Diffuse liver diseases have recently received increasing consideration due to their mounting incidence, with particular attention to hepatic steatosis [1], which is related to two main clinical-pathological entities: alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD). NAFLD affects approximately 90% of the obese population, as well as 15%-40% of the general population. NAFLD can result in a multistep progressive disease, potentially evolving into nonalcoholic steatohepatitis (NASH), advanced fibrosis (in approximately 25% of cases), cirrhosis (10%-20% of cases), and hepatocellular carcinoma (4% of cases) [2-4]. In NAFLD patients, the most important clinical end-points are the differentiation of NASH from simple hepatic steatosis and the identification of advanced fibrosis. Considering the increased risk of liver failure and hepatocellular carcinoma in patients with cirrhosis, it is of the utmost relevance to follow-up fibrosis evolution noninvasively in order to establish an appropriate treatment and avoid disease progression [5].

The reference standard for the diagnosis of hepatic fibrosis is liver biopsy, an invasive procedure with known complications that is prone to sampling errors, intra- and inter-observer variability, and limited repeatability. Among the various noninvasive methods as alternative tools for staging hepatic fibrosis, the currently mostused technique in clinical practice is transient elastography (TE; FibroScan, Echosens, Paris, France). However, this technique has some limitations, such as obesity (which was partially overcome by the introduction of a new XL probe), narrow intercostal spaces, and the presence of ascites. When using the conventional M probe, in patients with steatosis of >66% at liver biopsy, TE provides a higher false-positive rate in terms of liver stiffness (LS) measurements. Therefore, TE (using the M probe) may overestimate liver fibrosis in patients with a body mass index (BMI) >30 kg/m² and severe steatosis [6].

Point shear-wave elastography (p-SWE) may represent an alternative to TE. SWE is integrated into conventional ultrasound equipment, enabling a rapid quantitative evaluation of LS [7]. SWE allows the operator to precisely visualize where the measurements are performed on B-mode ultrasound images, even in presence of ascites [8]. Preliminary results have shown high accuracy of p-SWE for the assessment of liver fibrosis in patients affected by chronic viral hepatitis [9-11], but few data are available regarding the comparison between p-SWE and TE, especially in patients with NAFLD [12,13] and to our knowledge, no prior study has assessed NAFLD using an RS80A ultrasound system. Therefore, in the last version of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines on the clinical use of liver ultrasound elastography, recommendations are still lacking on the preferred first-line method for the assessment of hepatic fibrosis in patients with NAFLD [14].

The aim of our study was to prospectively assess the accuracy of p-SWE for the quantitative evaluation of LS in patients with NAFLD, in comparison with TE and liver biopsy, and to determine the optimal cutoff values for significant and advanced fibrosis.

This prospective study was approved by the Ethics Committee of University Hospital, a tertiary center for the treatment of chronic liver disease (Palermo 1 ID-2014). All subjects provided written informed consent for this study in accordance with the Declaration of Helsinki.

Our study demonstrated that p-SWE provided accurate results for the assessment of hepatic fibrosis in patients with biopsy-proven NAFLD, with a fair-to-good performance for the diagnosis of significant and advanced fibrosis. Compared to TE, there were no significant differences in diagnostic performances of SWE-10, SWE-5, or SWE-3 for the diagnosis of both significant (P=0.301) and advanced (P=0.496) fibrosis, although SWE-10 and SWE-5 had higher performance. Moreover, TE and different p-SWE measurements showed significant correlations with the fibrosis grade evaluated on biopsy specimens. Considering the widespread prevalence of NAFLD in the general population related to the increased prevalence of obesity and metabolic syndrome, our results may have significant relevance for the appropriate first-line noninvasive assessment of patients with NAFLD. Indeed, the presence of significant and advanced fibrosis is an independent predictor of liver-related mortality, and has been associated with an increased risk of hepatocellular carcinoma, cardiovascular mortality, and type 2 diabetes mellitus [19].

Limited literature exists comparing different methods for LS measurements in the same study population affected by NAFLD, especially in comparison with biopsy results [12,17,20,21]. Our results are concordant with those of Furlan et al. [20], who reported comparable diagnostic accuracy of SWE to conventional TE for the identification of significant and advanced fibrosis in NAFLD patients. In our study, the optimal cutoffs of ≥8.4 kPa and ≥9.1 kPa obtained by SWE-10 provided a sensitivity of 74.0% and a specificity of 73.7% for the diagnosis of significant fibrosis, and a sensitivity of 72.2% and a specificity of 78.5% for the diagnosis of advanced fibrosis, respectively. This evidence supports the use of p-SWE in clinical practice as a valuable alternative noninvasive method for the quantification of LS and a potential alternative to liver biopsy for the staging and follow-up of patients with NAFLD. SWE may have advantages over TE in patients with ascites or obesity, and may enable a simultaneous evaluation of focal liver lesions and LS measurements in patients undergoing surveillance for NAFLD [6].

Moreover, our study assessed the performance of the p-SWE technique with fewer measurements. In agreement with other recent evidence evaluating cohorts with different etiologies of chronic liver disease, we observed that SWE-5 provided the highest diagnostic performance (AUROC), sensitivity, and specificity for both significant (0.809, 77.8%, and 73.4%, respectively) and advanced fibrosis (0.809, 77.8%, and 75.0%, respectively) with respect to SWE-10 and for significant fibrosis with respect to TE, even if the differences were not statistically significant [22,23]. Interestingly, when exploring alternative cutoffs for maximizing sensitivity and specificity, SWE-5 with a cutoff of ≥7.6 kPa yielded an increase in sensitivity to 94.4%, with only a slight drop in specificity (60.7%) for the diagnosis of advanced fibrosis. In contrast, SWE-3 showed the lowest performance (AUROC, sensitivity, and specificity) for both significant (0.714, 66.7%, and 63.2%, respectively) and advanced fibrosis (0.736, 66.7%, and 71.4%, respectively). Although current guidelines still recommend a minimum of 10 valid measurements for the appropriate p-SWE examinations, conducting an evaluation with five valid LS measurements may potentially save time during examinations in clinical practice, without compromising the diagnostic performance for the assessment of hepatic fibrosis [14].

In our study, LS measurements by TE and p-SWE showed significant correlations with fibrosis grade, while no correlations were observed for BMI, histopathological markers of NASH, or laboratory results. However, in a non-negligible proportion of patients (17.8% of the initial cohort), LS measurements by p-SWE failed. In particular, patients with failed p-SWE more frequently had advanced fibrosis (90.0% vs. 39.2%, P=0.006), and also had higher BMI (mean, 33.7±4.9 kg/m²; P=0.011) and higher TE measurements (mean, 28.9±25.4 kPa; P<0.001) than patients with valid LS measurements. Cassinotto et al. [12], along with other evidence, also reported fewer reliable results in patients with a BMI ≥30 kg/m² and a waist circumference ≥102 cm [16,24]. We speculate that, in our study population, this non-negligible percentage of failed p-SWE could be related to US equipment technology. Of note, the US equipment is undergoing constant updates, and the latest version deems the results to be reliable when the RMI is ≥0.4 instead of the previously suggested value of ≥0.6. This technical aspect could potentially decrease the percentages of failed p-SWE measurements, and applying this cutoff would have allowed us to include many more patients in our study.

It should also be noted that, on the basis of the current literature, each ultrasound equipment is different from the others, with particular reference to quantitative evaluation and optimal SWE cutoff values to classify significant and advanced liver fibrosis, which are specific for each ultrasound machine. Indeed, different software methods can be used to measure shear wave arrival time and speed [25]. This could be considered a limitation of p-SWE, since a reliable follow-up should always be performed in the same patient using the same US machine. In our study, according to EFSUMB guidelines, we evaluated all patients using the same US equipment by the same manufacturer; as such, we report our experience with this specific US equipment. Therefore, cutoff values are different for other US machines, even if the p-SWE technique has been well-known for some years. It should be also noted that an unquestionable advantage of TE with respect to p-SWE is the capability to quantify liver fatty content by using the controlled attenuation parameter (CAP), which measures ultrasound beam attenuation (a parameter directly related to the amount of steatosis), and enables the stratification of each patient in a different stage (no steatosis; mild, moderate, or severe steatosis) with a robust correlation with biopsy results. CAP measurements are important for the TE LS evaluation since LS can be overestimated in patients with high CAP values, which has led to the adjustment of TE cutoff values and the development of new ultrasound software [26-28]. Moreover, before performing SWE, confounding factors should be assessed to prevent the overestimation of LS measurements; patients with liver inflammation (AST and/or ALT elevation >5 times the normal limits), obstructive cholestasis, liver congestion, acute hepatitis, and infiltrative liver diseases should be excluded before measuring LS, as recommended by EFSUMB guidelines [14].

Our study has multiple limitations that need to be acknowledged. First, our study population was limited by the relatively small number of prospectively-enrolled patients in a single Institution related to our selection criteria and the RMI cutoff values considered to indicate reliable measurements. The final number of included patients and the exclusion of patients with failed SWE measurements may have limited the evaluation of differences in diagnostic performance between TE and p-SWE with different measurements. However, all the included subjects underwent histopathological examinations with percutaneous liver biopsy within 1 month and underwent laboratory tests on the same day of TE and p-SWE evaluation. Second, p-SWE was performed by a single radiologist, therefore, inter-reader agreement could not be evaluated. Other studies have already investigated the inter- and intra-reader reproducibility of SWE techniques [29]. Finally, our population included only four patients lacking fibrosis (F0) on biopsy specimens.

In conclusion, TE and p-SWE had similar fair-to-good diagnostic performance for the diagnosis of biopsy-proven significant and advanced fibrosis in patients with NAFLD.