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Replacing a crystal ball with a calculator in predicting liver disease outcomes
Focus
Replacing a crystal ball with a calculator in predicting liver disease outcomes Scott L. Friedman⇑ Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States See Articles, pages 934–939 and pages 948–954
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] or HCV [2] 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 noninvasive 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
Received 23 January 2014; accepted 23 January 2014 q DOI of original article: http://dx.doi.org/10.1016/j.jhep.2013.12.023, http:// dx.doi.org/10.1016/j.jhep.2013.12.016. ⇑ Address: Division of Liver Diseases, Box 1123, Mount Sinai School of Medicine, 1425 Madison Ave., Room 1170C, New York, NY 10029, United States. Tel.: +1 212 659 9501; fax: +1 212 849 2574. E-mail address: [email protected]
quantifies collagen content in liver biopsy specimens, rather than relying solely on semi-quantitative scoring systems [3]. In this new study, however, the investigators have directly compared the accuracy of this method with the scoring systems of either Laennec [4], Kumar [5] or Nagula [6] 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]. 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]. Because collagen continues to accumulate even when the biopsy stage is ‘cirrhosis’ [8], 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
Journal of Hepatology 2014 vol. 60 j 905–906
Focus 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 [9,10], serum markers [11], hepatic venous pressure gradient measurement [12], 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] and hepatic fibrosis [14] 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.
906
Conflict of interest 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, GenentechRoche, Gilead, Intercept, Immuron, Intermune, Galectin Therapeutics, Kinemed, Nimbus, Nitto Denko, Novartis, Sanofi Aventis, Takeda, Tobira, and Vaccinex. References [1] Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, 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;381:468–475. [2] D’Ambrosio R, Aghemo A, Rumi MG, Ronchi G, Donato MF, 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;56:532–543. [3] Manousou P, Dhillon AP, Isgro G, Calvaruso V, Luong TV, 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;17:178–188. [4] Kim MY, Cho MY, Baik SK, Park HJ, Jeon HK, Im CK, et al. Histological subclassification of cirrhosis using the Laennec fibrosis scoring system correlates with clinical stage and grade of portal hypertension. J Hepatol 2011;55:1004–1009. [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;27:771–779. [6] Nagula S, Jain D, Groszmann RJ, Garcia-Tsao G. Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol 2006;44:111–117. [7] Sethasine S, Jain D, Groszmann RJ, Garcia-Tsao G. Quantitative histologicalhemodynamic correlations in cirrhosis. Hepatology 2012;55:1146–1153. [8] Goodman ZD, Becker Jr RL, Pockros PJ, Afdhal NH. Progression of fibrosis in advanced chronic hepatitis C: evaluation by morphometric image analysis. Hepatology 2007;45:886–894. [9] Everson GT, Shiffman ML, Hoefs JC, Morgan TR, Sterling RK, Wagner DA, 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;55:1019–1029. [10] Lalazar 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;15:716–728. [11] Schmeltzer PA, Talwalkar JA. Noninvasive tools to assess hepatic fibrosis: ready for prime time? Gastroenterol Clin North Am 2011;40:507–521. [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;133:481–488. [13] Corrado RL, Torres DM, Harrison SA. Review of treatment options for nonalcoholic fatty liver disease. Med Clin North Am 2014;98:55–72. [14] Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 2013;5:167sr161.
Journal of Hepatology 2014 vol. 60 j 905–906
Replacing a crystal ball with a calculator in predicting liver disease outcomes Scott L. Friedman⇑ Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States See Articles, pages 934–939 and pages 948–954
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] or HCV [2] 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 noninvasive 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
Received 23 January 2014; accepted 23 January 2014 q DOI of original article: http://dx.doi.org/10.1016/j.jhep.2013.12.023, http:// dx.doi.org/10.1016/j.jhep.2013.12.016. ⇑ Address: Division of Liver Diseases, Box 1123, Mount Sinai School of Medicine, 1425 Madison Ave., Room 1170C, New York, NY 10029, United States. Tel.: +1 212 659 9501; fax: +1 212 849 2574. E-mail address: [email protected]
quantifies collagen content in liver biopsy specimens, rather than relying solely on semi-quantitative scoring systems [3]. In this new study, however, the investigators have directly compared the accuracy of this method with the scoring systems of either Laennec [4], Kumar [5] or Nagula [6] 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]. 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]. Because collagen continues to accumulate even when the biopsy stage is ‘cirrhosis’ [8], 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
Journal of Hepatology 2014 vol. 60 j 905–906
Focus 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 [9,10], serum markers [11], hepatic venous pressure gradient measurement [12], 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] and hepatic fibrosis [14] 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.
906
Conflict of interest 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, GenentechRoche, Gilead, Intercept, Immuron, Intermune, Galectin Therapeutics, Kinemed, Nimbus, Nitto Denko, Novartis, Sanofi Aventis, Takeda, Tobira, and Vaccinex. References [1] Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, 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;381:468–475. [2] D’Ambrosio R, Aghemo A, Rumi MG, Ronchi G, Donato MF, 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;56:532–543. [3] Manousou P, Dhillon AP, Isgro G, Calvaruso V, Luong TV, 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;17:178–188. [4] Kim MY, Cho MY, Baik SK, Park HJ, Jeon HK, Im CK, et al. Histological subclassification of cirrhosis using the Laennec fibrosis scoring system correlates with clinical stage and grade of portal hypertension. J Hepatol 2011;55:1004–1009. [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;27:771–779. [6] Nagula S, Jain D, Groszmann RJ, Garcia-Tsao G. Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol 2006;44:111–117. [7] Sethasine S, Jain D, Groszmann RJ, Garcia-Tsao G. Quantitative histologicalhemodynamic correlations in cirrhosis. Hepatology 2012;55:1146–1153. [8] Goodman ZD, Becker Jr RL, Pockros PJ, Afdhal NH. Progression of fibrosis in advanced chronic hepatitis C: evaluation by morphometric image analysis. Hepatology 2007;45:886–894. [9] Everson GT, Shiffman ML, Hoefs JC, Morgan TR, Sterling RK, Wagner DA, 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;55:1019–1029. [10] Lalazar 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;15:716–728. [11] Schmeltzer PA, Talwalkar JA. Noninvasive tools to assess hepatic fibrosis: ready for prime time? Gastroenterol Clin North Am 2011;40:507–521. [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;133:481–488. [13] Corrado RL, Torres DM, Harrison SA. Review of treatment options for nonalcoholic fatty liver disease. Med Clin North Am 2014;98:55–72. [14] Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 2013;5:167sr161.
Journal of Hepatology 2014 vol. 60 j 905–906