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      Liver Stiffness Measurement among Patients with Chronic Hepatitis B and C: Results from a 5-Year Prospective Study

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          Abstract

          Liver stiffness measurement (LSM) is widely used to evaluate liver fibrosis, but longitudinal studies are rare. The current study was aimed to monitor LSM during follow-up, and to evaluate the association of LSM data with mortality and liver-related outcomes. We included all patients with chronic viral hepatitis and valid LSM using Fibroscan. Information about liver biopsy, antiviral treatment, and clinical outcome was obtained from medical records and national registers. The study included 845 patients: 597 (71%) with hepatitis C virus (HCV), 235 (28%) with hepatitis B virus (HBV) and 13 (2%) with dual infection. The initial LSM distribution (<7/7–9.9/10–16.9/≥17 kPa) was 58%/16%/14%/12%. Among patients with initial LSM values of 7–9.9 kPa, 60% of HCV patients and 83% of HBV patients showed LSM values of <7 kPa at the latest follow-up. Progression rates (defined as >20% and >2 kPa increase, with one measure >7 kPa) were 3.4/100 person years (PY) for HCV and 1.5/100 PY for HBV infected patients. Patients with LSM values of ≥17 kPa had the same liver-related complication incidence as patients with biopsy-proven cirrhosis (11.1 versus 12.1/100 PY). Thirteen liver-related deaths occurred among HCV patients (0.6/100 PY), but none among HBV patients. Among patients who died of liver-related causes, all but one had baseline LSM values of ≥17 kPa. Overall, patients with LSM values <17 kPa were not associated with adverse outcomes. In contrast, LSM values ≥17 kPa were associated with significant risk of liver-related problems. The results of the current study suggest that clinical decisions should not be taken based on a single LSM measurement.

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          Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy.

          Transient elastography is a non-invasive method, for the assessment of hepatic fibrosis, developed as an alternative to liver biopsy. We studied the performance of elastography for diagnosis of fibrosis using meta-analysis. MEDLINE, EMBASE, SCI, Cochrane Library, conference abstracts books, and article references were searched. We included studies using biopsy as a reference standard, with the data necessary to calculate the true and false positive, true and false negative diagnostic results of elastography for a fibrosis stage, and with a 3-month maximum interval between tests. The quality of the studies was rated with the QUADAS tool. We identified 40 eligible studies. Summary sensitivity and specificity was 0.79 (95% CI 0.74-0.82) and 0.78 (95% CI 0.72-0.83) for F2 stage and 0.83 (95% CI 0.79-0.86) and 0.89 (95% CI 0.87-0.91) for cirrhosis. After an elastography result at/over the threshold value for F2 or cirrhosis ("positive" result), the corresponding post-test probability for their presence (if pre-test probability was 50%) was 78%, and 88% respectively, while, if values were below these thresholds ("negative" result), the post-test probability was 21% and 16%, respectively. No optimal stiffness cut-offs for individual fibrosis stages were validated in independent cohorts and cut-offs had a wide range and overlap within and between stages. Elastography theoretically has good sensitivity and specificity for cirrhosis (and less for lesser degrees of fibrosis); however, it should be cautiously applied to everyday clinical practice because there is no validation of the stiffness cut-offs for the various stages. Such validation is required before elastography is considered sufficiently accurate for non-invasive staging of fibrosis. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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            Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases.

            Liver stiffness was measured by transient elastography (FibroScan) in 228 consecutive patients with chronic viral hepatitis, with (115) or without cirrhosis (113), to study its correlations with serum transaminases [alanine aminotransferase (ALT)], fibrosis stage and surrogate noninvasive markers of fibrosis (APRI, FORNS, FibroTest and hyaluronic acid). The dynamic profiles of serum transaminases and liver stiffness were compared by multiple testing in 31 patients during a 6-month follow-up. We identified 8.3 and 14 kPa as the fibrosis >/=F2 and cirrhosis cut-offs, respectively: their sensitivities were 85.2%/78.3%; specificities 90.7%/98.2%; positive predictive values 93.9%/97.8%; negative predictive values 78.8%/81.6%; diagnostic accuracies 87.3%/88.2%. FibroScan performed better than the other surrogate markers of fibrosis (P < 0.001). Other than fibrosis, other factors independently associated with liver stiffness were ALT for all patients and chronic hepatitis patients (P < 0.001), and 12-month persistently normal ALT (biochemical remission, P < 0.001) in cirrhotics. In patients with biochemical remission either spontaneous or after antiviral therapy (48 of 228, 21%), liver stiffness was lower than in patients with identical fibrosis stage, but elevated ALT (P < 0.001). The liver stiffness dynamic profiles paralleled those of ALT, increasing 1.3- to 3-fold during ALT flares in 10 patients with hepatitis exacerbations. Liver stiffness remained unchanged in 21 with stable biochemical activity (P = 0.001). In conclusion, transient elastography is a new liver parameter that behaves as a reliable surrogate marker of fibrosis in chronic viral hepatitis patients, provided that its relationship with major changes of biochemical activity is taken into account.
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              Liver stiffness is directly influenced by central venous pressure.

              Liver stiffness (LS) as measured by transient elastography [Fibroscan] offers a novel non-invasive approach to assess liver cirrhosis. Since Fibroscan seems to be unreliable in patients with congestive heart failure, it remains to be determined whether hemodynamic changes affect LS irrespective of fibrosis. Using landrace pigs, we studied the direct relationship between the central venous pressure and LS measured by Fibroscan. Clamping of the inferior caval vein increased LS from 3.1 to 27.8kPa while reopening reversed LS within 5min to almost normal values of 5.1kPa. We then studied LS as a function of venous pressure in the isolated pig liver by clamping the upper and lower caval, portal vein and hepatic artery. The stepwise increase of intravenous pressure to 36cm of water column (3.5kPa) linearly and reversibly increased LS to the upper detection limit of 75kPa. We finally measured LS in 10 patients with decompensated congestive heart failure before and after recompensation. Initial LS was elevated in all patients, in 8 of them to a degree that suggested liver cirrhosis (median 40.7kPa). Upon recompensation with a median weight loss of 3.0kg, LS decreased in all 10 patients down to a median LS of 17.8kPa. Inflammation could not account for increased LS since initial liver enzyme counts were only slightly elevated and did not change significantly. LS is a direct function of central venous pressure which should be considered when assessing the degree of fibrosis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                4 November 2014
                : 9
                : 11
                : e111912
                Affiliations
                [1]Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
                Kanazawa Medical University, Japan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: KC CP PBC. Performed the experiments: KC BKM JFH EFJ PBC. Analyzed the data: KC BKM JFH EFJ CP PBC. Wrote the paper: KC BKM JFH EFJ CP PBC.

                Article
                PONE-D-14-15328
                10.1371/journal.pone.0111912
                4219798
                25369038
                0f3e589d-55a2-40d9-ac9a-402912cde408
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 April 2014
                : 27 August 2014
                Page count
                Pages: 8
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Biology and Life Sciences
                Plant Science
                Plant Pathology
                Infectious Disease Epidemiology
                Medicine and health sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Gastrointestinal Imaging
                Liver and Spleen Scan
                Epidemiology
                Biomarker Epidemiology
                Cancer Epidemiology
                Clinical Epidemiology
                Disease Dynamics
                Natural History of Disease
                Gastroenterology and hepatology
                Liver diseases
                Infectious hepatitis
                Hepatitis B
                Hepatitis C
                Chronic Liver Disease
                Cirrhosis
                Hepatocellular Carcinoma
                Liver Fibrosis
                Portal Hypertension
                Research and Analysis Methods
                Imaging Techniques
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. According to Danish legislation, before the data can be delivered, an applicant will need to apply to the URL below to obtain permission to receive the data. http://www.datatilsynet.dk/erhverv/forskere-og-medicinalfirmaer/standard-terms-for-research-projects/ for researchers who meet the criteria for access to confidential data.

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