Replacing a crystal ball with a calculator in predicting liver disease outcomes
Authors: Scott L. Friedman
Journal: Journal of Hepatology (2014)

Collagen proportionate area is superior to other histological methods for sub-classifying cirrhosis and determining prognosisJournal of HepatologyVol. 60Issue 5PreviewOne-year survival in cirrhosis ranges from 1 to 57% depending on the clinical stage. Accurate sub-classification has important prognostic implications but there is no stage beyond cirrhosis using current qualitative histological systems. We compared the performance of all histological semi-quantitative and quantitative methods specifically developed for sub-classifying cirrhosis that have been described to date, with collagen proportionate area (CPA), to evaluate how well they distinguish patients with and without hepatic clinical decompensation at presentation, and in predicting future decompensating events. Full-Text PDF Open AccessRole of magnetic resonance elastography in compensated and decompensated liver diseaseJournal of HepatologyVol. 60Issue 5PreviewNon-invasive predictors identifying subjects with compensated liver disease at highest risk for transitioning to a decompensated state are lacking. We hypothesized that liver shear stiffness as measured by magnetic resonance elastography is an important non-invasive predictor of hepatic decompensation. Full-Text PDF There is growing optimism about the potential to stabilize or reverse advanced liver disease thanks to remarkable progress in the treatment of chronic viral hepatitis. Striking evidence of cirrhosis reversibility in patients treated with antiviral therapies for HBV [[1]Marcellin P. Gane E. Buti M. Afdhal N. Sievert W. Jacobson I.M. et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.Lancet. 2013; 381: 468-475Abstract Full Text Full Text PDF PubMed Scopus (1187) Google Scholar] or HCV [[2]D'Ambrosio R. Aghemo A. Rumi M.G. Ronchi G. Donato M.F. Paradis V. et al.A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.Hepatology. 2012; 56: 532-543Crossref PubMed Scopus (300) Google Scholar] raises the prospect of exploiting pathways of fibrosis regression to treat other chronic liver diseases, in particular alcoholic and non-alcoholic fatty liver diseases. In these latter illnesses, however, one must rely on evidence of improvement in either histology or other indices of liver structure or function, rather than the more straightforward prospect of measuring viral suppression as a determinant of improvement. It's worth noting that initially in early antiviral trials, regulatory agencies still required evidence of histologic improvement in association with viral suppression before relying solely on viral endpoints as an index of efficacy.It is also important to remember that improved histology alone does not guarantee improved outcomes, and the goal of any effective therapy is to enhance health and/or survival, not to improve a biopsy score. In that spirit there is intensified interest in identifying measures that can accurately predict clinical outcomes, whether they require invasive (i.e., biopsy) or non-invasive assessment. In fact, there has been scant evidence to date that standard liver biopsy staging systems correlate rigorously with outcomes, in part because traditional scoring systems rely on semi-quantitative staging rather than exact quantification of fibrosis content.Two complementary studies in this month's issue of the Journal address these key questions, the first by Tsochatzis et al., which uses a quantitative measure of collagen content in liver biopsies to establish a correlation with clinical outcomes, and the second by Asrani et al., which exploits the emerging technology of magnetic resonance elastography to correlate liver stiffness with the risk of decompensation.The study by Tsochatzis and colleagues from the Royal Free Hospital/University College London builds upon their previously described method of collagen proportionate area, or CPA, which quantifies collagen content in liver biopsy specimens, rather than relying solely on semi-quantitative scoring systems [[3]Manousou P. Dhillon A.P. Isgro G. Calvaruso V. Luong T.V. Tsochatzis E. et al.Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C virus 1 year after liver transplantation.Liver Transpl. 2011; 17: 178-188Crossref PubMed Scopus (69) Google Scholar]. In this new study, however, the investigators have directly compared the accuracy of this method with the scoring systems of either Laennec [[4]Kim M.Y. Cho M.Y. Baik S.K. Park H.J. Jeon H.K. Im C.K. et al.Histological subclassification of cirrhosis using the Laennec fibrosis scoring system correlates with clinical stage and grade of portal hypertension.J Hepatol. 2011; 55: 1004-1009Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar], Kumar [[5]Kumar M. Sakhuja P. Kumar A. Manglik N. Choudhury A. Hissar S. et al.Histological subclassification of cirrhosis based on histological-haemodynamic correlation.Aliment Pharmacol Ther. 2008; 27: 771-779Crossref PubMed Scopus (40) Google Scholar] or Nagula [[6]Nagula S. Jain D. Groszmann R.J. Garcia-Tsao G. Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis.J Hepatol. 2006; 44: 111-117Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar] in the same patient cohort to determine their relative value in predicting outcomes among 69 patients who were followed for a mean of 65 months following biopsy. The CPA requires staining of liver biopsy specimens with sirius red, followed by digital morphometric quantification of stained tissue, expressed as a percentage of total area [[3]Manousou P. Dhillon A.P. Isgro G. Calvaruso V. Luong T.V. Tsochatzis E. et al.Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C virus 1 year after liver transplantation.Liver Transpl. 2011; 17: 178-188Crossref PubMed Scopus (69) Google Scholar]. In addition to specialized software with a one-time cost of ∼7800 Euros, the CPA requires an additional 10 min per sample of the pathologist's (or technician's) time to gather data. In this study, a number of histologic variables were quantified, including septal thickness, nodule size, as well as fibrosis stage for each of the scoring systems, yet CPA was the only biopsy variable independently associated with clinical decompensation, and was comparable to MELD in this respect. These data reinforce the value of quantitative assessment of collagen content as a more accurate determinant of prognosis than standard staging systems. Interestingly, this kind of digital assessment is routinely used in animal models that test anti-fibrotic drugs, yet clinical pathologists have been slow to embrace the technology.Of course, the obvious criticism is that CPA, while more accurate than standard staging systems, still requires invasive liver biopsy via either the trans-jugular or percutaneous route, and, moreover, that the tissue specimen must be sufficiently large to minimize sampling variability. Furthermore, many patients with apparent cirrhosis by clinical and or imaging assessment are unlikely to undergo biopsy if the etiology is already known, and one could not justify performing a liver biopsy simply to predict prognosis by CPA, particularly if the MELD is already abnormal, since MELD correlates perfectly well with outcomes. Still, the method reinforces the importance of quantitative collagen content in determining risk of decompensation, as reported by others as well [[7]Sethasine S. Jain D. Groszmann R.J. Garcia-Tsao G. Quantitative histological-hemodynamic correlations in cirrhosis.Hepatology. 2012; 55: 1146-1153Crossref PubMed Scopus (70) Google Scholar]. Because collagen continues to accumulate even when the biopsy stage is 'cirrhosis' [[8]Goodman Z.D. Becker Jr., R.L. Pockros P.J. Afdhal N.H. Progression of fibrosis in advanced chronic hepatitis C: evaluation by morphometric image analysis.Hepatology. 2007; 45: 886-894Crossref PubMed Scopus (124) Google Scholar], this and related morphometric methods can continuously quantify collagen accumulation across the full spectrum of disease with no upper limit.To avoid the reliance on biopsy, non-invasive methods to assess liver structure or function offer an obvious advantage because of their markedly reduced risk and ability to acquire data repeatedly over time. Among these, both transient- and magnetic resonance-elastography (MRE) are methods that quantify tissue stiffness as a reflection of fibrosis content and/or inflammation and edema. Hundreds of studies have evaluated these technologies, and the United States Food and Drug Administration recently approved transient elastography for management of patients with chronic viral hepatitis and fatty liver disease, in line with the technology's earlier widespread acceptance elsewhere in the world. MRE offers the theoretical advantage over transient elastography of sampling the entire liver rather than a small region of interest. In the cross-sectional study of 430 patients reported by Asrani et al., mean liver stiffness by MRE was significantly higher in those with decompensated liver disease than in those who were compensated. More importantly, in 167 patients from this study followed prospectively for a mean of 27 months, those patients with a mean value of >5.8 kPa had an almost five-fold hazard of decompensation.How would one use this information to impact clinical decision-making or improve outcomes? At the least, accurate stratification of decompensation risk by MRE could be used to increase the frequency of clinical follow-up, seek evidence of esophageal varices, or avoid disease-specific therapies that might provoke decompensation. In addition, MRE could help identify a subgroup of patients at high risk who might benefit most from effective anti-fibrotic therapies once they are available.But the holy grail of non-invasive diagnostics is not simply to predict risk of decompensation. Rather, an ideal diagnostic must also correlate with improved outcomes following therapeutic intervention in order to justify its use in place of biopsy in clinical trials or practice. In addition to elastography, other methods undergoing evaluation for this purpose include functional breath or clearance tests [9Everson G.T. Shiffman M.L. Hoefs J.C. Morgan T.R. Sterling R.K. Wagner D.A. et al.Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis trial.Hepatology. 2012; 55: 1019-1029Crossref PubMed Scopus (41) Google Scholar, 10Lalazar G. Pappo O. Hershcovici T. Hadjaj T. Shubi M. Ohana H. et al.A continuous 13C methacetin breath test for noninvasive assessment of intrahepatic inflammation and fibrosis in patients with chronic HCV infection and normal ALT.J Viral Hepat. 2008; 15: 716-728Crossref PubMed Scopus (42) Google Scholar], serum markers [[11]Schmeltzer P.A. Talwalkar J.A. Noninvasive tools to assess hepatic fibrosis: ready for prime time?.Gastroenterol Clin North Am. 2011; 40: 507-521Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar], hepatic venous pressure gradient measurement [[12]Ripoll C. Groszmann R. Garcia-Tsao G. Grace N. Burroughs A. Planas R. et al.Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.Gastroenterology. 2007; 133: 481-488Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar], Doppler/ultrasound and CT/MRI. Ultimately, a combination of tests may yield the greatest precision in quantifying risk and documenting response to therapy.The prospect of effective therapies for both fatty liver disease [[13]Corrado R.L. Torres D.M. Harrison S.A. Review of treatment options for nonalcoholic fatty liver disease.Med Clin North Am. 2014; 98: 55-72Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar] and hepatic fibrosis [[14]Friedman S.L. Sheppard D. Duffield J.S. Violette S. Therapy for fibrotic diseases: nearing the starting line.Sci Transl Med. 2013; 5: 167sr161Crossref Scopus (470) Google Scholar] has heightened the sense of urgency in identifying non-invasive measures that correlate with clinical outcomes. The importance of progress in addressing this challenge was evident in the jointly sponsored AASLD-FDA endpoints conference held in September, 2013, to help clarify endpoints for clinical trials that evaluate therapies for NAFLD (http://www.aasld.org/additionalmeetings/Pages/aasldfdanash.aspx). A written summary of the meeting recommendations is anticipated soon. Together with studies like those of Tsochatzis et al. and Asrani et al., these recommendations will help us replace a crystal ball that prophesizes the prognosis of liver diseases with a calculator that can quantify its consequences.Conflict of interestThe author is a consultant for several companies in the area of diagnostics and therapeutics for fatty liver disease and/or fibrosis, including Abbvie, Alnylam, Angion, Boehringer Ingelheim, Bristol Myers Squibb, Conatus, Echosens, Exalenz, Fibrogen, Genentech-Roche, Gilead, Intercept, Immuron, Intermune, Galectin Therapeutics, Kinemed, Nimbus, Nitto Denko, Novartis, Sanofi Aventis, Takeda, Tobira, and Vaccinex. There is growing optimism about the potential to stabilize or reverse advanced liver disease thanks to remarkable progress in the treatment of chronic viral hepatitis. Striking evidence of cirrhosis reversibility in patients treated with antiviral therapies for HBV [[1]Marcellin P. Gane E. Buti M. Afdhal N. Sievert W. Jacobson I.M. et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.Lancet. 2013; 381: 468-475Abstract Full Text Full Text PDF PubMed Scopus (1187) Google Scholar] or HCV [[2]D'Ambrosio R. Aghemo A. Rumi M.G. Ronchi G. Donato M.F. Paradis V. et al.A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.Hepatology. 2012; 56: 532-543Crossref PubMed Scopus (300) Google Scholar] raises the prospect of exploiting pathways of fibrosis regression to treat other chronic liver diseases, in particular alcoholic and non-alcoholic fatty liver diseases. In these latter illnesses, however, one must rely on evidence of improvement in either histology or other indices of liver structure or function, rather than the more straightforward prospect of measuring viral suppression as a determinant of improvement. It's worth noting that initially in early antiviral trials, regulatory agencies still required evidence of histologic improvement in association with viral suppression before relying solely on viral endpoints as an index of efficacy. It is also important to remember that improved histology alone does not guarantee improved outcomes, and the goal of any effective therapy is to enhance health and/or survival, not to improve a biopsy score. In that spirit there is intensified interest in identifying measures that can accurately predict clinical outcomes, whether they require invasive (i.e., biopsy) or non-invasive assessment. In fact, there has been scant evidence to date that standard liver biopsy staging systems correlate rigorously with outcomes, in part because traditional scoring systems rely on semi-quantitative staging rather than exact quantification of fibrosis content. Two complementary studies in this month's issue of the Journal address these key questions, the first by Tsochatzis et al., which uses a quantitative measure of collagen content in liver biopsies to establish a correlation with clinical outcomes, and the second by Asrani et al., which exploits the emerging technology of magnetic resonance elastography to correlate liver stiffness with the risk of decompensation. The study by Tsochatzis and colleagues from the Royal Free Hospital/University College London builds upon their previously described method of collagen proportionate area, or CPA, which quantifies collagen content in liver biopsy specimens, rather than relying solely on semi-quantitative scoring systems [[3]Manousou P. Dhillon A.P. Isgro G. Calvaruso V. Luong T.V. Tsochatzis E. et al.Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C virus 1 year after liver transplantation.Liver Transpl. 2011; 17: 178-188Crossref PubMed Scopus (69) Google Scholar]. In this new study, however, the investigators have directly compared the accuracy of this method with the scoring systems of either Laennec [[4]Kim M.Y. Cho M.Y. Baik S.K. Park H.J. Jeon H.K. Im C.K. et al.Histological subclassification of cirrhosis using the Laennec fibrosis scoring system correlates with clinical stage and grade of portal hypertension.J Hepatol. 2011; 55: 1004-1009Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar], Kumar [[5]Kumar M. Sakhuja P. Kumar A. Manglik N. Choudhury A. Hissar S. et al.Histological subclassification of cirrhosis based on histological-haemodynamic correlation.Aliment Pharmacol Ther. 2008; 27: 771-779Crossref PubMed Scopus (40) Google Scholar] or Nagula [[6]Nagula S. Jain D. Groszmann R.J. Garcia-Tsao G. Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis.J Hepatol. 2006; 44: 111-117Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar] in the same patient cohort to determine their relative value in predicting outcomes among 69 patients who were followed for a mean of 65 months following biopsy. The CPA requires staining of liver biopsy specimens with sirius red, followed by digital morphometric quantification of stained tissue, expressed as a percentage of total area [[3]Manousou P. Dhillon A.P. Isgro G. Calvaruso V. Luong T.V. Tsochatzis E. et al.Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C virus 1 year after liver transplantation.Liver Transpl. 2011; 17: 178-188Crossref PubMed Scopus (69) Google Scholar]. In addition to specialized software with a one-time cost of ∼7800 Euros, the CPA requires an additional 10 min per sample of the pathologist's (or technician's) time to gather data. In this study, a number of histologic variables were quantified, including septal thickness, nodule size, as well as fibrosis stage for each of the scoring systems, yet CPA was the only biopsy variable independently associated with clinical decompensation, and was comparable to MELD in this respect. These data reinforce the value of quantitative assessment of collagen content as a more accurate determinant of prognosis than standard staging systems. Interestingly, this kind of digital assessment is routinely used in animal models that test anti-fibrotic drugs, yet clinical pathologists have been slow to embrace the technology. Of course, the obvious criticism is that CPA, while more accurate than standard staging systems, still requires invasive liver biopsy via either the trans-jugular or percutaneous route, and, moreover, that the tissue specimen must be sufficiently large to minimize sampling variability. Furthermore, many patients with apparent cirrhosis by clinical and or imaging assessment are unlikely to undergo biopsy if the etiology is already known, and one could not justify performing a liver biopsy simply to predict prognosis by CPA, particularly if the MELD is already abnormal, since MELD correlates perfectly well with outcomes. Still, the method reinforces the importance of quantitative collagen content in determining risk of decompensation, as reported by others as well [[7]Sethasine S. Jain D. Groszmann R.J. Garcia-Tsao G. Quantitative histological-hemodynamic correlations in cirrhosis.Hepatology. 2012; 55: 1146-1153Crossref PubMed Scopus (70) Google Scholar]. Because collagen continues to accumulate even when the biopsy stage is 'cirrhosis' [[8]Goodman Z.D. Becker Jr., R.L. Pockros P.J. Afdhal N.H. Progression of fibrosis in advanced chronic hepatitis C: evaluation by morphometric image analysis.Hepatology. 2007; 45: 886-894Crossref PubMed Scopus (124) Google Scholar], this and related morphometric methods can continuously quantify collagen accumulation across the full spectrum of disease with no upper limit. To avoid the reliance on biopsy, non-invasive methods to assess liver structure or function offer an obvious advantage because of their markedly reduced risk and ability to acquire data repeatedly over time. Among these, both transient- and magnetic resonance-elastography (MRE) are methods that quantify tissue stiffness as a reflection of fibrosis content and/or inflammation and edema. Hundreds of studies have evaluated these technologies, and the United States Food and Drug Administration recently approved transient elastography for management of patients with chronic viral hepatitis and fatty liver disease, in line with the technology's earlier widespread acceptance elsewhere in the world. MRE offers the theoretical advantage over transient elastography of sampling the entire liver rather than a small region of interest. In the cross-sectional study of 430 patients reported by Asrani et al., mean liver stiffness by MRE was significantly higher in those with decompensated liver disease than in those who were compensated. More importantly, in 167 patients from this study followed prospectively for a mean of 27 months, those patients with a mean value of >5.8 kPa had an almost five-fold hazard of decompensation. How would one use this information to impact clinical decision-making or improve outcomes? At the least, accurate stratification of decompensation risk by MRE could be used to increase the frequency of clinical follow-up, seek evidence of esophageal varices, or avoid disease-specific therapies that might provoke decompensation. In addition, MRE could help identify a subgroup of patients at high risk who might benefit most from effective anti-fibrotic therapies once they are available. But the holy grail of non-invasive diagnostics is not simply to predict risk of decompensation. Rather, an ideal diagnostic must also correlate with improved outcomes following therapeutic intervention in order to justify its use in place of biopsy in clinical trials or practice. In addition to elastography, other methods undergoing evaluation for this purpose include functional breath or clearance tests [9Everson G.T. Shiffman M.L. Hoefs J.C. Morgan T.R. Sterling R.K. Wagner D.A. et al.Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis trial.Hepatology. 2012; 55: 1019-1029Crossref PubMed Scopus (41) Google Scholar, 10Lalazar G. Pappo O. Hershcovici T. Hadjaj T. Shubi M. Ohana H. et al.A continuous 13C methacetin breath test for noninvasive assessment of intrahepatic inflammation and fibrosis in patients with chronic HCV infection and normal ALT.J Viral Hepat. 2008; 15: 716-728Crossref PubMed Scopus (42) Google Scholar], serum markers [[11]Schmeltzer P.A. Talwalkar J.A. Noninvasive tools to assess hepatic fibrosis: ready for prime time?.Gastroenterol Clin North Am. 2011; 40: 507-521Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar], hepatic venous pressure gradient measurement [[12]Ripoll C. Groszmann R. Garcia-Tsao G. Grace N. Burroughs A. Planas R. et al.Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.Gastroenterology. 2007; 133: 481-488Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar], Doppler/ultrasound and CT/MRI. Ultimately, a combination of tests may yield the greatest precision in quantifying risk and documenting response to therapy. The prospect of effective therapies for both fatty liver disease [[13]Corrado R.L. Torres D.M. Harrison S.A. Review of treatment options for nonalcoholic fatty liver disease.Med Clin North Am. 2014; 98: 55-72Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar] and hepatic fibrosis [[14]Friedman S.L. Sheppard D. Duffield J.S. Violette S. Therapy for fibrotic diseases: nearing the starting line.Sci Transl Med. 2013; 5: 167sr161Crossref Scopus (470) Google Scholar] has heightened the sense of urgency in identifying non-invasive measures that correlate with clinical outcomes. The importance of progress in addressing this challenge was evident in the jointly sponsored AASLD-FDA endpoints conference held in September, 2013, to help clarify endpoints for clinical trials that evaluate therapies for NAFLD (http://www.aasld.org/additionalmeetings/Pages/aasldfdanash.aspx). A written summary of the meeting recommendations is anticipated soon. Together with studies like those of Tsochatzis et al. and Asrani et al., these recommendations will help us replace a crystal ball that prophesizes the prognosis of liver diseases with a calculator that can quantify its consequences. Conflict of interestThe author is a consultant for several companies in the area of diagnostics and therapeutics for fatty liver disease and/or fibrosis, including Abbvie, Alnylam, Angion, Boehringer Ingelheim, Bristol Myers Squibb, Conatus, Echosens, Exalenz, Fibrogen, Genentech-Roche, Gilead, Intercept, Immuron, Intermune, Galectin Therapeutics, Kinemed, Nimbus, Nitto Denko, Novartis, Sanofi Aventis, Takeda, Tobira, and Vaccinex. The author is a consultant for several companies in the area of diagnostics and therapeutics for fatty liver disease and/or fibrosis, including Abbvie, Alnylam, Angion, Boehringer Ingelheim, Bristol Myers Squibb, Conatus, Echosens, Exalenz, Fibrogen, Genentech-Roche, Gilead, Intercept, Immuron, Intermune, Galectin Therapeutics, Kinemed, Nimbus, Nitto Denko, Novartis, Sanofi Aventis, Takeda, Tobira, and Vaccinex.