Liver stiffness accuracy by magnetic resonance elastography in histologically proven non-alcoholic fatty liver disease patients: a Spanish cohort

1130-0108/2023/115/4/160-165 • REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS REV ESP ENFERM DIG 2023:115(4):160-165 DOI: 10.17235/reed.2022.8777/2022 © Copyright 2023 y Creative Commons (CC-BY-NC-ND). Sociedad Española de Patología Digestiva (SEPD) y © Arán Ediciones S.L. ABSTRACT Objectives: to evaluate the performance of magnetic resonance elastography (MRE) to stage liver fibrosis in patients with histologically confirmed nonalcoholic fatty liver disease (NAFLD) and to assess the impact of potential confounding factors in MRE diagnostic accuracy. The secondary objective was to compare MRE with other non-invasive methods for staging fibrosis such as transient elastography (TE) and non-invasive scores (APRI and FIB-4). Methods: sixty-five histologically confirmed NAFLD patients were prospectively enrolled at the Hospital Universitario Virgen del Rocío (Seville, Spain). Liver stiffness was measured by MRE, TE and non-invasive scores (APRI and FIB-4). Fibrosis was assessed by liver biopsy using the steatosis, activity and fibrosis (SAF) score. Patients were classified into three groups according to the consistency between MRE and histopathological findings: underestimation, concordance and overestimation groups. Areas under the ROC curve (AUROC) and diagnostic performance were evaluated. Results: the area under the ROC curve (AUROC) of MRE in advanced fibrosis (≥ F3) was 0.90 (0.82-0.97), while TE AUROC was 0.82 (0.72-0.93) (p = 0.22) and lower for the non-invasive test (FIB-4 0.67 and APRI 0.62). Inflammatory activity, steatosis grade and higher levels of liver biochemistry appeared to overestimate MRE results in the univariate analysis, but only gamma-glutamyl transferase (GGT) was statistically significant in the multivariate analysis (p < 0.01). Age, sex, body mass index (BMI), weight, diabetes mellitus (DM), high blood pressure (HBP), platelets or lipidic profile did not affect MRE accuracy. Conclusions: MRE is an effective and non-invasive method for detecting and staging liver fibrosis in NAFLD patients. MRE is more accurate than TE and allows the study of liver anatomy. Histological inflammation and surrogate biomarkers of inflammation can overestimate liver stiffness, but only GGT was statistically significant in the multivariate analysis. Important features of NAFLD patients such as obesity, DM, or lipidic profile did not affect MRE accuracy. Keywords: Magnetic resonance elastography. Liver stiffness. Fibrosis. Non-alcoholic fatty liver disease. INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide, affecting approximately 25 % of the global population (1). Several studies have demonstrated that the presence of liver fibrosis is the most important predictor of mortality in NAFLD. In fact, the risk of all-cause mortality is positively correlated with fibrosis stage and the risk of liver-related mortality increas- ORIGINAL PAPER Liver stiffness accuracy by magnetic resonance elastography in histologically proven non-alcoholic fatty liver disease patients: a Spanish cohort Carmen Lara Romero1,2, Jia-Xu Liang1,2,3, Isabel Fernández-Lizaranzu1,4, Javier Ampuero Herrojo1,2, Javier Castell5, Carmen del Prado Alba6, Inmaculada Domínguez Pascual7, Manuel Romero-Gómez1,2 1Digestive Diseases CMU and Ciberehd. Hospital Universitario Virgen del Rocío. Sevilla, Spain. 2Institute of Biomedicine of Seville (HUVR/CSIC/US). Universidad de Sevilla. Sevilla, Spain. 3Department of Diagnostic Radiology. People’s Hospital of Zhengzhou. Zhengzhou, China. 4Interdisciplinary Physics Group. Universidad de Sevilla. Sevilla, Spain. Departments of 5Diagnostic Radiology, 6Anatomic Pathology, and 7Clinical Analysis. Hospital Universitario Virgen del Rocío. Sevilla, Spain Received: 17/03/2022 · Accepted: 01/07/2022 Correspondence: Manuel Romero-Gómez. Digestive Diseases CMU. Hospital Universitario Virgen del Rocío. Av. Manuel Siurot, s/n. 41013 Sevilla, Spain. e-mail: [email protected] Conflict of interest: the authors declare no conflict of interest. Acknowledgments: LITMUS Project (IMI-2 Grant number: 777377) that supported this research. Lara Romero C, Liang J-X, Fernández-Lizaranzu I, Ampuero Herrojo J, Castell J, del Prado Alba C, Domínguez Pascual I, Romero-Gómez M. Liver stiffness accuracy by magnetic resonance elastography in histologically proven non-alcoholic fatty liver disease patients: a Spanish cohort. Rev Esp Enferm Dig 2023;115(4):160-165 DOI: 10.17235/reed.2022.8777/2022 REV ESP ENFERM DIG 2023:115(4):160-165 DOI: 10.17235/reed.2022.8777/2022 161 Liver stiffness accuracy by magnetic resonance elastography in histologically proven non-alcoholic fatty liver disease patients: a Spanish cohort The time interval between clinical MRI and liver biopsy was < 3 months. Patients with a history of alcohol consumption (more than 20 g in women and 30 g in men daily), a personal history of other liver diseases such as chronic hepatitis, drug use associated with fatty liver (amiodarone, methotrexate, tamoxifen, valproic acid and glucocorticoids) or weight reduction, thyroid disorders, personal history of liver surgery or transplant were excluded. Demographic and clinicopathological characteristics such as age, sex, BMI, high blood pressure, dyslipidemia and type II DM were analyzed. Blood test parameters included fasting plasma glucose, HbA1c, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, aspartate aminostransferase (AST), alanine aminostransferase (ALT), GGT, total bilirubin, platelets and albumin. Histopathologic evaluation Liver biopsy samples were obtained from all patients with NAFLD using a 16-gauge needle biopsy kit according to a standard protocol. A single pathologist scored liver biopsy as an adequate sample when it was > 20 mm in length and/ or with > 10 portal tracts. Steatosis, inflammation and fibrosis were classified following the SAF classification (15). Transient elastography Liver stiffness was obtained using a TE (M and L probe, Fibro- Scan®: EchoSens, Paris, France) by one operator. Details of the technique and the examination procedure have been described in previous reports (16). At the same time, hepatic steatosis was assessed using the controlled attenuation parameter (CAP) value provided by the device, only when the LSM was valid for the same signals, ensuring that the liver ultrasonic attenuation was obtained simultaneously from the same volume of liver parenchyma as the LSM. Scoring systems The following scores were calculated for each patient based on a review of the literature: Fibrosis-4 index (17) and AST to platelet ratio index (18). Magnetic resonance elastography The image acquisitions were performed on 3.0T wholebody scanners (Philips Ingenia 3.0T, The Netherlands) with patients imaged in the supine position. MRE was performed using commercially available software and hardware (Resoundant Inc., Rochester, MN). Briefly, an acoustic passive driver is secured with an elastic band over the body wall, anterior to the liver and connected by a flexible plastic tube to an acoustic active driver outside the MRI room. Continuous vibrations at 60 Hz are generated by the active driver and delivered by the tube to the passive driver, which then transmits the vibrations into the body, thereby producing shear waves in the liver. A 2D FFE MRE pulse sequence is performed, TR: 50 ms, TE: shortest, FOV: 450 x 450 mm, SENSE: 2, while the vibrations are transmitted, and four noncontiguous axial slices (10-mm thick, 1 mm interslice gap) are acquired in a 17.7-second breath-hold through es exponentially with the increasing fibrosis stage (2-4). Therefore, the accurate detection and staging of liver fibrosis are essential for the management of patients with NAFLD. Liver biopsy is the gold standard to assess liver fibrosis stage in these patients. However, it cannot be widely used in clinical practice due to its limitations and risks, such as sample errors, poor tolerance, high cost and side effects. Due to these limitations, several non-invasive blood and imaging-based methods for staging liver fibrosis have been developed (5). These include ultrasound-based tests (transient elastography [TE], acoustic radiation force impulse imaging [ARFI]) or magnetic resonance elastography (MRE). MRE is a magnetic resonance imaging (MRI) based technique that images the propagation of acoustic shear waves in the liver and applies a mathematical algorithm to compute cross-sectional images displaying the magnitude of the complex shear modulus of liver tissue (6-8) . There are emerging data on the head-to-head comparison between various elastography-based methods with liver biopsy assessment as a reference. Several studies (9,10) have reported that MRE has a higher diagnostic ability than ultrasound-based imaging tests to assess liver fibrosis stage in patients with NAFLD. MRE also has a better utility over TE and ARFI in morbidly obese individuals and patients with ascites, as well as lower failure rates than TE. However, there are a few shortcomings for MRE. First, there is no universally accepted cut-off value for diagnosing different fibrosis stages, because the majority of original research on MRE technology until now has been performed on small cohorts and other etiologies. Although several conventional meta-analyses on MRE have been published in the last decade, they could not provide optimized cut-offs with high predictive values due to the heterogeneity of the analyzed studies and the limitations inherent in conventional meta-analyses. Second, although MRE has the highest diagnostic accuracy for staging liver fibrosis in imaging technology, a discrepancy between pathological liver fibrosis stage and MRE-based liver stiffness measurement (LSM) occasionally occurs. Several studies have observed that inflammatory activity grade may increase liver stiffness measured using MRE, but the majority of patients included in these studies had viral hepatitis (12,13). Despite its limitations, MRE is an emerging technique that provides a highly accurate, non-invasive measure of liver stiffness. Furthermore, it evaluates a larger portion of the liver with the option of choosing the region of interest, can be performed in conjunction with a conventional MRI, has a high inter-observer correlation and overcomes limitations in interpretation due to obesity or ascites, making it highly applicable (14). Taken all together, the aim of this study was to evaluate the diagnostic accuracy of MRE for staging hepatic fibrosis in patients with histologically confirmed NAFLD and analyze the confounding factors of MRE. METHODS This cross-sectional study included patients evaluated at the Hospital Universitario Virgen del Rocío (Sevilla, Spain). The cohort consisted of 65 patients prospectively included, all of whom had a liver biopsy diagnosis of NAFLD and were enrolled between December 2019 and March 2022. REV ESP ENFERM DIG 2023:115(4):160-165 DOI: 10.17235/reed.2022.8777/2022 162 C. Lara Romero et al. the widest transverse dimension of the liver. The proton density fat fraction (PDFF) was obtained using the Dixonquant (Philips) algorithm to calculate quantitative images of the water, fat and PDFF. MRE and PDFF analysis were performed by an expert reader with over three years of experience (J.C.) in interpreting MRE, who were blinded to all clinical, histological and biochemical information. All patients were divided into three groups (underestimation, concordance and overestimation) based on the concordance between MRE and histopathological findings according to the cut-offs established in a recent IPD meta-analysis (19), which defined 2.61 kPa for any fibrosis (≥ F1); 2.97 kPa for significant fibrosis (≥F2); 3.62 kPa for advanced fibrosis (≥ F3); and 4.69 kPa for cirrhosis (F4). The study protocol was reviewed and approved by the ethics review committee of the institution, and all subjects provided written informed consent before examination. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was conducted with the approval of the local Ethics Committee. Statistical analysis All statistical analyses were performed using the MedCalc software (version 19.7, MedCalc Software Inc., Ostend, Belgium) and IBM SPSS Statistics for Windows (version 20, IBM Corp., Armonk, NY). A p-value < 0.05 was considered as statistically significant. Data were reported as the mean ± SD for normal distribution and median (interquartile range) for non-normal distribution continuous variables, while numbers and percentages were used for categorical variables. Receiver operating characteristic curves (ROC) were used to determine the diagnostic accuracy of MRE in staging hepatic fibrosis. To explore the confounding factor of the diagnostic accuracy of MRE, ANOVA test with post hoc LSD analysis and Kruskall-Wallis test with post hoc Dunn’s analysis were applied between the three groups (underestimation, concordance and overestimation) for continuous variables. Chi-squared test or Fisher’s exact test were used for categorical variables, in case of p < 0.05. Furthermore, two-way comparison with the Bonferroni method was performed. Univariate and subsequent multivariate analyses using logistic regression were performed to identify the correlation between possible confounding factors in the three groups (concordance between MRE and histopathological findings). RESULTS A total of 65 subjects were prospectively enrolled. There were 33 male patients and 32 females, with a mean age of 59.83 ± 11.35 years. The mean BMI was 31.46 ± 6.09. Sixty patients had histological steatosis S0-S2 and five had steatosis grade 3. Forty-seven patients had inflammation grade A0-A2 and 22 inflammation grade A3-A4. Forty patients had fibrosis stage F0-F2 and 25 patients F3-F4. Liver stiffness by MRE distribution was as follows: F0 = 19 patients, F1 = 13 patients, F2 = 8, F3 = 18 and F4 = 7. Details of the clinical and laboratory features of the enrolled subjects, as well as histologic characteristics, are summarized in table 1. The median liver stiffness values in MRE were 2.60 kPa (2.24-2.82), 2.71 kPa (2.25-3.48), 3.40 kPa (3.03-3.81), 4.20 kPa (3.60-4.93) and 4.43 kPa (3.91-5.34) for F0, F1, F2, F3 and F4, respectively. Mean intrahepatic fat quantification measured by PDFF was 9.10 ± 6.36 % for S1 patients and 17.38 ± 7.68 % for patients with moderate-to-severe steatosis (S2-S3). To investigate the diagnostic accuracy of MRE for liver fibrosis, the AUROC curves and potential cut-off values for the diagnosis of liver fibrosis in NAFLD patients were calculated (Fig. 1). The area under the ROC curve (AUROC) for MRE advanced fibrosis (≥ F3) was 0.90 (0.82-0.97), while transient elastography AUROC was 0.82 (0.72-0.93) (p = 0.22), FIB-4 0.67 (0.54-0.81) (p = 0.003) and APRI 0.62 (0.47-0.76) (p < 0.001). In cirrhotic F4 patients, AUROC curve in MRE was 0.90 (0.81-0.98), transient elastography AUROC 0.83 (0.73-0.93) (p = 0.3), APRI AUROC 0.69 (0.54-0.81) (p < 0.001) and FIB-4 AUROC 0.62 (0.48-0.77) (< 0.001). Of the 65 patients, five (7.7 %) were classified as underestimation, 48 (73.8 %) as concordance and 12 (18.4 %) as overestimation. There were no factors that could underestimate MRE accuracy. According to the univariate analysis, there were statistically significant higher levels of inflammatory activity (A3-4, p < 0.01), steatosis grade (S2-3, p = 0.02) and liver biochemistry (ALT 35.00 [22.75-72.00], p = 0.02; AST 35.00 [22.75-67.00], p < 0.01; GGT 58.00 [32.75- 90.75], p < 0.01) in those patients whose MRE stiffness could overestimate liver fibrosis. However, only GGT was statistically significant in the multivariate analysis (OR 1.02 [1.01- 1.04], p = 0.01). There were no differences in age, sex, BMI, weight, DM, HBP, platelets or lipidic profile (Table 2). Table 1. Clinical, analytical and histopathologic features of the patients All (n = 65) Age 59.83 ± 11.35 Sex (M/F) 33/32 BMI (kg/m2) 31.46 ± 6.09 Weight (kg) 86.58 ± 18.63 T2DM 35/28 ALT (U/l) 46.5 (23.0-71.0) AST (U/l) 39.5 (23.0-72.0) GGT (U/l) 64.00 (36.00-120.00) Albumin (g/dl) 4.45 (4.30-4.57) Triglyceride (mg/dl) 158.00 (101.50-183.50) Cholesterol (mg/dl) 190.39 ± 51.52 Platelets 103/µl 217.00 ± 78.70 HDL (mg/dl) 45.00 (38.50-55.75) LDL (mg/dl) 105.50 (80.00-134.00) Steatosis grade 0/1/2/3 8/30/22/5 Inflammation activity A (0-4) 7/10/26/14/8 Fibrosis stage (F0-4) 19/13/8/19/6 MRI-PDFF 12.54 ± 8.02 BMI: body mass index; T2DM: type 2 diabetes mellitus; HBP: high blood pressure; ALT: alanine transaminase; HDL: high density lipoprotein; LDL: low-density lipoprotein. REV ESP ENFERM DIG 2023:115(4):160-165 DOI: 10.17235/reed.2022.8777/2022 163 Liver stiffness accuracy by magnetic resonance elastography in histologically proven non-alcoholic fatty liver disease patients: a Spanish cohort Table 2. Univariate and multivariate analysis of confounding factors for MR elastography between the overestimation and concordance groups Overestimation (n = 12) Concordance (n = 48) Univariate p OR (95 % CI) Multiple p Age 60.18 ± 12.30 59.73 ± 11.47 0.91 Sex (M/F) 5/7 24/24 0.75 BMI (kg/m2) 33.14 ± 5.40 31.14 ± 6.40 0.32 T2DM (yes/no) 5/7 28/18 0.33 ALT (U/l) 65.00 (43.00-107.00) 35.00 (22.75-72.00) 0.02 1.00 (0.97-1.03) 0.84 AST (U/l) 69.00 (43.75-109.50) 35.00 (22.75-67.00) < 0.01 0.96 (0.90-1.03) 0.27 GGT (U/l) 173.00 (140.75-407.75) 58.00 (32.75-90.75) < 0.01 1.02 (1.01-1.04) 0.01 Albumin 4.50 (4.32-4.69) 4.45 (4.30-4.56) 0.57 Triglyceride (mg/dl) 166.00 (133.25-222.50) 129.00 (100.00-192.75) 0.25 Cholesterol (mg/dl) 214.00 ± 48.85 187.31 ± 53.18 0.14 Platelets 103/µl 238.00 ± 111.61 211.36 ± 73.15 0.33 HDL (mg/dl) 43.00 (40.50-50.00) 47.00 (37.75-56.00) 0.47 LDL (mg/dl) 125.00 (88.25-163.50) 101.50 (79.00-133.00) 0.19 Steatosis grade (S0-1/2-3) 3/9 32/16 0.02 0.22 (0.03-1.71) 0.15 Inflammatory activity (A0-2/3-4) 4/8 37/11 < 0.01 0.20 (0.03-1.48) 0.12 MRI-PDFF 14.91 ± 7.81 11.74±8.15 0.23 BMI: body mass index; T2DM: type 2 diabetes mellitus; HBP: high blood pressure; ALT: alanine transaminase; HDL: high density lipoprotein; LDL: low-density lipoprotein. Fig. 1. Comparison of ROC curves between MRE, transient elastography, FIB-4 and APRI for ≥ F3 (A) and ≥ F4 (B). B A REV ESP ENFERM DIG 2023:115(4):160-165 DOI: 10.17235/reed.2022.8777/2022 164 C. Lara Romero et al. DISCUSSION The detection of liver fibrosis is a clinically important feature of NAFLD as liver fibrosis and the presence of advanced fibrosis (stages 3 to 4) has been shown to be associated with increased liver-related outcomes and mortality in NAFLD patients (2,3). Liver biopsy has always been the gold standard for fibrosis assessment and staging. However, only 1/50,000th of the whole liver tissue is evaluated in a liver biopsy and the limitations are well recognized, including the risk of complications and elevated costs. In addition, the accuracy of the procedure used to assess the severity of liver fibrosis and steatosis is questionable because of intra- and inter-observer variation (20) and sampling error reported in patients with NASH (21). As NAFLD occurs in 25 % of all adults in many countries, it is impossible to perform a liver biopsy in all NAFLD patients. Therefore, alternatives to liver biopsy have been investigated, such as clinical scoring systems (22), TE and MRE, which can be used repeatedly because of high safety. MRE has several advantages compared to liver biopsy or TE: MRE uses compressional and continuous waves; the elastic waves generated by the vibrator could be effective in patients with ascites or obesity, including patients with a BMI > 28 kg/m2 (23). In fact, obesity did not affect the MRE results in our study, as reported previously in an individual patient data (IPD) meta-analysis (11). However, probably the most important advantage is that the area measured in the liver is larger in MRE than by biopsy or TE, which can avoid sampling variability caused by the heterogeneity of advanced fibrosis (23). MRE has some limitations: it may not be tolerated in a subset of patients who are too obese for the MRI scanner, have incompatible metallic implants or claustrophobia. Furthermore, MRI is more costly than TE. However, a cost-effectiveness analysis for the detection of cirrhosis in patients with NAFLD demonstrated that MRE was more cost-effective than proceeding to a biopsy after FIB-4 (24). Even though our study did not include a cost analysis, MRI costs are presumably higher than other non-invasive tests and MRI can be used to scan the whole liver with the objective of detecting hepatocellular carcinoma. MRE is an effective, non-invasive method for detecting/ staging hepatic fibrosis in NAFLD and has a good performance in discriminating significant and advanced fibrosis, as shown in a few prospective studies (19,25,26). However, most studies are retrospective and were performed using different equipment, including different magnetic fields (27,28). Loomba et al. (29) demonstrated in 117 consecutive patients that 2D-MRE had a high diagnostic accuracy for discriminating advanced fibrosis with an AUROC > 0.924 (p < 0.0001). With similar values to our study, Imajo et al. (27) also concluded that AUROC for MRE is higher than transient elastography AUROC (0.91 vs 0.82). Although several scoring systems for the diagnosis of liver fibrosis in patients with NAFLD have been previously reported, the Fibrosis-4 index and APRI fibrosis score exhibited good performance characteristics to assess fibrosis (30,31). However, these scoring systems have limitations and the positive predictive value is very low, although the negative predictive value is higher so its use is currently relegated to screening in patients with risk factors for NAFLD (32,33). Steatosis measured by MRE-PDFF is more accurate than liver biopsy (34) and has already been validated in multiple studies (35). Our study showed that MRI-PDFF was not different between the three groups, which indicates that the degree of hepatic steatosis does not affect the diagnostic accuracy of MRE. Interestingly, prevalent characteristics in NAFLD patients such as T2DM or BMI did not affect MRE results. However, inflammation activity can be associated with the overestimation of liver stiffness, as shown in our study by the univariate analysis but not in the multivariate analysis. Ichikawa et al. also observed that hepatitis activity grade may also influence liver stiffness measured using MRE (36). On the contrary, in the meta-analysis by Singh et al. (11), the diagnostic accuracy of MRE for the detection of significant or advanced fibrosis was not significantly influenced by the presence of severe necroinflammation. Large and prospective studies are needed to study the influence of inflammation on MRE-measured liver stiffness. Optimal thresholds for MRE significant stiffness have also been addressed with some discrepancies among the literature ranging from 3.35 to 6.7 kPa (8,24,37). A generally accepted cut-off value for diagnosing the different stages of fibrosis is an unmet clinical need because most of the published studies are based on small and heterogeneous cohorts. The cut-offs were chosen from a pooled analysis of IPD with NAFLD by Hsu et al. (16) as a reference. This seems to be the most accurate and reliable study to date reporting the optimal threshold for MRE fibrosis stages, with an advanced fibrosis stage of 3.63 kPa, which is very close to the cut-off in our study of 3.54 kPa. AUROC curves for MRE in our study are comparable to those reported in the cited meta-analysis by Hsu et al.: > F2 = 0.92 (95 % CI, 0.88-0.96) (p = 0.03) and 0.93 (95 % CI, 0.89-0.96) (p = 0.001) for advanced fibrosis (stage F3). The study strengths are its prospective design with biopsy proven NAFLD patients, comprising the first Spanish cohort to be published, showing favorable data for MRE diagnostic accuracy. Our study had several limitations. First, the study included a small patient cohort, which limited the performance of multivariate analysis and decreased statistical power. Second, the drawing of ROIs on the MRE image is not yet fully standardized and the mean of three ROIs were measured to decrease measurement bias in this study. Finally, there may be patient selection bias as liver biopsies were more likely performed on NAFLD patients at risk of NASH with advanced fibrosis. In conclusion, MRE is an effective, non-invasive method for detecting and staging hepatic fibrosis in NAFLD patients with a high accuracy. Liver inflammatory activity may affect the diagnostic accuracy of MRE. Further studies must be performed to explore the prognostic value of the results of this diagnostic technique to determine the long-term outcomes of patients with NAFLD. REFERENCES 1. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease - Meta‐analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64(1). DOI: 10.1002/hep.28431 2. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonal- REV ESP ENFERM DIG 2023:115(4):160-165 DOI: 10.17235/reed.2022.8777/2022 165 Liver stiffness accuracy by magnetic resonance elastography in histologically proven non-alcoholic fatty liver disease patients: a Spanish cohort coholic fatty liver disease. Gastroenterology 2015;149(2):389-97.e10. DOI: 10.1053/j.gastro.2015.04.043 3. Ekstedt M, Hagstrom H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015;61(5):1547-54. DOI: 10.1002/hep.27368 4. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 2017;65(5):1557-65. DOI: 10.1002/hep.29085 5. Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012;142:1293-302. DOI: 10.1053/j.gastro.2012.02.017 6. Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J Magn Reson Imaging 2013;37(3):544-55. DOI: 10.1002/jmri.23731 7. Yin M, Glaser KJ, Talwalkar JA, et al. Hepatic MR elastography: clinical performance in a series of 1377 consecutive examinations. Radiology 2016;278(1):114-24. DOI: 10.1148/radiol.2015142141 8. Chen J, Yin M, Talwalkar JA, et al. Diagnostic performance of MR elastography and vibration controlled transient elastography in the detection of hepatic fibrosis in patients with severe to morbid obesity. Radiology 2017;283(2):418-28. DOI: 10.1148/radiol.2016160685 9. Sanyal AJ. Past, present and future perspectives in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2019;16:377-86. DOI: 10.1038/ s41575-019-0144-8 10. Trout AT, Sheridan RM, Serai SD, et al. Diagnostic performance of MR elastography for liver fibrosis in children and young adults with a spectrum of liver diseases. Radiology 2018;287(3):824-32. DOI: 10.1148/radiol.2018172099 11. Singh S, Venkatesh SK, Loomba R, et al. Magnetic resonance elastography for staging liver fibrosis in non-alcoholic fatty liver disease: a diagnostic accuracy systematic review and individual participant data pooled analysis. Eur Radiol 2016;26(5):1431-40. DOI: 10.1007/s00330-015-3949-z 12. Shi Y, Guo Q, Xia F, et al. MR elastography for the assessment of hepatic fibrosis in patients with chronic hepatitis B infection: does histologic necroinflammation influence the measurement of hepatic stiffness? Radiology 2014;273(1):88-98. DOI: 10.1148/radiol.14132592 13. Ichikawa S, Motosugi U, Nakazawa T, et al. Hepatitis activity should be considered a confounder of liver stiffness measured with MR elastography. J Magn Reson Imaging 2014. DOI: 10.1002/jmri.24666 14. Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J Magn Reson Imaging 2013;37:544-55. DOI: 10.1002/jmri.23731 15. Hagström H, Nasr P, Ekstedt M, et al. SAF score and mortality in NAFLD after up to 41 years of follow-up. Scand J Gastroenterol 2017;52(1):87-91. DOI: 10.1080/00365521.2016.1230779 16. Sandrin L, Tanter M, Gennisson JL, et al. Shear elasticity probe for soft tissues with 1-D transient elastography. IEEE Trans Ultrason Ferroelectr Freq Control 2002;49:436-46. DOI: 10.1109/58.996561 17. Sumida Y, Yoneda M, Hyogo H, et al.; Japan Study Group of Nonalcoholic Fatty Liver Disease (JSGNAFLD). Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol 2012;12:2. DOI: 10.1186/1471-230X-12-2 18. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38(2):518-26. DOI: 10.1053/jhep.2003.50346 19. Hsu C, Caussy C, Imajo K, et al. Magnetic resonance vs transient elastography analysis of patients with nonalcoholic fatty liver disease: a systematic review and pooled analysis of individual participants. Clin Gastroenterol Hepatol 2019;17(4):630-7.e8. 2DOI: 10.1016/j.cgh.2018.05.059 20. Bedossa P, Carrat F. Liver biopsy: the best, not the gold standard. J Hepatol 2009;50:1-3. DOI: 10.1016/j.jhep.2008.10.014 21. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898-906. DOI: 10.1053/j.gastro.2005.03.084 22. Ampuero J, Pais R, Aller R, et al. Development and validation of Hepamet fibrosis scoring system - A simple, noninvasive test to identify patients with nonalcoholic fatty liver disease with advanced fibrosis. Clin Gastroenterol Hepatol 2020;18(1):216-25.e5. DOI: 10.1016/j.cgh.2019.05.051 23. Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of the liver: technique, analysis, and clinical applications. J Magn Reson Imaging 2013;37:544-555 DOI: 10.1002/jmri.23731 24. Hines CD, Bley TA, Lindstrom MJ, et al. Repeatability of magnetic resonance elastography for quantification of hepatic stiffness. J Magn Reson Imaging 2010;31:725-31. DOI: 10.1002/jmri.22066 25. Vilar-Gómez E, Lou Z, Kong N, et al. Cost effectiveness of different strategies for detecting cirrhosis in patients with nonalcoholic fatty liver disease based on United States health care system. Clin Gastroenterol Hepatol 2020;18(10):2305e2314e2312. DOI: 10.1016/j.cgh.2020.04.017 26. Kennedy P, Wagner M, Castra L, et al. Quantitative elastography methods in liver disease: current evidence and future directions. Radiology 2018;286(3):738-63. DOI: 10.1148/radiol.2018170601 27. Imajo K, Kessoku T, Honda Y, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology 2016;150(3):626-37. e7. DOI: 10.1053/j.gastro.2015.11.048 28. Yin M, Talwalkar JA, Glaser KJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol 2007;5(10):1207-13.e2. DOI: 10.1016/j.cgh.2007.06.012 29. Loomba R, Wolfson T, Ang B, et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology 2014;60(6):1920-8. DOI: 10.1002/hep.27362. Erratum in: Hepatology 2015;62(5):1646. 30. Sumida Y, Yoneda M, Hyogo H, et al.; Japan Study Group of Nonalcoholic Fatty Liver Disease (JSGNAFLD). Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol 2012;12:2. DOI: 10.1186/1471-230X-12-2 31. Borsoi Viana MS, Takei K, Collarile Yamaguti DC, et al. Use of AST platelet ratio index (APRI Score) as an alternative to liver biopsy for treatment indication in chronic hepatitis C. Ann Hepatol 2009;8(1):26-31. DOI: 10.1016/ S1665-2681(19)31807-1 32. Lazarus JV, Mark HE, Anstee QM, et al. Advancing the global public health agenda for NAFLD: a consensus statement. Nat Rev Gastroenterol Hepatol 2022;19:60-78. DOI: 10.1038/s41575-021-00523-4 33. Liguori A, Zoncapè M, Tsochatzis EA. Non-invasive liver fibrosis tests in non-alcoholic fatty liver disease. Rev Esp Enferm Digest 2022;114(4):191-4. DOI: 10.17235/reed.2022.8718/2022 34. Noureddin M, Lam J, Peterson MR, et al. Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology 2013;58(6):1930-4. DOI: 10.1002/hep.26455 35. Loomba R, Neuschwander-Tetri BA, Sanyal A, et al. NASH Clinical Research Network. Multicenter validation of association between decline in MRI-PDFF and histologic response in NASH. Hepatology 2020;72(4):1219-29. DOI: 10.1002/hep.31121 36. Ichikawa S, Motosugi U, Nakazawa T, et al. Hepatitis activity should be considered a confounder of liver stiffness measured with MR elastography. J Magn Reson Imaging 2015;41(5):1203-8. DOI: 10.1002/jmri.24666 37. Park CC, Nguyen P, Hernández C, et al. Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease. Gastroenterology 2017;152:598-607e2. DOI: 10.1053/j.gastro.2016.10.026