Noninvasive Assessment of Liver Fibrosis and Portal Hypertension With Transient Elastography

Hepatic fibrogenesis, the “final” common result of injury to the liver, is believed to be a critical factor leading to hepatic dysfunction and may be important in the pathogenesis of portal hypertension. Thus, accurate assessment of the degree of fibrosis is important clinically. For many years, examination of hepatic histopathology has been considered to be the “gold standard” tool used to assess fibrosis. However, liver biopsy is invasive, and in many instances not favored by patients or physicians. Thus, alternative approaches to measure liver fibrosis would be extremely attractive. To the extent that transient elastography is able to measure “liver stiffness,” which is proportional to the degree of liver fibrosis, this technique holds great promise. Hepatic fibrogenesis, the “final” common result of injury to the liver, is believed to be a critical factor leading to hepatic dysfunction and may be important in the pathogenesis of portal hypertension. Thus, accurate assessment of the degree of fibrosis is important clinically. For many years, examination of hepatic histopathology has been considered to be the “gold standard” tool used to assess fibrosis. However, liver biopsy is invasive, and in many instances not favored by patients or physicians. Thus, alternative approaches to measure liver fibrosis would be extremely attractive. To the extent that transient elastography is able to measure “liver stiffness,” which is proportional to the degree of liver fibrosis, this technique holds great promise. Hepatic fibrosis is the final result of a wide variety of types of liver injury. Fibrosis is a wound healing response, which is similar mechanistically to that observed in essentially all organs.1Wynn T.A. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.J Clin Invest. 2007; 117: 524-529Google Scholar One of the most remarkable aspects of the wounding response in the liver (and in all tissues) is enhanced extracellular matrix production, or fibrogenesis. Injury-induced fibrogenesis is characterized by a multifold increase in interstitial collagens such as type I and type III, and many other extracellular matrix constituents.Hepatic wounding is an integrated response, involving many cellular, biochemical, and molecular events (Figure 1). A critical feature is the transformation of resident stellate cells (also lipocytes, Ito cells, or perisinusoidal cells) from the quiescent to the activated state (Figure 1).2Friedman S.L. Rockey D.C. Bissell D.M. Hepatic fibrosis 2006: report of the third AASLD Single Topic Conference.Hepatology. 2007; 45: 242-249Google Scholar Among the most prominent functional changes associated with activation is a striking increase in secretion of extracellular matrix proteins,3Maher J.J. McGuire R.F. Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo.J Clin Invest. 1990; 86: 1641-1648Google Scholar presumably responsible for the overall fibrogenic response. Several other cell types, including bone marrow–derived precursors, portal fibroblasts, and perhaps others, may also play a role in fibrogenesis.The Relationship of Fibrosis and Portal Hypertension: PathophysiologyElevated portal pressure resulting from liver injury has been postulated to include elements of increased intrahepatic resistance as well as increased flow through the splanchnic system (eg, a hyperdynamic circulation). Increased intrahepatic resistance is an early and consistent feature of liver injury; potential causes include impaired blood flow owing to regenerative nodules, intrahepatic shunts, hepatocyte swelling, extinction of typical vascular units after cycles of injury/repair, and perisinusoidal constriction. The latter mechanism has been proposed to be due to stellate cells, which also morphologically resemble tissue pericytes, a smooth muscle–like cell that regulates blood flow via pericapillary constriction.4Sims D.E. Recent advances in pericyte biology: implications for health and disease.Can J Cardiol. 1991; 7: 431-443Google ScholarAn additional feature of stellate cell activation is the de novo expression of smooth muscle–specific proteins, including smooth muscle α actin,5Rockey D.C. Boyles J.K. Gabbiani G. et al.Rat hepatic lipocytes express smooth muscle actin upon activation in vivo and in culture.J Submicrosc Cytol Pathol. 1992; 24: 193-203Google Scholar presumably imparting an exaggerated contractile phenotype on stellate cells,6Rockey D.C. Housset C.N. Friedman S.L. Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo.J Clin Invest. 1993; 92: 1795-1804Google Scholar, 7Bauer M. Paquette N.C. Zhang J.X. et al.Chronic ethanol consumption increases hepatic sinusoidal contractile response to endothelin-1 in the rat.Hepatology. 1995; 22: 1565-1576Google Scholar consistent with enhanced perisinusoidal constriction and increased intrahepatic resistance.7Bauer M. Paquette N.C. Zhang J.X. et al.Chronic ethanol consumption increases hepatic sinusoidal contractile response to endothelin-1 in the rat.Hepatology. 1995; 22: 1565-1576Google Scholar Furthermore, stellate cells respond to a number of “vasoactive peptides.”8Rockey D.C. Vascular mediators in the injured liver.Hepatology. 2003; 37: 4-12Google Scholar Therefore, stellate cell activation leads to both fibrosis and contractility, raising the possibility that the processes may be linked. Furthermore, in the context of emerging data emphasizing endothelial dysfunction after liver injury, there is a compelling pathophysiologic basis for increased intrahepatic resistance typical of early forms of liver injury.9Liu S. Premont R.T. Kontos C.D. et al.A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertension.Nat Med. 2005; 11: 952-958Google ScholarWhy Is Quantitation of Fibrosis Important?Precise measurement of the fibrotic lesion is important for several reasons. First, progressive fibrosis is believed to predict progression to cirrhosis in patients with hepatitis C virus (HCV) infection10Poynard T. Bedossa P. Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.Lancet. 1997; 349: 825-832Google Scholar and other diseases.2Friedman S.L. Rockey D.C. Bissell D.M. Hepatic fibrosis 2006: report of the third AASLD Single Topic Conference.Hepatology. 2007; 45: 242-249Google Scholar Additionally, the fibrosis stage may predict the likelihood of response to interferon-based antiviral therapy in patients with HCV; for example, patients with F3 or F4 fibrosis typically have a lower response rate to therapy.11Dienstag J.L. McHutchison J.G. American Gastroenterological Association technical review on the management of hepatitis C.Gastroenterology. 2006; 130 (quiz 214–217): 231-264Google Scholar Finally, therapy may be intentionally withheld in patients with minimal fibrosis or slow progression.Data suggesting a relationship between fibrosis and outcome are emerging. In 116 patients with HCV infection undergoing liver biopsy (and hepatic venous pressure gradient [HVPG] measurement) after liver transplantation, a METAVIR fibrosis score of >F2 predicted clinical decompensation (AUC: 0.80).12Blasco A. Forns X. Carrion J.A. et al.Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation.Hepatology. 2006; 43: 492-499Google Scholar In a long-term cohort study of 160 patients with primary biliary cirrhosis, for every stage increase of fibrosis identified (on a 1- to 4-point fibrosis scale) on initial liver biopsy, there was a 2-fold increase in future complications or death (relative risk, 2.4; 95% confidence interval [CI], 1.6–3.6).13Mayo M. Parks J. Huet B. et al.Serum fibrosis markers predict future clinical decompensation in primary biliary cirrhosis better than liver biopsy, bilirubin, or Mayo risk score.Hepatology. 2006; 44: 630AGoogle Scholar Finally, patients with fibrosis regression may be protected from developing clinical complications.14Colletta C. Smirne C. Fabris C. et al.Regression of fibrosis among long-term responds to antiviral treatment for chronic viral hepatitis.Hepatology. 2007; 46: 300-301AGoogle ScholarAlthough fibrosis is commonly accepted as the precursor to cirrhosis, and therefore is likely to be associated with adverse outcomes, a word of caution is essential in unequivocally assigning its importance. For example, in a cohort of patients with chronic HCV and histologic (only) cirrhosis, it appeared that only patients who developed a complication had an adverse outcome.15Fattovich G. Giustina G. Degos F. et al.Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.Gastroenterology. 1997; 112: 463-472Abstract Full Text Full Text PDF Scopus (1245) Google Scholar Perhaps the most difficult issue in this area is understanding what predicts whether a patient with fibrosis will develop a complication.Tools Used to Quantitate FibrosisThe historical “gold standard” for assessment of fibrosis is histologic assessment of the liver (liver biopsy).16Sherlock S. Aspiration liver biopsy, technique and diagnostic application.Lancet. 1945; ii: 397Google Scholar However, liver biopsy is invasive and is associated with serious potential complications, requires substantial training and skill, makes both patients and physicians anxious, and can be associated with substantial sampling error. For example, in a series of 124 patients with chronic HCV infection who underwent laparoscopy-guided biopsy of the right and left lobes, 33.1% had a difference of ≥1 histologic stage (modified Scheuer system) between lobes.17Regev A. Berho M. Jeffers L.J. et al.Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection.Am J Gastroenterol. 2002; 97: 2614-2618Google Scholar Furthermore, in 51 patients with nonalcoholic steatohepatitis (NASH) undergoing sequential biopsies, 6 of 17 patients with bridging fibrosis on 1 sample had only mild or no fibrosis on the other.18Ratziu V. Charlotte F. Heurtier A. et al.Sampling variability of liver biopsy in nonalcoholic fatty liver disease.Gastroenterology. 2005; 128: 1898-1906Abstract Full Text Full Text PDF Scopus (1472) Google ScholarBecause liver biopsy is invasive, and histologic assessment of the liver imperfect, there has been great interest in noninvasive measurement of fibrosis; many methods have been proposed (Table 1). Bedside clinical signs are generally evident only when cirrhosis and portal hypertension are present; they are of little value in assessing early stages of liver fibrosis. Routine laboratory values such as platelet count are abnormal primarily in patients with advanced disease.19D’Amico G. Pagliaro L. Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Google Scholar In patients with HCV, an aspartate aminotransferase (AST) to alanine aminotransferase ratio >1 may suggest the presence of cirrhosis.20Giannini E. Risso D. Botta F. et al.Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease.Arch Intern Med. 2003; 163: 218-224Google Scholar A model using the AST and platelet count (AST to platelet ratio index [APRI]), has value in fibrosis assessment.21Wai C.T. Greenson J.K. Fontana R.J. et al.A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C.Hepatology. 2003; 38: 518-526Google Scholar Serum markers, either individually or combined as panels may predict liver fibrosis.22Rockey D.C. Bissell D.M. Noninvasive measures of liver fibrosis.Hepatology. 2006; 43: S113-S120Google Scholar Additionally, many radiographic tests have been examined; ultrasound, computed tomography, and magnetic resonance imaging are generally capable of detecting evidence of portal hypertension, but are typically insensitive for mild or moderate fibrosis. Finally, models including combinations of clinical signs, routine laboratory tests, radiologic imaging modalities, and/or quantitative assays of liver function may predict liver fibrosis.22Rockey D.C. Bissell D.M. Noninvasive measures of liver fibrosis.Hepatology. 2006; 43: S113-S120Google Scholar An ideal noninvasive diagnostic test for hepatic fibrosis would be simple, readily available, inexpensive, and accurate. Unfortunately, at the current time, neither individual tests nor a combination of tests meets these criteria.Table 1Noninvasive Methods to Assess Liver FibrosisTestExamplesAdvantagesaAll tests theoretically offer a measure of global fibrosis compared to the localized sample that liver biopsy and histology provides.DisadvantagesCommentsPhysical examSpider angiomata, splenomegalyVery simple and readily available, inexpensiveIndirect, low sensitivity and specificityLimited usefulnessSimple blood testsPlatelet count, ASTVery simple and readily available, inexpensiveIndirect, low sensitivity and specificityLimited usefulnessSerum makersHyaluronic acidType I collagenFibronectinSimple, quantitativeIndirect, low sensitivity and specificity, availability limitedLimited usefulnessImagingUltrasoundMRICTSimple, readily available, large previous experienceLow sensitivity and specificity, generally costly, radiation with CTMay be helpful as a tip off to portal hypertensionMarker panels“ELF”“FPI”“Fibrotest”“Fibrospect”Enhanced sensitivity and specificity, quantitativeIndirect, availability limited, some are costlyMay also be useful for tracking a change in fibrosis statusTransient elastography“Fibroscan”Results immediately available, quantitative, enhanced sensitivity and specificitySome technical limitations, availability limitedCost unclear, may also be useful for tracking a change in fibrosis status, stiffness correlates with portal hypertensiona All tests theoretically offer a measure of global fibrosis compared to the localized sample that liver biopsy and histology provides. Open table in a new tab Transient ElastographyTransient elastography is a novel, ultrasound-based technology that involves acquisition of pulse-echo ultrasound signals to measure liver stiffness23Sandrin L. Fourquet B. Hasquenoph J.M. et al.Transient elastography: a new noninvasive method for assessment of hepatic fibrosis.Ultrasound Med Biol. 2003; 29: 1705-1713Google Scholar (Figure 2). In brief, the tip of an ultrasound transducer probe is placed between ribs over the right lobe of the liver. The probe transmits a low-amplitude (vibration and frequency) signal to the liver, which in turn induces an elastic shear wave that propagates through liver tissue. The pulse-echo ultrasound allows measurement of wave velocity, expressed in kilopascals, a measure of liver stiffness. Normal liver stiffness is reported to be in the range of 4–6 kilopascals, whereas cirrhosis is generally present at levels >12–14 kilopascals.24Ziol 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: 48-54Google Scholar, 25Castera L. Foucher J. Bertet J. et al.FibroScan and FibroTest to assess liver fibrosis in HCV with normal aminotransferases.Hepatology. 2006; 43 (author reply 375–376): 373-374Google Scholar, 26Fraquelli 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: 968-973Google ScholarFigure 2The figure depicts an overview of the technique. Briefly, a pulse-echo ultrasound signal is obtained by placing a transducer probe between ribs over the right lobe of the liver. The low amplitude signal transmitted to the liver induces an elastic shear wave that propagates through liver tissue. The pulse-echo ultrasound allows measurement of wave velocity obtained provides a measure of liver stiffness.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Transient elastography is associated with attractive features beyond the fact that it is noninvasive. Most important, it assesses a relatively large sample-across an area of 1–2 cm of the liver, estimated to be some 100 times greater than a liver biopsy specimen. Additionally, transient elastography allows multiple readings to be taken (from slightly different areas, thereby providing data on an even larger sample). This is critical because sampling error associated with liver biopsy17Regev A. Berho M. Jeffers L.J. et al.Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection.Am J Gastroenterol. 2002; 97: 2614-2618Google Scholar, 18Ratziu V. Charlotte F. Heurtier A. et al.Sampling variability of liver biopsy in nonalcoholic fatty liver disease.Gastroenterology. 2005; 128: 1898-1906Abstract Full Text Full Text PDF Scopus (1472) Google Scholar is likely due to the small portion of the liver sampled.27Bedossa P. Dargere D. Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C.Hepatology. 2003; 38: 1449-1457Google ScholarTransient Elastography and FibrosisThe pathophysiologic basis of liver “stiffness,” and the degree to which fibrosis correlates with liver stiffness, is an area of active investigation. Indeed, the relationship of fibrosis to the “mechanical” or “physical” state of the liver is not well understood, although it has long been appreciated that the cirrhotic liver is stiff. Indeed, Rene Laennec, wrote many years ago28Laennec R. Traite de l’auscultation mediate. Hemorrhagic pleurisy of the left side with ascites and organic diseases of the liver. 1826.Google Scholar: “The liver, reduced to a third of its ordinary size …, one could not mash but a small portion: the rest gave to the touch the sensation of a piece of soft leather.” Investigation over the last 2 decades has more precisely evaluated tissue elasticity, typically using ultrasound technology.29O’Donnell M. Skovoroda A.R. Shapo B.M. et al.Internal displacement and strain imaging using ultrasonic speckle tracking.IEEE Trans Ultrason Ferroelectr Freq Control. 1994; 41: 314-325Google Scholar, 30Sarvazyan A.P. Rudenko O.V. Swanson S.D. et al.Shear wave elasticity imaging: a new ultrasonic technology of medical diagnostics.Ultrasound Med Biol. 1998; 24: 1419-1435Google Scholar, 31Erkamp R.Q. Wiggins P. Skovoroda A.R. et al.Measuring the elastic modulus of small tissue samples.Ultrason Imaging. 1998; 20: 17-28Google Scholar, 32Yeh W.C. Li P.C. Jeng Y.M. et al.Elastic modulus measurements of human liver and correlation with pathology.Ultrasound Med Biol. 2002; 28: 467-474Google Scholar One study evaluated the consistency of the liver as a change in a resonance frequency.33Kusaka K. Harihara Y. Torzilli G. et al.Objective evaluation of liver consistency to estimate hepatic fibrosis and functional reserve for hepatectomy.J Am Coll Surg. 2000; 191: 47-53Google Scholar In patients undergoing hepatic resections for various indications, liver stiffness was measured intraoperatively and correlated with both liver function and liver fibrosis.It is further known that the injured liver itself is contractile (and thus has elastic properties), presumably as a result of cellular elements within the liver such as myofibroblasts.34Irle C. Kocher O. Gabbiani G. Contractility of myofibroblasts during experimental liver cirrhosis.Journal of Submicroscopic Cytology. 1980; 12: 209-217Google Scholar Liver fibrosis appears to be characterized by elements of reversible and irreversible fibrosis; the irreversible component may be made up of relatively acellular bands of cross-linked collagen,35Issa R. Zhou X. Constandinou C.M. et al.Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking.Gastroenterology. 2004; 126: 1795-1808Google Scholar the latter possibly associated with reduced elasticity. Thus, a fundamental pathophysiologic question is this: Do elements at the cellular level play a role in determining tissue elasticity? This is highly likely; in fact, it was suggested that liver stiffness precedes fibrosis and stellate cell activation, raising the possibility even that fibrosis and liver stiffness may not be linked.36Georges P.C. Hui J.J. Gombos Z. et al.Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis.Am J Physiol Gastrointest Liver Physiol. 2007; (Oct 11; Epub ahead of print.)Google Scholar We know that liver fibrosis is a result of activation of effector cells (stellate cells, fibroblasts, fibrocytes) with subsequent fibrogenesis. Additionally, liver stiffness may be increased in the setting of hepatic inflammation; thus, a “cellular” contribution to liver stiffness is attractive. Nonetheless, further investigation is clearly required to test this possibility.Given this background, it is clear that there are many issues surrounding the use of transient elastography for quantitation of liver fibrosis including several highlighted below.1How accurate is transient elastography and can it differentiate no fibrosis from very early fibrosis stages? Will measurement of liver stiffness allow longitudinal quantitation of fibrosis as the patient transitions from F1 to F2 to F3?2How reproducible and reliable is it?3How much training is required?4Are differences in gender important?5What is the cost? Is it cost effective?6What are the limitations of transient elastography?7How might transient elastography be used in clinical practice?AccuracyTransient elastography has been shown to have a reasonably high sensitivity and specificity for fibrosis at both ends of the spectrum. Transient elastography appears to be able to tell us that the liver is either normal or cirrhotic. For example, in a prospective multicenter study of 327 chronic HCV patients, the AUROC for METAVIR stage ≥F2 and cirrhosis (F4) were 0.79 and 0.97, respectively.24Ziol 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: 48-54Google Scholar Many other studies have yielded similar results.25Castera L. Foucher J. Bertet J. et al.FibroScan and FibroTest to assess liver fibrosis in HCV with normal aminotransferases.Hepatology. 2006; 43 (author reply 375–376): 373-374Google Scholar, 37Colletta C. Smirne C. Fabris C. et al.Value of two noninvasive methods to detect progression of fibrosis among HCV carriers with normal aminotransferases.Hepatology. 2005; 42: 838-845Google Scholar, 38Nahon P. Thabut G. Ziol M. Hta et al.Liver stiffness measurement versus clinicians’ prediction or both for the assessment of liver fibrosis in patients with chronic hepatitis C.Am J Gastroenterol. 2006; 101 (??): 2744-2751Google Scholar, 39Foucher J. Chanteloup E. Vergniol J. et al.Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study.Gut. 2006; 55: 403-408Google Scholar, 40Foucher J. Castera L. Bernard P.H. et al.Prevalence and factors associated with failure of liver stiffness measurement using FibroScan in a prospective study of 2114 examinations.Eur J Gastroenterol Hepatol. 2006; 18: 411-412Google Scholar, 41Masaki N. Imamura M. Kikuchi Y. et al.Usefulness of elastometry in evaluating the extents of liver fibrosis in hemophiliacs coinfected with hepatitis C virus and human immunodeficiency virus.Hepatol Res. 2006; 35: 135-139Google Scholar, 42Ganne-Carrie 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: 1511-1517Google Scholar, 43Friedrich-Rust M. Ong M.F. Herrmann E. et al.Real-time elastography for noninvasive assessment of liver fibrosis in chronic viral hepatitis.AJR Am J Roentgenol. 2007; 188: 758-764Google Scholar, 44Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology. In press.Google Scholar Liver stiffness measurements have been shown to correlate with fibrosis in a variety of liver diseases, including primary biliary cirrhosis,45Corpechot 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: 1118-1124Google Scholar primary sclerosing cholangitis,45Corpechot 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: 1118-1124Google Scholar NASH,46Yoneda M. Fujita K. Inamori M. et al.Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD).Gut. 2007; 56: 1330-1331Google Scholar and others.39Foucher J. Chanteloup E. Vergniol J. et al.Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study.Gut. 2006; 55: 403-408Google ScholarIt is likely that transient elastography can be used in combination with other (noninvasive) tests to more accurately assess fibrosis stage. In a prospective analysis comparing transient elastography, serum markers, and the APRI in a cohort of 183 chronic HCV patients with evenly matched F1–F4 disease, the performance of the various noninvasive tests was similar (the AUROC for transient elastography, serum tests, and APRI were 0.83, 0.85, and 0.78, respectively, for METAVIR F ≥2).47Castera 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: 343-350Abstract Full Text Full Text PDF Scopus (2026) Google Scholar However, the best overall performance was obtained by combining transient elastography and serum markers (AUROC of 0.88 for F ≥ 2, 0.95 for F ≥ 3, and 0.95 for F = 4).Although the “global” accuracy of transient elastography is high, it is imprecise in quantitating intermediate levels of fibrosis (as is the case with serum markers). Thus, it is difficult to differentiate the normal liver from METAVIR stage F1, stage F1 from F2 disease or even stage F2 from F3 disease. To the degree that this degree of differentiation may be important from a clinical management standpoint, the use of transient elastography will be limited.Reproducibility and ReliabilityTransient elastography is reported to have good reproducibility with low variability. Intraobserver and interobserver agreement were analyzed using the intraclass correlation coefficient (ICC) and correlated with different patient-related and liver disease-related covariates, in one study.26Fraquelli 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: 968-973Google Scholar In 800 examinations (in 200 patients), the overall interobserver agreement ICC was 0.98 (95% CI, 0.977–0.987). Increased body mass index (BMI, .25 kg/m2), steatosis, and low staging grades ( 28.GenderThere may be differences in liver stiffness among men and women. In a cohort of normal individuals, the median liver stiffness value was 4.8 kPa (range, 2.5–6.9) and did not correlate with age, body weight, or height, but it was significantly higher in men than in women (5.2 ± 0.7 vs 4.5 ± 1.0; P < .01); other variables did not differ among the genders.49Corpechot C. El Naggar A. Poupon R. Gender and liver: is the liver stiffness weaker in weaker sex?.Hepatology. 2006; 44: 513-514Google Scholar These data suggest an intrinsic difference in fibrogenesis in men and women. Experimental data support the possibility that female hormones protect against fibrosis.50Yasuda M. Shimizu I. Shiba M. et al.Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats.Hepatology. 1999; 29: 719-727Google Scholar Larger studies of normal individuals are required to more robustly assess this issue.LimitationsIn addition to the issues related to accuracy and extension of its use in populations other than those with known liver disease, several important technical limitations merit c