been suspected. Thus, it remains a great scientific challenge to further elucidate the functional importance of the genes involved in the CRS with regards to fibrogenesis in HCV infection. Based on this knowledge new interventional anti-fibrotic strategies for patients who fail to respond to current or future antiviral therapies might be developed. In such studies the CRS might guide the selection of patients who would most benefit from anti-fibrotic therapies. Furthermore, the CRS should be tested in other fibrotic liver diseases (including alcoholic, NASH, or biliary disease) in order to better understand the predictive and pathophysiological impact of this score and its genes across different etiologies. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Work in the lab of the authors is supported by the Deutsche Forschungsgemeinschaft (SFB-TRR57) and Aachen University (IZKF grants to HEW).