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Transient elastography for liver fibrosis diagnosis
European Journal of Internal Medicine 20 (2009) 339–342
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Review article
Transient elastography for liver fibrosis diagnosis Ellen Sloth Andersen a,⁎, Peer Brehm Christensen b, Nina Weis a a b
Department of Infectious Diseases, Hvidovre University Hospital, Denmark Department of Infectious Diseases, Odense University Hospital, Denmark
a r t i c l e
i n f o
Article history: Received 29 August 2008 Accepted 24 September 2008 Available online 11 November 2008 Keywords: Transient elastography FibroScan Viral hepatitis Fibrosis Cirrhosis
a b s t r a c t Liver biopsy is considered the “golden standard” for assessment of hepatic fibrosis. However, the procedure has limitations because of inconvenience and rare but serious complications as bleeding. Furthermore, sampling errors are frequent, and interobserver variability often poses problems. Recently, a modified ultrasound scanner (transient elastography) has been developed to assess fibrosis. The device measures liver elasticity, which correlates well with the degree of fibrosis. Studies have shown that transient elastography is more accurate in diagnosing cirrhosis than minor to moderate fibrosis. Most of the studies have been conducted on patients with chronic hepatitis but a few studies have also covered fibrosis and cirrhosis due to other etiologies, and they also demonstrate the high sensitivity and specificity. Transient elastography for assessment of fibrosis may turn out to be a valuable diagnostic procedure and follow-up of patients with chronic liver diseases. © 2008 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Fibrosis in the liver evolves as part of a healing process in response to liver damage. Among other causes, fibrosis can develop following a viral infection, alcohol abuse or drug intoxication. Liver cirrhosis is associated with increased morbidity and mortality [1]. WHO estimates that 350 million people are infected with chronic hepatitis B and 180 million with chronic hepatitis C [2]. Studies have shown that among patients chronically infected with hepatitis C, 50% develop fibrosis and 20% cirrhosis after a number of years [3]. Liver biopsy most commonly is used to determine the stage of fibrosis. Knowledge of the degree of liver fibrosis is important for the treatment of chronic hepatitis and diagnosis of cirrhosis is a prerequisite to prevent the various forms of complications. A new principle for diagnosis of fibrosis was recently introduced with a non-invasive, modified ultrasound device that measures elasticity in the liver (see Fig. 1). Several studies have shown that transient elastography in most cases can be used instead of liver biopsy to diagnose fibrosis. We here give a review of the latest progress in the field.
during the nineties as illustrated by the Metavir system with score from F0 to F4 (F0: no fibrosis; F4 cirrhosis) [4]. However liver biopsy is far from a perfect tool: Several studies indicate that sampling errors may have led to under-diagnosis of cirrhosis in 10–20% of the patients [5]. The smaller the biopsy size, the higher the risk for under-diagnosis of fibrosis or cirrhosis [6,7]. Furthermore, in interobserver studies pathologists disagree on fibrosis score in more than 20% of cases [8]. In addition, liver biopsy is an invasive procedure with a small but significant risk of morbidity and mortality. Pain and hypotension are the most frequent complications of the procedure. Intraperitoneal bleeding is considered the most serious complication. The mortality is about 1 in 10 000 [9]. For these reasons, patients may reject the procedure and thereby leaving their possible fibrosis undiagnosed. Performing liver biopsies generally has substantial socioeconomic cost, since the patients must be observed for bleeding after the procedure. For persons with bleeding disorders, percutaneous liver biopsy is often contraindicated. Multiple attempts have been made to substitute this invasive procedure with serological markers but none has gained universal acceptance. These markers are not covered by this article and the reader is referred to other review articles [10].
2. Liver biopsy Liver biopsy is the “golden standard” for fibrosis assessment. Numerical scoring systems for fibrosis graduation became accepted
⁎ Corresponding author. Department of Infectious Diseases, Hvidovre University Hospital, Kettegård Alle 30, DK-2650 Hvidovre, Denmark. Tel.: +45 36322695. E-mail address: [email protected] (E.S. Andersen).
3. Transient elastography The basic principle of transient elastography is that propagation velocity of a wave through a homogeneous tissue is proportional to its elasticity (stiffness). The elasticity has been demonstrated to correlate to the amount of fibrosis in the liver [11]. In technical terms liver elasticity, E, is a measure of the forces with which the tissue opposes dimensional change and is quantified by the
0953-6205/$ – see front matter © 2008 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2008.09.020
340
E.S. Andersen et al. / European Journal of Internal Medicine 20 (2009) 339–342
Fig. 1. The FibroScan instrument [13].
Young's modulus with the approximation that liver is a soft, isotropic, non-viscous medium: E = 3p × V
2
where p is the mass density (in liver tissue close to a constant) and V is the velocity [12]. The transducer is placed over the liver and transmits a low-frequency (50 Hz) wave that propagates through the liver and the velocity of the wave is then measured by pulse-echo ultrasound. If the liver is fibrotic, the elastic waves propagate more rapid than in a normal liver [12]. Fig. 2
shows elastograms illustrating the propagation of elastic waves in liver tissue for different stages of fibrosis, where the x-axis is time in ms and y-axis the depth of tissue. The inclination of the wave represents the velocity in the tissue [13]. Generally, ten valid measurements should be obtained to examine a patient with transient elastography. The median value of the ten valid measurements is considered as representative of liver elasticity. A measurement can be invalid if the transducer is held incorrectly, for example above a costae or the lung. The success rate is calculated as the number of valid measurements divided by the total number of measurements. Examinations with a success rate higher than 60% are considered reliable. The examination takes a few minutes and is without discomfort and known side effects for the patient [13]. The examination can be performed by paramedics and nurses after a 2 week training period of 25–50 examinations (Jim Long, Mediplast, personal communication). The elasticity is measured at a depth of 25 to 65 mm under the skin surface. The measurement volume has the form of a cylinder with a diameter of 1 cm and a length of 4 cm. This volume is at least 100 times the size of that used for a liver biopsy [14]. In 5–10% of patients, ten valid measurements cannot be obtained. Invalid measurements are generally due to overweight, narrow intercostal space and ascites. 25% of patients with a BMI N 30 cannot be scanned [14]. Studies have shown high intraobserver and interobserver agreement (interclass correlation coefficiency 0.96–0.98% and 0.89–0.98) [15]. Currently there is only one available liver stiffness measurement device: FibroScan® from the French company, Echosens, marketed since 2001. At the time of writing there are 250 machines globally. The price for the FibroScan Equipment is 88500€ (Jim Long, Mediplast, personal communication). Like other ultrasound equipments it has very low running cost except for calibration of the probe twice yearly. Lately results were published using a new device by Hitachi and it is hoped that competition will lead to better and cheaper hardware solutions [16]. The cost of a liver biopsy is reported to range from 703 to 1566€ in a hepatogastroenterologic department in a French Hospital with a one day observation period [17]. The cost per examination with FibroScan is reported to be around 100€ with 150 examinations annually [18]. However an important advantage of transient elastography is the possibility to repeat measurements with shorter intervals e.g. every year instead of the 5 year interval recommended for repeated biopsies. By performing more examinations the cost per measurement will be considerably lower. 4. Literature Results from the first study of transient elastography were published by Sandrin et al. in 2003. In total, 91 patients with chronic hepatitis C were examined with liver biopsy as well as liver elasticity
Fig. 2. Different velocities of the elastically propagating wave can be deducted from these three elastograms showing local strain of the tissue. The first elastogram corresponds to an elasticity of 3 kPa (no significant fibrosis), the next to an elasticity of 9 kPa (moderate fibrosis), and the third to an elasticity of 40 kPa (cirrhosis) [13].
E.S. Andersen et al. / European Journal of Internal Medicine 20 (2009) 339–342
341
Table 1 Results of eight studies from the use of the FibroScan technique for assessment of fibrosis as compared to liver biopsy[12,19,21,23,30,36–38]. Study Sandrin et al. Ziol et al. Castera et al. Foucher et al. Takeda et al. Ganne–Carrie et al. Blanc et al. Kettaneh et al.
Year 2003 2005 2005 2005 2006 2006 2007 2007
Included 91 327 193 758 287 1257 508 935
F2
F2
F4
F4
F2
F4
Sensitivity
Specificity
Sensitivity
Specificity
Auroc
Auroc
56% 67% 64%
91% 89% 85%
86% 87% 77%
96% 91% 97%
0.88 0.79 0.83 0.80 0.81
91%
87%
0.99 0.97 0.95 0.96 0.88 0.95 0.95 0.91
measurements. Twenty-four patients were excluded, five because 10 valid measurements could not be obtained, and 19 because the liver biopsies were not considered suitable for fibrosis grading. The study demonstrated good correlation between histological grading and liver elasticity. Transient elastography was 99% effective in detecting cirrhosis and 88% effective in detecting fibrosis [12]. Since the first study was published in 2003, many studies have followed, mostly in France but also in Italy, Japan, Spain, Singapore and USA [17,19–24]. Most studies have examined the correlation between liver elasticity and results from biopsies on hepatitis C patients. Results from some of the larger studies can be seen in Table 1. Ganne–Carrié et al. published in 2006 the largest study so far, examining the correlation between results from liver biopsy and elastography [19]. In total, 1257 patients with chronic liver diseases of various causes were examined with liver elasticity measurements and liver biopsy. The study exclusively focused on the use of transient elastography for diagnosis of cirrhosis. Of the patients included in the study, 132 patients (10.5%) had liver biopsies that were unsuitable for classification and 118 patients (9.3%) had unreliable liver stiffness measurements. The investigators found that optimal cut-off values were different for cirrhosis of different etiology. The optimal cut-off value regarding sensitivity and specificity for cirrhosis in hepatitis B patients was lower than for hepatitis C patients. Furthermore, the optimal cut-off value for patients with cirrhosis because of alcohol abuse or NASH was higher [19]. In a meta-analysis including 50 studies available from abstract or articles with inclusion criteria were comparison of transient elastography and liver biopsy and assessment of the area under the receiver operating characteristic curve (AUROC). In this large meta-analysis, optimal cut-off values were found to be 7.7 kPa for F2 of 13.0 kPa for F4 (cirrhosis) [25]. Roulot et al. published in 2008 a study of normal values for liver stiffness. 429 healthy persons were examined with FibroScan [26]. The study demonstrated that liver stiffness for 95% of all persons of normal weight and without metabolic syndrome was below 7.8 kPa for women and 8.0 kPa for men. An earlier study also suggested that men have a slightly higher liver stiffness than women [27]. 5. Fibrosis with other etiologies than hepatitis Most studies have focused on the correlation between liver stiffness measurements and biopsy in mono-infected patients with hepatitis C. However, in a study that included 220 patients with hepatitis B, Marcellin et al. have found the same accuracy for diagnosing fibrosis and cirrhosis [28]. Furthermore, two studies related to patients co-infected with HIV and hepatitis have also shown high sensitivity and specificity for detection of fibrosis and cirrhosis [22,29]. Vergara et al. found a specificity of 88% and sensitivity of 91% when diagnosing cirrhosis (cutoff value 14.6 kPa) on co-infected HIV/hepatitis C patients, and 83% sensitivity and 66% specificity on diagnosing significant fibrosis of grade F2 (cut-off 7.2 kPa) [22]. The correlation between liver stiffness values and liver biopsies does not seem to be affected by steatosis [30].
0.8 0.79
F0-1
F2-3
F4
40% 35% 26% 31% 57% n/a n/a 50%
46% 46% 49% 42% 30% n/a n/a 40%
14% 19% 25% 27% 13% n/a n/a 10%
There is much interest in the possibility of using transient elastography to identify fibrosis for patients with other types of liver diseases than hepatitis. In a study including 101 patients with primary biliary cirrhosis or primary sclerosing cholangitis, who were examined with both liver biopsy and elasticity measurements, a higher sensitivity and specificity to identify cirrhosis rather than moderate fibrosis (F4: sensitivity 0.93 and specificity 0.95; F2: sensitivity 0.84 and specificity 0.87) was demonstrated [31]. Furthermore, results from a study of the use of transient elastograph for diagnosing fibrosis for patients with NAFLD (nonalcoholic fatty liver disease) demonstrated the same accuracy between liver biopsy and stiffness values with an AUC (Area under the receiver operating curve) of 0.90 for F2 and 0.99 for F4 [32]. Recently, two studies describe high liver stiffness values for patients with acute hepatitis [33,34]. Sagir et al. described in one study that 75% of patients with acute hepatitis had a stiffness value of 12.5 kPa, indicating cirrhosis. 73% of these patients had a liver biopsy performed which for most patients showed fibrosis stage of F1 and a few with F2. None of the liver biopsies were classified as cirrhosis. Stiffness values decreased as the acute hepatitis phase finished [33]. 6. Discussion Most of the studies of transient elastography concentrate on the accuracy of diagnosing cirrhosis and fibrosis using liver biopsy as a reference. In a study of 10 000 liver biopsies, Bedossa demonstrated that only in 65% of the biopsies with a length of 15 mm and 75% of biopsies with a length of 25 mm the stage of fibrosis was correctly diagnosed [7]. Hence, when evaluating transient elastography studies, it should be noted, that a liver biopsy does not necessarily provide the definite truth. Most studies show that elastography measurements are more accurate in diagnosing severe fibrosis and cirrhosis than less or moderate fibrosis. This is important since F2 is a threshold for initiating treatment against viral hepatitis. FibroScan is not approved for examination of children, who have more narrow intercostal spaces than adults, but in 2008 a smaller probe for children was introduced and later this year a probe developed to obese patients is awaited (Jim Long, Mediplast, personal communication). Different studies suggest different cut-off values but so far there is no consensus on which values to use in practice. The vast majority of published studies have deducted an optimal cut-off from their study population after the trial. This will lead to over-fitting of the data and lower diagnostic accuracy is to be expected when these cut-offs are applied on different populations as was lately reported [35]. Furthermore, it is also still unclear whether fibrosis of different etiologies should be diagnosed with different cut-off values. Recently, it has been demonstrated that liver stiffness measurement is unsuitable for detecting fibrosis in patients with acute hepatitis [33,34]. There are speculations that measurement of liver stiffness in patients with chronic liver diseases may be misleading during intermittent flares in liver inflammation. This is still to be investigated.
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It is still unclear to which degree transient elastography may replace liver biopsies. Castera et al. suggested that 77% of all liver biopsies (among patients with viral hepatitis) could be avoided by the use of liver stiffness measurement combined with biomarkers [36]. 7. Conclusion Transient elastography is a promising new technique to assess liver fibrosis. It has a very high sensitivity and specificity especially in determining cirrhosis. The technique is likely to be introduced in the clinical work within the next few years and has the potential to replace the majority of liver biopsies for staging fibrosis among patients with known liver diseases. 8. Learning points • Liver biopsy is considered the “golden standard” in the assessment of hepatic fibrosis. • Liver biopsy has many drawbacks, including increased morbidity and mortality, sampling errors and intraobserver variability. • Elastography measures liver stiffness by a modified ultrasound technique. • Liver stiffness is correlated to the degree of liver fibrosis and cirrhosis. • Elastography has no discomfort or known side effect. Acknowledgments We thank Professor, Dr. med. Jens Ole Nielsen for highly valuable ideas and comments to this review article. References [1] Rojkind M, Greenwel P. Pathophysiology of liver fibrosis. In: Arias I, Boyer J, Chisari F, Fausto N, Schachter D, Shafritz D, editors. The Liver Biology and Pathobiology. Philadelphia: Lippencott Williams & Williams; 2001. p. 721–38. [2] WHO fact sheet, revised 2000. [3] Christensen P, Krarup H, Møller A, Laursen A, Kjaer M, Orholm M, et al. Liver biopsy performance and histological findings among patients with chronic viral hepatitis: A Danish Database study. Scand J Inf Dis 2006;39:245–9. [4] Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. Hepatol 1996;24:289–94. [5] Regev A, Berho M, Jeffers L, Milikowski C, Molina E, Pyrsopoulos N, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. A J Gastroenterol 2002;97(10):2613–8. [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;39:239–44. [7] Bedossa P, Dargére D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatol 2003;38:1449–57. [8] Groenbaek K, Christensen P, Hamilton-Dutait S, Federspiel B, Hage E, Jensen O, et al. Interobserver variation in interpretation of serial liver biopsies from patients with chronic hepatitis C. J Viral Hep 2002;9:443–9. [9] Bravo A, Sheth S, Chopra S. Liver biopsy. N Engl J Med 2001;344(7):495–500. [10] Manning D, Afdhal N. Diagnosis and quantitation of fibrosis. Gastroenterol 2008;134:1670–81. [11] Yeh W, Li P, Jeng Y, Hsu H, Kuo P, Li M, et al. Elastic modulus measurements of human liver and correlation with pathology. Ultra Med Bio 2002;28(4):467–74. [12] Sandrin L, Fourquet B, Hasquenoph J, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultra Med Bio 2003;29(12):1705–13. [13] Echosens. FibroScan Manual. Version 1.30; 2006. [14] Castéra L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008;48:835–47.
[15] Fraquelli M, Rigamonti C, Casazza G, Conte D, Donato M, Ronchi G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007;56:968–73. [16] Tatsumi C, Kudo M, Ueshima K, Kitai S, Takahashi S, Inoue T, et al. Noninvasive evaluation of hepatic fibrosis using serum fibrotic markers, transient elastography (FibroScan) and real-time tissue elastography. Intervirol 2008;51(Suppl 1):27–33. [17] Blanc J, Bioulac-Sage P, Balabaud C, Desmouliére A. Investigation of liver fibrosis in clinical practice. Hepatol Res 2005;32:1–8. [18] The Canadian Agency for Drugs and Technologies in Health (CADTH). Transient Elastography (FibroScan) for Non-invasive Assessment of Liver Fibrosis; 2006. [19] Ganne-Carrié N, Ziol M, de Lédinghen V, Douvin C, Marcellin P, Castéra L, et al. Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases. Hepatol 2006;44:1511–7. [20] Kim K, Choi W, Park S, Yu E, Lee S, Lim Y, et al. Diagnosis of hepatic steatosis and fibrosis by transient elastography in asymptomatic healthy individuals: a prospective study of living related potential liver donors. J Gastroenterol 2007;42:382–8. [21] Takeda T, Yasuda T, Nakayama Y, Nakaya M, Kimura M, Yamashita M, et al. Usefulness of noninvasive transient elastography for assessment of liver fibrosis stage in chronic hepatitis C. W J Gastroenterol 2006;12:7768–73. [22] Vergara S, Macias J, Rivero A, Gutiérrez-Valencia A, González-Serrano M, Merino D, et al. The use of transient elastometry for assessing liver fibrosis in patients with HIV and hepatitis C virus coinfection. CID 2007;45:969–74. [23] Foucher J, Chanteloup E, Vergniol J, Castéra L, Le Bail B, Adhoute X, et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006;55: 403–8. [24] Khohkar A, Farnan R, MacFarlane C, Bacon B, McHutchison J, Afdhal N. Liver stiffness and biomarkers: correlation with cirrhosis, portal hypertension and hepatic synthetic function. Hepatol 2005;42(Suppl 1):433A. [25] Friedrich-Rust M, Ong M, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a metaanalysis. Gastroenterol 2008;134:960–74. [26] Roulot D, Czernichow S, Le Clésiau H, Costes J, Vergnaud A, Beaugrand M. Liver stiffness values in apparently healthy subjects: influence of gender and metabolic syndrome. J Hepatol 2008;48:606–13. [27] Corpechot C, El Naggar A, Poupon R. Gender and liver: is the liver stiffness weaker in weaker sex? Hepatol 2006;44:513–4. [28] Marcellin P, de Lédinghen V, Dhumeaux D, Poupon R, Ziol M, Bedossa P. Noninvasive assessment of liver fibrosis in chronic hepatitis B using FibroScan. Hepatol 2005;42:715A–6A. [29] de Lédinghen V, Douvin C, Kettaneh A, Ziol M, Roulot D, Marcellin P, et al. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatic C viruscoinfected patients. J Acquir Immune Defic Syndr 2006;41:175–9. [30] Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatol 2005;41:48–54. [31] Corpechot C, El Naggar A, Poujol-Robert A, Ziol M, Wendum D, Chazouilléres O, et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatol 2006;43:1118–24. [32] Yoneda M, Yoneda M, Mawatari H, Fujita K, Endo H, Lida H, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). Dig Liv Dis 2008;40:371–8. [33] Sagir A, Erhardt A, Schmitt M, Häussinger D. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatol 2008;47: 592–5. [34] Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatol 2008;47: 380–4. [35] Mössner B, Jørgensen T, Skamling M, Pedersen C, Christensen P. Outreach screening of drug users with Fibroscan identifies a high proportion of severe fibrosis not previously recognized. J Hepatol 2008;48(Supl 2):S276. [36] Castéra L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterol 2005;128:343–50. [37] Blanc P, Gabbuti A, Marino N. Liver stiffness in chronic hepatitis C: will it modify the assessment of patients? J Hepatol 2007;46(Suppl 1):S201A. [38] Kettaneh A, Marcellin P, Douvin C, Poupon R, Ziol M, Beaugrand M, et al. Features associated with success rate and performance of fibroscan measurements for the diagnosis of cirrhosis in HCV patients: a prospective study of 935 patients. J Hepatol 2007;46:628–34.
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Review article
Transient elastography for liver fibrosis diagnosis Ellen Sloth Andersen a,⁎, Peer Brehm Christensen b, Nina Weis a a b
Department of Infectious Diseases, Hvidovre University Hospital, Denmark Department of Infectious Diseases, Odense University Hospital, Denmark
a r t i c l e
i n f o
Article history: Received 29 August 2008 Accepted 24 September 2008 Available online 11 November 2008 Keywords: Transient elastography FibroScan Viral hepatitis Fibrosis Cirrhosis
a b s t r a c t Liver biopsy is considered the “golden standard” for assessment of hepatic fibrosis. However, the procedure has limitations because of inconvenience and rare but serious complications as bleeding. Furthermore, sampling errors are frequent, and interobserver variability often poses problems. Recently, a modified ultrasound scanner (transient elastography) has been developed to assess fibrosis. The device measures liver elasticity, which correlates well with the degree of fibrosis. Studies have shown that transient elastography is more accurate in diagnosing cirrhosis than minor to moderate fibrosis. Most of the studies have been conducted on patients with chronic hepatitis but a few studies have also covered fibrosis and cirrhosis due to other etiologies, and they also demonstrate the high sensitivity and specificity. Transient elastography for assessment of fibrosis may turn out to be a valuable diagnostic procedure and follow-up of patients with chronic liver diseases. © 2008 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Fibrosis in the liver evolves as part of a healing process in response to liver damage. Among other causes, fibrosis can develop following a viral infection, alcohol abuse or drug intoxication. Liver cirrhosis is associated with increased morbidity and mortality [1]. WHO estimates that 350 million people are infected with chronic hepatitis B and 180 million with chronic hepatitis C [2]. Studies have shown that among patients chronically infected with hepatitis C, 50% develop fibrosis and 20% cirrhosis after a number of years [3]. Liver biopsy most commonly is used to determine the stage of fibrosis. Knowledge of the degree of liver fibrosis is important for the treatment of chronic hepatitis and diagnosis of cirrhosis is a prerequisite to prevent the various forms of complications. A new principle for diagnosis of fibrosis was recently introduced with a non-invasive, modified ultrasound device that measures elasticity in the liver (see Fig. 1). Several studies have shown that transient elastography in most cases can be used instead of liver biopsy to diagnose fibrosis. We here give a review of the latest progress in the field.
during the nineties as illustrated by the Metavir system with score from F0 to F4 (F0: no fibrosis; F4 cirrhosis) [4]. However liver biopsy is far from a perfect tool: Several studies indicate that sampling errors may have led to under-diagnosis of cirrhosis in 10–20% of the patients [5]. The smaller the biopsy size, the higher the risk for under-diagnosis of fibrosis or cirrhosis [6,7]. Furthermore, in interobserver studies pathologists disagree on fibrosis score in more than 20% of cases [8]. In addition, liver biopsy is an invasive procedure with a small but significant risk of morbidity and mortality. Pain and hypotension are the most frequent complications of the procedure. Intraperitoneal bleeding is considered the most serious complication. The mortality is about 1 in 10 000 [9]. For these reasons, patients may reject the procedure and thereby leaving their possible fibrosis undiagnosed. Performing liver biopsies generally has substantial socioeconomic cost, since the patients must be observed for bleeding after the procedure. For persons with bleeding disorders, percutaneous liver biopsy is often contraindicated. Multiple attempts have been made to substitute this invasive procedure with serological markers but none has gained universal acceptance. These markers are not covered by this article and the reader is referred to other review articles [10].
2. Liver biopsy Liver biopsy is the “golden standard” for fibrosis assessment. Numerical scoring systems for fibrosis graduation became accepted
⁎ Corresponding author. Department of Infectious Diseases, Hvidovre University Hospital, Kettegård Alle 30, DK-2650 Hvidovre, Denmark. Tel.: +45 36322695. E-mail address: [email protected] (E.S. Andersen).
3. Transient elastography The basic principle of transient elastography is that propagation velocity of a wave through a homogeneous tissue is proportional to its elasticity (stiffness). The elasticity has been demonstrated to correlate to the amount of fibrosis in the liver [11]. In technical terms liver elasticity, E, is a measure of the forces with which the tissue opposes dimensional change and is quantified by the
0953-6205/$ – see front matter © 2008 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2008.09.020
340
E.S. Andersen et al. / European Journal of Internal Medicine 20 (2009) 339–342
Fig. 1. The FibroScan instrument [13].
Young's modulus with the approximation that liver is a soft, isotropic, non-viscous medium: E = 3p × V
2
where p is the mass density (in liver tissue close to a constant) and V is the velocity [12]. The transducer is placed over the liver and transmits a low-frequency (50 Hz) wave that propagates through the liver and the velocity of the wave is then measured by pulse-echo ultrasound. If the liver is fibrotic, the elastic waves propagate more rapid than in a normal liver [12]. Fig. 2
shows elastograms illustrating the propagation of elastic waves in liver tissue for different stages of fibrosis, where the x-axis is time in ms and y-axis the depth of tissue. The inclination of the wave represents the velocity in the tissue [13]. Generally, ten valid measurements should be obtained to examine a patient with transient elastography. The median value of the ten valid measurements is considered as representative of liver elasticity. A measurement can be invalid if the transducer is held incorrectly, for example above a costae or the lung. The success rate is calculated as the number of valid measurements divided by the total number of measurements. Examinations with a success rate higher than 60% are considered reliable. The examination takes a few minutes and is without discomfort and known side effects for the patient [13]. The examination can be performed by paramedics and nurses after a 2 week training period of 25–50 examinations (Jim Long, Mediplast, personal communication). The elasticity is measured at a depth of 25 to 65 mm under the skin surface. The measurement volume has the form of a cylinder with a diameter of 1 cm and a length of 4 cm. This volume is at least 100 times the size of that used for a liver biopsy [14]. In 5–10% of patients, ten valid measurements cannot be obtained. Invalid measurements are generally due to overweight, narrow intercostal space and ascites. 25% of patients with a BMI N 30 cannot be scanned [14]. Studies have shown high intraobserver and interobserver agreement (interclass correlation coefficiency 0.96–0.98% and 0.89–0.98) [15]. Currently there is only one available liver stiffness measurement device: FibroScan® from the French company, Echosens, marketed since 2001. At the time of writing there are 250 machines globally. The price for the FibroScan Equipment is 88500€ (Jim Long, Mediplast, personal communication). Like other ultrasound equipments it has very low running cost except for calibration of the probe twice yearly. Lately results were published using a new device by Hitachi and it is hoped that competition will lead to better and cheaper hardware solutions [16]. The cost of a liver biopsy is reported to range from 703 to 1566€ in a hepatogastroenterologic department in a French Hospital with a one day observation period [17]. The cost per examination with FibroScan is reported to be around 100€ with 150 examinations annually [18]. However an important advantage of transient elastography is the possibility to repeat measurements with shorter intervals e.g. every year instead of the 5 year interval recommended for repeated biopsies. By performing more examinations the cost per measurement will be considerably lower. 4. Literature Results from the first study of transient elastography were published by Sandrin et al. in 2003. In total, 91 patients with chronic hepatitis C were examined with liver biopsy as well as liver elasticity
Fig. 2. Different velocities of the elastically propagating wave can be deducted from these three elastograms showing local strain of the tissue. The first elastogram corresponds to an elasticity of 3 kPa (no significant fibrosis), the next to an elasticity of 9 kPa (moderate fibrosis), and the third to an elasticity of 40 kPa (cirrhosis) [13].
E.S. Andersen et al. / European Journal of Internal Medicine 20 (2009) 339–342
341
Table 1 Results of eight studies from the use of the FibroScan technique for assessment of fibrosis as compared to liver biopsy[12,19,21,23,30,36–38]. Study Sandrin et al. Ziol et al. Castera et al. Foucher et al. Takeda et al. Ganne–Carrie et al. Blanc et al. Kettaneh et al.
Year 2003 2005 2005 2005 2006 2006 2007 2007
Included 91 327 193 758 287 1257 508 935
F2
F2
F4
F4
F2
F4
Sensitivity
Specificity
Sensitivity
Specificity
Auroc
Auroc
56% 67% 64%
91% 89% 85%
86% 87% 77%
96% 91% 97%
0.88 0.79 0.83 0.80 0.81
91%
87%
0.99 0.97 0.95 0.96 0.88 0.95 0.95 0.91
measurements. Twenty-four patients were excluded, five because 10 valid measurements could not be obtained, and 19 because the liver biopsies were not considered suitable for fibrosis grading. The study demonstrated good correlation between histological grading and liver elasticity. Transient elastography was 99% effective in detecting cirrhosis and 88% effective in detecting fibrosis [12]. Since the first study was published in 2003, many studies have followed, mostly in France but also in Italy, Japan, Spain, Singapore and USA [17,19–24]. Most studies have examined the correlation between liver elasticity and results from biopsies on hepatitis C patients. Results from some of the larger studies can be seen in Table 1. Ganne–Carrié et al. published in 2006 the largest study so far, examining the correlation between results from liver biopsy and elastography [19]. In total, 1257 patients with chronic liver diseases of various causes were examined with liver elasticity measurements and liver biopsy. The study exclusively focused on the use of transient elastography for diagnosis of cirrhosis. Of the patients included in the study, 132 patients (10.5%) had liver biopsies that were unsuitable for classification and 118 patients (9.3%) had unreliable liver stiffness measurements. The investigators found that optimal cut-off values were different for cirrhosis of different etiology. The optimal cut-off value regarding sensitivity and specificity for cirrhosis in hepatitis B patients was lower than for hepatitis C patients. Furthermore, the optimal cut-off value for patients with cirrhosis because of alcohol abuse or NASH was higher [19]. In a meta-analysis including 50 studies available from abstract or articles with inclusion criteria were comparison of transient elastography and liver biopsy and assessment of the area under the receiver operating characteristic curve (AUROC). In this large meta-analysis, optimal cut-off values were found to be 7.7 kPa for F2 of 13.0 kPa for F4 (cirrhosis) [25]. Roulot et al. published in 2008 a study of normal values for liver stiffness. 429 healthy persons were examined with FibroScan [26]. The study demonstrated that liver stiffness for 95% of all persons of normal weight and without metabolic syndrome was below 7.8 kPa for women and 8.0 kPa for men. An earlier study also suggested that men have a slightly higher liver stiffness than women [27]. 5. Fibrosis with other etiologies than hepatitis Most studies have focused on the correlation between liver stiffness measurements and biopsy in mono-infected patients with hepatitis C. However, in a study that included 220 patients with hepatitis B, Marcellin et al. have found the same accuracy for diagnosing fibrosis and cirrhosis [28]. Furthermore, two studies related to patients co-infected with HIV and hepatitis have also shown high sensitivity and specificity for detection of fibrosis and cirrhosis [22,29]. Vergara et al. found a specificity of 88% and sensitivity of 91% when diagnosing cirrhosis (cutoff value 14.6 kPa) on co-infected HIV/hepatitis C patients, and 83% sensitivity and 66% specificity on diagnosing significant fibrosis of grade F2 (cut-off 7.2 kPa) [22]. The correlation between liver stiffness values and liver biopsies does not seem to be affected by steatosis [30].
0.8 0.79
F0-1
F2-3
F4
40% 35% 26% 31% 57% n/a n/a 50%
46% 46% 49% 42% 30% n/a n/a 40%
14% 19% 25% 27% 13% n/a n/a 10%
There is much interest in the possibility of using transient elastography to identify fibrosis for patients with other types of liver diseases than hepatitis. In a study including 101 patients with primary biliary cirrhosis or primary sclerosing cholangitis, who were examined with both liver biopsy and elasticity measurements, a higher sensitivity and specificity to identify cirrhosis rather than moderate fibrosis (F4: sensitivity 0.93 and specificity 0.95; F2: sensitivity 0.84 and specificity 0.87) was demonstrated [31]. Furthermore, results from a study of the use of transient elastograph for diagnosing fibrosis for patients with NAFLD (nonalcoholic fatty liver disease) demonstrated the same accuracy between liver biopsy and stiffness values with an AUC (Area under the receiver operating curve) of 0.90 for F2 and 0.99 for F4 [32]. Recently, two studies describe high liver stiffness values for patients with acute hepatitis [33,34]. Sagir et al. described in one study that 75% of patients with acute hepatitis had a stiffness value of 12.5 kPa, indicating cirrhosis. 73% of these patients had a liver biopsy performed which for most patients showed fibrosis stage of F1 and a few with F2. None of the liver biopsies were classified as cirrhosis. Stiffness values decreased as the acute hepatitis phase finished [33]. 6. Discussion Most of the studies of transient elastography concentrate on the accuracy of diagnosing cirrhosis and fibrosis using liver biopsy as a reference. In a study of 10 000 liver biopsies, Bedossa demonstrated that only in 65% of the biopsies with a length of 15 mm and 75% of biopsies with a length of 25 mm the stage of fibrosis was correctly diagnosed [7]. Hence, when evaluating transient elastography studies, it should be noted, that a liver biopsy does not necessarily provide the definite truth. Most studies show that elastography measurements are more accurate in diagnosing severe fibrosis and cirrhosis than less or moderate fibrosis. This is important since F2 is a threshold for initiating treatment against viral hepatitis. FibroScan is not approved for examination of children, who have more narrow intercostal spaces than adults, but in 2008 a smaller probe for children was introduced and later this year a probe developed to obese patients is awaited (Jim Long, Mediplast, personal communication). Different studies suggest different cut-off values but so far there is no consensus on which values to use in practice. The vast majority of published studies have deducted an optimal cut-off from their study population after the trial. This will lead to over-fitting of the data and lower diagnostic accuracy is to be expected when these cut-offs are applied on different populations as was lately reported [35]. Furthermore, it is also still unclear whether fibrosis of different etiologies should be diagnosed with different cut-off values. Recently, it has been demonstrated that liver stiffness measurement is unsuitable for detecting fibrosis in patients with acute hepatitis [33,34]. There are speculations that measurement of liver stiffness in patients with chronic liver diseases may be misleading during intermittent flares in liver inflammation. This is still to be investigated.
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It is still unclear to which degree transient elastography may replace liver biopsies. Castera et al. suggested that 77% of all liver biopsies (among patients with viral hepatitis) could be avoided by the use of liver stiffness measurement combined with biomarkers [36]. 7. Conclusion Transient elastography is a promising new technique to assess liver fibrosis. It has a very high sensitivity and specificity especially in determining cirrhosis. The technique is likely to be introduced in the clinical work within the next few years and has the potential to replace the majority of liver biopsies for staging fibrosis among patients with known liver diseases. 8. Learning points • Liver biopsy is considered the “golden standard” in the assessment of hepatic fibrosis. • Liver biopsy has many drawbacks, including increased morbidity and mortality, sampling errors and intraobserver variability. • Elastography measures liver stiffness by a modified ultrasound technique. • Liver stiffness is correlated to the degree of liver fibrosis and cirrhosis. • Elastography has no discomfort or known side effect. Acknowledgments We thank Professor, Dr. med. Jens Ole Nielsen for highly valuable ideas and comments to this review article. References [1] Rojkind M, Greenwel P. Pathophysiology of liver fibrosis. In: Arias I, Boyer J, Chisari F, Fausto N, Schachter D, Shafritz D, editors. The Liver Biology and Pathobiology. Philadelphia: Lippencott Williams & Williams; 2001. p. 721–38. [2] WHO fact sheet, revised 2000. [3] Christensen P, Krarup H, Møller A, Laursen A, Kjaer M, Orholm M, et al. Liver biopsy performance and histological findings among patients with chronic viral hepatitis: A Danish Database study. Scand J Inf Dis 2006;39:245–9. [4] Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. Hepatol 1996;24:289–94. [5] Regev A, Berho M, Jeffers L, Milikowski C, Molina E, Pyrsopoulos N, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. A J Gastroenterol 2002;97(10):2613–8. [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;39:239–44. [7] Bedossa P, Dargére D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatol 2003;38:1449–57. [8] Groenbaek K, Christensen P, Hamilton-Dutait S, Federspiel B, Hage E, Jensen O, et al. Interobserver variation in interpretation of serial liver biopsies from patients with chronic hepatitis C. J Viral Hep 2002;9:443–9. [9] Bravo A, Sheth S, Chopra S. Liver biopsy. N Engl J Med 2001;344(7):495–500. [10] Manning D, Afdhal N. Diagnosis and quantitation of fibrosis. Gastroenterol 2008;134:1670–81. [11] Yeh W, Li P, Jeng Y, Hsu H, Kuo P, Li M, et al. Elastic modulus measurements of human liver and correlation with pathology. Ultra Med Bio 2002;28(4):467–74. [12] Sandrin L, Fourquet B, Hasquenoph J, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultra Med Bio 2003;29(12):1705–13. [13] Echosens. FibroScan Manual. Version 1.30; 2006. [14] Castéra L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008;48:835–47.
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