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ESPS Manuscript NO: 111
Columns: REVIEW
Clinical application of liver stiffness measurement using transient elastography in chronic liver disease from longitudinal perspectives
Kim BK et al. Longitudinal aspects of transient elastography
Beom Kyung Kim, James Fung, Man-Fung Yuen, Seung Up Kim
Beom Kyung Kim, Seung Up Kim, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 120-740, South Korea
Beom Kyung Kim, Seung Up Kim, Liver Cirrhosis Clinical Research Center, Seoul 120-740, South Korea
James Fung, Man-Fung Yuen, Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
Author contribution: Kim BK and Kim SU contributed to the study idea, study design, literature search, manuscript writing and final revision of the article; Fung J and Yuen MF contributed to manuscript writing and final revision of the article.
Supported by Liver Cirrhosis Clinical Research Center, in part by a grant from the Korea Healthcare technology R and D project, Ministry of Health and Welfare, Republic of Korea (No A102065), and by the Yonsei Liver Blood Bank (YLBB), in part by a grant from sanofi-aventis Korea.
Correspondence to: Seung Up Kim, MD, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemungu, Seoul 120752, South Korea. HYPERLINK "mailto:ksukorea@yuhs.ac" ksukorea@yuhs.ac
Telephone: +82222281982 Fax: +8223936884
Received: August 10, 2012 Revised: August 29, 2012
Accepted:
Published online:
Abstract
Accurate determination of the presence and degree of fibrosis in liver is of great importance, because the prognosis and management strategies for chronic liver disease depend mainly on these factors. To date, liver biopsy (LB) remains the gold standard for assessing the severity of liver fibrosis; however, LB is often limited by its invasiveness, sampling error, and intra/inter-observer variability in histological interpretation. Furthermore, repeated LB examinations within a short time interval are indeed ineligible in a real clinical practice. Thus, due to the pressing need for non-invasive surrogates for liver fibrosis, transient elastography (TE), as a novel ultrasound based technology, has allowed a noninvasive measurement of liver stiffness and has gained in popularity over recent years. In the past few years, additional roles for transient TE beyond the initial purpose of a non-invasive surrogate for LB have included the prediction of the most two critical consequences of fibrosis progression: the development of portal hypertension-related complications and hepatocellular carcinoma. This indicates that the role of transient TE is not merely limited to reducing the need for LB, but transient TE can enable the establishment of tailored management strategies by providing more detailed prognostic information. In particular, under the concept in which the clinical course of liver fibrosis is dynamic and bidirectional, especially when appropriate intervention is commenced, transient TE can be used to track the dynamic changes in fibrotic burden during antiviral or antifibrotic treatment. This review discussed extended applications of transient TE in prediction of the development of real clinical endpoints from a longitudinal perspective.
2012 Baishideng. All rights reserved.
Key words: Liver stiffness; Transient elastography; Fibroscan; Fibrosis; Longitudinal; Outcome
Kim BK, Fung J, Yuen MF, Kim SU. Clinical application of liver stiffness measurement using transient elastography in chronic liver disease from longitudinal perspectives. World J Gastroenterol 2012; 18
Available from: URL: http://www.wjgnet.com/1007-9327/full/v18/
DOI: http://dx.doi.org/10.3748/wjg.v18.
INTRODUCTION
The prognosis and management of chronic liver disease (CLD) depend mainly on the amount and progression of liver fibrosis, which is defined as the excessive accumulation of extracellular matrix proteins, resulting from chronic liver insults ADDIN EN.CITE ADDIN EN.CITE.DATA [1, 2]. The initiation of its deposition is an important phase of CLD. As liver fibrosis eventually progresses without appropriate intervention, this process will lead to architectural change of the liver, followed by deterioration of liver function and hemodynamics, complications due to portal hypertension, and an increased tendency for hepatocarcinogenesis ADDIN EN.CITE Pungpapong200744444417Pungpapong, S.Kim, W. R.Poterucha, J. J.Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.Natural history of hepatitis B virus infection: an update for cliniciansMayo Clin ProcMayo Clin Proc967-758282007/08/04AdultAntiviral Agents/therapeutic useCarcinoma, Hepatocellular/virologyCarrier State/virologyHepatitis B/immunology/ physiopathologyHepatitis B Surface Antigens/analysisHepatitis B e Antigens/analysisHepatitis B virus/immunology/physiologyHepatitis B, Chronic/immunology/physiopathologyHumansImmune Tolerance/immunologyInfantInfant, NewbornLiver Cirrhosis/virologyLiver Neoplasms/virologyVirus Replication/immunology/physiology2007Aug0025-6196 (Print)
0025-6196 (Linking)17673066S0025-6196(11)61339-6 [pii]
10.4065/82.8.967 [doi]eng[3].
Thus, accurate determination of the presence and degree of liver fibrosis is of paramount importance in choosing treatment strategies, evaluating responses to treatment and the risks of developing liver-related complications, and predicting prognosis in patients with CLD. To assess the severity of liver fibrosis, liver biopsy (LB) remains the gold standard. However, LB is often limited by its invasiveness and rare, but serious, complications, including bleeding, pneumothorax, and procedure-related death ADDIN EN.CITE ADDIN EN.CITE.DATA [4, 5]. Moreover, repeated LB examinations within a short time interval are impractical. Additionally, concerning the reliability of pathological examinations, not only sampling error inherent in the percutaneous approach, but also intra- and inter-observer variability in histological interpretation may still occur ADDIN EN.CITE Regev200219191917Regev, A.Berho, M.Jeffers, L. J.Milikowski, C.Molina, E. G.Pyrsopoulos, N. T.Feng, Z. Z.Reddy, K. R.Schiff, E. R.Division of Hepatology, Center for Liver Diseases, University of Miami School of Medicine, Florida 33136, USA.Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infectionAm J GastroenterolAm J Gastroenterol2614-897102002/10/19AdultAgedBiopsy, NeedleFemaleFibrosisHepatitis C, Chronic/ pathologyHumansInflammationLiver/ pathologyMaleMiddle AgedObserver VariationSpecimen Handling2002Oct0002-9270 (Print)
0002-9270 (Linking)1238544810.1111/j.1572-0241.2002.06038.x [doi]eng[6]. Even if the LB is performed by an experienced physician and interpreted by an expert pathologist, it has an up to 20% error rate in disease staging ADDIN EN.CITE ADDIN EN.CITE.DATA [7, 8].
Ideally, a method of evaluating liver fibrosis should accurately determine the presence of significant fibrosis, and be readily available, highly reproducible, and widely applicable to liver diseases of various etiologies. Although LB does not fulfil all these criteria, it has remained the gold standard, likely due to the absence of a better alternative. Recently, liver stiffness measurement using transient elastography (TE) was introduced as a promising non-invasive method for assessment of liver fibrosis ADDIN EN.CITE ADDIN EN.CITE.DATA [9-15]. In many studies, TE proved to be a reliable and accurate surrogate for LB in terms of prediction of significant fibrosis or cirrhosis ADDIN EN.CITE ADDIN EN.CITE.DATA [8, 16-19]. In a large-scale meta-analysis including 50 studies, the mean areas under the receiver operating characteristic curves (AUROCs) for the diagnosis of significant fibrosis and cirrhosis were 0.84 and 0.94, respectively, with optimal cutoff values of 7.6 and 13.1 kPa, respectively ADDIN EN.CITE ADDIN EN.CITE.DATA [20].
Most studies to date have focused on assessing the performance of TE, reflected by AUROC, from a cross-sectional perspective, with reference to histological fibrosis. However, because LB as a reference standard is imperfect, it may have only limited clinical implications in terms of increasing the AUROC of TE to 1 (i.e., perfect concordance with LB). Thus, additional roles for TE, namely prediction of long-term prognosis of the disease and monitoring clinical courses, have recently begun to attract attention. This indicates that the role of TE is not merely limited to lessening the frequency of unnecessary LB, but TE can also enable establishment of tailored management strategies by providing more detailed prognostic information ADDIN EN.CITE Kim201011117Kim, S. U.Han, K. H.Ahn, S. H.Non-invasive assessment of liver fibrosis: time to move from cross-sectional studies to longitudinal onesJ Gastroenterol HepatolJ Gastroenterol Hepatol1472-32592010/08/28Biological Markers/bloodBiopsyClinical Enzyme TestsCross-Sectional StudiesElasticity Imaging TechniquesEsophageal and Gastric Varices/diagnosis/virologyHepatitis B, Chronic/complicationsHepatitis C, Chronic/complicationsHumansHypertension, Portal/diagnosis/virologyLiver/enzymology/ pathology/virologyLiver Cirrhosis/blood/ diagnosis/pathology/virologyLongitudinal StudiesPlatelet CountPredictive Value of TestsPrognosisResearch DesignSeverity of Illness Index2010Sep1440-1746 (Electronic)
0815-9319 (Linking)20796140JGH6432 [pii]
10.1111/j.1440-1746.2010.06432.x [doi]eng[21]. In this regard, the classical end-points of static liver fibrosis in recent cross-sectional studies on TE are shifting to the real and solid end-points of the development of clinical events related to liver fibrosis progression, including hepatic decompensation, hepatocellular carcinoma (HCC), or liver-related death in a longitudinal study from a prospective cohort with long-term follow-up. Additionally, the performance of non-invasive methods is being judged and compared from this viewpoint.
In this article, we reviewed recent studies that focused on the prognostic value of TE for prediction of clinical end-points related to liver fibrosis progression, such as decompensation events, HCC development, or liver-related death, from a longitudinal perspective.PREDICTION OF THE DEVELOPMENT OF LIVER-RELATED COMPLICATIONS
Portal hypertension-related complications
The development of portal hypertension is a common consequence of fibrosis progression, leading to the formation of esophageal and gastric varices responsible for variceal bleeding, and other severe complications, such as portosystemic encephalopathy, spontaneous bacterial peritonitis and sepsis ADDIN EN.CITE ADDIN EN.CITE.DATA [22-24]. Measurement of the hepatic venous pressure gradient (HVPG) is the gold standard for portal hypertension assessment in patients with cirrhosis; however, it is invasive and is routinely available only in experienced centers ADDIN EN.CITE ADDIN EN.CITE.DATA [25-29]. Although TE was initially proposed for assessment of l i v e r b r o s i s , a g o o d c o r r e l a t i o n b e t w e e n T E v a l u e s a n d H V P G h a s b e e n r e p o r t e d , a s w e l l a s t h e p r e s e n c e o f e s o p h a g e a l v a r i c e s , s u g g e s t i n g t h a t i t m a y b e a v a l u a b l e t o o l f o r t h e n o n - i n v a s i v e e v a l u a t i o n o f p o r t a l h y p e r t e n s i o n A D D I N E N . C I T E A D D I N E N . C I T E . D ATA [30-32]. Subsequent studies have investigated correlations between TE values and the hepatic decompensation due to increased portal hypertension. A significant correlation between TE values and portal hypertension, expressed as the HVPG, was reported by Vizzutti et al ADDIN EN.CITE Vizzutti200754545417Vizzutti, F.Arena, U.Romanelli, R. G.Rega, L.Foschi, M.Colagrande, S.Petrarca, A.Moscarella, S.Belli, G.Zignego, A. L.Marra, F.Laffi, G.Pinzani, M.Dipartimento di Medicina Interna, Center for Research, Higher Education and Transfer DENOThe, Firenze, Italy.Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosisHepatologyHepatology1290-74552007/04/28AdultAgedDiagnostic Techniques, Digestive System/adverse effectsElasticityEsophageal and Gastric Varices/diagnosisFemaleHepatic VeinsHepatitis C, Chronic/ complicationsHumansHypertension, Portal/ diagnosisLiver/ physiopathologyLiver Cirrhosis/ complications/physiopathologyMaleMiddle AgedRegression Analysis2007May0270-9139 (Print)
0270-9139 (Linking)1746497110.1002/hep.21665 [doi]eng[33] suggesting that TE may reflect a progressive rise in portal pressure due primarily to increased hepatic vascular resistance, caused by fibrillar extracellular matrix accumulation. Based on this concept, Foucher et al ADDIN EN.CITE Foucher200653535317Foucher, J.Chanteloup, E.Vergniol, J.Castera, L.Le Bail, B.Adhoute, X.Bertet, J.Couzigou, P.de Ledinghen, V.Service d'Hepato-Gastroenterologie, Hopital Haut Leveque, Avenue Magellan, 33604 Pessac, France.Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective studyGutGut403-85532005/07/16AdultAgedBiopsyElasticityFemaleHumansLiver Cirrhosis/ diagnosis/etiology/pathologyMaleMiddle AgedProspective StudiesROC CurveSeverity of Illness IndexStatistics, NonparametricVibration2006Mar0017-5749 (Print)
0017-5749 (Linking)16020491gut.2005.069153 [pii]
10.1136/gut.2005.069153 [doi]eng[34] first reported that cutoff values of 27.5, 37.5, 49.1, 53.7, and 62.7 kPa had > 90% negative predictive values for the presence of large esophageal varices (stage 2/3), Child-Pugh score B or C, past history of ascites, HCC, and esophageal bleeding, respectively.
As variceal bleeding is a life-threatening complication of portal hypertension, the relationship between TE values and the presence of esophageal varices has been investigated in several studies ADDIN EN.CITE ADDIN EN.CITE.DATA [35-40]. All demonstrated a significant correlation between TE values and the presence of esophageal varices and that TE values could predict the presence of large varices (more than grade 2) ADDIN EN.CITE ADDIN EN.CITE.DATA [38, 40]. Table 1 summarizes reports of the relationship between TE values and esophageal varices ADDIN EN.CITE ADDIN EN.CITE.DATA [33, 38, 40-44].
Although TE can predict the presence of esophageal varices and consequently assist in selection of candidates for endoscopic screening or prophylactic treatment, several issues remain unresolved. First, the cutoff values (range, 13.9-21.5 kPa) and performance of TE varied (AUROC range, 0.76-0.85) among studies ADDIN EN.CITE ADDIN EN.CITE.DATA [38-40]. Second, from data c u r r e n t l y a v a i l a b l e , d i a g n o s t i c p e r f o r m a n c e s o f T E a r e a c c e p t a b l e f o r t h e p r e d i c t i o n o f e s o p h a g e a l v a r i c e s , b u t f a r f r o m s a t i s f a c t o r y f o r s c r e e n i n g c i r r h o t i c p a t i e n t s w i t h o u t e n d o s c o p y c o n d e n t l y . T h u s , K i m e t a l A D D I N E N . C I T E <