Value of CAP for liver steatosis assessment.
The number of NAFLD patients is increasing in the developed world and non-invasive modalities for their evaluation are needed. Ultrasound-based methods are very useful for this approach, starting with standard ultrasound used for steatosis detection, and continuing with new modalities for steatosis, fibrosis, and inflammation quantification. Modern ultrasound systems can quantify all these parameters in NAFLD patients, thus making ultrasound a real Multiparameter Ultrasound (MPUS). The performance of ultrasound-based methods is very well documented with liver stiffness assessment as a marker of fibrosis, and more recently, for quantification of steatosis and viscoelastic properties as a marker of inflammation.
- nonalcoholic fatty liver disease (NAFLD)
- fatty liver
- liver elastography
- fat quantification
Currently, at least in the developed world, the focus of hepatology changed, from chronic viral hepatitis (B or C), which is now well controlled with efficient drugs, to the problem of fatty liver. This disease occurs in both non-alcoholic patients with metabolic conditions as well as in alcoholic patients . Nonalcoholic fatty liver disease (NAFLD) become more and more present in clinical practice, since it currently affects more than a quarter of the world population  and the prevalence is increasing . Overweight and obesity, type 2 diabetes, dyslipidemia, and sedentariness are increasing at a global level, at least in the developed world [4, 5]. For a long time, the fatty liver was considered to be a “benign” entity, but in the last years, the potential evolution of this disease to severe fibrosis and cirrhosis has been proven. Furthermore, in the last years, NAFLD became an important indication for liver transplantation [6, 7, 8].
Recently, new terminology for NAFLD was proposed, to better reflect its clinical spectrum: Metabolic Associated Fatty Liver Disease (MAFLD) [9, 10]. This new terminology is used more and more, having the advantage to underline the role of metabolic factors and to not exclude the use of alcohol. Thus, we must be focused to screen for fatty liver in the population at risk: patients with obesity, metabolic syndrome, and type 2 diabetes mellitus (DM).
Recent data showed that 650 million people around the world are obese and 1,9 billion are overweight (39% of the adult population)! Type 2 diabetes mellitus (type 2 DM) become a frequent cause of morbidity in the last decade (1 in 11 people of the developed countries have type 2 DM) . Furthermore, many of type 2 DM patients are overweight and obese. Association of obesity and type 2 DM increases the risk for fatty liver infiltration. Features of metabolic syndrome are frequent in the adult population; thus, all these conditions explain the increased incidence of fatty liver in daily practice.
These huge cohorts of patients should be evaluated, especially in regard to fibrosis severity, the main driver of fibrosis. Simple non-invasive biologic tests to predict significant fibrosis in patients with NAFLD are available, such as Fibrosis-4 (FIB-4) or APRI (which uses only transaminases serum levels, platelet count and age), with acceptable accuracy . Other biologic tests are more accurate [Enhanced Liver Fibrosis (ELF™) Test, FibroMax, others], but also more complex and more expensive.
In the last 15 years numerous ultrasound (US) based elastography techniques have been developed [Transient Elastography (TE), point Shear Wave Elastography (pSWE) or 2D-SWE], which have demonstrated their practical value in many studies. International Guidelines classify these US elastography techniques into: Strain Elastography (used mostly for breast, thyroid and prostate nodules) and Shear Waves Elastography (SWE - in which external impulses generate shear waves inside the liver, whose speed is measured by ultrasound) [13, 14]. The faster the shear-waves speed are, the stiffer the tissue and the fibrosis are more severe. Based on the generation of the external impulse and the technology used to measure the shear-waves speed, SWE elastography is subdivided into: Transient Elastography (with a mechanic external impulse), Point SWE (pSWE) [in which an Acoustic Radiation Force Impulse (ARFI) is used and the shear-waves speed is measured in a point], and real-time elastography which includes 2D-SWE and 3D-SWE (in which ARFI is used, shear-waves speed is measured in an area of interest and in the same time a color-coded elastogram is generated) [13, 14].
However, in patients with NAFLD, not only the evaluation of fibrosis is important, but also quantification of steatosis and inflammation is of practical value.
In this chapter, we aim to discuss the ultrasound-based methods for the evaluation of patients with NAFLD. In such patient’s evaluation and quantification of steatosis, fibrosis and inflammation are important. In practice, these methods are frequently used and more and more data are collected regarding their value.
2. Steatosis evaluation
In patients with NAFLD, the presence of steatosis is a common fact and then the evaluation of its severity is necessary.
Maybe the most important paper regarding the value of liver US for diagnosing fatty liver is a large meta-analysis , which included 49 studies and 4720 subjects. The sensitivity of US for moderate and severe steatosis was 84.8% (CI 95%: 79.5–88.9%), with a specificity of 93.6% (CI 95%: 87.2–97.0%).
Computer Assisted Diagnosis (CAD) was also evaluated as a tool to increase the accuracy of US for the detection and severity assessment of steatosis . In a study including 120 patients , CAD was able to correctly classify the severity of steatosis with an accuracy of 82.2%. More recently, Artificial Intelligence (AI) has been used for the same purpose .
All these papers are in favor to use liver ultrasound for the detection of steatosis in patients with risk factors. The latest update of the European Association for the Study of the Liver (EASL) Guidelines regarding the non-invasive evaluation in chronic liver disease  states that: “Conventional ultrasound should be used as a first-line tool for the diagnosis of steatosis in clinical practice, despite its well-known limitations”. This method can be used for a semi-quantitative assessment of the severity of fatty infiltration.
For a quantitative evaluation of liver steatosis, the most used method in this moment is Controlled Attenuation Parameter (CAP). It is a module implemented on a FibroScan device (Echosens, Paris, France), which measures the attenuation of the ultrasound beams throughout the liver to assess steatosis severity. CAP was first used on the M probe and latter also on the XL probe (Figure 3).
Many papers have been published on the value of CAP for liver steatosis assessment, comparing it to liver biopsy. In the next table, we resumed the main published papers concerning the value of CAP (Table 1).
|Study||No. of patients||Cut-off values for each steatosis grade (dB/m)|
|S ≥ 1||S ≥ 2||S ≥ 3|
|Chan 2014 ||105||263||281||283|
|De Ledinghen 2016 ||261||—||310||311|
|Imajo 2016 ||142||236||279||302|
|Park 2017 ||104||261||305||312|
|Naveau 2017 ||123||298||303||326|
|Sissiqui 2019 ||393||285||311||306|
|Shalimar 2020 ||219||285||331||348|
|Oeda 2019 ||137||—||264||289|
|Eddowes 2019 ||88||302||331||337|
|Petroff 2021 ||2346||294||310||331|
|Karlas 2017 ||2735||248||268||280|
|Kamali 2019 ||77||237||259||291|
|Zenovia 2021 ||204||245||273,5||333|
|Mikolasevic 2021 ||179||304||311||345|
|Park 2017 ||104||261||—||—|
|Gu 2021 ||1183/3295/2835||273.5||288.5||309|
Having in mind that the CAP module is available both in M and XL probes, the next question is if the same cut-off values can be used in practice for both probes? Chan et al. evaluated a cohort of 180 patients by liver biopsy and CAP with both M and XL probes . The group had a mean age of 53.7 ± 10.8 years and NAFLD was identified in 86.7% of them, the sensitivity, specificity, PPV, and NPV of CAP using the M/XL probe for the diagnosis of steatosis grade ≥ S1 was 93.9%/93.3%, 58.8%/58.8%, 95.6%/95.6%, and 50.0%/47.6%, respectively. Thus, the authors concluded that the same cut-off values for CAP may be used for the M and XL probes for the diagnosis of hepatic steatosis grade.
However, in another prospective study on 100 adults , which compared CAP with the M vs. the XL probe for quantification of hepatic fat content, using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as the standard, the mean CAP values by M probe (310 ± 62 db/m) were significantly lower than by the XL probe (317 ± 63 db/m) (
In the last years,
In another study, in which liver histology was used as a reference in a series of 108 subjects, it has been reported that the degree of steatosis was the only significant determinant factor for the ATI results and that the AUROCs for different grades of steatosis ranged from 0.84 to 0.93 .
In a study that used once again MRI-PDFF as reference , in a cohort of 87 patients, the AUROCs of ATI for detection of hepatic steatosis ≥5% and ≥ 10%, were 0.76 and 0.88, respectively (95% CI: 0.66–0.85 and 0.79–0.94) and the correlation of ATI with MRI-PDFF was moderate (
In another study in a cohort of 215 NAFLD patients using Aixplorer MACH 30 system  for the evaluation of steatosis, Sound Speed Plane-wave UltraSound (
All these results concerning the quantification of liver steatosis using ultrasound are very promising and every day new papers are published in well-known medical journals considering the rapid development of this field.
3. Evaluation of fibrosis
In the early times of non-invasive assessment of patients with chronic liver disease, the main field of research was liver fibrosis. Replacing in many cases liver biopsy, this assessment is essential for the prognosis of patients [46, 47]. Early papers in this field evaluated Transient Elastography (TE) as a predictor of fibrosis in NAFLD . Later, ARFI technologies (Acustic Radiation Force Impulse) with pSWE and 2D-SWE became fields of research . In Table 2 we presented the main papers evaluating TE and SWE methods for the assessment of liver fibrosis in NAFLD patients.
|Study||No of patients||Elastography||Cut-off values for each fibrosis stage|
|Petta 2016 ||324||TE||—||>10.5 kPa||>12.5 kPa||—|
|Yoneda 2007 ||67||TE||>5.6 kPa||>6.65 kPa||>8 kPa||>17 kPa|
|Gaia 2011 ||72||TE||>5.5 kPa||>7 kPa||>8 kPa||>10.5 kPa|
|Kumar 2013 ||205||TE||>6.1 kPa||>7 kPa||>9 kPa||>11.8 kPa|
|Lupsor 2010 ||72||TE||—||>6.8 kPa||>10.4 kPa||—|
|Petta 2011 ||169||TE||—||>7.25 kPa||>8.75 kPa||—|
|Ratziu 2010 ||53||TE||>5.1 kPa||>9.1 kPa||>11.1 kPa||>14.5 kPa|
|Yoneda 2008 ||50||TE||—||>6.6 kPa||>9.8 kPa||>17.5 kPa|
|Nobili 2008 ||52||TE||—||>7.4 kPa||>10.2 kPa||—|
|Wong 2010 ||146||TE||—||>7 kPa||>8.7 kPa||>10.3 kPa|
|Wong 2012 ||193||TE||—||>6.2 kPa||>7.2 kPa||>7.9 kPa|
|Musso 2011 ||60||TE||—||>7 kPa||>8.7 kPa||—|
|Yoneda 2010 ||54||TE||—||—||>9.9 kPa||>16 kPa|
|Mahadeva 2013 ||131||TE||—||>6.65 kPa||>7.1 kPa||>10.6 kPa|
|Imajo 2016 ||152||TE||—||>11 kPa||>11.4 kPa||>14 kPa|
|Pathik 2015 ||89||TE||—||>9.1 kPa||>12 kPa||>20 kPa|
|Kumar 2013 ||207||TE||—||>7 kPa||>9 kPa||>11.8 kPa|
|Cassinotto 2016 ||291||TE||—||>6.2 kPa||>8.2 kPa||>9.5 kPa|
|Kamali 2019 ||77||TE||—||>8 kPa||>11 kPa||>16 kPa|
|Eddowes 2019 ||88||TE||—||>8.2 kPa||>9.7 kPa||>13.6 kPa|
|Park 2017 ||104||TE||—||>6.10 kPa||—||—|
|Seki 2017 ||171||TE||>7.2 kPa||—||>10.0 kPa||—|
|Lee 2017 ||94||TE||—||>7.4 kPa||> 8 kPa||>10.8 kPa|
|Hsu 2018 ||230||TE||>6.2 kPa||>7.6 kPa||>8.8 kPa||>11.8 kPa|
|Attia 2016 ||61||TE||—||>7.0 kPa||>11.8 kPa||>15.0 kPa|
|Myers 2010 ||50||TE||—||—||>10.3 kPa||>11.1 kPa|
|Myers 2012 ||276||TE||—||—||—||>16 kPa|
|Furlan 2020 ||59||TE||—||>8.8 kPa||>6.7 kPa||—|
|Leong 2020 ||100||TE||>7.68 kPa||>9.13 kPa||>9.28 kPa||>13.4 kPa|
|Imajo 2020 ||221||TE||>6.95 kPa||>8.14 kPa||>13.8 kPa||>19.5 kPa|
|Yoneda 2010 ||54||pSWE||—||—||>1.77 m/s||>1.9 m/s|
|Fierbinteanu 2013 ||64||pSWE||—||—||>1.48 m/s||>1.63 m/s|
|Cassinotto 2013 ||165||pSWE||—||>1.3 m/s||>1.51 m/s||>1.61 m/s|
|Friedrich-Rust 2012 ||50||pSWE||—||>1.37 m/s||—||—|
|Osaki 2010 ||101||pSWE||>1.34 m/s||>1.79 m/s||>2.2 m/s||>2.9 m/s|
|Lee 2017 ||94||pSWE||—||>1.35 m/s||>1.43 m/s||>1.50 m/s|
|Attia 2016 ||61||pSWE||—||>1.18 m.s||>1.45 m/s||>1.95 m/s|
|Palmeri 2011 ||172||pSWE||—||—||>1.49 m/s||—|
|Cui 2016 ||114||pSWE||—||>1.29 m/s||>1.34 m/s||>2.48 m/s|
|Li 2016 ||136||pSWE||—||>1.30 m/s||>1.36 m/s||>1.41 m/s|
|Leong 2020 ||100||pSWE||>6.83 kPa||>6.98 kPa||>7.02 kPa||>11.5 kPa|
|Sharpton 2021 ||114||pSWE||>7.8 kPa||>6.8 kPa||>8.7 kPa||>10.6 kPa|
|Cassinotto 2016 ||291||2D-SWE||—||>6.3 kPa||>8.3 kPa||>10.5 kPa|
|Herrmann 2017 ||156||2D-SWE||—||>7.1 kPa||>9.2 kPa||>13 kPa|
|Takeuchi 2018 ||71||2D-SWE||>6.6 kPa||>11.6 kPa||>13.1 kPa||>15.7 kPa|
|Jamialahmadi 2019 ||90||2D-SWE||>5.6 kPa||>6.6 kPa||>6.8 kPa||>6.8 kPa|
|Lee 2017 ||94||2D-SWE||—||>8.3 kPa||>10.7 kPa||>15.1 kPa|
|Furlan 2020 ||57||2D-SWE||—||>5.7 kPa||>8.1 kPa||—|
|Sharpton 2021 ||114||2D-SWE||>7.5 kPa||>7.7 kPa||>7.7 kPa||>9.3 kPa|
|Imajo 2020 ||221||2D-SWE||>6.65 kPa||>8.04 kPa||>10.6 kPa||>12.37 kPa|
Considering the practical value of different systems, TE is the oldest system, a semi-blind method of evaluation, it can assess fibrosis severity as well as steatosis (with CAP) in the same machine, is not possible to be performed in patients with ascites and in some areas TE and CAP measurements are made by technicians. ARFI technologies (pSWE and 2D-SWE) are included in standard ultrasound systems and fibrosis assessment (and others parameters) can be performed immediately after B-mode examination and can evaluate to the patients with ascites. International published guidelines regarding the practical values of all these techniques have been published [13, 14]. Barr et al.  showed the advantages and disadvantages of each method. The most recent guideline (from 2021) is the EASL Guideline for the use of the main non-invasive tests, with the important recommendations in this field .
4. Evaluation of inflammation
In patients with NAFLD, it is of crucial importance to differentiate between simple steatosis and steatohepatitis (NASH: non-alcoholic steatohepatitis). The best method for this is liver biopsy. However, having in mind the huge number of subjects with NAFLD (1/4 of the population in the developed countries), this invasive technique is not feasible in practice for all the patients. It has been demonstrated that using only biologic tests (such as aminotransferases or Cytokeratin 18) is not enough, thus new methods that accurately assess inflammation are necessary .
The newest high-end US machines include modules that evaluate the viscoelastic properties of the liver. This parameter is considered to be an expression of inflammation in the fatty liver, useful for the diagnosis of steatohepatitis (NASH).
Such a paper was published recently. Detection of steatosis, fibrosis and inflammation in 102 patients with NAFLD in comparison with liver biopsy was performed using a high-end US machine .
In a prospective study performed in a cohort of 120 consecutive adults who underwent liver biopsy for suspected NAFLD, Multiparametric US was used for liver assessment . Three US parameters:
Although, there are still many steps to go to reach an accurate software for the detection of inflammation using US waves, these early papers are encouraging for the noninvasive assessment of patients with NAFLD. All necessary information can be obtained using the Multiparametric Ultrasound (MPUS), and this is an ideal technique for NAFLD patients (quantification of fibrosis, steatosis and inflammation in less than 5 minutes) (Figure 9).
In this moment, the main challenge in this field is to start the screening of the population at risk (MAFLD patients) for all the parameters of NAFLD . Using simple biological tests  or maybe more sophisticated systems, such as ultrasound based or maybe MRI-based elastography, we can identify patients with advanced disease. Then intensive measures for such patients must be implemented.
Ultrasound methods are very useful for the evaluation of NAFLD patients. Identification of steatosis can be performed with standard ultrasound. Quantification of steatosis, fibrosis and inflammation can be assessed quickly with new high-tech ultrasound machines. Screening of patients at risk for the fatty liver with these modern tools is a challenge for the near future.
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