Semin Liver Dis 2015; 35(02): 166-183
DOI: 10.1055/s-0035-1550059
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Diagnosis of Liver Fibrosis: Present and Future

Keyur Patel
1   Division of Gastroenterology, Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina
,
Pierre Bedossa
2   Department of Pathology, Physiology and Imaging, Hôpital Beaujon, Clichy, France
,
Laurent Castera
3   Department of Hepatology, Hôpital Beaujon, Clichy, France
› Author Affiliations
Further Information

Publication History

Publication Date:
14 May 2015 (online)

Abstract

The diagnostic assessment of liver fibrosis, a major determinant of disease severity, is an important step in the management of patients with chronic liver diseases. Liver biopsy is still considered the gold standard for the assessment of necroinflammation and fibrosis; however, recent technical advances have resulted in the development of numerous serum biomarkers and imaging tools as noninvasive alternatives to biopsy. These tests include biological (serum biomarker algorithms), physical (imaging assessment of tissue stiffness), and physiological (breath test) methods. Accumulating evidence shows that noninvasive tests provide prognostic information of clinical relevance, which has led to their incorporation into clinical guidelines and everyday practice. Here, the authors review and compare invasive and noninvasive tests for the diagnosis of liver fibrosis. They discuss emerging functional genomic, microparticle, protein-profiling, and bioimaging tools, focusing on novel sensitive tools that are able to assess the dynamic nature of fibrogenesis, a key requirement for the assessment of the efficacy of antifibrotic compounds in the future.

 
  • References

  • 1 European Association for Study of Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60 (2) 392-420
  • 2 Chalasani N, Younossi Z, Lavine JE , et al; American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterologyh. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012; 142 (7) 1592-1609
  • 3 Bedossa P, Paradis V. Liver extracellular matrix in health and disease. J Pathol 2003; 200 (4) 504-515
  • 4 Mehta SH, Lau B, Afdhal NH, Thomas DL. Exceeding the limits of liver histology markers. J Hepatol 2009; 50 (1) 36-41
  • 5 Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008; 134 (6) 1670-1681
  • 6 Wong JB, Koff RS. Watchful waiting with periodic liver biopsy versus immediate empirical therapy for histologically mild chronic hepatitis C. A cost-effectiveness analysis. Ann Intern Med 2000; 133 (9) 665-675
  • 7 Merriman RB, Ferrell LD, Patti MG , et al. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease. Hepatology 2006; 44 (4) 874-880
  • 8 Ratziu V, Charlotte F, Heurtier A , et al; LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128 (7) 1898-1906
  • 9 Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003; 38 (6) 1449-1457
  • 10 Cholongitas E, Senzolo M, Standish R , et al. A systematic review of the quality of liver biopsy specimens. Am J Clin Pathol 2006; 125 (5) 710-721
  • 11 Standish RA, Cholongitas E, Dhillon A, Burroughs AK, Dhillon AP. An appraisal of the histopathological assessment of liver fibrosis. Gut 2006; 55 (4) 569-578
  • 12 Schiano TD, Azeem S, Bodian CA , et al. Importance of specimen size in accurate needle liver biopsy evaluation of patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2005; 3 (9) 930-935
  • 13 Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol 2003; 39 (2) 239-244
  • 14 Regev A, Berho M, Jeffers LJ , et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002; 97 (10) 2614-2618
  • 15 Bedossa P ; FLIP Pathology Consortium. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology 2014; 60 (2) 565-575
  • 16 Altamirano J, Miquel R, Katoonizadeh A , et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014; 146 (5) 1231-9.e1 , 6
  • 17 Venturi C, Sempoux C, Bueno J , et al. Novel histologic scoring system for long-term allograft fibrosis after liver transplantation in children. Am J Transplant 2012; 12 (11) 2986-2996
  • 18 Westin J, Lagging LM, Wejstål R, Norkrans G, Dhillon AP. Interobserver study of liver histopathology using the Ishak score in patients with chronic hepatitis C virus infection. Liver 1999; 19 (3) 183-187
  • 19 Younossi ZM, Gramlich T, Liu YC , et al. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. Mod Pathol 1998; 11 (6) 560-565
  • 20 Kleiner DE, Brunt EM, Van Natta M , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41 (6) 1313-1321
  • 21 Bedossa P, Poynard T ; The METAVIR Cooperative Study Group. An algorithm for the grading of activity in chronic hepatitis C. Hepatology 1996; 24 (2) 289-293
  • 22 Baptista A, Bianchi L, De Groote J , et al. The diagnostic significance of periportal hepatic necrosis and inflammation. Histopathology 1988; 12 (6) 569-579
  • 23 Mariño Z, Mensa L, Crespo G , et al. Early periportal sinusoidal fibrosis is an accurate marker of accelerated HCV recurrence after liver transplantation. J Hepatol 2014; 61 (2) 270-277
  • 24 Cooksley WG, Bradbear RA, Robinson W , et al. The prognosis of chronic active hepatitis without cirrhosis in relation to bridging necrosis. Hepatology 1986; 6 (3) 345-348
  • 25 Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of cirrhosis: definition, nomenclature, and classification. Bull World Health Organ 1977; 55 (4) 521-540
  • 26 Hytiroglou P, Snover DC, Alves V , et al. Beyond “cirrhosis”: a proposal from the International Liver Pathology Study Group. Am J Clin Pathol 2012; 137 (1) 5-9
  • 27 Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: in search of a pathophysiological classification of cirrhosis. Hepatology 2010; 51 (4) 1445-1449
  • 28 Nakano M, Worner TM, Lieber CS. Perivenular fibrosis in alcoholic liver injury: ultrastructure and histologic progression. Gastroenterology 1982; 83 (4) 777-785
  • 29 Tiniakos DG. Liver biopsy in alcoholic and non-alcoholic steatohepatitis patients. Gastroenterol Clin Biol 2009; 33 (10-11) 930-939
  • 30 Harrison SA, Brunt EM, Goodman ZD, Di Bisceglie AM. Diabetic hepatosclerosis: diabetic microangiopathy of the liver. Arch Pathol Lab Med 2006; 130 (1) 27-32
  • 31 Knodell RG, Ishak KG, Black WC , et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1 (5) 431-435
  • 32 Yano M, Kumada H, Kage M , et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996; 23 (6) 1334-1340
  • 33 Younossi ZM, Stepanova M, Rafiq N , et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011; 53 (6) 1874-1882
  • 34 Rastogi A, Maiwall R, Bihari C , et al. Cirrhosis histology and Laennec staging system correlate with high portal pressure. Histopathology 2013; 62 (5) 731-741
  • 35 Kim MY, Cho MY, Baik SK , 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 (5) 1004-1009
  • 36 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 (1) 111-117
  • 37 Friedman SL, Bansal MB. Reversal of hepatic fibrosis —fact or fantasy?. Hepatology 2006; 43 (2) (Suppl. 01) S82-S88
  • 38 Pérez-Tamayo R. Cirrhosis of the liver: a reversible disease?. Pathol Annu 1979; 14 (Pt 2) 183-213
  • 39 Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 2000; 124 (11) 1599-1607
  • 40 Poynard T, McHutchison J, Manns M , et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122 (5) 1303-1313
  • 41 Chang TT, Liaw YF, Wu SS , et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010; 52 (3) 886-893
  • 42 Shiratori Y, Imazeki F, Moriyama M , et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000; 132 (7) 517-524
  • 43 Asselah T, Marcellin P. Long-term results of treatment with nucleoside and nucleotide analogues (entecavir and tenofovir) for chronic hepatitis B. Clin Liver Dis 2013; 17 (3) 445-450
  • 44 Marcellin P, Chang TT, Lim SG , et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2008; 48 (3) 750-758
  • 45 Serpaggi J, Carnot F, Nalpas B , et al. Direct and indirect evidence for the reversibility of cirrhosis. Hum Pathol 2006; 37 (12) 1519-1526
  • 46 D'Ambrosio R, Aghemo A, Rumi MG , 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 (2) 532-543
  • 47 Tsochatzis E, Bruno S, Isgro G , et al. Collagen proportionate area is superior to other histological methods for sub-classifying cirrhosis and determining prognosis. J Hepatol 2014; 60 (5) 948-954
  • 48 Calvaruso V, Burroughs AK, Standish R , et al. Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient. Hepatology 2009; 49 (4) 1236-1244
  • 49 Calvaruso V, Dhillon AP, Tsochatzis E , et al. Liver collagen proportionate area predicts decompensation in patients with recurrent hepatitis C virus cirrhosis after liver transplantation. J Gastroenterol Hepatol 2012; 27 (7) 1227-1232
  • 50 Manousou P, Burroughs AK, Tsochatzis E , et al. Digital image analysis of collagen assessment of progression of fibrosis in recurrent HCV after liver transplantation. J Hepatol 2013; 58 (5) 962-968
  • 51 Sandrini J, Boursier J, Chaigneau J , et al. Quantification of portal-bridging fibrosis area more accurately reflects fibrosis stage and liver stiffness than whole fibrosis or perisinusoidal fibrosis areas in chronic hepatitis C. Mod Pathol 2014; 27 (7) 1035-1045
  • 52 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 (4) 886-894
  • 53 Goodman ZD, Stoddard AM, Bonkovsky HL , et al; HALT-C Trial Group. Fibrosis progression in chronic hepatitis C: morphometric image analysis in the HALT-C trial. Hepatology 2009; 50 (6) 1738-1749
  • 54 McHutchison J, Goodman Z, Patel K , et al; Farglitizar Study Investigators. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection. Gastroenterology 2010; 138 (4) 1365-1373 , 1373.e1–1373.e2
  • 55 Pilette C, Rousselet MC, Bedossa P , et al. Histopathological evaluation of liver fibrosis: quantitative image analysis vs semi-quantitative scores. Comparison with serum markers. J Hepatol 1998; 28 (3) 439-446
  • 56 Gadd VL, Skoien R, Powell EE , et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology 2014; 59 (4) 1393-1405
  • 57 Hu DD, Habib S, Li XM, Wang TL, Wang BE, Zhao XY. Angiogenesis: a new surrogate histopathological marker is capable of differentiating between mild and significant portal hypertension. Histol Histopathol 2015; 30 (2) 205-212
  • 58 Tai DC, Tan N, Xu S , et al. Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy. J Biomed Opt 2009; 14 (4) 044013
  • 59 Chen AC, McNeilly C, Liu AP , et al. Second harmonic generation and multiphoton microscopic detection of collagen without the need for species specific antibodies. Burns 2011; 37 (6) 1001-1009
  • 60 Gailhouste L, Le Grand Y, Odin C , et al. Fibrillar collagen scoring by second harmonic microscopy: a new tool in the assessment of liver fibrosis. J Hepatol 2010; 52 (3) 398-406
  • 61 Xu S, Wang Y, Tai DC , et al. qFibrosis: a fully-quantitative innovative method incorporating histological features to facilitate accurate fibrosis scoring in animal model and chronic hepatitis B patients. J Hepatol 2014; 61 (2) 260-269
  • 62 Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 2010; 7 (8) 425-436
  • 63 Guha IN, Myers RP, Patel K, Talwalkar JA. Biomarkers of liver fibrosis: what lies beneath the receiver operating characteristic curve?. Hepatology 2011; 54 (4) 1454-1462
  • 64 Wai CT, Greenson JK, Fontana RJ , et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003; 38 (2) 518-526
  • 65 Leroy V, Monier F, Bottari S , et al. Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid. Am J Gastroenterol 2004; 99 (2) 271-279
  • 66 Sud A, Hui JM, Farrell GC , et al. Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index. Hepatology 2004; 39 (5) 1239-1247
  • 67 Lok AS, Ghany MG, Goodman ZD , et al. Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: results of the HALT-C cohort. Hepatology 2005; 42 (2) 282-292
  • 68 Islam S, Antonsson L, Westin J, Lagging M. Cirrhosis in hepatitis C virus-infected patients can be excluded using an index of standard biochemical serum markers. Scand J Gastroenterol 2005; 40 (7) 867-872
  • 69 Hui AY, Chan HL, Wong VW , et al. Identification of chronic hepatitis B patients without significant liver fibrosis by a simple noninvasive predictive model. Am J Gastroenterol 2005; 100 (3) 616-623
  • 70 Zeng MD, Lu LG, Mao YM , et al. Prediction of significant fibrosis in HBeAg-positive patients with chronic hepatitis B by a noninvasive model. Hepatology 2005; 42 (6) 1437-1445
  • 71 Fontana RJ, Kleiner DE, Bilonick R , et al; Virahep-C Study Group. Modeling hepatic fibrosis in African American and Caucasian American patients with chronic hepatitis C virus infection. Hepatology 2006; 44 (4) 925-935
  • 72 Koda M, Matunaga Y, Kawakami M, Kishimoto Y, Suou T, Murawaki Y. FibroIndex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C. Hepatology 2007; 45 (2) 297-306
  • 73 Sterling RK, Lissen E, Clumeck N , et al; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006; 43 (6) 1317-1325
  • 74 Fontana RJ, Goodman ZD, Dienstag JL , et al; HALT-C Trial Group. Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C. Hepatology 2008; 47 (3) 789-798
  • 75 Angulo P, Hui JM, Marchesini G , et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45 (4) 846-854
  • 76 Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 2008; 57 (10) 1441-1447
  • 77 Forns X, Ampurdanès S, Llovet JM , et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 2002; 36 (4 Pt 1) 986-992
  • 78 Vallet-Pichard A, Mallet V, Nalpas B , et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Hepatology 2007; 46 (1) 32-36
  • 79 Lin ZH, Xin YN, Dong QJ , et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology 2011; 53 (3) 726-736
  • 80 Amorim TG, Staub GJ, Lazzarotto C , et al. Validation and comparison of simple noninvasive models for the prediction of liver fibrosis in chronic hepatitis C. Ann Hepatol 2012; 11 (6) 855-861
  • 81 Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T ; MULTIVIRC Group. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001; 357 (9262) 1069-1075
  • 82 Patel K, Gordon SC, Jacobson I , et al. Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients. J Hepatol 2004; 41 (6) 935-942
  • 83 Rosenberg WM, Voelker M, Thiel R , et al; European Liver Fibrosis Group. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004; 127 (6) 1704-1713
  • 84 Adams LA, Bulsara M, Rossi E , et al. Hepascore: an accurate validated predictor of liver fibrosis in chronic hepatitis C infection. Clin Chem 2005; 51 (10) 1867-1873
  • 85 Calès P, Oberti F, Michalak S , et al. A novel panel of blood markers to assess the degree of liver fibrosis. Hepatology 2005; 42 (6) 1373-1381
  • 86 Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection. Ann Intern Med 2013; 159 (5) 372
  • 87 Sebastiani G, Halfon P, Castera L , et al. Comparison of three algorithms of non-invasive markers of fibrosis in chronic hepatitis C. Aliment Pharmacol Ther 2012; 35 (1) 92-104
  • 88 Boursier J, de Ledinghen V, Zarski JP , et al; multicentric groups from SNIFF 32, VINDIAG 7, and ANRS/HC/EP23 FIBROSTAR studies. Comparison of eight diagnostic algorithms for liver fibrosis in hepatitis C: new algorithms are more precise and entirely noninvasive. Hepatology 2012; 55 (1) 58-67
  • 89 Sebastiani G, Castera L, Halfon P , et al. The impact of liver disease aetiology and the stages of hepatic fibrosis on the performance of non-invasive fibrosis biomarkers: an international study of 2411 cases. Aliment Pharmacol Ther 2011; 34 (10) 1202-1216
  • 90 Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43 (8) 617-649
  • 91 Cusi K, Chang Z, Harrison S , et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 2014; 60 (1) 167-174
  • 92 Festi D, Schiumerini R, Marzi L , et al. Review article: the diagnosis of non-alcoholic fatty liver disease — availability and accuracy of non-invasive methods. Aliment Pharmacol Ther 2013; 37 (4) 392-400
  • 93 Castera L, Vilgrain V, Angulo P. Noninvasive evaluation of NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10 (11) 666-675
  • 94 Shaheen AA, Myers RP. Systematic review and meta-analysis of the diagnostic accuracy of fibrosis marker panels in patients with HIV/hepatitis C coinfection. HIV Clin Trials 2008; 9 (1) 43-51
  • 95 Naveau S, Gaudé G, Asnacios A , et al. Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease. Hepatology 2009; 49 (1) 97-105
  • 96 Castera L. Hepatitis B: are non-invasive markers of liver fibrosis reliable?. Liver Int 2014; 34 (Suppl. 01) 91-96
  • 97 Salkic NN, Jovanovic P, Hauser G, Brcic M. FibroTest/Fibrosure for significant liver fibrosis and cirrhosis in chronic hepatitis B: a meta-analysis. Am J Gastroenterol 2014; 109 (6) 796-809
  • 98 Mayo MJ, Parkes J, Adams-Huet B , et al. Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay. Hepatology 2008; 48 (5) 1549-1557
  • 99 Dinesen L, Caspary WF, Chapman RW, Dietrich CF, Sarrazin C, Braden B. 13C-methacetin-breath test compared to also noninvasive biochemical blood tests in predicting hepatic fibrosis and cirrhosis in chronic hepatitis C. Dig Liver Dis 2008; 40 (9) 743-748
  • 100 Everson GT, Shiffman ML, Hoefs JC , et al; HALT-C Trial Group. 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 (4) 1019-1029
  • 101 Karsdal MA, Krarup H, Sand JM , et al. Review article: the efficacy of biomarkers in chronic fibroproliferative diseases - early diagnosis and prognosis, with liver fibrosis as an exemplar. Aliment Pharmacol Ther 2014; 40 (3) 233-249
  • 102 Poynard T, Lenaour G, Vaillant JC , et al. Liver biopsy analysis has a low level of performance for diagnosis of intermediate stages of fibrosis. Clin Gastroenterol Hepatol 2012; 10 (6) 657-63.e7
  • 103 Calès P, de Ledinghen V, Halfon P , et al. Evaluating the accuracy and increasing the reliable diagnosis rate of blood tests for liver fibrosis in chronic hepatitis C. Liver Int 2008; 28 (10) 1352-1362
  • 104 Patel K, Remlinger KS, Walker TG , et al. Multiplex protein analysis to determine fibrosis stage and progression in patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2014; 12 (12) 2113-20.e1 , 3
  • 105 Nielsen MJ, Veidal SS, Karsdal MA , et al. Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C. Liver Int 2015; 35 (2) 429-437
  • 106 Poynard T, Moussalli J, Munteanu M , et al; FibroFrance-GHPS group. Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C. J Hepatol 2013; 59 (4) 675-683
  • 107 Ngo Y, Munteanu M, Messous D , et al. A prospective analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic hepatitis C. Clin Chem 2006; 52 (10) 1887-1896
  • 108 Vergniol J, Foucher J, Terrebonne E , et al. Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C. Gastroenterology 2011; 140 (7) 1970-1979 , 1979.e1–1979.e3
  • 109 Poynard T, Vergniol J, Ngo Y , et al; FibroFrance Study Group; Epic3 Study Group; Bordeaux HCV Study Group. Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest™) and transient elastography (FibroScan®). J Hepatol 2014; 60 (4) 706-714
  • 110 Parkes J, Roderick P, Harris S , et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. Gut 2010; 59 (9) 1245-1251
  • 111 Vergniol J, Boursier J, Coutzac C , et al. Evolution of noninvasive tests of liver fibrosis is associated with prognosis in patients with chronic hepatitis C. Hepatology 2014; 60 (1) 65-76
  • 112 Ghany MG, Lok AS, Everhart JE , et al; HALT-C Trial Group. Predicting clinical and histologic outcomes based on standard laboratory tests in advanced chronic hepatitis C. Gastroenterology 2010; 138 (1) 136-146
  • 113 Kim D, Kim WR, Kim HJ, Therneau TM. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2013; 57 (4) 1357-1365
  • 114 Angulo P, Bugianesi E, Bjornsson ES , et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (4) 782-9.e4
  • 115 Schuppan D, Pinzani M. Anti-fibrotic therapy: lost in translation?. J Hepatol 2012; 56 (Suppl. 01) S66-S74
  • 116 Trépo E, Potthoff A, Pradat P , et al. Role of a cirrhosis risk score for the early prediction of fibrosis progression in hepatitis C patients with minimal liver disease. J Hepatol 2011; 55 (1) 38-44
  • 117 Estrabaud E, Vidaud M, Marcellin P, Asselah T. Genomics and HCV infection: progression of fibrosis and treatment response. J Hepatol 2012; 57 (5) 1110-1125
  • 118 Dongiovanni P, Donati B, Fares R , et al. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol 2013; 19 (41) 6969-6978
  • 119 Hannivoort RA, Hernandez-Gea V, Friedman SL. Genomics and proteomics in liver fibrosis and cirrhosis. Fibrogenesis Tissue Repair 2012; 5 (1) 1
  • 120 Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 2013; 10 (9) 542-552
  • 121 Murakami Y, Toyoda H, Tanahashi T , et al. Comprehensive miRNA expression analysis in peripheral blood can diagnose liver disease. PLoS ONE 2012; 7 (10) e48366
  • 122 Murphy SK, Yang H, Moylan CA , et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (5) 1076-1087
  • 123 Lemoinne S, Thabut D, Housset C , et al. The emerging roles of microvesicles in liver diseases. Nat Rev Gastroenterol Hepatol 2014; 11 (6) 350-361
  • 124 Takahashi K, Yan I, Haga H, Patel T. Long noncoding RNA in liver diseases. Hepatology 2014; 60 (2) 744-753
  • 125 Berzigotti A, Castera L. Update on ultrasound imaging of liver fibrosis. J Hepatol 2013; 59 (1) 180-182
  • 126 Sandrin L, Fourquet B, Hasquenoph JM , et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003; 29 (12) 1705-1713
  • 127 Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012; 142 (6) 1293-1302.e4
  • 128 Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008; 48 (5) 835-847
  • 129 Castéra L, Foucher J, Bernard PH , et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010; 51 (3) 828-835
  • 130 Tapper EB, Castera L, Afdhal NH. FibroScan (vibration-controlled transient elastography): where does it stand in the United States practice. Clin Gastroenterol Hepatol 2015; 13 (1) 27-36
  • 131 Muthupillai R, Lomas DJ, Rossman PJ, Greenleaf JF, Manduca A, Ehman RL. Magnetic resonance elastography by direct visualization of propagating acoustic strain waves. Science 1995; 269 (5232) 1854-1857
  • 132 Castéra L, Vergniol J, Foucher J , et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005; 128 (2) 343-350
  • 133 Ziol M, Handra-Luca A, Kettaneh A , et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005; 41 (1) 48-54
  • 134 Corpechot C, El Naggar A, Poujol-Robert A , et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatology 2006; 43 (5) 1118-1124
  • 135 Ganne-Carrié N, Ziol M, de Ledinghen V , et al. Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases. Hepatology 2006; 44 (6) 1511-1517
  • 136 Foucher J, Chanteloup E, Vergniol J , et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006; 55 (3) 403-408
  • 137 Fraquelli M, Rigamonti C, Casazza G , et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007; 56 (7) 968-973
  • 138 Coco B, Oliveri F, Maina AM , et al. Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases. J Viral Hepat 2007; 14 (5) 360-369
  • 139 Arena U, Vizzutti F, Abraldes JG , et al. Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C. Gut 2008; 57 (9) 1288-1293
  • 140 Yoneda M, Yoneda M, Mawatari H , et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). Dig Liver Dis 2008; 40 (5) 371-378
  • 141 Nobili V, Vizzutti F, Arena U , et al. Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology 2008; 48 (2) 442-448
  • 142 Nguyen-Khac E, Chatelain D, Tramier B , et al. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests. Aliment Pharmacol Ther 2008; 28 (10) 1188-1198
  • 143 Nahon P, Kettaneh A, Tengher-Barna I , et al. Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease. J Hepatol 2008; 49 (6) 1062-1068
  • 144 Marcellin P, Ziol M, Bedossa P , et al. Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver Int 2009; 29 (2) 242-247
  • 145 Chan HL, Wong GL, Choi PC , et al. Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B. J Viral Hepat 2009; 16 (1) 36-44
  • 146 Wong VW, Vergniol J, Wong GL , et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010; 51 (2) 454-462
  • 147 Degos F, Perez P, Roche B , et al; FIBROSTIC study group. Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol 2010; 53 (6) 1013-1021
  • 148 Petta S, Di Marco V, Cammà C, Butera G, Cabibi D, Craxì A. Reliability of liver stiffness measurement in non-alcoholic fatty liver disease: the effects of body mass index. Aliment Pharmacol Ther 2011; 33 (12) 1350-1360
  • 149 Gaia S, Carenzi S, Barilli AL , et al. Reliability of transient elastography for the detection of fibrosis in non-alcoholic fatty liver disease and chronic viral hepatitis. J Hepatol 2011; 54 (1) 64-71
  • 150 Zarski JP, Sturm N, Guechot J , et al; ANRS HCEP 23 Fibrostar Group. Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study. J Hepatol 2012; 56 (1) 55-62
  • 151 Cardoso AC, Carvalho-Filho RJ, Stern C , et al. Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C. Liver Int 2012; 32 (4) 612-621
  • 152 Myers RP, Pomier-Layrargues G, Kirsch R , et al. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology 2012; 55 (1) 199-208
  • 153 Wong VW, Vergniol J, Wong GL , et al. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2012; 107 (12) 1862-1871
  • 154 Afdhal NH, Bacon BR, Patel K , et al. Accuracy of Fibroscan, Compared with Histology, in Analysis of Liver Fibrosis in Patients With Hepatitis B or C: A United States Multicenter Study. Clin Gastroenterol Hepatol 2014;
  • 155 Lupşor M, Badea R, Stefănescu H , et al. Analysis of histopathological changes that influence liver stiffness in chronic hepatitis C. Results from a cohort of 324 patients. J Gastrointestin Liver Dis 2008; 17 (2) 155-163
  • 156 Oliveri F, Coco B, Ciccorossi P , et al. Liver stiffness in the hepatitis B virus carrier: a non-invasive marker of liver disease influenced by the pattern of transaminases. World J Gastroenterol 2008; 14 (40) 6154-6162
  • 157 Friedrich-Rust M, Ong MF, Martens S , et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134 (4) 960-974
  • 158 Tsochatzis EA, Gurusamy KS, Ntaoula S, Cholongitas E, Davidson BR, Burroughs AK. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol 2011; 54 (4) 650-659
  • 159 Chon YE, Choi EH, Song KJ , et al. Performance of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B: a meta-analysis. PLoS ONE 2012; 7 (9) e44930
  • 160 Fraquelli M, Rigamonti C, Casazza G , et al. Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C. J Hepatol 2011; 54 (4) 621-628
  • 161 Maimone S, Calvaruso V, Pleguezuelo M , et al. An evaluation of transient elastography in the discrimination of HBeAg-negative disease from inactive hepatitis B carriers. J Viral Hepat 2009; 16 (11) 769-774
  • 162 Castéra L, Bernard PH, Le Bail B , et al. Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive hepatitis B carriers. Aliment Pharmacol Ther 2011; 33 (4) 455-465
  • 163 Nierhoff J, Chávez Ortiz AA, Herrmann E, Zeuzem S, Friedrich-Rust M. The efficiency of acoustic radiation force impulse imaging for the staging of liver fibrosis: a meta-analysis. Eur Radiol 2013; 23 (11) 3040-3053
  • 164 Bota S, Herkner H, Sporea I , et al. Meta-analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis. Liver Int 2013; 33 (8) 1138-1147
  • 165 Ferraioli G, Tinelli C, Dal Bello B, Zicchetti M, Filice G, Filice C ; Liver Fibrosis Study Group. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology 2012; 56 (6) 2125-2133
  • 166 Leung VY, Shen J, Wong VW , et al. Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B carriers: comparison of shear-wave elastography and transient elastography with liver biopsy correlation. Radiology 2013; 269 (3) 910-918
  • 167 Cassinotto C, Lapuyade B, Mouries A , et al. Non-invasive assessment of liver fibrosis with impulse elastography: comparison of Supersonic Shear Imaging with ARFI and FibroScan®. J Hepatol 2014; 61 (3) 550-557
  • 168 Lupsor M, Badea R, Stefanescu H , et al. Performance of unidimensional transient elastography in staging non-alcoholic steatohepatitis. J Gastrointestin Liver Dis 2010; 19 (1) 53-60
  • 169 Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med 1978; 299 (17) 926-930
  • 170 Poynard T, Halfon P, Castera L , et al; FibroPaca Group. Standardization of ROC curve areas for diagnostic evaluation of liver fibrosis markers based on prevalences of fibrosis stages. Clin Chem 2007; 53 (9) 1615-1622
  • 171 Corpechot C, Carrat F, Poujol-Robert A , et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology 2012; 56 (1) 198-208
  • 172 Gómez-Domínguez E, Mendoza J, Rubio S, Moreno-Monteagudo JA, García-Buey L, Moreno-Otero R. Transient elastography: a valid alternative to biopsy in patients with chronic liver disease. Aliment Pharmacol Ther 2006; 24 (3) 513-518
  • 173 Bardou-Jacquet E, Legros L, Soro D , et al. Effect of alcohol consumption on liver stiffness measured by transient elastography. World J Gastroenterol 2013; 19 (4) 516-522
  • 174 Mueller S, Millonig G, Sarovska L , et al. Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis. World J Gastroenterol 2010; 16 (8) 966-972
  • 175 Trabut JB, Thépot V, Nalpas B , et al. Rapid decline of liver stiffness following alcohol withdrawal in heavy drinkers. Alcohol Clin Exp Res 2012; 36 (8) 1407-1411
  • 176 Carrión JA, Navasa M, Bosch J, Bruguera M, Gilabert R, Forns X. Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation. Liver Transpl 2006; 12 (12) 1791-1798
  • 177 Vizzutti F, Arena U, Romanelli RG , et al. Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology 2007; 45 (5) 1290-1297
  • 178 Shi KQ, Fan YC, Pan ZZ , et al. Transient elastography: a meta-analysis of diagnostic accuracy in evaluation of portal hypertension in chronic liver disease. Liver Int 2013; 33 (1) 62-71
  • 179 Castera L, Pinzani M, Bosch J. Non invasive evaluation of portal hypertension using transient elastography. J Hepatol 2012; 56 (3) 696-703
  • 180 Calvaruso V, Bronte F, Conte E, Simone F, Craxì A, Di Marco V. Modified spleen stiffness measurement by transient elastography is associated with presence of large oesophageal varices in patients with compensated hepatitis C virus cirrhosis. J Viral Hepat 2013; 20 (12) 867-874
  • 181 Colecchia A, Montrone L, Scaioli E , et al. Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis. Gastroenterology 2012; 143 (3) 646-654
  • 182 Sharma P, Kirnake V, Tyagi P , et al. Spleen stiffness in patients with cirrhosis in predicting esophageal varices. Am J Gastroenterol 2013; 108 (7) 1101-1107
  • 183 Stefanescu H, Grigorescu M, Lupsor M, Procopet B, Maniu A, Badea R. Spleen stiffness measurement using Fibroscan for the noninvasive assessment of esophageal varices in liver cirrhosis patients. J Gastroenterol Hepatol 2011; 26 (1) 164-170
  • 184 Elkrief L, Rautou PE, Ronot M , et al. Prospective Comparison of Spleen and Liver Stiffness by Using Shear-Wave and Transient Elastography for Detection of Portal Hypertension in Cirrhosis. Radiology 2014; 141210
  • 185 Procopet B, Berzigotti A, Abraldes JG , et al. Real-time shear-wave elastography: Applicability, reliability and accuracy for clinically significant portal hypertension. J Hepatol 2014;
  • 186 Takuma Y, Nouso K, Morimoto Y , et al. Measurement of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices. Gastroenterology 2013; 144 (1) 92-101.e2
  • 187 Colecchia A, Colli A, Casazza G , et al. Spleen stiffness measurement can predict clinical complications in compensated HCV-related cirrhosis: a prospective study. J Hepatol 2014; 60 (6) 1158-1164
  • 188 Masuzaki R, Tateishi R, Yoshida H , et al. Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography. Hepatology 2009; 49 (6) 1954-1961
  • 189 Fung J, Lai CL, Seto WK, Wong DK, Yuen MF. Prognostic significance of liver stiffness for hepatocellular carcinoma and mortality in HBeAg-negative chronic hepatitis B. J Viral Hepat 2011; 18 (10) 738-744
  • 190 Jung KS, Kim SU, Ahn SH , et al. Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement (FibroScan). Hepatology 2011; 53 (3) 885-894
  • 191 Robic MA, Procopet B, Métivier S , et al. Liver stiffness accurately predicts portal hypertension related complications in patients with chronic liver disease: a prospective study. J Hepatol 2011; 55 (5) 1017-1024
  • 192 Corpechot C, Gaouar F, El Naggar A , et al. Baseline values and changes in liver stiffness measured by transient elastography are associated with severity of fibrosis and outcomes of patients with primary sclerosing cholangitis. Gastroenterology 2014; 146 (4) 970-979 , quiz e15–e16
  • 193 Kim SU, Lee JH, Kim Y , et al. Prediction of liver-related events using fibroscan in chronic hepatitis B patients showing advanced liver fibrosis. PLoS ONE 2012; 7 (5) e36676
  • 194 Bohte AE, de Niet A, Jansen L , et al. Non-invasive evaluation of liver fibrosis: a comparison of ultrasound-based transient elastography and MR elastography in patients with viral hepatitis B and C. Eur Radiol 2014; 24 (3) 638-648
  • 195 Huwart L, Sempoux C, Vicaut E , et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008; 135 (1) 32-40
  • 196 Van Beers BE, Daire JL, Garteiser P. New imaging techniques for liver diseases. J Hepatol 2015; 62 (3) 690-700