|
|
MedGenMed. 2005; 7(4): 39. Published online 2005 November 9. | PMCID: PMC1681713 |
Noninvasive Diagnosis of Liver Fibrosis in Patients With Chronic Hepatitis C Laurent Castera, MD, Hepatologist and Jean-Michel Pawlotsky, MD, PhD, Director The prognosis and management of chronic liver diseases greatly depends on the degree and progression of liver fibrosis. Until recently, liver biopsy was the only way to evaluate fibrosis in the liver. [1] However, liver biopsy is an invasive and painful procedure, [2, 3] with rare but potentially life-threatening complications. [1] Thus, many patients are reluctant to undergo liver biopsies, and patients with chronic hepatitis C may be discouraged from starting therapy for this reason. The accuracy of liver biopsy in assessing fibrosis has also been questioned in relation to sampling errors and intra- and interobserver variability that may lead to over- or understaging. [4– 9] Even when an experienced physician performs liver biopsy and an expert pathologist reads and interprets the findings, up to a 20% error rate in disease staging has been reported. [10] In a recent study, Bedossa and colleagues, [7] using the METAVIR scoring system, showed that only 65% of 15-mm biopsies (the currently recommended size) and 75% of 25-mm biopsies were correctly staged. Regev and colleagues [5] found a difference of at least 1 fibrosis stage between the right and left lobes in 33% of 124 patients, whereas Siddique and colleagues [8] observed a difference of at least 1 fibrosis stage between 2 specimens of at least 15 mm taken at the same puncture site in 45% of patients. Finally, Colloredo and colleagues [6] reported a tendency to underscore fibrosis as the size of the biopsy sample diminished. These findings emphasize the need for accurate noninvasive methods to measure the degree of liver fibrosis. Ideally, a noninvasive marker of liver fibrosis should be liver-specific, easy to perform, reliable, and inexpensive. In addition, it should be accurate not only for the grading of fibrosis, but also for the monitoring of disease progression and the efficacy of antiviral therapy. To date, almost all of the data regarding the use of noninvasive markers of fibrosis have been generated in patients with chronic hepatitis C, and these data need to be extended to other liver diseases. Surrogate Serum Markers of Liver Fibrosis A variety of surrogate markers of fibrosis have been evaluated for their ability to assess liver fibrosis, primarily in patients with chronic hepatitis C. [11, 12] Tested parameters included serum hyaluronate, [13] procollagen III N-peptide, [14] laminin, [15] type IV collagen, [16] matrix metalloproteases, [17] tissue inhibitory metalloprotease-1, [18] transforming growth factor-beta, [19] YKL-40, [20] prothrombin index, [21] platelet count, [22] and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio. [23] From a clinical standpoint, these markers, when used individually, have limited accuracy for the diagnosis of “clinically significant” fibrosis (ie, METAVIR score F2 or greater), the threshold for initiation of antiviral therapy in patients with chronic hepatitis C. [24]The limitations of single parameters to assess liver fibrosis have led to the development of algorithms or indices combining the results of panels of markers that substantially improve diagnostic accuracy ( Table). Imbert-Bismut and colleagues [25] were the first to propose an index based on a mathematical formula combining 5 variables: total bilirubin, gamma-glutamyltranspeptidase (gamma-GT), haptoglobin, alpha 2-macroglobulin, and apoliprotein A1. The results of this test, known as the FibroTest (BioPredictive; Paris, France), are scored from 0 to 1. In the initial report, a score < 0.1 allowed for the exclusion of significant fibrosis (METAVIR score F2 or greater), with a 100% negative predictive value, whereas a score > 0.6 allowed for the diagnosis of significant fibrosis, with a 90% positive predictive value, using liver biopsy as a reference. Overall, liver biopsy could have been avoided in 46% of the patients on the basis of these study findings. FibroTest has been extensively evaluated by the developers [26– 31] and other groups. [32– 35] This test is now licensed in several European countries as well as in the United States. When using FibroTest in clinical practice, the interpretation of the findings should take into account each of the 5 components individually so as to avoid false-positive results related to hemolysis (decrease in haptoglobin), Gilbert syndrome (increase in bilirubin), or false-negative results related to inflammation (increase in haptoglobin or in alpha 2-macroglobulin levels). [36] | TableDiagnostic Performance of Currently Available Surrogate Serum Markers of Fibrosis in Patients With Chronic Hepatitis C |
Forns and colleagues [37] reported a fibrosis index based on age, platelet count, gamma-GT, and cholesterol levels. The lower cut-off value (4.2) had a 96% negative predictive value for excluding significant fibrosis, whereas the upper cut-off value (6.9) had a 66% positive predictive value for diagnosing significant fibrosis. This test was shown to be useful in excluding patients with minimal fibrosis, but was of limited utility in identifying patients with more advanced fibrosis. Concerns were also raised regarding the impact of serum lipid abnormalities and modifications induced by cholesterol altering medications. The AST-to-Platelet Ratio Index (APRI) is another simple tool and is based on AST measurement and platelet count. [38] Patients with and without significant fibrosis could be excluded with negative and positive predictive values of 86% and 88%, respectively. This test is very simple, but is subject to issues related to the reproducibility of AST measurement and platelet count. [39]Several other indices have been developed as well, including FibroSpect (Prometheus Laboratories Inc.; San Diego, California), [40] the Sud score, [41] Leroy's score, [42] and the European Liver Fibrosis (ELF) Study score (see Table). [43]Although the diagnostic performance of these indices is generally good, with areas under the ROC (receiver operating characteristic) curves ranging from 0.77 to 0.88, more than half of patients are not appropriately classified relative to findings on liver biopsy. Another limitation of these markers is that none is liver-specific and they may be influenced by changes in their clearance and excretion. Additionally, in clinical practice, the reproducibility in the measurement of some parameters, such as AST levels or platelet count, is questionable. Ultrasonography is a noninvasive method that has been used to assess fibrosis in the entire liver. [44, 45] The sensitivity of this imaging modality can be as high as 90% for diagnosing cirrhosis, but it is not widely used in practice because the results are operator-dependent and the performance has been shown to be inferior to clinical examination and laboratory tests. [21]Recently, transient elastography ( FibroScan; Echosens; Paris, France), a novel noninvasive method, was proposed as a tool for assessing liver fibrosis by measuring liver stiffness. [46] With this method, an ultrasound transducer probe is mounted on the axis of a vibrator. Vibrations of mild amplitude and low frequency are transmitted by the transducer, inducing an elastic shear wave that propagates through the underlying tissues. Pulse-echo ultrasound acquisitions are then used to follow the propagation of the shear wave and measure its velocity, which is directly related to tissue stiffness (the elastic modulus): The stiffer the tissue, the faster the shear wave propagates. Transient elastography measures liver stiffness in a volume that approximates a cylinder 1 cm wide and 4 cm long, with a measurement depth between 25 mm and 65 mm below the skin surface. This volume is at least 100 times larger than a biopsy sample and is therefore far more representative of the hepatic parenchyma. Transient elastography is painless, rapid (takes less than 5 minutes), and easy to perform at the bedside or in the outpatient clinic. The results are immediately available and independent from the operator. Transient elastography has been shown to be reliable in the assessment of liver fibrosis in patients with chronic hepatitis C. [47] In a recent prospective study involving 183 patients with chronic hepatitis C, our group assessed the performance of transient elastography in comparison with liver biopsy, FibroTest, and APRI, all performed on the same day. [33] Among the 3 noninvasive methods and their various combined applications, combined use of transient elastography and FibroTest offered the best diagnostic performance, for detecting both significant fibrosis (F ≥ 2) and severe fibrosis-cirrhosis (F3-F4). When transient elastography and FibroTest results agreed, which was the case in 70% to 80% of patients, the findings were consistent with those of liver biopsy in 84% of patients with significant fibrosis (F ≥ 2), in 95% of patients with severe fibrosis (F ≥ 3), and in 94% of patients with cirrhosis (F = 4). However, transient elastography also has limitations. Measurement of liver stiffness can be difficult in obese patients and impossible in patients who have ascites. [46] Indeed, approximately 5% of the patients in both of the studies discussed previously, [33, 47] all of whom were overweight or obese, could not be properly assessed. Specific probes are being developed for obese patients. A very attractive application of noninvasive markers would be to use these tools not only to diagnose liver fibrosis, but also to monitor disease progression and the antifibrotic efficacy of antiviral therapy. The relationship between antiviral response and results of FibroTest performed before and after therapy has been studied retrospectively in 2 reports. [48, 49] Patients who achieved sustained eradication of hepatitis C virus (successful response to therapy) had a substantial reduction in FibroTest scores compared with those who did not respond or who relapsed. These data support the concept that serologic markers of fibrosis could be used to monitor the liver response to therapy. In patients with chronic hepatitis C, we have shown (using transient elastography) that liver stiffness measurements ranged from 2.4 to 75 kPa with a cut-off value for cirrhosis of 12.6 kPa. [33] These results suggest that in cirrhotic patients, transient elastography values can range from 12.6 to 75 kPa. Preliminary results from our group suggest that liver stiffness values are related to the severity of cirrhosis, as assessed by clinical parameters (past history of bleeding varices or ascites, hepatocellular carcinoma), Child-Pugh score, biological parameters (platelets, prothrombin time, V factor, albumin and bilirubin), and morphologic parameters (esophageal varices stage 2/3, splenomegaly on ultrasound, and dysmorphy). [50] If confirmed, these results suggest that transient elastography could also be used in the management of patients with cirrhosis. Significant progress has been made in the noninvasive assessment of hepatic fibrosis, particularly in patients with chronic hepatitis C. An increasing number of reliable noninvasive methods is now available. Of these, FibroTest has been the most extensively studied and validated, whereas transient elastography appears as a promising emerging tool. The combination of both of these approaches as first-line assessment of liver fibrosis may allow liver biopsy to be avoided in the majority of patients with chronic hepatitis C. This strategy deserves further evaluation in other populations of patients. Readers are encouraged to respond to George Lundberg, MD, Editor of MedGenMed, for the editor's eye only or for possible publication via email: glundberg/at/medscape.net. Laurent Castera, Department of Hepatology and Gastroenterology, C.H.U. Bordeaux, Hôpital Haut Lévêque, Pessac, France; Jean-Michel Pawlotsky, Department of Virology, INSERM U635, Hôpital Henri Mondor, Université Paris XII, Créteil, France; 1. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001;344:495–500. [PubMed] 2. Castera L, Negre I, Samii K, Buffet C. Pain experienced during percutaneous liver biopsy. Hepatology. 1999;30:1529–1530. [PubMed] 3. Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology. 2000;32:477–481. [PubMed] 4. Maharaj B, Maharaj RJ, Leary WP, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet. 1986;1:523–525. [PubMed] 5. Regev A, Berho M, Jeffers LJ, Milikowski C, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97:2614–2618. [PubMed] 6. 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;39:239–244. [PubMed] 7. Bedossa P, Dargere D, Paradise V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449–1457. [PubMed] 8. Siddique I, El-Naga HA, Madda JP, Memon A, Hasan F. Sampling variability on percutaneous liver biopsy in patients with chronic hepatitis C virus infection. Scand J Gastroenterol. 2003;38:427–432. [PubMed] 9. The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology. 1994;20:15–20. [PubMed] 10. Afdhal NH. Diagnosing fibrosis in hepatitis C: is the pendulum swinging from biopsy to blood tests? Hepatology. 2003;37:972–974. [PubMed] 11. Fontana RJ, Lok AS. Noninvasive monitoring of patients with chronic hepatitis C. Hepatology. 2002;36:S57–S64. [PubMed] 12. Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol. 2004;99:1160–1174. [PubMed] 13. Patel K, Lajoie A, Heaton S, et al. Clinical use of hyaluronic acid as a predictor of fibrosis change in hepatitis C. J Gastroenterol Hepatol. 2003;18:253–257. [PubMed] 14. Guechot J, Laudat A, Loria A, Serfaty L, Poupon R, Giboudeau J. Diagnostic accuracy of hyaluronan and type III procollagen amino-terminal peptide serum assays as markers of liver fibrosis in chronic viral hepatitis C evaluated by ROC curve analysis. Clin Chem. 1996;42:558–563. [PubMed] 15. 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;28:439–446. [PubMed] 16. Castera L, Hartmann DJ, Chapel F, et al. Serum laminin and type IV collagen are accurate markers of histologically severe alcoholic hepatitis in patients with cirrhosis. J Hepatol. 2000;32:412–418. [PubMed] 17. Murawaki Y, Ikuta Y, Idobe Y, Kawasaki H. Serum matrix metalloproteinase-1 in patients with chronic viral hepatitis. J Gastroenterol Hepatol. 1999;14:138–145. [PubMed] 18. Boeker KH, Haberkorn CI, Michels D, Flemming P, Manns MP, Lichtinghagen R. Diagnostic potential of circulating TIMP-1 and MMP-2 as markers of liver fibrosis in patients with chronic hepatitis C. Clin Chim Acta. 2002;316:71–81. [PubMed] 19. Nelson DR, Gonzalez-Peralta RP, Qian K, et al. Transforming growth factor-beta 1 in chronic hepatitis C. J Viral Hepat. 1997;4:29–35. [PubMed] 20. Johansen JS, Christoffersen P, Moller S, et al. Serum YKL-40 is increased in patients with hepatic fibrosis. J Hepatol. 2000;32:911–920. [PubMed] 21. Oberti F, Valsesia E, Pilette C, Rousselet MC, et al. Noninvasive diagnosis of hepatic fibrosis or cirrhosis. Gastroenterology. 1997;113:1609–1616. [PubMed] 22. Pohl A, Behling C, Oliver D, Kilani M, Monson P, Hassanein T. Serum aminotransferase levels and platelet counts as predictors of degree of fibrosis in chronic hepatitis C virus infection. Am J Gastroenterol. 2001;96:3142–3146. [PubMed] 23. Imperiale TF, Said AT, Cummings OW, Born LJ. Need for validation of clinical decision aids: use of the AST/ALT ratio in predicting cirrhosis in chronic hepatitis C. Am J Gastroenterol. 2000;95:2328–2332. [PubMed] 24. NIH Consensus Statement on Management of Hepatitis C: 2002. Hepatology. 2002;36:S3–S20. [PubMed] 25. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357:1069–1075. [PubMed] 26. Myers RP, Ratziu V, Imbert-Bismut F, Charlotte F, Poynard T. Biochemical markers of liver fibrosis: a comparison with historical features in patients with chronic hepatitis C. Am J Gastroenterol. 2002;97:2419–2425. [PubMed] 27. Myers RP, De Torres M, Imbert-Bismut F, Ratziu V, Charlotte F, Poynard T. Biochemical markers of fibrosis in patients with chronic hepatitis C: a comparison with prothrombin time, platelet count, and age-platelet index. Dig Dis Sci. 2003;48:146–153. [PubMed] 28. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;3:8. [PubMed] 29. Munteanu M, Messous D, Thabut D, et al. Intra-individual fasting versus postprandial variation of biochemical markers of liver fibrosis (FibroTest) and activity (ActiTest). Comp Hepatol. 2004;3:3. [PubMed] 30. Imbert-Bismut F, Messous D, Thibaut V, et al. Intra-laboratory analytical variability of biochemical markers of fibrosis (Fibrotest) and activity (Actitest) and reference ranges in healthy blood donors. Clin Chem Lab. Med. 2004;42:323–333. [PubMed] 31. Halfon P, Imbert-Bismut F, Messous D, et al. A prospective assessment of the inter-laboratory variability of biochemical markers of fibrosis (FibroTest) and activity (ActiTest) in patients with chronic liver disease. Comp Hepatol. 2002;1:3. [PubMed] 32. Rossi E, Adams L, Prins A, et al. Validation of the FibroTest biochemical markers score in assessing liver fibrosis in hepatitis C patients. Clin Chem. 2003;49:450–454. [PubMed] 33. Castera 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;128:343–350. [PubMed] 34. Callewaert N, Van Vlierberghe H, Van Hecke A, et al. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med. 2004;10:429–434. [PubMed] 35. Halfon P, Bourliere M, Deydier R, et al. Independent prospective multicenter validation of biochemical markers (Fibrotest-Actitest) for the prediction of liver fibrosis and activity in patients with chronic hepatitis C (Abstract). Hepatology. 2003;38(suppl 1):188A. 36. Poynard T, Munteanu M, Imbert-Bismut F, et al. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C. Clin Chem. 2004;10:10. 37. Forns X, Ampurdanes S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology. 2002;36:986–992. [PubMed] 38. 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;38:518–526. [PubMed] 39. Piton A, Poynard T, Imbert-Bismut F, et al. Factors associated with serum alanine transaminase activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C. MULTIVIRC Group. Hepatology. 1998;27:1213–1219. [PubMed] 40. 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;41:935–942. [PubMed] 41. 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;39:1239–1247. [PubMed] 42. 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;99:271–279. [PubMed] 43. Rosenberg WM, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: A cohort study. Gastroenterology. 2004;127:1704–1713. [PubMed] 44. Gaiani S, Gramantieri L, Venturoli N, et al. What is the criterion for differentiating chronic hepatitis from compensated cirrhosis? A prospective study comparing ultrasonography and percutaneous liver biopsy. J Hepatol. 1997;27:979–985. [PubMed] 45. Aube C, Oberti F, Korali N, et al. Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis. J Hepatol. 1999;30:472–478. [PubMed] 46. Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29:1705–1713. [PubMed] 47. 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;41:48–54. [PubMed] 48. Poynard T, Imbert-Bismut F, Ratziu V, et al. Biochemical markers of liver fibrosis in patients infected by hepatitis C virus: longitudinal validation in a randomized trial. J Viral Hepat. 2002;9:128–133. [PubMed] 49. Poynard T, McHutchison J, Manns M, Myers RP, Albrecht J. Biochemical surrogate markers of liver fibrosis and activity in a randomized trial of peginterferon alfa-2b and ribavirin. Hepatology. 2003;38:481–492. [PubMed] 50. Foucher J, Chanteloup E, Vergniol J, et al. Diagnosis of cirrhosis by transient elastography (Fibroscan(R)): a prospective study. Gut. 2005 Jul 14; [Epub ahead of print]
|
