Beyond Confounders: Addressing Source of Measurement Variability and Error in Shear Wave Elastography

Beyond Confounders: Addressing Source of Measurement Variability and Error in Shear Wave Elastography

Beyond Confounders: Addressing Source of Measurement Variability and Error in Shear Wave Elastography

Chronic liver disease is a major problem in the general population and there is an unmet need to diagnose(and screen) for liver disease with using noninvasive, cost-effective and sensitive techniques.The investigators hypothesize that variation using ultrasound elastography for the estimation of stage of liver fibrosis and steatosis in patients with diffuse liver disease exists due to different methods of measurements, and/or different systems. The proposed investigation is a cross-sectional study using ultrasound elastography and fat quantification modalities. The investigators are planning to enroll 30 subjects 18 years old and older in whom diffuse liver disease is suspected, and who have undergone non-focal liver biopsy in the past 6 months or are scheduled to undergo biopsy within 3 months of enrollment, as part of their routine clinical care. The investigators will use 4 different ultrasound devices with their shear wave elastography and speed of sound functions. Specific aims; Compare shear wave elastography(SWE) measurements from different ultrasound systems; using histopathology as reference standards. Assess intra-operator and inter-operator reliability by measuring variability in elastography values by two operators on a single system. Determine the effect of deviations from guidelines(less number of measurements and measurements during active breath)

Liver disease and cirrhosis are important causes of morbidity and mortality in the United States and are a major public health problem with 40,000 deaths and more than 1.4 billion dollars spent on medical services. Hepatic fibrosis is the final common pathway for many different liver insults and is known to be a dynamic process, which is reversible if diagnosed early and treated. If untreated, fibrosis eventually progresses to cirrhosis, which is irreversible. The diagnosis of fibrosis relies on liver biopsy (the gold standard) however, is an invasive procedure with risks and sampling errors. Indirect biomarkers of fibrogenesis can measure some of these components to determine categories of fibrosis, with a sensitivity and specificity of 47% and 90% respectively.It is shown in the literature that, fat content of liver is related with fibrosis development. Biopsy is accepted as the most accurate technique to assess liver fat and fibrosis amount. Fibrotic livers demonstrate increased stiffness, a property that can be measured using technology named Ultrasound Elastography or sonoelastography (SWE). SWE is performed by insonating the patient with a low energy, amplitude, and frequency shear wave created by a vibrating probe. The propagated wave travels faster with increasing fibrosis: the stiffer the tissue, the faster the shear wave propagates. A pulse-echo ultrasound acquisition allows measurement of the wave velocity and the results are presented as kilopascals (kPa). Prior reports have described sensitivity and specificity for liver fibrosis detection of 80% and 97% respectively for SWE. The benefits of SWE are that it is inexpensive, reproducible, painless, rapid (< 10 min), easy to perform, and can be used for diagnosis, prognosis and monitoring disease progression. The objective of this study is to compare the variation in elastography values and study the factors that might cause these variations. The proposed investigation is a cross-sectional study using ultrasound elastography. The investigators are planning to enroll 30 subjects 18 years old and older in whom diffuse liver disease is suspected, and who have undergone non-focal liver biopsy in the past 6 months or are scheduled to undergo biopsy within 3 months of enrollment, as part of their routine clinical care. All subjects will be required to come to the MGH main campus for 2 study visits within 60 days of each other. In addition, subjects will need to fast for at least 4 hours prior to study visits There will be two visits in this study and maximum 60 days time frame between the visits is anticipated. Two operators will perform the ultrasound examination. Reproducibility and repeatability of the ultrasound devices will be estimated. Ultrasound examination including sonoelastography will be performed using four FDA-approved ultrasound units; Both operators will perform; Median Elastograpy (10 measurements) on regular and variable map at a depth(in the area between 2cm from capsule and 6.5cm from skin) Median SWE value with active/free breath(10measurements) Median SWE value with less number of acquisitions(3measurements) These measurements will be collected in subgroups using specific systems. In second visit, all measurements will be repeated with the same operators.

We collected guideline suggested shear wave elastography measurements from 20 patients. Guidelines suggest collecting 1) 10 measurements, 2) Asking patient to hold breath during the measurements. As a deviation from guideline suggestions, we collected measurements during free breath movements without asking patient to hold breath. As a deviation from the guideline suggestions, fewer number of measurements (3 measurements) were collected with asking the patient to hold breath during the measurements. All measurements were collected using one type of ultrasound system. All measurements were collected by 2 operators in 2 visits.

In 20 patients we collected 10 shear wave elastography measurements in m/s and kPA units. Using one of the available ultrasound systems, 2 operators collected these measurements in 2 visits. Theoretically, m/s to kPA conversion can be made using an equation. However, some systems provide opportunity to get data in both units. Although algebraically m/s and kPA can be converted to each other, we found some minor differences in terms of inter-operator and intra-operator agreement.

Inclusion Criteria: Adult Patients Men or Woman Suspected diffuse liver disease and have had a liver biopsy within the last 6 months or are scheduled for a liver biopsy in the next 3 months. Consent to participate in the study Exclusion Criteria: Pregnancy Acute illness/ cognitive impairment resulting in inability to cooperate with ultrasound Patients that do not consent to ultrasound examination

Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, Srishord M. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011 Jun;9(6):524-530.e1; quiz e60. doi: 10.1016/j.cgh.2011.03.020. Epub 2011 Mar 25.

Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH, Stanaway J, Murray CJ, Naghavi M. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med. 2014 Sep 18;12:145. doi: 10.1186/s12916-014-0145-y.

Pinzani M, Rombouts K. Liver fibrosis: from the bench to clinical targets. Dig Liver Dis. 2004 Apr;36(4):231-42. doi: 10.1016/j.dld.2004.01.003. Erratum In: Dig Liver Dis. 2004 Aug;36(8):562-3.

Scholmerich J, Holstege A. Aetiology and pathophysiology of chronic liver disorders. Drugs. 1990;40 Suppl 3:3-22. doi: 10.2165/00003495-199000403-00003.

Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014 Mar;14(3):181-94. doi: 10.1038/nri3623.

Actis GC, Olivero A, Lagget M, Pellicano R, Smedile A, Rizzetto M. The practice of percutaneous liver biopsy in a gastrohepatology day hospital: a retrospective study on 835 biopsies. Dig Dis Sci. 2007 Oct;52(10):2576-9. doi: 10.1007/s10620-006-9724-x. Epub 2007 Apr 12.

Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology. 2000 Sep;32(3):477-81. doi: 10.1053/jhep.2000.16602.

van der Poorten D, Kwok A, Lam T, Ridley L, Jones DB, Ngu MC, Lee AU. Twenty-year audit of percutaneous liver biopsy in a major Australian teaching hospital. Intern Med J. 2006 Nov;36(11):692-9. doi: 10.1111/j.1445-5994.2006.01216.x.

Sparchez Z. Complications after percutaneous liver biopsy in diffuse hepatopathies. Rom J Gastroenterol. 2005 Dec;14(4):379-84.

Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001 Feb 15;344(7):495-500. doi: 10.1056/NEJM200102153440706. No abstract available.

Rousselet MC, Michalak S, Dupre F, Croue A, Bedossa P, Saint-Andre JP, Cales P; Hepatitis Network 49. Sources of variability in histological scoring of chronic viral hepatitis. Hepatology. 2005 Feb;41(2):257-64. doi: 10.1002/hep.20535.

Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, Feng ZZ, Reddy KR, Schiff ER. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002 Oct;97(10):2614-8. doi: 10.1111/j.1572-0241.2002.06038.x.

Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003 Dec;38(6):1449-57. doi: 10.1016/j.hep.2003.09.022.

Friedrich-Rust M, Buggisch P, de Knegt RJ, Dries V, Shi Y, Matschenz K, Schneider MD, Herrmann E, Petersen J, Schulze F, Zeuzem S, Sarrazin C. Acoustic radiation force impulse imaging for non-invasive assessment of liver fibrosis in chronic hepatitis B. J Viral Hepat. 2013 Apr;20(4):240-7. doi: 10.1111/j.1365-2893.2012.01646.x. Epub 2012 Jul 31.

Fierbinteanu-Braticevici C, Andronescu D, Usvat R, Cretoiu D, Baicus C, Marinoschi G. Acoustic radiation force imaging sonoelastography for noninvasive staging of liver fibrosis. World J Gastroenterol. 2009 Nov 28;15(44):5525-32. doi: 10.3748/wjg.15.5525.

Ferraioli G, Tinelli C, Dal Bello B, Zicchetti M, Filice G, Filice C; Liver Fibrosis Study Group. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology. 2012 Dec;56(6):2125-33. doi: 10.1002/hep.25936. Epub 2012 Aug 31.

Poynard T, Munteanu M, Luckina E, Perazzo H, Ngo Y, Royer L, Fedchuk L, Sattonnet F, Pais R, Lebray P, Rudler M, Thabut D, Ratziu V. Liver fibrosis evaluation using real-time shear wave elastography: applicability and diagnostic performance using methods without a gold standard. J Hepatol. 2013 May;58(5):928-35. doi: 10.1016/j.jhep.2012.12.021. Epub 2013 Jan 12.

Chen S, Sanchez W, Callstrom MR, Gorman B, Lewis JT, Sanderson SO, Greenleaf JF, Xie H, Shi Y, Pashley M, Shamdasani V, Lachman M, Metz S. Assessment of liver viscoelasticity by using shear waves induced by ultrasound radiation force. Radiology. 2013 Mar;266(3):964-70. doi: 10.1148/radiol.12120837. Epub 2012 Dec 6.

Goertz RS, Zopf Y, Jugl V, Heide R, Janson C, Strobel D, Bernatik T, Haendl T. Measurement of liver elasticity with acoustic radiation force impulse (ARFI) technology: an alternative noninvasive method for staging liver fibrosis in viral hepatitis. Ultraschall Med. 2010 Apr;31(2):151-5. doi: 10.1055/s-0029-1245244. Epub 2010 Mar 19.

Takahashi H, Ono N, Eguchi Y, Eguchi T, Kitajima Y, Kawaguchi Y, Nakashita S, Ozaki I, Mizuta T, Toda S, Kudo S, Miyoshi A, Miyazaki K, Fujimoto K. Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: a pilot study. Liver Int. 2010 Apr;30(4):538-45. doi: 10.1111/j.1478-3231.2009.02130.x. Epub 2009 Oct 27.

Friedrich-Rust M, Wunder K, Kriener S, Sotoudeh F, Richter S, Bojunga J, Herrmann E, Poynard T, Dietrich CF, Vermehren J, Zeuzem S, Sarrazin C. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology. 2009 Aug;252(2):595-604. doi: 10.1148/radiol.2523081928.

Wang QB, Zhu H, Liu HL, Zhang B. Performance of magnetic resonance elastography and diffusion-weighted imaging for the staging of hepatic fibrosis: A meta-analysis. Hepatology. 2012 Jul;56(1):239-47. doi: 10.1002/hep.25610. Epub 2012 Jun 6.

Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006 Jun;43(6):1317-25. doi: 10.1002/hep.21178.

Cales P, Oberti F, Michalak S, Hubert-Fouchard I, Rousselet MC, Konate A, Gallois Y, Ternisien C, Chevailler A, Lunel F. A novel panel of blood markers to assess the degree of liver fibrosis. Hepatology. 2005 Dec;42(6):1373-81. doi: 10.1002/hep.20935.

Adams LA, Bulsara M, Rossi E, DeBoer B, Speers D, George J, Kench J, Farrell G, McCaughan GW, Jeffrey GP. Hepascore: an accurate validated predictor of liver fibrosis in chronic hepatitis C infection. Clin Chem. 2005 Oct;51(10):1867-73. doi: 10.1373/clinchem.2005.048389. Epub 2005 Jul 28.

Forns X, Ampurdanes S, Llovet JM, Aponte J, Quinto L, Martinez-Bauer E, Bruguera M, Sanchez-Tapias JM, Rodes J. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology. 2002 Oct;36(4 Pt 1):986-92. doi: 10.1053/jhep.2002.36128.

Crespo G, Fernandez-Varo G, Marino Z, Casals G, Miquel R, Martinez SM, Gilabert R, Forns X, Jimenez W, Navasa M. ARFI, FibroScan, ELF, and their combinations in the assessment of liver fibrosis: a prospective study. J Hepatol. 2012 Aug;57(2):281-7. doi: 10.1016/j.jhep.2012.03.016. Epub 2012 Apr 17.

Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, Hubscher S, Roskams T, Pinzani M, Arthur MJ; European Liver Fibrosis Group. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2004 Dec;127(6):1704-13. doi: 10.1053/j.gastro.2004.08.052.

Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003 Aug;38(2):518-26. doi: 10.1053/jhep.2003.50346.

Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T; MULTIVIRC Group. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001 Apr 7;357(9262):1069-75. doi: 10.1016/S0140-6736(00)04258-6.