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Quantification of Liver Fat Content with Ultrasound: A WFUMB Position Paper

      Abstract

      New ultrasound methods that can be used to quantitatively assess liver fat content have recently been developed. These quantitative ultrasound (QUS) methods are based on the analysis of radiofrequency echoes detected by the transducer, allowing calculation of parameters for quantifying the fat in the liver. In this position paper, after a section dedicated to the importance of quantifying liver steatosis in patients with non-alcoholic fatty liver disease and another section dedicated to the assessment of liver fat with magnetic resonance, the current clinical studies performed using QUS are summarized. These new methods include spectral-based techniques and techniques based on envelope statistics. The spectral-based techniques that have been used in clinical studies are those estimating the attenuation coefficient and those estimating the backscatter coefficient. Clinical studies that have used tools based on the envelope statistics of the backscattered ultrasound are those performed by using the acoustic structure quantification or other parameters derived from it, such as the normalized local variance, and that performed by estimating the speed of sound. Experts’ opinions are reported.

      Key Words

      Introduction

      The assessment of steatosis (liver fat content) is relevant in patients suspected of, or diagnosed with, chronic liver diseases. Steatosis is usually a diffuse process within the liver tissue, but a non-uniform distribution can sometimes be observed (focal fatty changes or zonal/regional steatosis, focal or segmental sparing).
      Conventional B-mode ultrasound (US) is the imaging modality most widely used for the non-invasive assessment of liver steatosis. Fatty liver infiltration is characterized by hyperechogenicity of the liver parenchyma and increasing attenuation of the US waves in the deeper parts with increasing steatosis (
      • Barr RG.
      Ultrasound of diffuse liver disease including elastography.
      ). The US findings of liver steatosis are based on the assessment of liver echogenicity, hepatorenal echo contrast, visualization of intrahepatic vessels and visualization of the liver parenchyma and the diaphragm. US evaluation of fatty livers relies on operator expertise; moreover, there is a subjective estimate of the entity of fatty infiltration in the liver, with a reported sensitivity of 60.9%–65.0% for the detection of mild steatosis (fat content >5% but <33%) (
      • Ferraioli G
      • Soares Monteiro LB.
      Ultrasound-based techniques for the diagnosis of liver steatosis.
      ). Despite these limitations, it must be highlighted that, as of today, B-mode US is the preferred first-line diagnostic imaging procedure suggested in adults with non-alcoholic fatty liver disease (NAFLD) by the clinical practice guidelines of the European Association for the Study of the Liver released together with the European Association for the Study of Diabetes and the European Association for the Study of Obesity (European Association for the Study of the
      European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
      ).
      New US methods able to quantitatively assess liver fat content have recently been developed. These quantitative US (QUS) methods are based on analysis of the radiofrequency (RF) echoes detected by the transducer, allowing calculation of parameters for quantifying the fat content in the liver. When an ultrasonic wave propagates through soft tissue, an interaction occurs between the mechanical energy of the wave and the local structure, generating energy absorption, reflection and scattering. The energy propagated back toward the ultrasonic transducer constitutes the ultrasonic echo signal called the RF signal. The RF signal contains a wealth of information and structural details that usually become lost during machine processing to produce the B-mode representation. In QUS, the RF data of the backscattered US signals are used; therefore, the measurement is not affected by the post-processing of the acquired data or by the settings of the US system.
      For decades, liver biopsy has been considered the reference standard for quantifying liver steatosis. At histology, the amount of fat in the liver is graded as S0, steatosis in <5% of hepatocytes; S1, 5%–33%; S2, 34%–66%; and S3, >66% (
      • Kleiner DE
      • Brunt EM
      • Van Natta M
      • Behling C
      • Contos MJ
      • Cummings OW
      • Ferrell LD
      • Liu YC
      • Torbenson MS
      • Unalp-Arida A
      • Yeh M
      • McCullough AJ
      • Sanyal AJ.
      Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
      ). Besides being invasive and not free of risk, liver biopsy is impractical for assessing liver fat content in the large number of NAFLD patients who may have simple steatosis, which constitute the majority of cases. On the other hand, liver steatosis is a dynamic process that may change in short periods, requiring a non-invasive technique that can be repeated multiple times to accurately assess progression or regression of disease.
      This World Federation for Ultrasound in Medicine and Biology position paper reports the utility of quantifying liver fat content in NAFLD and analyzes the literature on the currently available non-invasive methods for fat quantification, giving guidance on their use either in clinical settings or in research studies. A section is dedicated to the assessment of liver fat with magnetic resonance, which is currently an accepted reference standard (
      • El-Badry AM
      • Breitenstein S
      • Jochum W
      • Washington K
      • Paradis V
      • Rubbia-Brandt L
      • Puhan MA
      • Slankamenac K
      • Graf R
      • Clavien PA.
      Assessment of hepatic steatosis by expert pathologists: the end of a gold standard.
      ;
      • Roldan-Valadez E
      • Favila R
      • Martinez-Lopez M
      • Uribe M
      • Rios C
      • Mendez-Sanchez N.
      In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty liver disease: Correlation with biochemical method and morphometry.
      ;
      • Raptis DA
      • Fischer MA
      • Graf R
      • Nanz D
      • Weber A
      • Moritz W
      • Tian Y
      • Oberkofler CE
      • Clavien PA.
      MRI: The new reference standard in quantifying hepatic steatosis?.
      ;
      • Noureddin M
      • Lam J
      • Peterson MR
      • Middleton M
      • Hamilton G
      • Le TA
      • Bettencourt R
      • Changchien C
      • Brenner DA
      • Sirlin C
      • Loomba R.
      Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials.
      ;
      • Caussy C
      • Alquiraish MH
      • Nguyen P
      • Hernandez C
      • Cepin S
      • Fortney LE
      • Ajmera V
      • Bettencourt R
      • Collier S
      • Hooker J
      • Sy E
      • Rizo E
      • Richards L
      • Sirlin CB
      • Loomba R.
      Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis.
      ,
      • Caussy C
      • Reeder SB
      • Sirlin CB
      • Loomba R.
      Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials.
      ). Relevant literature was collected from PubMed database searches. The review of articles was based on the experts’ knowledge of the literature, selecting the articles that were felt to have the highest quality. Opinions were based on evidence from existing publications and discussions between the experts. The statements have gone through multiple rounds of review for comments and refinement, and all authors approved the final versions of the statements.

      NAFLD: Why it is so important to quantify liver steatosis?

      NAFLD is defined by the presence of hepatic fat content (steatosis) in ≥5% of hepatocytes and is currently the most common liver disease worldwide. Its prevalence is proportional to obesity and components of metabolic syndrome, with an estimated prevalence of 5%–30% in the general population depending on geographical area and around 55%–80% in patients with type 2 diabetes (European Association for the Study of the
      European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
      ;
      • Chalasani N
      • Younossi Z
      • Lavine JE
      • Charlton M
      • Cusi K
      • Rinella M
      • Harrison SA
      • Brunt EM
      • Sanyal AJ.
      The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases.
      ;
      • Younossi ZM.
      Non-alcoholic fatty liver disease—A global public health perspective.
      ), resulting in more than 1 billion individuals being affected (
      • Loomba R
      • Sanyal AJ.
      The global NAFLD epidemic.
      ). The spectrum of NAFLD is wide, ranging from simple steatosis to more severe forms, histologically featuring parenchymal inflammation, hepatocyte ballooning and fibrosis associated with increased fat content, termed steatohepatitis (non-alcoholic steatohepatitis [NASH]) (European Association for the Study of the
      European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
      ;
      • Chalasani N
      • Younossi Z
      • Lavine JE
      • Charlton M
      • Cusi K
      • Rinella M
      • Harrison SA
      • Brunt EM
      • Sanyal AJ.
      The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases.
      ) (Table 1). The latter form can progress to end-stage cirrhosis and its complications of portal hypertension, liver dysfunction and hepatocellular carcinoma (European Association for the Study of the et al. 2016;
      • Chalasani N
      • Younossi Z
      • Lavine JE
      • Charlton M
      • Cusi K
      • Rinella M
      • Harrison SA
      • Brunt EM
      • Sanyal AJ.
      The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases.
      ).
      Table 1Histological grading of steatosis and staging of steatohepatitis
      NAS components
      ItemScoreExtent
      Steatosis0<5%
      15%–33%
      2>33%–66%
      3>66%
      Lobular inflammation0No foci
      1<2 foci/200 ×
      22–4 foci/200 ×
      3>4 foci/200 ×
      Hepatocyte ballooning0None
      1Few balloon cells
      2Many cells/prominent ballooning
      Fibrosis stage (not part of NAS)
      ItemScoreExtent
      Fibrosis0None
      1Perisinusoidal or periportal
      1AMild, zone 3, perisinusoidal
      1BModerate, zone 3, perisinusoidal
      1CPortal/periportal
      2Perisinusoidal and portal/periportal
      3Bridging fibrosis
      4Cirrhosis
      NAS score = non-alcoholic fatty liver disease activity score.
      The total NAS score is the sum of scores for steatosis, parenchymal (lobular) inflammation and ballooning, and ranges from 0 to 8. Fibrosis is evaluated separately.
      The diagnosis of NAFLD is based on the presence of three criteria in clinical practice: (i) absence of significant alcohol intake, (ii) presence of hepatic steatosis and (iii) exclusion of other causes of liver diseases. Despite the availability of non-invasive methods to confirm the diagnosis of NAFLD, to grade steatosis and to stage NASH, liver biopsy remains the gold standard. There is a clear need for non-invasive, simpler methods to confirm or exclude the presence of steatosis as the first step in the diagnostic pathway in light of the extremely large number of patients. Furthermore, an accurate non-invasive quantification of steatosis is not only highly desirable at the time of diagnosis, but also repeatedly during the follow-up, especially to monitor the impact of any intervention or occurring event. Such quantification would help in monitoring patients longitudinally together with other non-invasive tools, to identify those who are or are not improving after lifestyle changes and/or upcoming pharmacological therapies for NASH in real-life scenarios, where repeated liver biopsies are at least difficult or usually impossible to obtain.
      Hepatic steatosis not only occurs as a consequence of metabolic syndrome and overweight, but is also frequently observed in patients with chronic liver disease of other etiologies, for instance because of a direct steatogenic effect of the injury (e.g., chronic hepatitis C virus genotype 3 or alcohol-related liver disease), or as an effect of drugs (e.g., steroids, oncology chemotherapy) or in drug-induced liver disease (e.g., psychotropic drugs, chronic non-steroidal anti-inflammatory drugs). Obviously, more than one cause, including the metabolic syndrome, may be present. Importantly, in most settings, the presence and amount of steatosis hold prognostic value. For instance, in the setting of severe fibrosis caused by chronic hepatitis C virus, steatosis accelerates the progression of fibrosis (
      • Leandro G
      • Mangia A
      • Hui J
      • Fabris P
      • Rubbia-Brandt L
      • Colloredo G
      • Adinolfi LE
      • Asselah T
      • Jonsson JR
      • Smedile A
      • Terrault N
      • Pazienza V
      • Giordani MT
      • Giostra E
      • Sonzogni A
      • Ruggiero G
      • Marcellin P
      • Powell EE
      • George J
      • Negro F
      HCV Meta-analysis (on) Individual Patients’ Data Study Group. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: A meta-analysis of individual patient data.
      ), and in patients undergoing liver resection, NAFLD is an independent risk factor for postoperative complications and death (
      • de Meijer VE
      • Kalish BT
      • Puder M
      • Ijzermans JN.
      Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection.
      ). Finally, in the setting of liver transplantation, the presence of macrovesicular steatosis in the graft increases the 1-y risk of graft failure (
      • Spitzer AL
      • Lao OB
      • Dick AA
      • Bakthavatsalam R
      • Halldorson JB
      • Yeh MM
      • Upton MP
      • Reyes JD
      • Perkins JD.
      The biopsied donor liver: Incorporating macrosteatosis into high-risk donor assessment.
      ). It is worth mentioning that small amounts of liver fatty infiltration (i.e., 5%–20%, included in NAFLD activity score 1 for steatosis) may already cause laboratory abnormalities triggering investigations and contribute to disease progression, but are hardly detected and consequently not monitored by current routine imaging techniques such as conventional US. In this regard, it must be highlighted that a recent study in a nationwide Swedish cohort found that the hazard ratio for overall mortality was significantly higher in all NAFLD patients, including those with simple steatosis, than in controls (
      • Simon TG
      • Roelstraete B
      • Khalili H
      • Hagstrom H
      • Ludvigsson JF.
      Mortality in biopsy-confirmed nonalcoholic fatty liver disease: Results from a nationwide cohort.
      ).
      Together these data underline that quantification of steatosis, whatever its cause, may have an important role in the assessment of liver disease in several patients.

      Proton density fat fraction—MRI and MRS: A new reference standard

      Recently developed magnetic resonance (MR) techniques enable accurate non-invasive quantification of liver steatosis. There are two widely used MR techniques for liver fat quantification: MR spectroscopy (MRS, proton MRS in contrast to phosphorus MRS (
      • Abrigo JM
      • Shen J
      • Wong VW
      • Yeung DK
      • Wong GL
      • Chim AM
      • Chan AW
      • Choi PC
      • Chan FK
      • Chan HL
      • Chu WC.
      Non-alcoholic fatty liver disease: Spectral patterns observed from an in vivo phosphorus magnetic resonance spectroscopy study.
      )) and proton density fat fraction (PDFF) derived from MR chemical shift imaging (CSI). In MRS, chemical components within specific tissue can be directly measured as MRS can exhibit a signal intensity peak of specific chemical composition in the tissue on the frequency domain (
      • Cassidy FH
      • Yokoo T
      • Aganovic L
      • Hanna RF
      • Bydder M
      • Middleton MS
      • Hamilton G
      • Chavez AD
      • Schwimmer JB
      • Sirlin CB.
      Fatty liver disease: MR imaging techniques for the detection and quantification of liver steatosis.
      ). In liver tissue, most protons are in the water and fat. MRS of liver parenchyma directly visualizes the water proton as a single peak at 4.7 parts per million (ppm). In contrast, fat protons appear as multiple peaks because of various chemical bonds between the fat protons and other atoms. Because MRS can directly measure the signal intensity of water protons and fat protons, the fat fraction of the liver can be easily obtained as the ratio of signal intensity from the fat protons in the liver divided by the sum of signal intensities originating from both fat and water protons (
      • Lee DH.
      Imaging evaluation of non-alcoholic fatty liver disease: focused on quantification.
      ). Thus, calculation of the fat fraction of the liver using MRS is straightforward in principle. In MRS acquisition, typically a 2 × 2 × 2- to 3 × 3 × 3-cm-sized voxel is manually placed onto the right posterior segment of liver parenchyma, where liver motion is expected to be minimal. MRS images for liver steatosis quantification can also be acquired within a single breath hold because of the large signal intensities from both fat and water protons in the liver. Therefore, a respiratory motion-related artifact is not a problem in MRS (
      • Cassidy FH
      • Yokoo T
      • Aganovic L
      • Hanna RF
      • Bydder M
      • Middleton MS
      • Hamilton G
      • Chavez AD
      • Schwimmer JB
      • Sirlin CB.
      Fatty liver disease: MR imaging techniques for the detection and quantification of liver steatosis.
      ;
      • Pineda N
      • Sharma P
      • Xu Q
      • Hu X
      • Vos M
      • Martin DR.
      Measurement of hepatic lipid: High-speed T2-corrected multiecho acquisition at 1H MR spectroscopy—A rapid and accurate technique.
      ). Although the principle underlying the use of MRS for liver steatosis quantification is straightforward, biases including, the T1 and T2 relaxation effects, still exist. The use of long repetition times can minimize the T1 relaxation effect, and the use of multiple echo data obtained from different echo times can correct the T2 relaxation effect. Many previous studies have reported the excellent diagnostic performance of MRS in quantifying liver steatosis, and MRS has outperformed computed tomography (CT) and US in the detection of mild degrees of liver steatosis (
      • Lee SS
      • Park SH
      • Kim HJ
      • Kim SY
      • Kim MY
      • Kim DY
      • Suh DJ
      • Kim KM
      • Bae MH
      • Lee JY
      • Lee SG
      • Yu ES.
      Non-invasive assessment of hepatic steatosis: Prospective comparison of the accuracy of imaging examinations.
      ;
      • Bohte AE
      • Koot BG
      • van der Baan-Slootweg OH
      • van Werven JR
      • Bipat S
      • Nederveen AJ
      • Jansen PL
      • Benninga MA
      • Stoker J.
      US cannot be used to predict the presence or severity of hepatic steatosis in severely obese adolescents.
      ). Moreover, several studies reported that MRS could reflect actual fat content in the liver assessed by biochemical lipid assays more accurately than the histopathology examination, which is the gold standard method (
      • Roldan-Valadez E
      • Favila R
      • Martinez-Lopez M
      • Uribe M
      • Rios C
      • Mendez-Sanchez N.
      In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty liver disease: Correlation with biochemical method and morphometry.
      ;
      • Raptis DA
      • Fischer MA
      • Graf R
      • Nanz D
      • Weber A
      • Moritz W
      • Tian Y
      • Oberkofler CE
      • Clavien PA.
      MRI: The new reference standard in quantifying hepatic steatosis?.
      ). In addition, MRS provides excellent measurement reproducibility, which is another limitation of histopathology assessment stemming from the large intra- and inter-observer variability between different pathologists (
      • El-Badry AM
      • Breitenstein S
      • Jochum W
      • Washington K
      • Paradis V
      • Rubbia-Brandt L
      • Puhan MA
      • Slankamenac K
      • Graf R
      • Clavien PA.
      Assessment of hepatic steatosis by expert pathologists: the end of a gold standard.
      ). One important limitation of MRS is a small voxel size, usually less than 3 × 3 × 3 cm, covering only small portion of the liver. Because of this small voxel size, accurate quantification of liver steatosis using MRS might be limited for patients with uneven fat infiltration in the liver.
      Since Dixon first described the basic principle (
      • Dixon WT.
      Simple proton spectroscopic imaging.
      ), CSI MR imaging has been widely used for quantitative assessment of liver steatosis because of its excellent diagnostic performance and easy applicability. In contrast to MRS, which can directly measure the signal intensity originating from the specific chemical composition on the frequency domain, CSI uses the difference in resonance frequency between protons in water and protons in fat: protons in water precess slightly faster than protons in fat by about 3.5 ppm, and thus, two protons oscillate at regular intervals (
      • Cassidy FH
      • Yokoo T
      • Aganovic L
      • Hanna RF
      • Bydder M
      • Middleton MS
      • Hamilton G
      • Chavez AD
      • Schwimmer JB
      • Sirlin CB.
      Fatty liver disease: MR imaging techniques for the detection and quantification of liver steatosis.
      ). On the opposed phase (OP), the signals from fat protons are subtracted from the signals from water protons because the vectors from two protons are in opposite directions. However, on in-phase (IP), the signals from the fat protons add to the signals from the water protons because the vectors from two protons are in the same direction. IP and OP repeat at regular intervals, which is affected by magnetic field strength B0: For example, 4.6 ms in a 1.5-T MR unit (
      • Lee SS
      • Park SH.
      Radiologic evaluation of nonalcoholic fatty liver disease.
      ). The amount of signal intensity from fat protons can be obtained by calculating the signal intensity difference between IP and OP, and thereby, PDFF can be obtained. For the simplest method, dual-echo CSI, PDFF can be calculated using an OP and IP pair. However, dual-echo CSI has several intrinsic biases, such as the T1 relaxation effect and the T2*-related signal decay in the quantification of liver steatosis. The T1 relaxation time differs between water protons and fat protons, and this difference in the T1 relaxation time affects the signal intensities on both IP and OP. To minimize the T1 relaxation effect, a low flip angle can be used. When the T2*-related signal decay is markedly enhanced by the presence of paramagnetic substances such as iron in the liver, the signal intensity of IP can markedly decrease compared with that of OP because the transient elastography (TE) of IP is longer than that of OP. In this situation, the calculation of PDFF from dual-echo CSI has an error in quantifying liver steatosis (
      • Westphalen AC
      • Qayyum A
      • Yeh BM
      • Merriman RB
      • Lee JA
      • Lamba A
      • Lu Y
      • Coakley FV.
      Liver fat: Effect of hepatic iron deposition on evaluation with opposed-phase MR imaging.
      ). Use of the multiple echo acquisition method, usually using six echoes, can correct the T2*-related signal decay, enabling the accurate quantification of liver steatosis (
      • O'Regan DP
      • Callaghan MF
      • Wylezinska-Arridge M
      • Fitzpatrick J
      • Naoumova RP
      • Hajnal JV
      • Schmitz SA.
      Liver fat content and T2*: Simultaneous measurement by using breath-hold multiecho MR imaging at 3.0 T—Feasibility.
      ;
      • Guiu B
      • Petit JM
      • Loffroy R
      • Ben Salem D
      • Aho S
      • Masson D
      • Hillon P
      • Krause D
      • Cercueil JP
      Quantification of liver fat content: Comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy.
      ). In contrast to water protons, fat protons have a complex chemical composition, with multiple peaks with slightly different resonance frequencies. To reflect the chemical complexity of the fat protons, spectral fat modeling was recently introduced. Thus, derivation of the PDFF from CSI with T1-independent, T2*-corrected multi-echo CSI and spectral fat modeling enables accurate quantification of liver steatosis with excellent results (
      • Hines CD
      • Yu H
      • Shimakawa A
      • McKenzie CA
      • Brittain JH
      • Reeder SB.
      T1 independent, T2* corrected MRI with accurate spectral modeling for quantification of fat: Validation in a fat–water–SPIO phantom.
      ;
      • Reeder SB
      • Robson PM
      • Yu H
      • Shimakawa A
      • Hines CD
      • McKenzie CA
      • Brittain JH.
      Quantification of hepatic steatosis with MRI: The effects of accurate fat spectral modeling.
      ). In addition, the PDFF derived from CSI can cover the entire liver, allowing the accurate quantification of liver steatosis even in patients with uneven fat infiltration, which is an important limitation of MRS. Although the two modalities involve different techniques and regions of interest, head-to-head comparisons revealed that MRS and PDFF from CSI correlate excellently with each other (
      • Noureddin M
      • Lam J
      • Peterson MR
      • Middleton M
      • Hamilton G
      • Le TA
      • Bettencourt R
      • Changchien C
      • Brenner DA
      • Sirlin C
      • Loomba R.
      Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials.
      ). For practical purposes, studies using either of these techniques can be directly compared.
      In summary, both MRS and the PDFF derived from T1-independent T2*-corrected multi-echo CSI with spectral fat modeling provide excellent diagnostic performance in quantifying liver steatosis (
      • Roldan-Valadez E
      • Favila R
      • Martinez-Lopez M
      • Uribe M
      • Rios C
      • Mendez-Sanchez N.
      In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty liver disease: Correlation with biochemical method and morphometry.
      ;
      • Raptis DA
      • Fischer MA
      • Graf R
      • Nanz D
      • Weber A
      • Moritz W
      • Tian Y
      • Oberkofler CE
      • Clavien PA.
      MRI: The new reference standard in quantifying hepatic steatosis?.
      ;
      • Noureddin M
      • Lam J
      • Peterson MR
      • Middleton M
      • Hamilton G
      • Le TA
      • Bettencourt R
      • Changchien C
      • Brenner DA
      • Sirlin C
      • Loomba R.
      Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials.
      ;
      • Caussy C
      • Alquiraish MH
      • Nguyen P
      • Hernandez C
      • Cepin S
      • Fortney LE
      • Ajmera V
      • Bettencourt R
      • Collier S
      • Hooker J
      • Sy E
      • Rizo E
      • Richards L
      • Sirlin CB
      • Loomba R.
      Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis.
      ). Currently, both MR techniques are widely accepted non-invasive methods for diagnosing and quantifying liver steatosis and are used in many clinical trials as an alternative reference standard method to liver biopsy (
      • El-Badry AM
      • Breitenstein S
      • Jochum W
      • Washington K
      • Paradis V
      • Rubbia-Brandt L
      • Puhan MA
      • Slankamenac K
      • Graf R
      • Clavien PA.
      Assessment of hepatic steatosis by expert pathologists: the end of a gold standard.
      ;
      • Caussy C
      • Reeder SB
      • Sirlin CB
      • Loomba R.
      Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials.
      ).

      Conventional B-mode US

      Fatty liver infiltration is characterized by hyperechogenicity of the liver parenchyma and increasing attenuation of the US waves in the deeper parts with increasing steatosis. With US, this feature of “bright liver” (diffuse, smooth and tightly packed echoes) is often eye catching and enables instant diagnosis (
      • Barr RG.
      Ultrasound of diffuse liver disease including elastography.
      ). However, grading of steatosis with US is more difficult as the operator has to assess the amount of fatty infiltration qualitatively based on a subjective visual impression. The degree of hepatic steatosis is usually graded using a 4-point scale: normal (grade 0), mild (grade 1), moderate (grade 2) and severe (grade 3) (
      • Barr RG.
      Ultrasound of diffuse liver disease including elastography.
      ) (Fig. 1). However, particularly in the mild forms of steatosis, ultrasound B-mode has limited accuracy in assessing mild changes in steatosis over time (
      • Barr RG.
      Ultrasound of diffuse liver disease including elastography.
      ).
      Fig 1
      Fig. 1B-Mode findings in steatosis. With increasing steatosis (fatty deposition), the echogenicity of the liver increases, and visualization of the vascular structure changes. (a) Normal. (b) Grade 1. (c) Grade 2. (d) Grade 3. Note the difference in visualization of the vessels at the various grades of liver steatosis.
      In a meta-analysis performed on 34 studies comprising 2815 patients with liver biopsy as a reference standard, the pooled sensitivity and specificity of US in differentiating between no steatosis and moderate/severe steatosis were respectively 85% and 93% (
      • Hernaez R
      • Lazo M
      • Bonekamp S
      • Kamel I
      • Brancati FL
      • Guallar E
      • Clark JM.
      Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: A meta-analysis.
      ). In a prospective study, US was 90% sensitive in detecting steatosis in ≥20% of hepatocytes, but it became less sensitive for lower degrees of liver fat content (
      • Dasarathy S
      • Dasarathy J
      • Khiyami A
      • Joseph R
      • Lopez R
      • McCullough AJ.
      Validity of real time ultrasound in the diagnosis of hepatic steatosis: A prospective study.
      ).
      Semiquantitatively, steatosis on US can be defined as mild when the echogenicity of the liver is minimally increased and as moderate when posterior beam attenuation is absent or limited to posterior segments of the right lobe of the liver (impaired diaphragm visualization) and the echogenicity of the walls of the portal vessels is reduced; severe steatosis is defined when posterior beam attenuation impairs the visualization of anterior segments of the liver, and blurring of intrahepatic vessels is observed (
      • Scatarige JC
      • Scott WW
      • Donovan PJ
      • Siegelman SS
      • Sanders RC.
      Fatty infiltration of the liver: ultrasonographic and computed tomographic correlation.
      ).
      Steatosis is often homogenously distributed in the liver, but 10%–15% manifest an atypical non-homogenous distribution. Focal fatty changes are hyperechogenic parts of the liver (most often located close to the gallbladder or adjacent to ligaments and to the portal vein, rarely multifocal), typically with geographic shape. In contrast, hypo-echogenic areas are termed focal sparing and represent different concentrations of steatosis.
      From a practical point of view, a US imaging pointing out steatosis implies the presence of at least 20% hepatic fat content. However, smaller amounts of steatosis cannot be reliably detected by standard B-mode US.
      Given these observations, accurate methods to exactly and numerically quantify steatosis by sonography in different areas of interest have been developed and are described in this article.

      Semiquantitative method: Computerized calculation of the hepatorenal index

      In 1996 a method was developed to diagnose fatty livers based on histogram analysis comparing liver and renal cortex echo amplitudes (
      • Osawa H
      • Mori Y.
      Sonographic diagnosis of fatty liver using a histogram technique that compares liver and renal cortical echo amplitudes.
      ). The hepatorenal index (HRI) was later defined as the ratio of the echo intensities of the liver parenchyma and renal cortex. A significant correlation was found between histologic steatosis and the HRI. Furthermore, HRI was reported to be an accurate method for quantification of hepatic steatosis, with an accuracy >90%, and highly correlated with MRI-PDFF in patients without advanced liver fibrosis (
      • Mancini M
      • Prinster A
      • Annuzzi G
      • Liuzzi R
      • Giacco R
      • Medagli C
      • Cremone M
      • Clemente G
      • Maurea S
      • Riccardi G
      • Rivellese AA
      • Salvatore M.
      Sonographic hepatic–renal ratio as indicator of hepatic steatosis: Comparison with 1H magnetic resonance spectroscopy.
      ;
      • Webb M
      • Yeshua H
      • Zelber-Sagi S
      • Santo E
      • Brazowski E
      • Halpern Z
      • Oren R
      Diagnostic value of a computerized hepatorenal index for sonographic quantification of liver steatosis.
      ;
      • Marshall RH
      • Eissa M
      • Bluth EI
      • Gulotta PM
      • Davis NK.
      Hepatorenal index as an accurate, simple, and effective tool in screening for steatosis.
      ). One way of estimating HRI is to use echolevel measurements of the mean intensity of pixels within a user-defined area. In some scanners, the intensity data from raw data per pixel are used to calculate the average intensity of pixels. Raw data pixel measurements imply that there is no influence of gain, dynamic range, time-gain compensation or other scanner parameters. HRI can also be given as a difference between liver and kidney echo intensities. The HRI method was further developed by adding fuzzy stretching, edge tracking and a neural learning algorithm (
      • Kim KB
      • Kim CW.
      Quantification of hepatorenal index for computer-aided fatty liver classification with self-organizing map and fuzzy stretching from ultrasonography.
      ). Currently, several manufacturers offer the possibility of automatically calculating the HRI using their US systems. In a recent study, liver/kidney B-mode ratio was calculated using the Aixplorer system (Hologic Co., Marlborough, MA, USA, formerly Supersonic Imagine) in a series of patients who underwent liver biopsy and controlled attenuation parameter (CAP) evaluation on the same day (
      • Moret A
      • Boursier J
      • Houssel Debry P
      • Riou J
      • Crouan A
      • Dubois M
      • Michalak Provost S
      • Aube C
      • Paisant A
      Evaluation of the hepatorenal B-mode ratio and the “controlled attenuation parameter” for the detection and grading of steatosis [e-pub ahead of print].
      ). Both B-mode ratio and CAP performed well in detecting liver steatosis but had limited value in differentiating higher grades of steatosis. The areas under the receiver operating characteristic curves (AUROCs) of B-mode ratio for S ≥1, S ≥2 and S=3 were, respectively, 0.90, 0.77 and 0.73, and the best cutoff values were 1.22 for S ≥1 (sensitivity = 76.4%, specificity = 93.2%), 1.42 for S ≥2 (sensitivity = 70.2%, specificity = 71.2%) and 1.54 for S = 3 (sensitivity = 68.4%, specificity = 69.8%). The B-mode ratio was better at ruling in, and the CAP was better at ruling out, liver steatosis. Spearman's correlation coefficient was 0.57 for the correlation with morphometry and 0.61 for the correlation with MRI (Fig. 2).
      Fig 2
      Fig. 2Hepatorenal index (HRI). In this case of a patient with non-alcoholic fatty liver disease, regions of interest were placed in the liver and kidney at the same depth, and the system calculated the HRI. In this case, the result is 1.19, suggestive of moderate steatosis.

      Quantitative US imaging techniques for fat quantification

      Newer US techniques include the spectral-based techniques and the techniques based on envelope statistics. The spectral-based techniques that have been used in clinical studies are that estimating the attenuation coefficient (AC) and that estimating the backscatter coefficient. The AC measures the loss of US energy in tissue, whereas the backscatterer coefficient is a measure of the US energy returned from tissue, which is related to tissue microstructure (
      • Oelze ML
      • Mamou J.
      Review of quantitative ultrasound: Envelope statistics and backscatter coefficient imaging and contributions to diagnostic ultrasound.
      ). Clinical studies that have used tools based on the envelope statistics of the backscattered US are those performed by using the acoustic structure quantification (ASQ) or other parameters derived from ASQ, such as the normalized local variance (NLV), and that based on the estimation of the speed of sound.

      QUS: Spectral-based parameters

      Techniques based on calculation of the attenuation coefficient

      These techniques calculate the attenuation of the US beam transmitted into the tissue by analyzing the RF echo signals detected by the transducer. The techniques for which there are published clinical studies are CAP, available on the Fibroscan system (Echosens, Paris, France); 2-D attenuation imaging (ATI) on the Aplio i800 (or higher) series US systems (Canon Medical Systems, Otawara, Japan), attenuation coefficient (ATT) on the Aloka-Arietta systems (Fujifilm, previously Hitachi Ltd., Japan), the US-guided attenuation parameter (UGAP) on the LOGIQ E9 (or higher) series (General Electric, Schenectady, NY, USA) and the US-derived fat fraction (UDFF) on the Acuson S3000 or Sequoia US platform (Siemens Healthineers, Erlangen, Germany). This list may become longer after the publication of this article.

      Controlled attenuation parameter (EchoSens)

      The CAP is a tool available since 2010, and hundreds of studies have been published to date. It has become a point-of-care technique for the quantification of liver steatosis, even though a large overlap between consecutive grades of liver steatosis does exist. Here we report on the value of CAP in the diagnostic workup of patients with chronic liver disease based on published studies.

      Technical aspects

      The CAP, available on the FibroScan 502 Touch and 630 systems, was the first tool commercially available for the quantification of liver steatosis through calculation of an AC (Fig. 3). The CAP measures the attenuation of the US beam as it traverses the liver tissue, and the results are given in decibels per meter (dB/m), ranging from 100–400 dB/m. CAP is measured at the same time, on the same volume and on the same signal as liver stiffness measurement (LSM) with TE (
      • Sasso M
      • Beaugrand M
      • de Ledinghen V
      • Douvin C
      • Marcellin P
      • Poupon R
      • Sandrin L
      • Miette V.
      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.
      ). The CAP measurements, which were initially available only with the medium (M) probe, have also been implemented on the extra large (XL) probe. The software of the FibroScan system automatically controls the choice of the probe based on the skin-to-liver capsule distance. Generally, the XL probe is chosen when this distance is >25 mm. The rate of failures is around 3% when both probes are available (
      • Vuppalanchi R
      • Siddiqui MS
      • Van Natta ML
      • Hallinan E
      • Brandman D
      • Kowdley K
      • Neuschwander-Tetri BA
      • Loomba R
      • Dasarathy S
      • Abdelmalek M
      • Doo E
      • Tonascia JA
      • Kleiner DE
      • Sanyal AJ
      • Chalasani N
      • Network NCR.
      Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease.
      ;
      • Eddowes PJ
      • Sasso M
      • Allison M
      • Tsochatzis E
      • Anstee QM
      • Sheridan D
      • Guha IN
      • Cobbold JF
      • Deeks JJ
      • Paradis V
      • Bedossa P
      • Newsome PN.
      Accuracy of FibroScan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease.
      ). The agreement in measurements between observers is high (intraclass correlation coefficient [ICC] = 0.82–0.84), but it seems to decrease in subjects with body mass index >30 kg/m2, for CAP values <240 dB/m or with the use of the XL probe (
      • Recio E
      • Cifuentes C
      • Macias J
      • Mira JA
      • Parra-Sanchez M
      • Rivero-Juarez A
      • Almeida C
      • Pineda JA
      • Neukam K.
      Interobserver concordance in controlled attenuation parameter measurement, a novel tool for the assessment of hepatic steatosis on the basis of transient elastography.
      ;
      • Ferraioli G
      • Tinelli C
      • Lissandrin R
      • Zicchetti M
      • Rondanelli M
      • Perani G
      • Bernuzzi S
      • Salvaneschi L
      • Filice C.
      Interobserver reproducibility of the controlled attenuation parameter (CAP) for quantifying liver steatosis.
      ;
      • Vuppalanchi R
      • Siddiqui MS
      • Van Natta ML
      • Hallinan E
      • Brandman D
      • Kowdley K
      • Neuschwander-Tetri BA
      • Loomba R
      • Dasarathy S
      • Abdelmalek M
      • Doo E
      • Tonascia JA
      • Kleiner DE
      • Sanyal AJ
      • Chalasani N
      • Network NCR.
      Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease.
      ).
      Fig 3
      Fig. 3Controlled attenuation parameter (CAP) by Echosens. A patient with non-alcoholic fatty liver disease with severe steatosis. The Fibroscan system gives the attenuation coefficient in decibels per meter together with the stiffness assessment in kilopascals.
      No specific quality criteria are provided by the manufacturer; therefore, in published studies, investigators have generally used those recommended for LSM. There are conflicting results on specific quality criteria: One study found that the accuracy of CAP increased when the interquartile range of 10 acquisitions was ≤40 dB/m (
      • Wong VW
      • Petta S
      • Hiriart JB
      • Camma C
      • Wong GL
      • Marra F
      • Vergniol J
      • Chan AW
      • Tuttolomondo A
      • Merrouche W
      • Chan HL
      • Le Bail B
      • Arena U
      • Craxi A
      • de Ledinghen V
      Validity criteria for the diagnosis of fatty liver by M probe-based controlled attenuation parameter.
      ), another study reported that this value should be <30 dB/m (
      • Caussy C
      • Alquiraish MH
      • Nguyen P
      • Hernandez C
      • Cepin S
      • Fortney LE
      • Ajmera V
      • Bettencourt R
      • Collier S
      • Hooker J
      • Sy E
      • Rizo E
      • Richards L
      • Sirlin CB
      • Loomba R.
      Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis.
      ), whereas a subsequent study did not confirm these findings (
      • Eddowes PJ
      • Sasso M
      • Allison M
      • Tsochatzis E
      • Anstee QM
      • Sheridan D
      • Guha IN
      • Cobbold JF
      • Deeks JJ
      • Paradis V
      • Bedossa P
      • Newsome PN.
      Accuracy of FibroScan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease.
      ). In the last study, all included patients underwent liver biopsy for NAFLD, which raises questions regarding patients lacking steatosis on biopsy (“controls”). Because this finding could be owing to sampling variability or fluctuating liver fat, the study might be suboptimal in evaluating the quality criteria of CAP, and new studies on the topic are needed.

      Value of CAP in NASH

      As the presence of steatosis in ≥5% of hepatocytes is the basis for diagnosis of NAFLD (European Association for the Study of the
      European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
      ;
      • Wong VW
      • Petta S
      • Hiriart JB
      • Camma C
      • Wong GL
      • Marra F
      • Vergniol J
      • Chan AW
      • Tuttolomondo A
      • Merrouche W
      • Chan HL
      • Le Bail B
      • Arena U
      • Craxi A
      • de Ledinghen V
      Validity criteria for the diagnosis of fatty liver by M probe-based controlled attenuation parameter.
      ;
      • Chalasani N
      • Younossi Z
      • Lavine JE
      • Charlton M
      • Cusi K
      • Rinella M
      • Harrison SA
      • Brunt EM
      • Sanyal AJ.
      The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases.
      ), there has been much interest in the evaluation of CAP as a diagnostic and monitoring tool for NAFLD. In an individual patient data meta-analysis of 19 studies including patients with different etiologies (20% with NAFLD), CAP had an AUROC of 0.82 in detecting any hepatic steatosis, with 69% sensitivity and 82% specificity at a cutoff of 248 dB/m (
      • Karlas T
      • Petroff D
      • Sasso M
      • Fan JG
      • Mi YQ
      • de Ledinghen V
      • Kumar M
      • Lupsor-Platon M
      • Han KH
      • Cardoso AC
      • Ferraioli G
      • Chan WK
      • Wong VW
      • Myers RP
      • Chayama K
      • Friedrich-Rust M
      • Beaugrand M
      • Shen F
      • Hiriart JB
      • Sarin SK
      • Badea R
      • Jung KS
      • Marcellin P
      • Filice C
      • Mahadeva S
      • Wong GL
      • Crotty P
      • Masaki K
      • Bojunga J
      • Bedossa P
      • Keim V
      • Wiegand J.
      Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis.
      ). In another systematic review and meta-analysis of 9 studies involving 1297 patients with biopsy-proven NAFLD, the pooled sensitivity and specificity of CAP for mild steatosis were 87% and 91%, respectively (
      • Pu K
      • Wang Y
      • Bai S
      • Wei H
      • Zhou Y
      • Fan J
      • Qiao L.
      Diagnostic accuracy of controlled attenuation parameter (CAP) as a non-invasive test for steatosis in suspected non-alcoholic fatty liver disease: A systematic review and meta-analysis.
      ). One study from the United States used MRI-PDFF as the reference standard in 119 adults with suspected NAFLD. While CAP also had an AUROC of 0.80 for an MRI-PDFF ≥5%, the optimal CAP cutoff was 288 dB/m (
      • Caussy C
      • Reeder SB
      • Sirlin CB
      • Loomba R.
      Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials.
      ). A higher CAP cutoff value for the diagnosis of steatosis in NAFLD has been confirmed in a very recent individual patient data meta-analysis reporting an optimal cutoff of 294 dB/m in the 1277 NAFLD subjects (
      • Petroff D
      • Blank V
      • Newsome PN
      • Shalimar
      • Voican CS
      • Thiele M
      • de Ledinghen V
      • Baumeler S
      • Chan WK
      • Perlemuter G
      • Cardoso AC
      • Aggarwal S
      • Sasso M
      • Eddowes PJ
      • Allison M
      • Tsochatzis E
      • Anstee QM
      • Sheridan D
      • Cobbold JF
      • Naveau S
      • Lupsor-Platon M
      • Mueller S
      • Krag A
      • Irles-Depe M
      • Semela D
      • Wong GL
      • Wong VW
      • Villela-Nogueira CA
      • Garg H
      • Chazouilleres O
      • Wiegand J
      • Karlas T
      Assessment of hepatic steatosis by controlled attenuation parameter using the M and XL probes: An individual patient data meta-analysis.
      ). This difference in cutoffs is likely owing to a spectrum effect caused by the inclusion of higher risk patients with higher CAP values in general (
      • Ferraioli G.
      CAP for the detection of hepatic steatosis in clinical practice.
      ).
      Because CAP is a point-of-care test that can be performed simultaneously with liver stiffness measurement, a few studies have used this technique to determine the prevalence of NAFLD and advanced fibrosis in the general population or among high-risk patients such as those with type 2 diabetes (
      • Kwok R
      • Choi KC
      • Wong GL
      • Zhang Y
      • Chan HL
      • Luk AO
      • Shu SS
      • Chan AW
      • Yeung MW
      • Chan JC
      • Kong AP
      • Wong VW.
      Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: A prospective cohort study.
      ;
      • Petta S
      • Di Marco V
      • Pipitone RM
      • Grimaudo S
      • Buscemi C
      • Craxi A
      • Buscemi S.
      Prevalence and severity of nonalcoholic fatty liver disease by transient elastography: Genetic and metabolic risk factors in a general population.
      ;
      • Lee HW
      • Wong GL
      • Kwok R
      • Choi KC
      • Chan CK
      • Shu SS
      • Leung JK
      • Chim AM
      • Luk AO
      • Ma RC
      • Chan HL
      • Chan JC
      • Kong AP
      • Wong VW.
      Serial transient elastography examinations to monitor patients with type 2 diabetes: A prospective cohort study.
      ). What is less clear is the use of CAP to monitor changes in hepatic steatosis during routine follow-up or in clinical trials. In a phase 2a study, PF-05221304, an acetyl-CoA carboxylase inhibitor, reduced both CAP and MRI-PDFF in a dose–response manner, though CAP appeared to be less discriminating (
      • Tuthill T
      • Carvajal-Gonzalez S
      • Amin N.
      Ultrasound-based controlled attenuation parameter (CAP) to detect longitudinal changes in liver fat when effect size is large—Experience from a phase 2a, dose-ranging study assessing MRI-proton density fat fraction (PDFF) and CAP in parallel.
      ). Future studies need to correlate CAP changes with serial liver histology and define the change in CAP that is clinically meaningful.

      Value of CAP in other liver diseases

      CAP is useful in detecting the presence of fatty liver in patients with other chronic liver diseases, namely, chronic hepatitis B (
      • Chan WK
      • Nik Mustapha NR
      • Mahadeva S
      Controlled attenuation parameter for the detection and quantification of hepatic steatosis in nonalcoholic fatty liver disease.
      ), chronic hepatitis C (
      • Sasso M
      • Tengher-Barna I
      • Ziol M
      • Miette V
      • Fournier C
      • Sandrin L
      • Poupon R
      • Cardoso AC
      • Marcellin P
      • Douvin C
      • de Ledinghen V
      • Trinchet JC
      • Beaugrand M.
      Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan((R)): Validation in chronic hepatitis C.
      ), alcohol-related liver disease and other chronic liver diseases (
      • de Ledinghen V
      • Vergniol J
      • Foucher J
      • Merrouche W
      • le Bail B.
      Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography.
      ). CAP results are available simultaneously with LSMs when a patient is undergoing TE examination (
      • Wong GL.
      Non-invasive assessments for liver fibrosis: The crystal ball we long for.
      ); hence, it is a convenient non-invasive method for screening fatty liver in patients with known or suspected chronic liver diseases (
      • Shi KQ
      • Tang JZ
      • Zhu XL
      • Ying L
      • Li DW
      • Gao J
      • Fang YX
      • Li GL
      • Song YJ
      • Deng ZJ
      • Wu JM
      • Tang KF.
      Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: A meta-analysis of diagnostic accuracy.
      ).

      Prognostic value of CAP

      While the presence of metabolic syndrome (which is closely related to hepatic steatosis) increases the risk of liver fibrosis progression and cirrhosis in patients with chronic hepatitis B (
      • Wong GL
      • Wong VW
      • Choi PC
      • Chan AW
      • Chim AM
      • Yiu KK
      • Chan HY
      • Chan FK
      • Sung JJ
      • Chan HL.
      Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B.
      ,
      • Wong GL
      • Chan HL
      • Yu Z
      • Chan AW
      • Choi PC
      • Chim AM
      • Chan HY
      • Tse CH
      • Wong VW.
      Coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B—A prospective cohort study with paired transient elastography examinations.
      ) and chronic hepatitis C (
      • Everhart JE
      • Lok AS
      • Kim HY
      • Morgan TR
      • Lindsay KL
      • Chung RT
      • Bonkovsky HL
      • Ghany MG
      Group HALT-C Trial Group
      Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial.
      ), CAP was not significantly associated with liver-related events, cancer or cardiovascular events in the largest study published so far, neither in the overall population, nor in a subgroup of 1542 consecutive patients with CAP ≥248 dB/m and no other causes of liver disease (NAFLD population) (
      • Liu K
      • Wong VW
      • Lau K
      • Liu SD
      • Tse YK
      • Yip TC
      • Kwok R
      • Chan AY
      • Chan HL
      • Wong GL.
      Prognostic value of controlled attenuation parameter by transient elastography.
      ). Three additional studies focused on patients with compensated advanced chronic liver disease as defined as liver stiffness by TE >10 kPa. Two of them included a minority of NASH patients (15% in both), and CAP exhibited no association with prognosis in one (
      • Scheiner B
      • Steininger L
      • Semmler G
      • Unger LW
      • Schwabl P
      • Bucsics T
      • Paternostro R
      • Ferlitsch A
      • Trauner M
      • Reiberger T
      • Mandorfer M.
      Controlled attenuation parameter does not predict hepatic decompensation in patients with advanced chronic liver disease.
      ) and a mild, but significant positive association with liver-related events in another one (
      • Margini C
      • Murgia G
      • Stirnimann G
      • De Gottardi A
      • Semmo N
      • Casu S
      • Bosch J
      • Dufour JF
      • Berzigotti A.
      Prognostic significance of controlled attenuation parameter in patients with compensated advanced chronic liver disease.
      ). In a recent study including overweight/obese patients assessed with the XL probe, 56% of whom had NASH, an absence of steatosis by CAP exhibited an inverse association with clinical events (
      • Mendoza Y
      • Cocciolillo S
      • Murgia G
      • Chen T
      • Margini C
      • Sebastiani G
      • Berzigotti A.
      Noninvasive markers of portal hypertension detect decompensation in overweight or obese patients with compensated advanced chronic liver disease.
      ) independent of liver stiffness. These results have not been validated so far but might reflect the negative prognostic meaning of loss of steatosis in this specific etiology (“burnt out NASH”) (
      • Noureddin M
      • Chan JL
      • Barradas K
      • Dimick-Santos L
      • Schabel E
      • Omokaro SO
      • Anania FA
      • Myers RP
      • Miller V
      • Sanyal AJ
      • Chalasani N
      Liver Forum NCWG. Attribution of nonalcoholic steatohepatitis as an etiology of cirrhosis for clinical trials eligibility: Recommendations from the Multi-stakeholder Liver Forum.
      ).

      ATI technology (Canon Medical Systems, Japan)

      Physics and examination technique

      Attenuation imaging (ATI) is the technique implemented in the Aplio i-series US systems (Canon Medical Systems). The degree of attenuation of the US beam is color-coded and obtained in a large region of interest (ROI) in real-time. Vessels or strong artifacts are automatically filtered out by the software and appear as blank areas in the color mapping. The influence of the gain and US beam profiles is also automatically removed for calculation of the AC in decibels per centimeter per megahertz (dB/cm/MHz). In the ATI display mode, the B-mode image is shown on the left side and the corresponding ATI color-coded image is shown on the right side. A single measurement box is placed in the ROI, guided by the B-mode image (Fig. 4). A dark orange area, which may be present in the upper part of the ROI, or dark blue areas posterior to blood vessels or at the bottom of the ROI must not be included in the measurement box because they are artifacts caused by reverberation or high noise with weak echo signal by less penetration. The AC value is the median value of five consecutive measurements. To improve the reliability of the measurement, the ATI acquisition protocol should be further standardized because the AC value may vary depending on the location and size of the ROI. The reliability of the measurement is displayed as an R2 value: an AC value of best quality should have an R2 ≥0.90, as recommended by the manufacturer. ATI is a new technology; therefore, few studies have been published so far.
      Fig 4
      Fig. 4Attenuation imaging (ATI) technique by Canon. ATI measurement in a 45-y-old healthy woman. The B-mode image and corresponding ATI color-coded image are shown side by side. The rectangle with yellow sides outlines the fixed measurement box.

      Reproducibility

      It has been reported that intra-observer reproducibility, assessed by means of ICC, ranges from 0.81–0.98, whereas inter-observer reproducibility ranges from 0.79–0.92 (
      • Ferraioli G
      • Maiocchi L
      • Raciti MV
      • Tinelli C
      • De Silvestri A
      • Nichetti M
      • De Cata P
      • Rondanelli M
      • Chiovato L
      • Calliada F
      • Filice C.
      Detection of liver steatosis with a novel ultrasound-based technique: A pilot study using MRI-derived proton density fat fraction as the gold standard.
      ;
      • Jeon SK
      • Lee JM
      • Joo I
      • Yoon JH
      • Lee DH
      • Lee JY
      • Han JK.
      prospective evaluation of hepatic steatosis using ultrasound attenuation imaging in patients with chronic liver disease with magnetic resonance imaging proton density fat fraction as the reference standard.
      ,
      • Yoo J
      • Lee JM
      • Joo I
      • Lee DH
      • Yoon JH
      • Kang HJ
      • Ahn SJ.
      Reproducibility of ultrasound attenuation imaging for the noninvasive evaluation of hepatic steatosis.
      ).

      Accuracy and cutoff values

      As of March 2021, five studies using histologic steatosis grade as reference standard and three studies using MRI-PDFF as reference have been published. The results of these studies are summarized in Table 2. In a series of 102 patients with increased levels of liver enzymes or suspicion of NAFLD, liver biopsy performed immediately after US evaluation was used as the reference standard (
      • Lee DH
      • Cho EJ
      • Bae JS
      • Lee JY
      • Yu SJ
      • Kim H
      • Lee KB
      • Han JK
      • Choi BI.
      Accuracy of two-dimensional shear wave elastography and attenuation imaging for evaluation of patients with nonalcoholic steatohepatitis.
      ). Interestingly, a risk scoring system to detect NASH, based on the AC and shear wave dispersion slope, was developed. The score was able to identify patients with NASH with an AUROC of 0.93. By use of a multiparametric US approach, based on three US parameters (shear wave speed, shear wave dispersion slope and AC with ATI), 120 consecutive individuals with suspected NAFLD were evaluated before liver biopsy, which was performed immediately afterward (
      • Sugimoto K
      • Moriyasu F
      • Oshiro H
      • Takeuchi H
      • Abe M
      • Yoshimasu Y
      • Kasai Y
      • Sakamaki K
      • Hara T
      • Itoi T.
      The role of multiparametric US of the liver for the evaluation of nonalcoholic steatohepatitis.
      ). The combination of shear wave dispersion slope, AC and shear wave speed had an AUROC of 0.81 for the diagnosis of NASH. The performance of AC with ATI was assessed in a series of 108 consecutive patients who underwent liver biopsy for the evaluation of diffuse liver disease on the same day (
      • Bae JS
      • Lee DH
      • Lee JY
      • Kim H
      • Yu SJ
      • Lee JH
      • Cho EJ
      • Lee YB
      • Han JK
      • Choi BI.
      Assessment of hepatic steatosis by using attenuation imaging: A quantitative, easy-to-perform ultrasound technique.
      ). In this cohort, 33.6% individuals were at liver fibrosis stage F2 or higher. Fibrosis stage and necroinflammatory activity were not associated with the AC. Another study was performed in a series of 101 patients scheduled for liver biopsy for mixed etiologies of liver disease on the same day of the ATI exam (
      • Dioguardi Burgio M
      • Ronot M
      • Reizine E
      • Rautou PE
      • Castera L
      • Paradis V
      • Garteiser P
      • Van Beers B
      • Vilgrain V
      Quantification of hepatic steatosis with ultrasound: promising role of attenuation imaging coefficient in a biopsy-proven cohort.
      ). Notably, an R2 < 0.90 was considered measurement failure (2 patients, 1.9% of cases). Advanced fibrosis (F3–F4), which was present in 44.6% of cases, did not affect the AC value. In a study that included 148 patients with mixed etiologies of liver diseases, ATI exams were performed within 3 mo from liver biopsy (
      • Tada T
      • Iijima H
      • Kobayashi N
      • Yoshida M
      • Nishimura T
      • Kumada T
      • Kondo R
      • Yano H
      • Kage M
      • Nakano C
      • Aoki T
      • Aizawa N
      • Ikeda N
      • Takashima T
      • Yuri Y
      • Ishii N
      • Hasegawa K
      • Takata R
      • Yoh K
      • Sakai Y
      • Nishikawa H
      • Iwata Y
      • Enomoto H
      • Hirota S
      • Fujimoto J
      • Nishiguchi S.
      Usefulness of attenuation imaging with an ultrasound scanner for the evaluation of hepatic steatosis.
      ). The time delay between the non-invasive assessment and the liver biopsy is a limitation of this study. Indeed, hepatic fat content may change in a short period with lifestyle modifications (
      • Ryan MC
      • Itsiopoulos C
      • Thodis T
      • Ward G
      • Trost N
      • Hofferberth S
      • O'Dea K
      • Desmond PV
      • Johnson NA
      • Wilson AM.
      The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.
      ;
      • Hallsworth K
      • Adams LA.
      Lifestyle modification in NAFLD/NASH: Facts and figures.
      ). In a study that compared ATI performance with that of CAP using MRI-PDFF as the reference standard, the correlation of ATI with MRI-PDFF was higher than that of ATI with CAP (r = 0.81 vs. r = 0.65). ATI was more accurate than CAP, and this difference reached statistical significance for S > 1 (p = 0.04) (
      • Ferraioli G
      • Maiocchi L
      • Raciti MV
      • Tinelli C
      • De Silvestri A
      • Nichetti M
      • De Cata P
      • Rondanelli M
      • Chiovato L
      • Calliada F
      • Filice C.
      Detection of liver steatosis with a novel ultrasound-based technique: A pilot study using MRI-derived proton density fat fraction as the gold standard.
      ). The difference in the AC cutoff values between study cohorts is likely owing to differences in the number of patients for each grade of liver steatosis, that is, the spectrum bias, and to differences in the etiology of liver disease. Overall, for the detection of liver steatosis (S > 0) in patients suspected of having NAFLD, the cutoff was 0.63–0.69 dB/cm/MHz, with AUROCs ranging from 0.88–0.93 (
      • Ferraioli G
      • Maiocchi L
      • Raciti MV
      • Tinelli C
      • De Silvestri A
      • Nichetti M
      • De Cata P
      • Rondanelli M
      • Chiovato L
      • Calliada F
      • Filice C.
      Detection of liver steatosis with a novel ultrasound-based technique: A pilot study using MRI-derived proton density fat fraction as the gold standard.
      ;
      • Ferraioli G
      • Maiocchi L
      • Savietto G
      • Tinelli C
      • Nichetti M
      • Rondanelli M
      • Calliada F
      • Preda L
      • Filice C.
      Performance of the attenuation imaging technology in the detection of liver steatosis.
      ;
      • Lee DH
      • Cho EJ
      • Bae JS
      • Lee JY
      • Yu SJ
      • Kim H
      • Lee KB
      • Han JK
      • Choi BI.
      Accuracy of two-dimensional shear wave elastography and attenuation imaging for evaluation of patients with nonalcoholic steatohepatitis.
      ;
      • Sugimoto K
      • Moriyasu F
      • Oshiro H
      • Takeuchi H
      • Abe M
      • Yoshimasu Y
      • Kasai Y
      • Sakamaki K
      • Hara T
      • Itoi T.
      The role of multiparametric US of the liver for the evaluation of nonalcoholic steatohepatitis.
      ). It is worth noting that
      • Ferraioli G
      • Maiocchi L
      • Raciti MV
      • Tinelli C
      • De Silvestri A
      • Nichetti M
      • De Cata P
      • Rondanelli M
      • Chiovato L
      • Calliada F
      • Filice C.
      Detection of liver steatosis with a novel ultrasound-based technique: A pilot study using MRI-derived proton density fat fraction as the gold standard.
      determined that a cutoff of 0.70 dB/cm/MHz ruled in liver steatosis with a specificity of 97.2%. The US frequency used to calculate the AC should be taken into account because it may give a different AC value in the same patient (
      • Ferraioli G
      • Maiocchi L
      • Savietto G
      • Tinelli C
      • Nichetti M
      • Rondanelli M
      • Calliada F
      • Preda L
      • Filice C.
      Performance of the attenuation imaging technology in the detection of liver steatosis.
      ).
      Table 2Studies performed with ATI technology with liver biopsy or MRI-PDFF as the reference standard
      StudyEtiology (No. of patients)Reference standard intervalS0 vs. S1–S3S0–S1 vs. S2–S3S0–S2 vs. S3
      Reference standard: Liver biopsy
      • Bae JS
      • Lee DH
      • Lee JY
      • Kim H
      • Yu SJ
      • Lee JH
      • Cho EJ
      • Lee YB
      • Han JK
      • Choi BI.
      Quantitative assessment of fatty liver using ultrasound with normalized local variance technique [e-pub ahead of print].
      Mixed etiologies (108)On the same day0.63 dB/cm/MHz

      AUROC: 0.84

      Sensitivity: 74%

      Specificity: 77%
      0.70 dB/cm/MHz

      AUROC: 0.88

      Sensitivity: 86%

      Specificity: 81%
      0.74 dB/cm/MHz

      AUROC: 0.93

      Sensitivity: 100%

      Specificity: 82%
      • Dioguardi Burgio M
      • Ronot M
      • Reizine E
      • Rautou PE
      • Castera L
      • Paradis V
      • Garteiser P
      • Van Beers B
      • Vilgrain V
      Quantification of hepatic steatosis with ultrasound: promising role of attenuation imaging coefficient in a biopsy-proven cohort.
      Mixed etiologies (101)On the same day0.69 dB/cm/MHz

      AUROC: 0.80

      Sensitivity: 76 %

      Specificity: 86%
      0.72 dB/cm/MHz

      AUROC: 0.89

      Sensitivity: 96%

      Specificity: 74%






      • Lee DH
      • Cho EJ
      • Bae JS
      • Lee JY
      • Yu SJ
      • Kim H
      • Lee KB
      • Han JK
      • Choi BI.
      Accuracy of two-dimensional shear wave elastography and attenuation imaging for evaluation of patients with nonalcoholic steatohepatitis.
      Suspect NAFLD (102)On the same day0.64 dB/cm/MHz

      AUROC: 0.93

      Sensitivity: 75%

      Specificity: 95%
      0.70 dB/cm/MHz

      AUROC: 0.90

      Sensitivity: 84%

      Specificity: 76%
      0.73 dB/cm/MHz

      AUROC: 0.83

      Sensitivity: 86%

      Specificity: 69%
      • Sugimoto K
      • Moriyasu F
      • Oshiro H
      • Takeuchi H
      • Abe M
      • Yoshimasu Y
      • Kasai Y
      • Sakamaki K
      • Hara T
      • Itoi T.
      The role of multiparametric US of the liver for the evaluation of nonalcoholic steatohepatitis.
      Suspect NAFLD (120)On the same day0.67 dB/cm/MHz

      AUROC: 0.88

      Sensitivity: 75%

      Specificity: 100%
      0.72 dB/cm/MHz

      AUROC: 0.86

      Sensitivity: 90%

      Specificity: 66%
      0.86 dB/cm/MHz

      AUROC: 0.79

      Sensitivity: 61%

      Specificity: 100%
      • Tada T
      • Iijima H
      • Kobayashi N
      • Yoshida M
      • Nishimura T
      • Kumada T
      • Kondo R
      • Yano H
      • Kage M
      • Nakano C
      • Aoki T
      • Aizawa N
      • Ikeda N
      • Takashima T
      • Yuri Y
      • Ishii N
      • Hasegawa K
      • Takata R
      • Yoh K
      • Sakai Y
      • Nishikawa H
      • Iwata Y
      • Enomoto H
      • Hirota S
      • Fujimoto J
      • Nishiguchi S.
      Usefulness of attenuation imaging with an ultrasound scanner for the evaluation of hepatic steatosis.
      Mixed etiologies (148)Within 3 mo0.66 dB/cm/MHz

      AUROC: 0.85

      Sensitivity: 68%

      Specificity: 88%
      0.67 dB/cm/MHz

      AUROC: 0.91

      Sensitivity: 92%

      Specificity: 84%
      0.68 dB/cm/MHz
      Seven patients.


      AUROC: 0.91

      Sensitivity: 100%

      Specificity: 75%
      Reference standard: MRI-PDFF
      ATI tuned on an ultrasound frequency of 4.0 MHz.
      Suspect NAFLD (114)

      Healthy controls (15)
      Within 1 wk0.63 dB/cm/MHz

      AUROC: 0.91

      Sensitivity: 80%

      Specificity: 89%
      0.72 dB/cm/MHz

      AUROC: 0.95

      Sensitivity: 100%

      Specificity: 78%






      • Ferraioli G
      • Maiocchi L
      • Savietto G
      • Tinelli C
      • Nichetti M
      • Rondanelli M
      • Calliada F
      • Preda L
      • Filice C.
      Performance of the attenuation imaging technology in the detection of liver steatosis.
      ATI tuned on an ultrasound frequency of 3.0 MHz.
      Suspect NAFLD (72)Within 1 wk0.69 dB/cm/MHz

      AUROC: 0.90

      Sensitivity: 79%

      Specificity: 96%












      • Jeon SK
      • Lee JM
      • Joo I
      • Yoon JH
      • Lee DH
      • Lee JY
      • Han JK.
      prospective evaluation of hepatic steatosis using ultrasound attenuation imaging in patients with chronic liver disease with magnetic resonance imaging proton density fat fraction as the reference standard.
      Mixed etiologies (87)Within 3 mo0.59 dB/cm/MHz

      AUROC: 0.76

      Sensitivity: 88%

      Specificity: 62%












      ATI = attenuation imaging; AUROC = area under the receiver operating characteristic curve; NAFLD = non-alcoholic fatty liver disease; MRI-PDFF = magnetic resonance imaging-derived protein density fat fraction.
      low asterisk Seven patients.
      ATI tuned on an ultrasound frequency of 4.0 MHz.
      ATI tuned on an ultrasound frequency of 3.0 MHz.

      ATT technology (Fujifilm, previously Hitachi Medical Systems, Japan)

      Physics and examination technique

      ATT estimates hepatic steatosis from differences in attenuation of the received RF signals. Ultrasonic waves of different frequencies f0, f1 (f0 < f1) are transmitted to the same beamline, and ATT is determined by calculating the slope of the obtained received signal ratio (f0/f1).
      Attenuation measurements are obtained at depths of 40–100 mm, avoiding the influence of subcutaneous fat thickness. Therefore, the same probe can also be used in obese patients. ATT measurements are performed in the right intercostal space, and the measurement is obtained together with the stiffness value. ATT quantifies steatosis in a fixed area that is not user-adjustable, and there is no color map. The results are given together with LSMs (Fig. 5).
      Fig 5
      Fig. 5ATT technology from Hitachi. The Hitachi system simultaneously displays both stiffness and steatosis quantification with ATT (10 acquisitions).

      Accuracy and cutoff values

      As of March 2021, only three published studies are available. For the cutoff values, only one study is available. It was a multicenter prospective study performed in 351 patients with mixed etiologies of liver disease. All patients underwent liver biopsy and ATT measurement on the same day. The fat area (%) of biopsy specimens was quantified. ATT exhibited a moderate correlation with fat area (r = 0.50, p < 0.001). The AUROCs for S ≥1, S ≥2 and S =3 were 0.79, 0.87 and 0.96, respectively, and the cutoff values were 0.62 dB/cm/MHz (72% sensitivity, 82% specificity), 0.67 dB/cm/MHz (87% sensitivity, 72% specificity) and 0.73 dB/cm/MHz (82% sensitivity, 89% specificity) (
      • Tamaki N
      • Koizumi Y
      • Hirooka M
      • Yada N
      • Takada H
      • Nakashima O
      • Kudo M
      • Hiasa Y
      • Izumi N.
      Novel quantitative assessment system of liver steatosis using a newly developed attenuation measurement method.
      ). In a study on 94 patients with mixed etiologies of liver disease, the diagnostic performance of ATT was compared with that of CAP, using liver biopsy performed on the same day as the reference standard. CAP had a performance higher than that of ATT; however, the differences between the ROC curves were not statistically significant (p > 0.05) (
      • Koizumi Y
      • Hirooka M
      • Tamaki N
      • Yada N
      • Nakashima O
      • Izumi N
      • Kudo M
      • Hiasa Y.
      New diagnostic technique to evaluate hepatic steatosis using the attenuation coefficient on ultrasound B mode.
      ). In a study including 84 patients, unenhanced CT attenuation values were used as the reference standard for the detection and grading of liver steatosis. An ATT ≥0.66 dB/cm/MHz had a sensitivity of 100% and a specificity of 90% in diagnosing moderate-severe steatosis. The corresponding AUROC was 0.93. The ICC for the interobserver variability of ATT was 0.91 (
      • Cerit M
      • Sendur HN
      • Cindil E
      • Erbas G
      • Yalcin MM
      • Cerit ET
      • Allahverdiyeva S
      • Oktar SO
      • Yucel C.
      Quantification of liver fat content with ultrasonographic attenuation measurement function: Correlation with unenhanced multidimensional computerized tomography.
      ).

      UGAP technology (GE Healthcare, USA)

      Physics and examination technique

      The UGAP is the method for the detection and quantification of hepatic steatosis available on the LOGIQ E9 XDclear 2.0 US scanner (GE Healthcare, USA). The AC value is calculated according to the reference phantom method reported by
      • Yao LX
      • Zagzebski JA
      • Madsen EL.
      Backscatter coefficient measurements using a reference phantom to extract depth-dependent instrumentation factors.
      . In this method, an US phantom integrated into the US system, with known attenuation and backscatter coefficients, is used to compensate the characteristics of transmitting and receiving beamforming of the US system (Fig. 6).
      Fig 6
      Fig. 6Ultrasound-guided attenuation parameter (UGAP) technology from GE. Image of a patient with an attenuation of 0.47 dB/cm/MHz corresponding to S0 using UGAP technology.

      Accuracy and cutoff values

      To date, three studies have been published. With histopathology as the reference standard, a prospective study on 163 patients with chronic liver disease found that the AC with UGAP was positively correlated with the percentage of steatosis (r = 0.78, p < 0.001). The AUROCs of UGAP in predicting S ≥1, S ≥2 and S = 3 were 0.90, 0.95 and 0.96, respectively, with cutoff values of 0.53 dB/cm/MHz (sensitivity = 81.2%, specificity = 87.1%), 0.60 dB/cm/MHz (sensitivity = 85.7%, specificity = 81.5%) and 0.65 dB/cm/MHz (sensitivity = 80.4%, specificity = 90.0%). The ICCs for intra-observer and inter-observer agreement of AC measurements using UGAP were 0.86 and 0.84 (
      • Fujiwara Y
      • Kuroda H
      • Abe T
      • Ishida K
      • Oguri T
      • Noguchi S
      • Sugai T
      • Kamiyama N
      • Takikawa Y.
      The B-mode image-guided ultrasound attenuation parameter accurately detects hepatic steatosis in chronic liver disease.
      ). In this study, UGAP performed significantly better than CAP in identifying S ≥2 and S = 3 steatosis.
      In a study including 126 patients, MRI-PDFF was used as the reference standard for the detection and grading of liver steatosis. There was a high correlation between PDFF and AC (r = 0.75, p < 0.001). The AUROCs of AC for steatosis grades with S ≥1, S ≥2 and S = 3 were 0.92, 0.87 and 0.89, respectively. The cutoff value for the detection of steatosis (S ≥1) was 0.60 dB/cm/MHz (sensitivity = 85.5%, specificity = 88.5%, accuracy = 85.7%). However, for S ≥2 and S = 3 the cutoff was the same even though with different sensitivity and specificity (
      • Tada T
      • Kumada T
      • Toyoda H
      • Kobayashi N
      • Sone Y
      • Oguri T
      • Kamiyama N.
      Utility of attenuation coefficient measurement using an ultrasound-guided attenuation parameter for evaluation of hepatic steatosis: Comparison with MRI-determined proton density fat fraction.
      ). In another study, the value of AC determined by UGAP was highly correlated with MRI-PDFF and was less affected by liver stiffness (
      • Tada T
      • Kumada T
      • Toyoda H
      • Yasuda S
      • Sone Y
      • Hashinokuchi S
      • Ogawa S
      • Oguri T
      • Kamiyama N
      • Chuma M
      • Akita T
      • Tanaka J.
      Liver stiffness does not affect ultrasound-guided attenuation coefficient measurement in the evaluation of hepatic steatosis.
      ).

      Backscatter coefficient

      The studies described in this section were performed using the Siemens S3000 US system (Siemens Healthineers) with a direct US research interface option. The backscatter coefficient (BSC) was computed offline using an open-source software tool (
      • Lin SC
      • Heba E
      • Wolfson T
      • Ang B
      • Gamst A
      • Han A
      • Erdman Jr, JW
      • O'Brien Jr, WD
      • Andre MP
      • Sirlin CB
      • Loomba R.
      Noninvasive diagnosis of nonalcoholic fatty liver disease and quantification of liver fat using a new quantitative ultrasound technique.
      ;
      • Paige JS
      • Bernstein GS
      • Heba E
      • Costa EAC
      • Fereirra M
      • Wolfson T
      • Gamst AC
      • Valasek MA
      • Lin GY
      • Han A
      • Erdman Jr, JW
      • O'Brien Jr, WD
      • Andre MP
      • Loomba R
      • Sirlin CB.
      A pilot comparative study of quantitative ultrasound, conventional ultrasound, and MRI for predicting histology-determined steatosis grade in adult nonalcoholic fatty liver disease.
      ;
      • Han A
      • Andre MP
      • Deiranieh L
      • Housman E
      • Erdman Jr., JW
      • Loomba R
      • Sirlin CB
      • O'Brien Jr, WD
      Repeatability and reproducibility of the ultrasonic attenuation coefficient and backscatter coefficient measured in the right lobe of the liver in adults with known or suspected nonalcoholic fatty liver disease.
      • Han A
      • Byra M
      • Heba E
      • Andre MP
      • Erdman Jr, JW
      • Loomba R
      • Sirlin CB
      • O'Brien Jr, WD
      Noninvasive diagnosis of nonalcoholic fatty liver disease and quantification of liver fat with radiofrequency ultrasound data using one-dimensional convolutional neural networks.
      ).

      Physics and examination technique

      The BSC is a measure of the fraction of US energy returned from tissue (
      • Coila A
      • Oelze ML.
      Effects of acoustic nonlinearities on the ultrasonic backscatter coefficient estimation.
      ). It is estimated by a computer algorithm and a reference phantom to normalize US system effects (
      • Ferraioli G
      • Soares Monteiro LB.
      Ultrasound-based techniques for the diagnosis of liver steatosis.
      ). An external tissue-mimicking reference phantom with acoustic properties comparable to those of average human liver tissue is used. Consecutive frames are recorded from the same region of the liver. Thereafter, without changing any scanner settings, consecutive frames are recorded in the external phantom.

      Reproducibility

      In a study on the reproducibility of BSC in adults with known/suspected NAFLD, when each radiologist performed only one acquisition, the ICC of log BSC was 0.87; when five acquisitions were performed, it was 0.88 (
      • Han A
      • Labyed Y
      • Sy EZ
      • Boehringer AS
      • Andre MP
      • Erdman Jr, JW
      • Loomba R
      • Sirlin CB
      • O'Brien Jr, WD
      Inter-sonographer reproducibility of quantitative ultrasound outcomes and shear wave speed measured in the right lobe of the liver in adults with known or suspected non-alcoholic fatty liver disease.
      ).

      Accuracy and cutoff values

      The accuracy of BSC in diagnosing and quantifying hepatic steatosis was evaluated in a series of 204 individuals, with and without NAFLD, using MRI-PDFF as the reference standard (
      • Lin SC
      • Heba E
      • Wolfson T
      • Ang B
      • Gamst A
      • Han A
      • Erdman Jr, JW
      • O'Brien Jr, WD
      • Andre MP
      • Sirlin CB
      • Loomba R.
      Noninvasive diagnosis of nonalcoholic fatty liver disease and quantification of liver fat using a new quantitative ultrasound technique.
      ). The participants were randomly assigned to training and validation groups. There was a high correlation between MRI-PDFF and BSC (Spearman's ρ = 0.80, p < 0.0001). The AUROC of BSC for the diagnosis of steatosis was 0.98 in the training group, with an optimal cutoff value of 0.0038 1/cm-steradian (accuracy = 94%, sensitivity = 93%, specificity = 97%). The sensitivity and specificity in the validation group were 87% and 91%, respectively.

      BSC combined with other US quantitative parameters

      Custom-derived software

      With MRI-PDFF as reference in a study of 102 patients with known or suspected NAFLD, BSC was combined with AC and other QUS parameters, and two QUS multivariable models were developed and evaluated: a classifier to diagnose NAFLD, and a fat fraction estimator (
      • Han A
      • Zhang YN
      • Boehringer AS
      • Montes V
      • Andre MP
      • Erdman Jr, JW
      • Loomba R
      • Valasek MA
      • Sirlin CB
      • O'Brien Jr, WD
      Assessment of hepatic steatosis in nonalcoholic fatty liver disease by using quantitative US.
      ). The classifier model had an AUROC of 0.89 and an area under the precision-recall curve of 0.96. The fat fraction estimator was linearly correlated with MRI-PDFF for values ≤34%. By using these two QUS multivariable models, the same group has developed a deep learning algorithm that has 96% accuracy of the classifier for NAFLD diagnosis and a linear correlation with MRI-PDFF of the estimator for values ≤18% or less (
      • Han A
      • Byra M
      • Heba E
      • Andre MP
      • Erdman Jr, JW
      • Loomba R
      • Sirlin CB
      • O'Brien Jr, WD
      Noninvasive diagnosis of nonalcoholic fatty liver disease and quantification of liver fat with radiofrequency ultrasound data using one-dimensional convolutional neural networks.
      ).

      UDFF technology (Siemens Healthineers, Germany)

      The tool that has been implemented in the Acuson S3000 US system (Siemens Healthineers) eliminates the need to acquire reference phantom scans after each liver scan by having reference phantom data integrated into the US system. Additionally, it uses a fixed-acquisition ROI. The UDFF value is reported as a percentage of liver steatosis (Fig. 7).
      Fig 7
      Fig. 7Ultrasound-derived fat fraction (UDFF) technology from Siemens. The Siemens UDFF is an index correlated with the magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) and calculated from attenuation and backscatter estimates. The system provides both the liver stiffness (1.37 m/s [5.6 kPa] in this case) and the fat fraction as a percentage correlated with MR-PDFF, 12% in this case.
      A recent study on 101 patients reported that there was a high correlation of UDFF with MRI-PDFF (Pearson's r = 0.87) and that body mass index did not affect UDFF values (
      • Labyed Y
      • Milkowski A.
      Novel method for ultrasound-derived fat fraction using an integrated phantom.
      ). In the 90 patients for whom liver histology was available, the AUROCs of UDFF were 0.94, 0.88 and 0.83 for S ≥1, S ≥2 and S = 3, respectively. With MRI-PDFF as reference, the UDFF cutoff for detecting steatosis (PDFF >5%) was 6.34% (AUROC = 0.97, sensitivity = 0.94, specificity = 1.0).

      Techniques based on envelope statistics of backscattered US

      ASQ and NLV (Canon Medical Systems, Japan)

      Acoustic structure quantification (ASQ) is a method based on comparisons between theoretical and real US wave amplitude distributions (
      • Kuroda H
      • Kakisaka K
      • Kamiyama N
      • Oikawa T
      • Onodera M
      • Sawara K
      • Oikawa K
      • Endo R
      • Takikawa Y
      • Suzuki K.
      Non-invasive determination of hepatic steatosis by acoustic structure quantification from ultrasound echo amplitude.
      ). The theoretical echo amplitude distribution of the liver region is computed using the Rayleigh distribution function based on the assumption that the speckle pattern is obtained by only US beam interference from very small scattering objects (
      • Son JY
      • Lee JY
      • Yi NJ
      • Lee KW
      • Suh KS
      • Kim KG
      • Lee JM
      • Han JK
      • Choi BI.
      Hepatic steatosis: Assessment with acoustic structure quantification of US imaging.
      ). However, the real echo amplitude distribution of the liver parenchyma does not fit a Rayleigh distribution because of small structures, such as the hepatic vessel walls and bile ducts, which scatter the US beam and cause high variance of the US beam amplitude. By comparing the theoretical beam amplitude distribution with a real distribution, ASQ can provide quantitative information regarding changes in echotexture in liver steatosis. The ASQ method was also refined by applying a focal distribution ratio based on histogram analysis enabling steatosis but not fibrosis quantification (
      • Karlas T
      • Berger J
      • Garnov N
      • Lindner F
      • Busse H
      • Linder N
      • Schaudinn A
      • Relke B
      • Chakaroun R
      • Troltzsch M
      • Wiegand J
      • Keim V.
      Estimating steatosis and fibrosis: Comparison of acoustic structure quantification with established techniques.
      ).
      The NLV technique is a recently developed method based on ASQ technology (
      • Bae JS
      • Lee DH
      • Lee JY
      • Kim H
      • Yu SJ
      • Lee JH
      • Cho EJ
      • Lee YB
      • Han JK
      • Choi BI.
      Quantitative assessment of fatty liver using ultrasound with normalized local variance technique [e-pub ahead of print].
      ). In the NLV method, US amplitudes sampled from gray-scale US images are statistically analyzed. With liver histology as the reference, a study on 194 consecutive patients with clinical suspicion of diffuse liver disease or history of liver transplantation found that NLV values were associated with the degree of liver steatosis but not with fibrosis (
      • Bae JS
      • Lee DH
      • Lee JY
      • Kim H
      • Yu SJ
      • Lee JH
      • Cho EJ
      • Lee YB
      • Han JK
      • Choi BI.
      Quantitative assessment of fatty liver using ultrasound with normalized local variance technique [e-pub ahead of print].
      ). However, it is worth noting that the hepatic speckle pattern that contributes to NLV values becomes more heterogeneous with the progression of liver fibrosis. In this series, 77% of patients had no or mild fibrosis; therefore, the influence of fibrosis on NLV values is yet to be defined.

      Speed of sound

      It has been reported that the speed of sound varies according to fat content in soft tissues, and this also holds true in liver tissue. Because of the finding that speed of sound is lower in cases of steatosis (
      • Bamber JC
      • Hill CR.
      Acoustic properties of normal and cancerous human liver: I. Dependence on pathological condition.
      ;
      • Bamber JC
      • Hill CR
      • King JA.
      Acoustic properties of normal and cancerous human liver-II. Dependence of tissue structure.
      ;
      • Chen CF
      • Robinson DE
      • Wilson LS
      • Griffiths KA
      • Manoharan A
      • Doust BD.
      Clinical sound speed measurement in liver and spleen in vivo.
      ), different methods to measure with exactitude the speed of sound in the liver are being developed (
      • Jaeger M
      • Held G
      • Peeters S
      • Preisser S
      • Grunig M
      • Frenz M.
      Computed ultrasound tomography in echo mode for imaging speed of sound using pulse-echo sonography: Proof of principle.
      ;
      • Imbault M
      • Faccinetto A
      • Osmanski BF
      • Tissier A
      • Deffieux T
      • Gennisson JL
      • Vilgrain V
      • Tanter M.
      Robust sound speed estimation for ultrasound-based hepatic steatosis assessment.
      ;
      • Stahli P
      • Kuriakose M
      • Frenz M
      • Jaeger M.
      Improved forward model for quantitative pulse-echo speed-of-sound imaging.
      ). Among them, speed of sound estimation using assessment of the spatial coherence function of the backscattered echoes resulting from a US beam focusing in the medium has been tested in a proof of concept study (
      • Imbault M
      • Faccinetto A
      • Osmanski BF
      • Tissier A
      • Deffieux T
      • Gennisson JL
      • Vilgrain V
      • Tanter M.
      Robust sound speed estimation for ultrasound-based hepatic steatosis assessment.
      ). The quantification of speed of sound was obtained by post-processing analysis of raw data using in-house software. The method was tested using the Aixplorer US system (Hologic Co.) in a pilot study including 100 patients undergoing MRI-PDFF as a reference standard (
      • Dioguardi Burgio M
      • Imbault M
      • Ronot M
      • Faccinetto A
      • Van Beers BE
      • Rautou PE
      • Castera L
      • Gennisson JL
      • Tanter M
      • Vilgrain V
      Ultrasonic adaptive sound speed estimation for the diagnosis and quantification of hepatic steatosis: A pilot study.
      ). Speed of sound estimation exhibited very good reproducibility (ICC = 0.93), and with ≤1.537 mm/μs as a cutoff, steatosis of any grade (S1–S3) could be diagnosed with 80% sensitivity and 86% specificity. At ≤1.511 mm/μs, significant steatosis (S2–S3) was diagnosed with 100% sensitivity and 96% specificity (Figure 8). Studies in larger cohorts to validate these preliminary results are ongoing.
      Fig 8
      Fig. 8Speed of sound technology by Hologic. The Hologic system provides fat quantification based on speed of sound (SSp PLUS 1519 m/s) and attenuation (0.70 dB/cm/MHz).

      Experts’ opinions based on literature data

      • 1.
        The detection of hepatic steatosis, namely, the presence of fat content in ≥5% of hepatocytes, is the basis for the diagnosis of NAFLD (
        • Kleiner DE
        • Brunt EM
        • Van Natta M
        • Behling C
        • Contos MJ
        • Cummings OW
        • Ferrell LD
        • Liu YC
        • Torbenson MS
        • Unalp-Arida A
        • Yeh M
        • McCullough AJ
        • Sanyal AJ.
        Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
        ).
      • 2.
        Conventional B-mode US gives an estimate of the degree of fatty infiltration in the liver but has low sensitivity for the detection of mild steatosis (
        • Palmentieri B
        • de Sio I
        • La Mura V
        • Masarone M
        • Vecchione R
        • Bruno S
        • Torella R
        • Persico M
        The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis.
        ;
        • Dasarathy S
        • Dasarathy J
        • Khiyami A
        • Joseph R
        • Lopez R
        • McCullough AJ.
        Validity of real time ultrasound in the diagnosis of hepatic steatosis: A prospective study.
        ;
        • Lee SS
        • Park SH
        • Kim HJ
        • Kim SY
        • Kim MY
        • Kim DY
        • Suh DJ
        • Kim KM
        • Bae MH
        • Lee JY
        • Lee SG
        • Yu ES.
        Non-invasive assessment of hepatic steatosis: Prospective comparison of the accuracy of imaging examinations.
        ;
        • van Werven JR
        • Marsman HA
        • Nederveen AJ
        • Smits NJ
        • ten Kate FJ
        • van Gulik TM
        • Stoker J.
        Assessment of hepatic steatosis in patients undergoing liver resection: Comparison of US, CT, T1-weighted dual-echo MR imaging, and point-resolved 1H MR spectroscopy.
        ;
        • Bohte AE
        • van Werven JR
        • Bipat S
        • Stoker J.
        The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: A meta-analysis.
        ;
        • Macaluso FS
        • Maida M
        • Camma C
        • Cabibi D
        • Alessi N
        • Cabibbo G
        • Di Marco V
        • Craxi A
        • Petta S.
        Body mass index and liver stiffness affect accuracy of ultrasonography in detecting steatosis in patients with chronic hepatitis C virus genotype 1 infection.
        ;
        • Bril F
        • Ortiz-Lopez C
        • Lomonaco R
        • Orsak B
        • Freckleton M
        • Chintapalli K
        • Hardies J
        • Lai S
        • Solano F
        • Tio F
        • Cusi K.
        Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients.
        ;
        • Ferraioli G
        • Soares Monteiro LB.
        Ultrasound-based techniques for the diagnosis of liver steatosis.
        ).
      • 3.
        CAP enables quantification of liver steatosis with a large overlap of CAP values among consecutive grades of liver steatosis, thus limiting its use in follow-up studies evaluating changes over time (
        • Castera L.
        Noninvasive evaluation of nonalcoholic fatty liver disease.
        ;
        • Ferraioli G.
        The clinical value of the controlled attenuation parameter in the follow-up of HIV-infected patients.
        ;
        • Ferraioli G
        • Wong VW
        • Castera L
        • Berzigotti A
        • Sporea I
        • Dietrich CF
        • Choi BI
        • Wilson SR
        • Kudo M
        • Barr RG.
        Liver ultrasound elastography: An Update to the World Federation for Ultrasound in Medicine and Biology guidelines and recommendations.
        ).
      • 4.
        Quantitative US techniques available on US systems, particularly AC estimates, have good accuracy in quantifying hepatic steatosis (
        • Chan WK
        • Nik Mustapha NR
        • Mahadeva S
        • Wong VW
        • Cheng JY
        • Wong GL
        Can the same controlled attenuation parameter cut-offs be used for M and XL probes for diagnosing hepatic steatosis?.
        ;
        • Bae JS
        • Lee DH
        • Lee JY
        • Kim H
        • Yu SJ
        • Lee JH
        • Cho EJ
        • Lee YB
        • Han JK
        • Choi BI.
        Assessment of hepatic steatosis by using attenuation imaging: A quantitative, easy-to-perform ultrasound technique.
        ;
        • Ferraioli G
        • Maiocchi L
        • Raciti MV
        • Tinelli C
        • De Silvestri A
        • Nichetti M
        • De Cata P
        • Rondanelli M
        • Chiovato L
        • Calliada F
        • Filice C.
        Detection of liver steatosis with a novel ultrasound-based technique: A pilot study using MRI-derived proton density fat fraction as the gold standard.
        ;
        • Jeon SK
        • Lee JM
        • Joo I
        • Yoon JH
        • Lee DH
        • Lee JY
        • Han JK.
        prospective evaluation of hepatic steatosis using ultrasound attenuation imaging in patients with chronic liver disease with magnetic resonance imaging proton density fat fraction as the reference standard.
        ;
        • Dioguardi Burgio M
        • Ronot M
        • Reizine E
        • Rautou PE
        • Castera L
        • Paradis V
        • Garteiser P
        • Van Beers B
        • Vilgrain V
        Quantification of hepatic steatosis with ultrasound: promising role of attenuation imaging coefficient in a biopsy-proven cohort.
        ;
        • Labyed Y
        • Milkowski A.
        Novel method for ultrasound-derived fat fraction using an integrated phantom.
        ;
        • Sugimoto K
        • Moriyasu F
        • Oshiro H
        • Takeuchi H
        • Abe M
        • Yoshimasu Y
        • Kasai Y
        • Sakamaki K
        • Hara T
        • Itoi T.
        The role of multiparametric US of the liver for the evaluation of nonalcoholic steatohepatitis.
        ;
        • Petroff D
        • Blank V
        • Newsome PN
        • Shalimar
        • Voican CS
        • Thiele M
        • de Ledinghen V
        • Baumeler S
        • Chan WK
        • Perlemuter G
        • Cardoso AC
        • Aggarwal S
        • Sasso M
        • Eddowes PJ
        • Allison M
        • Tsochatzis E
        • Anstee QM
        • Sheridan D
        • Cobbold JF
        • Naveau S
        • Lupsor-Platon M
        • Mueller S
        • Krag A
        • Irles-Depe M
        • Semela D
        • Wong GL
        • Wong VW
        • Villela-Nogueira CA
        • Garg H
        • Chazouilleres O
        • Wiegand J
        • Karlas T
        Assessment of hepatic steatosis by controlled attenuation parameter using the M and XL probes: An individual patient data meta-analysis.
        ).
      • 5.
        Quantitative US techniques can be utilized to support the diagnosis of fatty liver when an US scan is non-diagnostic as they can detect small amounts of liver fat that are not clearly displayed on B-mode US (
        • Kwon EY
        • Kim YR
        • Kang DM
        • Yoon KH
        • Lee YH.
        Usefulness of US attenuation imaging for the detection and severity grading of hepatic steatosis in routine abdominal ultrasonography.
        ).
      • 6.
        MRI-PDFF is a quantitative biomarker that estimates liver fat content over a wide range and can be used as the non-invasive reference standard (
        • El-Badry AM
        • Breitenstein S
        • Jochum W
        • Washington K
        • Paradis V
        • Rubbia-Brandt L
        • Puhan MA
        • Slankamenac K
        • Graf R
        • Clavien PA.
        Assessment of hepatic steatosis by expert pathologists: the end of a gold standard.
        ;
        • Roldan-Valadez E
        • Favila R
        • Martinez-Lopez M
        • Uribe M
        • Rios C
        • Mendez-Sanchez N.
        In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty liver disease: Correlation with biochemical method and morphometry.
        ;
        • Raptis DA
        • Fischer MA
        • Graf R
        • Nanz D
        • Weber A
        • Moritz W
        • Tian Y
        • Oberkofler CE
        • Clavien PA.
        MRI: The new reference standard in quantifying hepatic steatosis?.
        ;
        • Noureddin M
        • Lam J
        • Peterson MR
        • Middleton M
        • Hamilton G
        • Le TA
        • Bettencourt R
        • Changchien C
        • Brenner DA
        • Sirlin C
        • Loomba R.
        Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials.
        ;
        • Caussy C
        • Alquiraish MH
        • Nguyen P
        • Hernandez C
        • Cepin S
        • Fortney LE
        • Ajmera V
        • Bettencourt R
        • Collier S
        • Hooker J
        • Sy E
        • Rizo E
        • Richards L
        • Sirlin CB
        • Loomba R.
        Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis.
        ,
        • Caussy C
        • Reeder SB
        • Sirlin CB
        • Loomba R.
        Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials.
        ).
      • 7.
        In cases of heterogeneous distribution of steatosis, caution in interpretation is needed as there is no reference standard in these cases.
      • 8.
        Given its suboptimal performance in quantifying liver fat content, CAP must not be used as the reference standard to assess the performance of the new US techniques for the quantification of liver steatosis (
        • Imajo K
        • Kessoku T
        • Honda Y
        • Tomeno W
        • Ogawa Y
        • Mawatari H
        • Fujita K
        • Yoneda M
        • Taguri M
        • Hyogo H
        • Sumida Y
        • Ono M
        • Eguchi Y
        • Inoue T
        • Yamanaka T
        • Wada K
        • Saito S
        • Nakajima A.
        Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography.
        ;
        • Park CC
        • Nguyen P
        • Hernandez C
        • Bettencourt R
        • Ramirez K
        • Fortney L
        • Hooker J
        • Sy E
        • Savides MT
        • Alquiraish MH
        • Valasek MA
        • Rizo E
        • Richards L
        • Brenner D
        • Sirlin CB
        • Loomba R.
        Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease.
        ;
        • Fujiwara Y
        • Kuroda H
        • Abe T
        • Ishida K
        • Oguri T
        • Noguchi S
        • Sugai T
        • Kamiyama N
        • Takikawa Y.
        The B-mode image-guided ultrasound attenuation parameter accurately detects hepatic steatosis in chronic liver disease.
        ;
        • Runge JH
        • Smits LP
        • Verheij J
        • Depla A
        • Kuiken SD
        • Baak BC
        • Nederveen AJ
        • Beuers U
        • Stoker J.
        MR spectroscopy-derived proton density fat fraction is superior to controlled attenuation parameter for detecting and grading hepatic steatosis.
        ;
        • Ferraioli G.
        CAP for the detection of hepatic steatosis in clinical practice.
        ;
        • Petroff D
        • Blank V
        • Newsome PN
        • Shalimar
        • Voican CS
        • Thiele M
        • de Ledinghen V
        • Baumeler S
        • Chan WK
        • Perlemuter G
        • Cardoso AC
        • Aggarwal S
        • Sasso M
        • Eddowes PJ
        • Allison M
        • Tsochatzis E
        • Anstee QM
        • Sheridan D
        • Cobbold JF
        • Naveau S
        • Lupsor-Platon M
        • Mueller S
        • Krag A
        • Irles-Depe M
        • Semela D
        • Wong GL
        • Wong VW
        • Villela-Nogueira CA
        • Garg H
        • Chazouilleres O
        • Wiegand J
        • Karlas T
        Assessment of hepatic steatosis by controlled attenuation parameter using the M and XL probes: An individual patient data meta-analysis.
        ).
      • 9.
        Until there is standardization of the procedures and interpretation for the techniques, the vendors’ recommendations should be used to acquire and interpret the values, including recommendations on how to assess the quality of the results.
      Institutional review boards gave approval, and subjects granted permission for the use of their data/images.

      Conflict of interest disclosure

      G.F. is on the speakers’ bureaus of Canon Medical Systems, Fujifilm previously Hitachi Ltd, Mindray Medical Systems and Philips Medical Systems.
      A.B. is on the advisory boards of General Electrics, Inventiva and Boehringer Ingelheim.
      R.G.B. has received research grants from Philips Ultrasound, Siemens Healthineers, Samsung, Canon and Mindray; is on the speakers’ bureaus of Philips Ultrasound, Mindray, Siemens Healthineers and Canon; and has received royalties from Thieme Publishers and Elsevier Publishers.
      O.H.G. has received speakers’ honoraria from AbbVie, Bracco, Almirall, GE Healthcare, Takeda AS, Meda AS, Ferring AS and Allergan; and is a consultant to Bracco, GE Healthcare, Takeda and Samsung.
      F.P. has an institutional research contract with and has received honoraria for advisory boards from ESAOTE; and is on the speakers’ bureaus or is a consultant to Alkermes, Astrazeneca, Bayer, Bracco, BMS, EISAI, GE, IPSEN, La Force Guerbet, Roche, Samsung, Siemens Healthcare and Tiziana Life Sciences.
      G.L.H.W. has served as an advisory committee member for Gilead Sciences and Janssen and as a speaker for Abbott, Abbvie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen and Roche; and has received research grant from Gilead Sciences.
      V.W.S.W. has served as an advisory committee member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Janssen, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, TARGET-NASH and Terns; was a speaker for Bristol-Myers Squibb, Echosens, Gilead Sciences and Merck; and has received a research grant from Gilead Sciences.
      C.F.D. received speaker honoraria from Bracco, Hitachi, GE, Mindray, Supersonic, Pentax, Olympus, Fuji, Boston Scientific, AbbVie, Falk Foundation, Novartis and Roche; is a member of the Advisory Boards of Hitachi, Mindray and Siemens; and has received research grants from GE, Mindray and SuperSonic.
      B.I.C., X.W.C., Y.D., J.Y.L., D.H.L., F.M. and K.S. have no conflicts of interest to declare.

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