Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is estimated to afflict approximately 1 billion individuals worldwide. In a subset of NAFLD patients, who have the progressive form of NAFLD termed nonalcoholic steatohepatitis (NASH), it can progress to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related morbidity and mortality. NASH is typically characterized by a specific pattern on liver histology, including steatosis, lobular inflammation, and ballooning with or without peri-sinusoidal fibrosis. Thus, key issues in NAFLD patients are the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis. Until now, liver biopsy has been the gold standard for identifying these 2 critical end points, but has well-known limitations, including invasiveness; rare but potentially life-threatening complications; poor acceptability; sampling variability; and cost. Furthermore, due to the epidemic proportion of individuals with NAFLD worldwide, liver biopsy evaluation is impractical, and noninvasive assessment for the diagnosis of NASH and fibrosis is needed. Although much of the work remains to be done in establishing cost-effective strategies for screening for NASH, advanced fibrosis, and cirrhosis, in this review, we summarize the current state of the noninvasive assessment of liver disease in NAFLD, and we provide an expert synthesis of how these noninvasive tools could be utilized in clinical practice. Finally, we also list the key areas of research priorities in this area to move forward clinical practice. Nonalcoholic fatty liver disease (NAFLD) is estimated to afflict approximately 1 billion individuals worldwide. In a subset of NAFLD patients, who have the progressive form of NAFLD termed nonalcoholic steatohepatitis (NASH), it can progress to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related morbidity and mortality. NASH is typically characterized by a specific pattern on liver histology, including steatosis, lobular inflammation, and ballooning with or without peri-sinusoidal fibrosis. Thus, key issues in NAFLD patients are the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis. Until now, liver biopsy has been the gold standard for identifying these 2 critical end points, but has well-known limitations, including invasiveness; rare but potentially life-threatening complications; poor acceptability; sampling variability; and cost. Furthermore, due to the epidemic proportion of individuals with NAFLD worldwide, liver biopsy evaluation is impractical, and noninvasive assessment for the diagnosis of NASH and fibrosis is needed. Although much of the work remains to be done in establishing cost-effective strategies for screening for NASH, advanced fibrosis, and cirrhosis, in this review, we summarize the current state of the noninvasive assessment of liver disease in NAFLD, and we provide an expert synthesis of how these noninvasive tools could be utilized in clinical practice. Finally, we also list the key areas of research priorities in this area to move forward clinical practice. Nonalcoholic fatty liver disease (NAFLD) affects around one-fourth of the general population worldwide.1Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84Crossref PubMed Scopus (1670) Google Scholar Nonalcoholic steatohepatitis (NASH), the active form of NAFLD, characterized by histological lobular inflammation and hepatocyte ballooning, is associated with faster fibrosis progression and affects around 1.5%–6.5% of the general population.1Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84Crossref PubMed Scopus (1670) Google Scholar NAFLD is frequently associated with metabolic comorbidities, such as obesity (51%; 95% confidence interval [CI], 41%–61%), type 2 diabetes (22%; 95% CI, 18%–28%), hyperlipidemia (69%; 95% CI, 50%–83%), hypertension (39%; 95% CI, 33%–%46), and metabolic syndrome (42%; 95% CI, 30%–56%).1Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84Crossref PubMed Scopus (1670) Google Scholar Although the most common cause of death in patients with NAFLD is cardiovascular disease, independent of other metabolic comorbidities, NAFLD is becoming a major cause of liver disease–related morbidity (eg, cirrhosis, end-stage liver disease, hepatocellular carcinoma, and liver transplantation), as well as mortality.2European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Abstract Full Text Full Text PDF PubMed Scopus (853) Google Scholar, 3Chalasani N. Younossi Z. Lavine J.E. et al.The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (736) Google Scholar NAFLD is expected in the next decade to become the leading indication for liver transplantation in the United States.4Goldberg D. Ditah I.C. Saeian K. et al.Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation.Gastroenterology. 2017; 152: 1090-1099 e1Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar It is estimated that liver-specific mortality and overall mortality among patients with NAFLD are 0.77 and 11.77 per 1000 person-years, whereas they are 15.44 and 25.56 per 1000 person-years among patients with NASH.1Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84Crossref PubMed Scopus (1670) Google Scholar The vast majority of NAFLD patients, however, will not progress, only a minority, namely those with NASH and advanced hepatic fibrosis, are at greatest risk of developing complications of chronic liver disease.5Singh S. Allen A.M. Wang Z. et al.Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.Clin Gastroenterol Hepatol. 2015; 13 (quiz e39–e40): 643-654 e1–e9Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar Indeed, advanced fibrosis has been shown to be the major driver for long-term outcome and mortality.6Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397.e10Abstract Full Text Full Text PDF PubMed Scopus (751) Google Scholar, 7Dulai P.S. Singh S. Patel J. et al.Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.Hepatology. 2017; 65: 1557-1565Crossref PubMed Scopus (284) Google Scholar, 8Hagstrom H. Nasr P. Ekstedt M. et al.Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD.J Hepatol. 2017; 67: 1265-1273Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Thus, key issues in patients with NAFLD are the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis. Given the huge number of at-risk patients, there is a substantial unmet need for efficient and cost-effective means for risk stratification of NAFLD patients for these 2 critical end points. Liver biopsy, the gold standard for identifying these 2 end points until now, appears unrealistic and unsuitable. In addition, it has well-known limitations, including invasiveness, poor acceptability, sampling variability, and cost. As a result, this has fueled the development of alternative noninvasive strategies, which have been an area of intensive research over the past decade.9European Association for Study of LiverAsociacion Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis.J Hepatol. 2015; 63: 237-264Abstract Full Text Full Text PDF PubMed Scopus (615) Google Scholar This review is aimed at discussing the performance, advantages, and limitations of noninvasive methods for the management of patients with NAFLD, including diagnosis and quantification of steatosis, differentation of NASH from simple steatosis, and identification of advanced hepatic fibrosis. Noninvasive methods rely on 2 different approaches: a “biological” approach based on the quantification of biomarkers in serum samples or a “physical” approach based on the measurement of liver stiffness, using either ultrasound- or magnetic resonance–based elastography techniques. Although these approaches are complementary, they are based on different rationales. Liver stiffness corresponds to a genuine and intrinsic physical property of liver parenchyma, whereas serum biomarkers indicate several, not strictly liver-specific, clinical and serum parameters that have been associated with NASH or fibrosis stage, as assessed by liver biopsy. Current serum biomarkers (summarized in Table 1) include predictive models for diagnosing or grading steatosis (such as the Fatty Liver Index) or staging fibrosis (eg, NAFLD Fibrosis Score), direct measures of hepatocellular damage (eg, circulating keratin 18 fragments) to differentiate patients with NASH from those with simple steatosis and direct measures of fibrosis (eg, PIIINP or Pro-C3) to discriminate patients with advanced fibrosis. Some are specific of NAFLD (eg, BARD and NAFLD fibrosis scores) whereas some have been initially designed in hepatitis C (aspartate transaminase [AST]/alanine transaminase [ALT] ratio, Aspartate Transaminase-to-Platelet Ratio Index [APRI], FIB-4). A few are proprietary formulas (FibroTest, Fibrometer, Hepascore, and Enhanced Liver Fibrosis [ELF] score) but most are nonpatented.Table 1Available Serum Biomarkers for Diagnosing Steatosis or for Staging Fibrosis in Patients With Nonalcoholic Fatty Liver DiseaseIndex (ref)Items, nAgeSexBMIDiabetesPlatelet countAST levelALT levelAST/ALTratioGGT levelTG levelOther componentsSteatosisFLI14Bedogni G. Bellentani S. Miglioli L. et al.The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population.BMC Gastroenterol. 2006; 6: 33Crossref PubMed Scopus (673) Google Scholar4XXXWaist circumferenceHSI15Lee J.H. Kim D. Kim H.J. et al.Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease.Dig Liver Dis. 2010; 42: 503-508Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar3XXX—SteatoTest13Poynard T. Ratziu V. Naveau S. et al.The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis.Comp Hepatol. 2005; 4: 10Crossref PubMed Scopus (199) Google Scholar12XXXXXXA2M, ApoA1, haptoglobin, T bilirubin, cholesterol, and glucoseLAP16Bedogni G. Kahn H.S. Bellentani S. et al.A simple index of lipid overaccumulation is a good marker of liver steatosis.BMC Gastroenterol. 2010; 10: 98Crossref PubMed Scopus (0) Google Scholar3XXWaist circumferenceION17Otgonsuren M. Estep M.J. Hossain N. et al.Single non-invasive model to diagnose non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).J Gastroenterol Hepatol. 2014; 29: 2006-2013Crossref PubMed Scopus (0) Google Scholar3/4XXXWaist-to-hip ratio (male yes; female no), and HOMANAFLD-LFS18Kotronen A. Peltonen M. Hakkarainen A. et al.Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors.Gastroenterology. 2009; 137: 865-872Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar4XXMetabolic syndrome and insulinFibrosisAPRI160Wai C.T. Greenson J.K. Fontana R.J. et al.A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C.Hepatology. 2003; 38: 518-526Crossref PubMed Scopus (2351) Google Scholar2XX—FIB-4161Sterling R.K. Lissen E. Clumeck N. et al.Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection.Hepatology. 2006; 43: 1317-1325Crossref PubMed Scopus (1452) Google Scholar4XXXX—FibroTest162Imbert-Bismut F. Ratziu V. Pieroni L. et al.Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study.Lancet. 2001; 357: 1069-1075Abstract Full Text Full Text PDF PubMed Scopus (1204) Google Scholar8XXXXA2M, ApoA1, haptoglobin, and total bilirubinFibrometer NAFLD163Cales P. Laine F. Boursier J. et al.Comparison of blood tests for liver fibrosis specific or not to NAFLD.J Hepatol. 2009; 50: 165-173Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar7XXXXglucose, ferritin and body weightELF164Rosenberg W.M. Voelker M. Thiel R. et al.Serum markers detect the presence of liver fibrosis: a cohort study.Gastroenterology. 2004; 127: 17041713Abstract Full Text Full Text PDF Scopus (705) Google Scholar3Hyaluronic acid, PIIINP and TIMP-1Hepacore165Adams L.A. George J. Bugianesi E. et al.Complex non-invasive fibrosis models are more accurate than simple models in non-alcoholic fatty liver disease.J Gastroenterol Hepatol. 2011; 26: 1536-1543Crossref PubMed Scopus (81) Google Scholar6XXXA2M, hyaluronic acid and total bilirubinBARD score166Ratziu V. Giral P. Charlotte F. et al.Liver fibrosis in overweight patients.Gastroenterology. 2000; 118: 1117-1123Abstract Full Text Full Text PDF PubMed Google Scholar3XXX—NFS167Angulo P. Hui J.M. Marchesini G. et al.The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.Hepatology. 2007; 45: 846-854Crossref PubMed Scopus (1179) Google Scholar6XXXXXAlbuminA2M, α2-macroglobulin; APOA1, apolipoprotein A1; FLI, fatty liver index; GGT, γ-glutamyltransferase; HSI, Hepatic Steatosis Index; ION, Index of NASH; LAP, lipid accumulation product; NAFLD-LFS, NAFLD liver fat score; NFS, NAFLD fibrosis score. Open table in a new tab A2M, α2-macroglobulin; APOA1, apolipoprotein A1; FLI, fatty liver index; GGT, γ-glutamyltransferase; HSI, Hepatic Steatosis Index; ION, Index of NASH; LAP, lipid accumulation product; NAFLD-LFS, NAFLD liver fat score; NFS, NAFLD fibrosis score. The practical advantages of analyzing serum biomarkers include their high applicability (>95%), their good inter-laboratory reproducibility, and their potential widespread availability (nonpatented). However, none are liver-specific—their results can be influenced by comorbid conditions and they require critical interpretation of results. There are 2 different kinds of elastography techniques: ultrasound-based or magnetic resonance-based. The first one uses ultrasound to detect the velocity of the microdisplacements (shear waves) induced in the liver tissue, whereas the latter uses the magnetic resonance scanner. The shear wave’s velocity is then converted into a liver stiffness measurement (LSM), expressed in kilopascals (kPa) or in meters per second. Vibration-controlled transient elastography (TE) has been the pioneer ultrasound-based technique and is the most widely used worldwide, but newer elastography modalities like point shear wave elastography (pSWE), which includes acoustic radiation force impulse imaging (ARFI), or 2-dimensional shear wave elastography (2D-SWE), integrated in conventional ultrasound systems, are emerging.10Dietrich C. Bamber J. Berzigotti A. et al.EFSUMB guidelines and recommendations on the clinical use of liver ultrasound elastography, Update 2017 (Long Version).Eur J Ultrasound. 2017; 38: e16-e47Google Scholar, 11Friedrich-Rust M. Poynard T. Castera L. Critical comparison of elastography methods to assess chronic liver disease.Nat Rev Gastroenterol Hepatol. 2016; 13: 402-411Crossref PubMed Scopus (116) Google Scholar, 12Ferraioli G. Wong V.W. Castera L. et al.Liver ultrasound elastography: an update to the world federation for ultrasound in medicine and biology guidelines and recommendations.Ultrasound Med Biol. 2018; 44: 2419-2440Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Their main characteristics, advantages, and limitations are summarized in Table 2. TE and magnetic resonance elastography (MRE) provide additional information in patients with NAFLD. The same machine can be used to determine whether steatosis is present: controlled attenuation parameter (CAP) for TE and calculation of the proton-density fat traction (PDFF) for MRE. Comprehensive technical details can be found in the Supplementary Material.Table 2Respective Characteristics, Advantages, and Limitations of the 4 Available Elastography Techniques for Liver Fibrosis StagingTechniquesPerformed byUnits (range)Steatosis gradingQuality criteriaFailure rate, %ConfoundersEvidence in NAFLD study patientsCostPoint of careInflammationObesityOthersTEHepatologist, trained nurse or techniciankPa (2–75)YesCAPWell-definedIQR/M <30%3–27++++XL-probeCongestion steatosis?n = 253862$YesMRERadiologistkPaaMRE is reported as shear modulus, while ultrasound elastography techniques are reported in Young modulus. The Young modulus is 3 times the shear modulus. (2–11)YesPDFFEmerging QIBA consensus statement0–2+–Congestion iron overloadn = 6676$$$NopSWE/ARFIRadiologist or ultrasonographerm/s (0.5–4.4)NoNot well-defined2+ ? limited data+ ? limited dataSimilar to TE? limited datan = 8834$$No2D-SWERadiologist or ultrasonographerkPa (2–150)NoNot well-defined13 ?+ ? limited data+ ? limited dataSimilar to TE? limited datan = 2447$$NoIQR/M, interquartile range/median; QIBA, Quantitative Imaging Biomarkers Alliance.a MRE is reported as shear modulus, while ultrasound elastography techniques are reported in Young modulus. The Young modulus is 3 times the shear modulus. Open table in a new tab IQR/M, interquartile range/median; QIBA, Quantitative Imaging Biomarkers Alliance. Several steatosis scores have been proposed for the detection of steatosis, including the SteatoTest,13Poynard T. Ratziu V. Naveau S. et al.The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis.Comp Hepatol. 2005; 4: 10Crossref PubMed Scopus (199) Google Scholar Fatty Liver Index,14Bedogni G. Bellentani S. Miglioli L. et al.The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population.BMC Gastroenterol. 2006; 6: 33Crossref PubMed Scopus (673) Google Scholar Hepatic Steatosis Index,15Lee J.H. Kim D. Kim H.J. et al.Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease.Dig Liver Dis. 2010; 42: 503-508Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar lipid accumulation product,16Bedogni G. Kahn H.S. Bellentani S. et al.A simple index of lipid overaccumulation is a good marker of liver steatosis.BMC Gastroenterol. 2010; 10: 98Crossref PubMed Scopus (0) Google Scholar the Index of NASH,17Otgonsuren M. Estep M.J. Hossain N. et al.Single non-invasive model to diagnose non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).J Gastroenterol Hepatol. 2014; 29: 2006-2013Crossref PubMed Scopus (0) Google Scholar and the NAFLD Liver Fat Score.18Kotronen A. Peltonen M. Hakkarainen A. et al.Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors.Gastroenterology. 2009; 137: 865-872Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar Their diagnostic performances have been summarized in a recent review.19Stern C. Castera L. Non-invasive diagnosis of hepatic steatosis.Hepatol Int. 2017; 11: 70-78Crossref PubMed Scopus (0) Google Scholar Although SteatoTest, Fatty Liver Index NAFLD Liver Fat Score, lipid accumulation product, and Hepatic Steatosis Index have been validated independently,20Poynard T. Lassailly G. Diaz E. et al.Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data.PLoS One. 2012; 7: e30325Crossref PubMed Scopus (78) Google Scholar, 21Fedchuk L. Nascimbeni F. Pais R. et al.Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease.Aliment Pharmacol Ther. 2014; 40: 1209-1222Crossref PubMed Scopus (95) Google Scholar, 22Cuthbertson D.J. Weickert M.O. Lythgoe D. et al.External validation of the fatty liver index and lipid accumulation product indices, using 1H-magnetic resonance spectroscopy, to identify hepatic steatosis in healthy controls and obese, insulin-resistant individuals.Eur J Endocrinol. 2014; 171: 561-569Crossref PubMed Scopus (57) Google Scholar, 23Calori G. Lattuada G. Ragogna F. et al.Fatty liver index and mortality: the Cremona study in the 15th year of follow-up.Hepatology. 2011; 54: 145-152Crossref PubMed Scopus (141) Google Scholar their diagnostic performances are difficult to compare, as they have been designed and validated against different standards: liver biopsy, ultrasonography, or magnetic resonance spectroscopy. Nevertheless, when the Fatty Liver Index, NAFLD Liver Fat Score, and Hepatic Steatosis Index were retrospectively compared in the same cohort of 324 patients with suspected NAFLD and liver biopsy, their area under the receiver operating characteristic (AUROC) values for the diagnosis of steatosis (>5%) did not differ (0.83, 0.80, and 0.81, respectively).21Fedchuk L. Nascimbeni F. Pais R. et al.Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease.Aliment Pharmacol Ther. 2014; 40: 1209-1222Crossref PubMed Scopus (95) Google Scholar Further studies are needed, but it should be acknowledged that these scores have not gained much popularity, as they do not add much to the information provided by clinical, laboratory, and imaging studies done routinely in patients with suspected NAFLD. Conventional ultrasonography is the most commonly used imaging method for the diagnosis of hepatic steatosis because it is widely available, well established, well tolerated, and cheap. Typical ultrasonography features are hyperechogenicity as compared to the right kidney parenchyma, distal attenuation, and the presence of areas of focal sparing.24Hernaez R. Lazo M. Bonekamp S. et al.Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis.Hepatology. 2011; 54: 1082-1090Crossref PubMed Scopus (498) Google Scholar The degree of steatosis can be subjectively scored as mild, moderate, and severe, or as reported in some studies by using ordinal ultrasonography scores.25Ballestri S. Lonardo A. Romagnoli D. et al.Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD.Liver Int. 2012; 32: 1242-1252Crossref PubMed Scopus (81) Google Scholar, 26Hamaguchi M. Kojima T. Itoh Y. et al.The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation.Am J Gastroenterol. 2007; 102: 2708-2715Crossref PubMed Scopus (383) Google Scholar In a large meta-analysis24Hernaez R. Lazo M. Bonekamp S. et al.Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis.Hepatology. 2011; 54: 1082-1090Crossref PubMed Scopus (498) Google Scholar (n = 34 studies, 2815 patients with suspected or known liver diseases), pooled sensitivities and specificities of ultrasonography to distinguish moderate-to-severe fatty liver from the absence of steatosis, taking liver biopsy as the reference, were 85% (80%–89%) and 93% (87%–97%), respectively. However, in clinical practice, mainly the presence or absence of steatosis is recorded and ultrasonography has the limitation that it can only detect steatosis with >2.5%–20% liver fat content27Bril F. Ortiz-Lopez C. Lomonaco R. et al.Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients.Liver Int. 2015; 35: 2139-2146Crossref PubMed Scopus (54) Google Scholar and, therefore, a relevant number of patients with steatosis starting at 5% liver fat content can be missed.28Paige J.S. Bernstein G.S. Heba E. et al.A Pilot comparative study of quantitative ultrasound, conventional ultrasound, and MRI for predicting histology-determined steatosis grade in adult nonalcoholic fatty liver disease.AJR Am J Roentgenol. 2017; 208: W168-W177Crossref PubMed Scopus (0) Google Scholar In addition, the accuracy of ultrasonography for diagnosis of liver steatosis is reduced in patients with obesity and coexistent renal disease.29de Moura Almeida A. Cotrim H.P. Barbosa D.B.V. et al.Fatty liver disease in severe obese patients: diagnostic value of abdominal ultrasound.World J Gastroenterol. 2008; 14: 1415-1418Crossref PubMed Scopus (53) Google Scholar, 30Mottin C.C. Moretto M. Padoin A.V. et al.The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients.Obes Surg. 2004; 14: 635-637Crossref PubMed Scopus (191) Google Scholar Recent studies obtained better results using quantitative ultrasound.28Paige J.S. Bernstein G.S. Heba E. et al.A Pilot comparative study of quantitative ultrasound, conventional ultrasound, and MRI for predicting histology-determined steatosis grade in adult nonalcoholic fatty liver disease.AJR Am J Roentgenol. 2017; 208: W168-W177Crossref PubMed Scopus (0) Google Scholar, 31Lin S.C. Heba E. Wolfson T. et al.Noninvasive diagnosis of nonalcoholic fatty liver disease and quantification of liver fat using a new quantitative ultrasound technique.Clin Gastroenterol Hepatol. 2015; 13: 1337-1345.e6Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Nevertheless, European guidelines for the management of NAFLD recommend using ultrasonography as first-choice imaging in adults at risk for NAFLD.2European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Abstract Full Text Full Text PDF PubMed Scopus (853) Google Scholar In the initial study assessing its performances in 115 patients with chronic liver diseases (15% with NAFLD only), CAP was able to accurately detect steatosis ≥11%, ≥33%, and ≥66% with AUROCs of 0.91, 0.95 and 0.89, respectively.32Sasso M. Beaugrand M. de Ledinghen V. et al.Controlled attenuation parameter (CAP): a novel VCTE guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes.Ultrasound Med Biol. 2010; 36: 1825-1835Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar Nevertheless, despite a good correlation with histological steatosis, overlapped results between different grades of steatosis suggest that CAP cannot differentiate adjacent grades of steatosis with good precision. A recent individual data meta-analysis33Karlas T. Petroff D. Sasso M. et al.Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis.J Hepatol. 2017; 66: 1022-1030Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar based on 19 studies using the M-probe and having included 2735 patients (537 with NAFLD; 19.6%) has reported for steatosis ≥11%, ≥33%, and ≥66%, AUROCs of 0.82, 0.86, and 0.88, respectively, sensitivities of 0.69, 0.77, and 0.88 and specificities of 0.82, 0.81 and 0.78, respectively. The authors proposed optimal cutoffs of 248 dB/m (95 % CI, 237–261 dB/m), 268 dB/m (95 % CI, 257–284 dB/m), and 280 dB/m (95 % CI, 268–294 dB/m), respectively. Interestingly, CAP values were influenced by several covariates, including NAFLD, diabetes, and body mass index (BMI). Other authors, using magnetic resonance imaging (MRI)-PDFF as reference have recently suggested 288 dB/m as an optimal cutoff for detection of ≥5% fat in the liver.34Caussy C. Alquiraish M.H. Nguyen P. et al.Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis.Hepatology. 2018; 67: 1348-1359Crossref PubMed Scopus (44) Google Scholar Table 3 summarizes the results of CAP in NAFLD patients.35Chan W.K. Nik Mustapha N.R. Mahadeva S. Controlled attenuation parameter for the detection and quantification of hepatic steatosis in nonalcoholic fatty liver disease.J Gastroenterol Hepatol. 2014; 29: 1470-1476Crossref PubMed Scopus (70) Google Scholar, 36Chan W.K. Nik Mustapha N.R. Wong G.L. et al.Controlled attenuation parameter using the FibroScan(R) XL probe for quantification of hepatic steatosis for non-alcoholic fatty liver disease in an Asian population.United European Gastroenterol J. 2017; 5: 76-85Crossref PubMed Scopus (23) Google Scholar, 37de Ledinghen V. Wong G.L. Vergniol J. et al.Controlled attenuation parameter for the diagnosis of steatosis in non-alcoholic fatty liver disease.J Gastroenterol Hepatol. 2016; 31: 848-855Crossref PubMed Scopus (30) Google Scholar, 38Friedrich-Rust M. Romen D. Vermehren J. et al.Acoustic radiation force i