Non invasive assessment of liver fi brosis ONLY. liver diseases liver biopsy liver fibrosis biomarkers fibrotest fibroscan

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1 Ann Transplant, 2008; 13(2): 5-11 Received: Accepted: Published: Key words Full-text PDF: Word count: 1979 Tables: 1 Figures: 2 References: 50 Author s address: Non invasive assessment of liver fi brosis Hanni Yeshua 1,2, Ran Oren 1 1 The Liver Unit, Deptartment Gastroenterology, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel 2 Clalit Health Services, and the Sackler faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel We are indebted to Philippe Halfon MD, PharmD, PhD for his careful review of the article along with his very important comments. Summary Liver fibrosis is the final common pathway of most chronic liver diseases of various etiologies.the development of fibrosis determines the management policy as well as the prognosis. In recent years it became clear that the fibrotic process is reversible. Therefore early detection of liver fibrosis is critical At present, liver biopsy is considered the gold standard for the detection of fibrosis. Nevertheless liver biopsy is an invasive procedure limiting both its acceptance by patients, and their compliance for repeated procedures. More over it is a questionable gold standard due to significant sample error and intra and inter observer variability. These limitations have led to the development of noninvasive techniques for assessing the presence and the degree of liver fibrosis, such as biomarkers and transient elastography. The accuracy of these methods as compared to liver biopsy, as well as their use and limitations are reviewed in the article. liver diseases liver biopsy liver fibrosis biomarkers fibrotest fibroscan Review Paper Ran Oren, The Liver Unit, Department of Gastroenterology, Tel-Aviv, Israel, roren@tasmc.health.gov.il 5

2 Review Paper Ann Transplant, 2008; 13(2): 5-11 BACKGROUND Liver fibrosis is the final common pathway of most chronic liver diseases of various etiologies such as hepatitis B, C and non alcoholic steatohepatitis (NASH). Moreover, up to 20% of patients with chronic liver diseases who seek medical attention for the first time already have cirrhosis. After years of disease, 10 20% of patients with hepatitis C will develop cirrhosis and its complications, including hepatocellular carcinoma [1]. Therefore early detection of liver fibrosis is critical [2].The development of fibrosis determines the management policy as well as the prognosis. In recent years, it became clear that the fibrotic process is reversible [2]. A number of different staging systems for fibrosis based on liver histology are in current use,most of them recognize 5 stages of fibrosis ranging from none [F=0] to severe fibrosis [F2-4] to cirrhosis[ Metavir,Batt&Ludwig, Ishak] [3 5]. At present, liver biopsy is considered the gold standard for the detection of fibrosis. Nevertheless liver biopsy is an invasive procedure limiting both its acceptance by patients, and their compliance for repeated procedures. Complications vary from pain (30%) to major complications (3/1000), including hemoperitoneum, bile peritonitis and pneumothorax to death (1/10000). In addition, the direct cost of liver biopsy is estimated to be $ , not including indirect cost time off work and hospital stay [6]. Most importantly, liver biopsy, which represents 1/ of the total mass of the liver, is a questionable gold standard due to significant sample error and intra and inter observer variability leading to over or under staging in up to 30 40% of biopsies in patients with hepatitis C and NASH [7 10]. These limitations have led to the development of noninvasive techniques for assessing the presence and the degree of liver fibrosis, such as biomarkers and transient elastography. BIOMARKERS Blood tests for liver fibrosis that are based on score taking in account several blood or clinical markers, have been available for about 10 years [11]. They are usually designed to diagnose significant fibrosis, which includes all stages above a cut-off of moderate bridging fibrosis [12]. 6 The result is a binary or qualitative diagnosis, as distinct from a quantitative diagnosis obtained by measuring parameters such as liver stiffness [13] or the area of fibrosis by a blood test [14]. Significant fibrosis has been adopted as a target because it can be identified using semi-quantitative histological staging in a patient with chronic hepatitis C, and because it is an indicator for treatment. The overall accuracy of several blood tests is considered as excellent. However, this accuracy is variable as a function of blood test values with a maximum accuracy at the extreme values and a minimum accuracy in the median interval. The reliability is the area of blood test values where the diagnostic accuracy of the diagnostic target is considered sufficiently reliable in decision analysis for an application in clinical practice. Usually, there liability interval is defined by the cut-offs provided by the 90% predictive values [15,16]. In these patients, a liver biopsy is considered as avoidable. The advantages of the biomarkers relate to the fact that they are non invasive, highly reproducible, can be rapidly done on hundreds of samples and requires a technicians that can be trained in a short period of time. The biomarkers are categorized as direct and indirect separating measurement of direct components of the liver matrix or reflection of liver function or hepatic inflammation. Another more pragmatic approach constitutes to share the tests as simple (based on ratio) tests, APRI (17) and Fib-4 [18], including indirect fibrosis markers, and sophisticated tests, based on algorithms provided by logistic regression including indirect markers and mixed tests, including indirect and direct: Fibrotest [15] markers: hepascore [19] and FibroMeter [14], ELF [20,21], Forns, Leroy, Fibrospect. DIRECT MARKERS The direct markers measures direct components of the liver matrix such as collagen and collagen fragments (Hyaluronic acid, collagen4, collagen6) and enzymes that regulate fibrogenesis and fibrolysis such as matrix metaloproteinases and their inhibitors, namely Tissue Inhibitor of Matrix Metalproteinase-1(TIMP-1). Recently a panel of direct markers consisting of TIMP-1, hyaluronic acid and aminoterminal peptide of procollagen 3 known as the Enhanced Liver Fibrosis panel (ELF) was studied on more than 1000 pa-

3 Ann Transplant, 2008; 13(2): 5-11 tients with chronic liver diseases. The ELF panel had an area under the curve of 0.77, 0.94 and 0.90 for distinguishing severe fibrosis in patients with hepatitis C, alcoholic liver disease and NASH respectively [22,23]. INDIRECT MARKERS The indirect markers are markers of liver function or hepatic inflammation. The first markers described included platelet count, PT, the ratio of AST to platelets count [APRI test], the combination of platelet count, GGT, cholesterol and age [Forns test]. These markers yielded good predictive values in certain populations but were not substituted for liver biopsy [22 24]. More recently the most widely used indirect biomarker the Fibrotest-Actitest (FT-AT) seems more promising. An algorithm was developed by Poynard and colleagues, assessing the degree of necroinflammatory activity and fibrosis adjusted for age and sex [25]. Fibrotest measures the degree of fibrosis and combines five serum biochemical markers- Alpha2macroglobulin, total bilirubin, Gammag lutamyltranspeptidase(ggt), apolipoproteina1 and haptoglobin. The outcome describe the degree of fibrosis [Fibrotest unit range from 0-no fibrosis to 1-cirhosis]. Actitest measures the degree of necrosis and inflammation by combining the above measures with ALT [Actitest unit range from 0-no inflammation to 1-high degree of inflammation]. The results are directly correlated to the METAVIR score. Recently, a new panel estimating also the degree of steatosis was introduced-the Steatotest (ST), combining the 5 components of Fibrotest adjusted for age, gender and BMI, plus serum glucose, triglycerides and cholesterol. ST scores range from zero to 1.00, with higher scores indicating a greater probability of significant steatosis [26,27].The ability of the FT to distinguish F0-1 from F2-4has been assessed on more than 1500-patients, most of them with hepatitis C. The area under the receiver operating characteristic curve (AUROC) range between 0.73 to 0.87 for the prediction of F2-4 patients, with a higher performance in identification patients with cirrhosis -AUROC reaching 0.90 [15 20]. Another interesting test is the Fibrometer with a 0.91 diagnostic performance of significant fibrosis (F2-4) [21]. Recent studies demonstrated that the diagnostic values of the FT were similar in chronic hepatitis B, alcoholic liver disease and NAFLD [28 35]. Yeshua H et al Non invasive assessment of liver fi brosis The main limitations of the test are its inability to be used in medical conditions that influenced its components such as an inflammatory process that raise serum haptoglobin levels, hemolysis that decreased serum haptoglobin levels, Gilbert s syndrome with increased serum bilirubin levels and in patients receiving drugs that can influence liver enzymes. TRANSIENT ELASTOGRAPHY-FIBROSCAN [36 39] Transient elastography, is a new medical device aimed to estimate liver fibrosis by measuring liver stiffness. It is an ultrasound based technique that measures the propagation velocity of elastic shear waves through the liver tissue. The harder the tissue the faster the shear wave propagates. The system is equipped with a probe including an ultrasonic transducer mounted on the axis of a vibrator. A vibration of mild amplitude and low frequency is transmitted from the vibrator towards the tissue by the transducer itself.this vibration induces an elastic shear wave that propagates through the tissue. In the meantime, pulse echo ultrasound acquisitions are performed to follow the propagation of the shear wave and measure its velocity. Only results obtained with 10 successful acquisitions in the same patients are considered reliable. The liver stiffness is measured in a volume that approximates a cylinder 1 cm wide and 4 cm long,representing 1/500 of liver tissue- a volume 100 times greater than a biopsy sample thus more widely reflecting the state of hepatic tissue in general. The examination takes place, with the patient lying down in the dorsal decubitus position with the right arm in maximal abduction. The tip of the probe transducer is placed on the skin, between the ribs at the level of the right lobe of the liver. The measurement depth is between 25 to 45 mm.the time needed for examination is less than 5 minutes.the examination can be carried out by qualified medical staff other than doctors nurses or technicians. It is easy to perform, painless, operator independent and reproducible. The results are expressed in kilopascals (kpa) and correspond to the median of 10 validated measurements. Liver stiffness values range from 2.5 to 75 kpa [36]. The Cut-off value are 7.1 to 8.8 for F > or = 2, for F > or = 3 and 12.5 to 14.6 for F=4 de- 7

4 Review Paper Ann Transplant, 2008; 13(2): 5-11 pending on whether diagnosis accuracy or sensitivity &specificity is maximized or not. Its ability to distinguish F0-1 from F2-4has been assessed in more than 500 -patients-most of them with hepatitis C. The AUROC range between 0.72 to 0.83 for the prediction of F2-4 fibrosis. The higher the fibrosis stage the better the area under the curve, specifically 0.79 to 0.88 for F > or = 2, 0.9 to0.91 for F > or = 3 and for F=4 [37 40]. Our group tested 300 patients that underwent fibroscan examination in 3 different sites in the right upper quadrant, measurement variability was found in 17% of patients, probably reflecting the heterogeneity of liver tissue [41]. Most studies were performed on patients with hepatitis C for the detection of significant hepatic fibrosis, and early detection of cirrhosis. Recently the fibroscan was also tested in several other groups of liver disease patients, including patients with biliary diseases, NASH, hepatitis B and HIV resulting in a good correlation with biopsy [42,43]. Another application of the fibroscan is to monitor the progression of fibrosis. Preliminary studies suggest that liver stiffness values are related to the severity of cirrhosis- the lower the elasticity the more likely the patients will develop severe complications (Figiure 1). In addition in patients with hepatitis C the fibroscan values corresponded to the degree of portal hypertension [39,42 48]. Table 1. Comparison with Blood Markers. 8 Figure 1. Prediction of cirrhosis complications. Limitations-Liver stiffness measurements can be difficult to perform in obese patients and individuals with narrow intercostal spaces, requiring the use of specific probes. It is also impossible to measure liver stiffness in patients with ascites, because the velocity wave does not propagate through the ascitic fluid. However, in these cases of failure, no results were obtained, preventing the risk of false measurements. Recently liver stiffness was found to be increased in acute viral hepatitis and therefore it is not accurate in that setting [49]. The practical advantage of fibroscan over liver biopsy is the ability of the former to monitor fibrosis progression by repeated examinations. This proved useful in patients with chronic liver diseases undergoing treatment. Castera et al found that the best performance was obtained by combining the fibroscan and FT, with areas under the ROC curve of 0.88 for F > or = 2, 0.95 for F > or = 3, and 0.95 for F = 4 (Table 1). When the fibroscan Etiology N of patient Diagnosis Markers AUROC Reference HCV 183 F > or =2 FS 0.83 Castera et al. Gastroenterology, 2005 (26) FT 0.85 APRI 0.78 Cirrhosis FS 0.95 FT 0.87 APRI 0.83 HCV 252 Cirrhosis FS 0.95 Castera et al. EASL, 2006 (39) FT 0.86 APRI 0.80 HCV+HIV 72 Cirrhosis FS 0.97 de Lédinghenet al. JAIDS, 2006 (31) APRI 0.76

5 Ann Transplant, 2008; 13(2): 5-11 Disagreement biopsy Follow up or treatment and FT results agreed, liver biopsy examination confirmed them in 84% of cases for F > or = 2, in 95% for F > or = 3, and in 94% for F = 4 [26]. Recent flow chart suggests the combination use of both of them as a substitute to biopsy in most patients with hepatitis C (Figure 2). The importance of liver biopsy in the diagnoses of liver diseases is unquestionable. Serum markers as well as fibroscan will never replace the range and complexity of information that can be obtained by biopsy. However its role in identification the stage of liver fibrosis in known liver diseases is not obvious, especially considering the risk-benefit ratio of biopsy. In fact, in a survey published recently in France, it was found that among 546 hepatologists, 81% used non-invasive biomarker (FT-AT) and 32% used fibroscan. At the same time there has been a dramatic decrease in the use of liver biopsy for more than 50% of patients with chronic hepatitis C, with a subsequent increase in the number of patients treated [50]. REFERENCES: FibroScan + FibroTest Minimum fibrosis (FS<7.1 kpa+ FT<F2) Follow up * Castera et al. Gastroenterology 2005 Agreement Moderate fibrosis (FS 7.1 kpa+ FT F2) Treatment 1. Niederau C, Lange S, Heintges T et al: Prognosis of chronic hepatitis. C: results of a large, prospective cohort study. Hepatology, 1998; 28 (6): Friedman SL, Bansal MB: Reversal of hepatic fibrosis fact or fantasy? Hepatology, 2006; 43(2 Suppl.1): S Bedossa P, Poynard T: An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology, 1996; 24: Batts KP, Ludwig J: Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol, 1995; 19(12): Severe fibrosis (FS 9.5 kpa+ F3 FT) Treatment and follow up for HCC Yeshua H et al Non invasive assessment of liver fi brosis Figure 2. A suggested flow chart. 5. Goldin RD, Goldin JG, Burt AD et al: Intra-observer and interobserver variation in the histopathological assessment of chronic viral hepatitis. J Hepatol, 1996; 25: 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(3): The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology, 1994; 20: Bedossa P, Dargère D, Paradis V: Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology, 2003; 38: 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: 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): Oberti F, Valsesia E, Pilette C et al: Noninvasive diagnosis of hepatic fibrosis or cirrhosis. Gastroenterology, 1997; 113: Sebastiani G, Alberti A: Non invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy. World J Gastroenterol, 2006; 12: Castera L, Foucher J, Le Bail B et al: Prospective and independent validation of the lok index for prediction of cirrhosis in patients with chronic hepatitis c: comparison with fibroscan, fibrotest and APRI. J Hepatolog, 2006; 44(Suppl.2) 14. Cales P, Oberti F, Michalak S et al: A novel panel of blood markers to assess the degree of liver fibrosis. Hepatology, 2005; 42:

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