Journal of Hepatology Volume 55 Issue 1 Pages 3-4 July 2011
Hermann E. Wasmuth, Christian Trautwein
Received 10 December 2010; received in revised form 9 February 2011; accepted 9 February 2011. published online 21 February 2011.
Refers to article:
Role of a cirrhosis risk score for the early prediction of fibrosis progression in hepatitis C patients with minimal liver disease , 09 December 2010
Eric Trépo, Andrej Potthoff, Pierre Pradat, Rakesh Bakshi, Bradford Young, Robert Lagier, Christophe Moreno, Laurine Verset, Richard Cross, Delphine Degré, Arnaud Lemmers, Thierry Gustot, Pascale Berthillon, William Rosenberg, Christian Trépo, John Sninsky, Michael Adler, Heiner Wedemeyer
Journal of Hepatology
July 2011 (Vol. 55, Issue 1, Pages 38-44)
Abstract Full Text Full-Text PDF (702 KB)
See Article, pages 38–44
Article Outline
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Conflict of interest
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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]. 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]. 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]. 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]. 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]. 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].
The validity and potential clinical applicability of the CRS was subsequently validated in a cohort from Italy [6]. 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 60months 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].
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]. Although both cohorts were significantly smaller than the number of patients investigated by Marcolongo et al. [6], 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]. 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]. 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]. 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]. 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] 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] and by estimation of the risk for ribavirin induced anemia by ITPA variants [12]. 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]. 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]. 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], 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.
Conflict of interest
The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Financial support
Work in the lab of the authors is supported by the Deutsche Forschungsgemeinschaft (SFB-TRR57) and Aachen University (IZKF grants to HEW).
References
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Medical Department III, University Hospital Aachen, RWTH Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany
PII: S0168-8278(11)00157-7
doi:10.1016/j.jhep.2011.02.003
© 2011 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
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