EDITORIAL Elastography in Overweight and Obese Patients With Chronic Liver Disease here is a growing recognition of the spectrum of nonalcoholic fatty liver disease (NAFLD) and its association with cirrhosis, liver cancer, liver failure, and the need for transplantation.1 In the United States, where obesity2 and metabolic syndrome are highly prevalent, we have witnessed an increase in NAFLD in clinics that manage patients with chronic liver disease (CLD). In addition, implementation of universal screening for hepatitis C infection (HCV) among persons born between 1945 and 1965 in the United States and the advent of highly effective treatment for HCV is expected to increase the volume of patients with CLD who seek specialist care. Integral to the care of patients with CLD is risk stratification through staging of hepatic fibrosis. Liver biopsy remains the gold standard in hepatic fibrosis staging3 despite sampling errors4 and intraobserver and interobserver variability.5 However, it is also an invasive procedure with a small but significant life-threatening risk.6 There is a pronounced need for reliable and accurate noninvasive markers and tools as alternatives or adjuncts to liver biopsy, especially in patients who are riskaverse or technically challenging. Noninvasive assessment of hepatic fibrosis in patients with HCV is now part of the European Association of the Study of the Liver guidelines.7 Cleared in 2013 by the Food and Drug Administration, noninvasive ultrasoundbased elastography is at the early stages of adoption in clinical practice in the United States. Elastography use (with any modality, ultrasound or magnetic resonance imaging) to determine advanced fibrosis or cirrhosis in patients with various etiologies of CLD is expected to increase as the technique gains popularity. Transient elastography (TE) (FibroScan; Echosens, Paris, France) is performed using a dedicated unidimensional ultrasound device that relies on measurement of the velocity of an elastic shear wave propagating through the liver, with increased liver stiffness associated with faster propagation. Supersonic shear wave imaging (SSI) (ShearWave, Aixplorer; Supersonic Imagine, Aix-en-Provence, France) also estimates the propagation of shear waves over a region of hepatic tissue with the advantage of being able to select the region of interest over which stiffness is estimated in real time (2-dimensional ultrasound). Furthermore, it can be incorporated with machines capable of complete ultrasound imaging. Both are relatively easy to use, can be performed at the bedside, and integrated in an outpatient gastroenterology or hepatology practice; however, both have a learning curve for reliable and
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successful examinations. Both have similar limitations with regards to factors that may overestimate the degree of fibrosis and also lead to unreliable examinations (eg, obesity, inflammation, passive congestion, and operator inexperience). There are 2 probes available for TE, with the use of the XL probe recommended in patients with a body mass index (BMI) greater than 30 kg/m2 instead of the standard M probe.8 The study by Yoneda et al9 in this issue of Clinical Gastroenterology and Hepatology utilized and compared 2 ultrasound elastography techniques TE and SSI in detecting severe fibrosis in a group of technically challenging patients in the United States. In this single-center study of 258 overweight and obese patients with CLD caused by various etiologies, both techniques measure liver stiffness as a surrogate for the degree of liver fibrosis. Because a large portion of the US population is either overweight or obese and the clinical usefulness of elastography is hampered by increased BMI,10 this study is of interest because it shows that liver stiffness measurements (LSMs) are obtainable and severe fibrosis can be determined accurately in overweight and obese patients. Reliable LSMs were reported in 96.1% of patients using the TE-XL probe and in 94.6% of patients using SSI of the right lobe. In a subset of 124 patients with concomitant liver biopsies, the area under the receiver operating curve (AUROC) values for detecting severe fibrosis (F3–F4) as a result of all causes were 0.96 for TE-XL and 0.95 for SSI of the right lobe; whereas for the subset of 102 patients with biopsy-proven HCV infection the AUROCs were 0.95 and 0.95, respectively. For detecting F4 fibrosis stage, the AUROC for TE-XL was 0.92 and for SSI right lobe was 0.93 in all causes; it was 0.91 and 0.91, respectively, in biopsy-proven HCV infection. Overall, noninvasive radiologic markers (TE and SSI) had better performance than noninvasive indirect serum markers of fibrosis (eg, aspartate aminotransferase to platelet ratio index and Fibrosis-4 score). The results of the study are timely and important because there is avid interest in defining the role of elastography in a US population that is skewed toward being overweight or obese. However, several salient features need to be noted with potential widespread incorporation of either technique. First, the study encompassed a gamut of CLD, 65% HCV, 14% NAFLD, 8% hepatitis B virus, 8% primary biliary cirrhosis or primary sclerosing cholangitis, and 5.4% with other liver diseases. Although the performance characteristics of the tests are impressive, applications of the study results is limited by spectrum bias; such a patient distribution seen in a tertiary referral center may be skewed to more severe liver disease, unlike community patient demographics, which may comprise more stable NAFLD, Clinical Gastroenterology and Hepatology 2015;-:-–-
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HCV, and alcoholic liver disease, which may slowly or never progress to advanced fibrosis. Second, there is no consensus on the acceptable threshold values for the presence of advanced fibrosis by TE-XL or SSI. The study recommended cut-off LSM values for SSI of the right lobe for severe fibrosis (F3) and liver cirrhosis (F4) of 9.3 kPa and 11.4 kPa for all etiologies of CLD (9.3 kPa and 11.9 kPa in the HCV subgroup, respectively), which are higher compared with earlier published reports.11,12 It is important to note that most of the experience and published data on TE are with the standard M probe because the XL probe is a new addition to the existing TE. The study’s cut-off value for TE-XL is lower for F4 fibrosis than previously proposed cut-off values (11.3 vs 15.1 kPa).13 Indeed, pairwise examination showed that LSM by the XL probe was 1.7 2.3 kPa lower than with the M probe (P < .001), a probe that may be used more widely.14 A recent review by Tapper et al15 offered a useful clinical framework for the interpretation of TE results that required knowledge of disease-specific cut-off values. If decisions are made on which patient should undergo a biopsy based on broad categorization by liver stiffness (normal, intermediate, or cirrhotic), then blurring of cut-off values is tolerated. However, if decisions are made with regard to screening for complications of cirrhosis or avoiding further testing, then a better justification of cut-off values is needed because management can differ from watchful monitoring to active and aggressive disease treatment. Third, important considerations include operator experience, the amount of inflammation or necroinflammatory activity, hepatic congestion from right heart failure, amount of alcohol consumed, cholestasis, and nonfasting state, which all can influence LSM.15 Operator experience is especially important in obtaining reliable results among obese patients.10,16 In obese patients (BMI 30 kg/m2), the rate of reliable LSMs was significantly higher for the more experienced operator compared with the novice, 73.4% vs 45.9%, respectively (P ¼ .03).17 Part of the difficulty is that even with the TE-XL probe, reliable measurements are obtainable in only 75% of the overall population and in 65% of patients with a BMI greater than 30 kg/m2 in another study.14 Contrast this to the 95% reliable measurements reported by Yoneda et al.9 The degree of reliable examinations will likely lie somewhere in between once this technology enters a wider clinical practice. Although this study was performed on overweight or obese patients, the upper BMI limit among the obese subjects was only 35.4 kg/m2 and a great majority of the patients had HCV. This is important because a BMI greater than 35 kg/m2 was associated independently with discordance (adjusted odds ratio, 9.09; 95% confidence interval, 1.10–75.43).14 Coexisting HCV and NAFLD/nonalcoholic steatohepatitis in Yoneda et al9 study’s group of patients with overweight or obese BMI was not described. In addition, the impact of inflammation, a well-established contributor to overestimation of liver stiffness, was not
Clinical Gastroenterology and Hepatology Vol.
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assessed. Hence, whether the contribution of being overweight to increased liver stiffness across different CLD categories would be different with the presence of inflammation (eg, steatosis vs steatohepatitis) also is not known. Finally, practical considerations are needed before widespread incorporation of TE-XL and SSI. Small practices would have to justify having the breadth of patient volume across the spectrum of CLD and ensure adequate operator experience with a low rate of interoperator variation. On the other hand, larger practices or tertiary centers with a high referral base would need to place the use of elastography in context with other tools that are readily available. One must be vigilant that one set of problems is not traded for another set of problems. Just as liver biopsy is derided for having sampling variability, discordant staging between pathologists, and potential for misclassification, will similar themes overshadow the widespread application of elastography (unreliable examinations, incomplete examinations, and overestimation of liver stiffness)? Undoubtedly, there is a greater demand for refinements in existing noninvasive methods to accurately and reliably evaluate fibrosis in an increasingly heavier patient population. Incorporation of any (relatively) novel technique has to start somewhere. Significant progress has been made, especially in noninvasive fibrosis staging in HCV in Europe, so that TE in combination with serum biomarkers are acceptable alternatives to liver biopsy in most patients in the European Association of the Study of the Liver guidelines.7 In the United States, one needs to be mindful that our patients here would be older and would be obese a third of the time; hence the need for prospective and larger studies. AVEGAIL FLORES, MD SUMEET K. ASRANI, MD, MSC Department of Medicine Baylor University Medical Center Dallas, Texas
References 1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346:1221–1231. 2. Flegal KM, Carroll MD, Kit BK, et al. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA 2012;307:491–497. 3. Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology 2009;49:1017–1044. 4. Maharaj B, Maharaj RJ, Leary WP, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet 1986;1:523–525. 5. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology 1994;20: 15–20. 6. Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the
-
2015 Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology 2000;32:477–481.
7. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014;60:392–420. 8. Myers RP, Pomier-Layrargues G, Kirsch R, et al. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology 2012;55:199–208. 9. Yoneda M, Thomas E, Sclair SN, et al. Supersonic shear imaging and transient elastography with the XL probe accurately detect fibrosis in overweight or obese patients with chronic liver disease. Clin Gastroenterol Hepatol 2015 Mar 21. Epub ahead of print. 10. Castera L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010;51:828–835. 11. Ferraioli G, Tinelli C, Dal Bello B, et al. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology 2012;56:2125–2133. 12. Cassinotto C, Lapuyade B, Mouries A, et al. Non-invasive assessment of liver fibrosis with impulse elastography: comparison of Supersonic Shear Imaging with ARFI and FibroScan®. J Hepatol 2014;61:550–557.
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13. Stebbing J, Farouk L, Panos G, et al. A meta-analysis of transient elastography for the detection of hepatic fibrosis. J Clin Gastroenterol 2010;44:214–219. 14. Wong VW, Vergniol J, Wong GL, et al. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2012;107:1862–1871. 15. Tapper EB, Castera L, Afdhal NH. FibroScan (vibrationcontrolled transient elastography): where does it stand in the United States practice. Clin Gastroenterol Hepatol 2015; 13:27–36. 16. Ferraioli G, Tinelli C, Zicchetti M, et al. Reproducibility of realtime shear wave elastography in the evaluation of liver elasticity. Eur J Radiol 2012;81:3102–3106. 17. Gradinaru-Tascau O, Sporea I, Bota S, et al. Does experience play a role in the ability to perform liver stiffness measurements by means of supersonic shear imaging (SSI)? Med Ultrason 2013;15:180–183.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2015.04.018
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successful examinations. Both have similar limitations with regards to factors that may overestimate the degree of fibrosis and also lead to unreliable examinations (eg, obesity, inflammation, passive congestion, and operator inexperience). There are 2 probes available for TE, with the use of the XL probe recommended in patients with a body mass index (BMI) greater than 30 kg/m2 instead of the standard M probe.8 The study by Yoneda et al9 in this issue of Clinical Gastroenterology and Hepatology utilized and compared 2 ultrasound elastography techniques TE and SSI in detecting severe fibrosis in a group of technically challenging patients in the United States. In this single-center study of 258 overweight and obese patients with CLD caused by various etiologies, both techniques measure liver stiffness as a surrogate for the degree of liver fibrosis. Because a large portion of the US population is either overweight or obese and the clinical usefulness of elastography is hampered by increased BMI,10 this study is of interest because it shows that liver stiffness measurements (LSMs) are obtainable and severe fibrosis can be determined accurately in overweight and obese patients. Reliable LSMs were reported in 96.1% of patients using the TE-XL probe and in 94.6% of patients using SSI of the right lobe. In a subset of 124 patients with concomitant liver biopsies, the area under the receiver operating curve (AUROC) values for detecting severe fibrosis (F3–F4) as a result of all causes were 0.96 for TE-XL and 0.95 for SSI of the right lobe; whereas for the subset of 102 patients with biopsy-proven HCV infection the AUROCs were 0.95 and 0.95, respectively. For detecting F4 fibrosis stage, the AUROC for TE-XL was 0.92 and for SSI right lobe was 0.93 in all causes; it was 0.91 and 0.91, respectively, in biopsy-proven HCV infection. Overall, noninvasive radiologic markers (TE and SSI) had better performance than noninvasive indirect serum markers of fibrosis (eg, aspartate aminotransferase to platelet ratio index and Fibrosis-4 score). The results of the study are timely and important because there is avid interest in defining the role of elastography in a US population that is skewed toward being overweight or obese. However, several salient features need to be noted with potential widespread incorporation of either technique. First, the study encompassed a gamut of CLD, 65% HCV, 14% NAFLD, 8% hepatitis B virus, 8% primary biliary cirrhosis or primary sclerosing cholangitis, and 5.4% with other liver diseases. Although the performance characteristics of the tests are impressive, applications of the study results is limited by spectrum bias; such a patient distribution seen in a tertiary referral center may be skewed to more severe liver disease, unlike community patient demographics, which may comprise more stable NAFLD, Clinical Gastroenterology and Hepatology 2015;-:-–-
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Flores and Asrani
HCV, and alcoholic liver disease, which may slowly or never progress to advanced fibrosis. Second, there is no consensus on the acceptable threshold values for the presence of advanced fibrosis by TE-XL or SSI. The study recommended cut-off LSM values for SSI of the right lobe for severe fibrosis (F3) and liver cirrhosis (F4) of 9.3 kPa and 11.4 kPa for all etiologies of CLD (9.3 kPa and 11.9 kPa in the HCV subgroup, respectively), which are higher compared with earlier published reports.11,12 It is important to note that most of the experience and published data on TE are with the standard M probe because the XL probe is a new addition to the existing TE. The study’s cut-off value for TE-XL is lower for F4 fibrosis than previously proposed cut-off values (11.3 vs 15.1 kPa).13 Indeed, pairwise examination showed that LSM by the XL probe was 1.7 2.3 kPa lower than with the M probe (P < .001), a probe that may be used more widely.14 A recent review by Tapper et al15 offered a useful clinical framework for the interpretation of TE results that required knowledge of disease-specific cut-off values. If decisions are made on which patient should undergo a biopsy based on broad categorization by liver stiffness (normal, intermediate, or cirrhotic), then blurring of cut-off values is tolerated. However, if decisions are made with regard to screening for complications of cirrhosis or avoiding further testing, then a better justification of cut-off values is needed because management can differ from watchful monitoring to active and aggressive disease treatment. Third, important considerations include operator experience, the amount of inflammation or necroinflammatory activity, hepatic congestion from right heart failure, amount of alcohol consumed, cholestasis, and nonfasting state, which all can influence LSM.15 Operator experience is especially important in obtaining reliable results among obese patients.10,16 In obese patients (BMI 30 kg/m2), the rate of reliable LSMs was significantly higher for the more experienced operator compared with the novice, 73.4% vs 45.9%, respectively (P ¼ .03).17 Part of the difficulty is that even with the TE-XL probe, reliable measurements are obtainable in only 75% of the overall population and in 65% of patients with a BMI greater than 30 kg/m2 in another study.14 Contrast this to the 95% reliable measurements reported by Yoneda et al.9 The degree of reliable examinations will likely lie somewhere in between once this technology enters a wider clinical practice. Although this study was performed on overweight or obese patients, the upper BMI limit among the obese subjects was only 35.4 kg/m2 and a great majority of the patients had HCV. This is important because a BMI greater than 35 kg/m2 was associated independently with discordance (adjusted odds ratio, 9.09; 95% confidence interval, 1.10–75.43).14 Coexisting HCV and NAFLD/nonalcoholic steatohepatitis in Yoneda et al9 study’s group of patients with overweight or obese BMI was not described. In addition, the impact of inflammation, a well-established contributor to overestimation of liver stiffness, was not
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
assessed. Hence, whether the contribution of being overweight to increased liver stiffness across different CLD categories would be different with the presence of inflammation (eg, steatosis vs steatohepatitis) also is not known. Finally, practical considerations are needed before widespread incorporation of TE-XL and SSI. Small practices would have to justify having the breadth of patient volume across the spectrum of CLD and ensure adequate operator experience with a low rate of interoperator variation. On the other hand, larger practices or tertiary centers with a high referral base would need to place the use of elastography in context with other tools that are readily available. One must be vigilant that one set of problems is not traded for another set of problems. Just as liver biopsy is derided for having sampling variability, discordant staging between pathologists, and potential for misclassification, will similar themes overshadow the widespread application of elastography (unreliable examinations, incomplete examinations, and overestimation of liver stiffness)? Undoubtedly, there is a greater demand for refinements in existing noninvasive methods to accurately and reliably evaluate fibrosis in an increasingly heavier patient population. Incorporation of any (relatively) novel technique has to start somewhere. Significant progress has been made, especially in noninvasive fibrosis staging in HCV in Europe, so that TE in combination with serum biomarkers are acceptable alternatives to liver biopsy in most patients in the European Association of the Study of the Liver guidelines.7 In the United States, one needs to be mindful that our patients here would be older and would be obese a third of the time; hence the need for prospective and larger studies. AVEGAIL FLORES, MD SUMEET K. ASRANI, MD, MSC Department of Medicine Baylor University Medical Center Dallas, Texas
References 1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346:1221–1231. 2. Flegal KM, Carroll MD, Kit BK, et al. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA 2012;307:491–497. 3. Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology 2009;49:1017–1044. 4. Maharaj B, Maharaj RJ, Leary WP, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet 1986;1:523–525. 5. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology 1994;20: 15–20. 6. Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the
-
2015 Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology 2000;32:477–481.
7. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014;60:392–420. 8. Myers RP, Pomier-Layrargues G, Kirsch R, et al. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology 2012;55:199–208. 9. Yoneda M, Thomas E, Sclair SN, et al. Supersonic shear imaging and transient elastography with the XL probe accurately detect fibrosis in overweight or obese patients with chronic liver disease. Clin Gastroenterol Hepatol 2015 Mar 21. Epub ahead of print. 10. Castera L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010;51:828–835. 11. Ferraioli G, Tinelli C, Dal Bello B, et al. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology 2012;56:2125–2133. 12. Cassinotto C, Lapuyade B, Mouries A, et al. Non-invasive assessment of liver fibrosis with impulse elastography: comparison of Supersonic Shear Imaging with ARFI and FibroScan®. J Hepatol 2014;61:550–557.
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13. Stebbing J, Farouk L, Panos G, et al. A meta-analysis of transient elastography for the detection of hepatic fibrosis. J Clin Gastroenterol 2010;44:214–219. 14. Wong VW, Vergniol J, Wong GL, et al. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2012;107:1862–1871. 15. Tapper EB, Castera L, Afdhal NH. FibroScan (vibrationcontrolled transient elastography): where does it stand in the United States practice. Clin Gastroenterol Hepatol 2015; 13:27–36. 16. Ferraioli G, Tinelli C, Zicchetti M, et al. Reproducibility of realtime shear wave elastography in the evaluation of liver elasticity. Eur J Radiol 2012;81:3102–3106. 17. Gradinaru-Tascau O, Sporea I, Bota S, et al. Does experience play a role in the ability to perform liver stiffness measurements by means of supersonic shear imaging (SSI)? Med Ultrason 2013;15:180–183.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2015.04.018
