Browsing by Author "Dasarathy, Srinivasan"
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Item Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease(JAMA Network, 2019-10-02) Kleiner, David E.; Brunt, Elizabeth M.; Wilson, Laura A.; Behling, Cynthia; Guy, Cynthia; Contos, Melissa; Cummings, Oscar; Yeh, Matthew; Gill, Ryan; Chalasani, Naga; Neuschwander-Tetri, Brent A.; Diehl, Anna Mae; Dasarathy, Srinivasan; Terrault, Norah; Kowdley, Kris; Loomba, Rohit; Belt, Patricia; Tonascia, James; Lavine, Joel E.; Sanyal, Arun J.; Nonalcoholic Steatohepatitis Clinical Research Network; Medicine, School of MedicineImportance: The histologic evolution of the full spectrum of nonalcoholic fatty liver disease (NAFLD) and factors associated with progression or regression remain to be definitively established. Objective: To evaluate the histologic evolution of NAFLD and the factors associated with changes in disease severity over time. Design, Setting, and Participants: A prospective cohort substudy from the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database study, a noninterventional registry, was performed at 8 university medical research centers. Masked assessment of liver histologic specimens was performed, using a prespecified protocol to score individual biopsies. Participants included 446 adults with NAFLD enrolled in the NASH CRN Database studies between October 27, 2004, and September 13, 2013, who underwent 2 liver biopsies 1 or more year apart. Data analysis was performed from October 2016 to October 2018. Main Outcomes and Measures: Progression and regression of fibrosis stage, using clinical, laboratory, and histologic findings, including the NAFLD activity score (NAS) (sum of scores for steatosis, lobular inflammation, and ballooning; range, 0-8, with 8 indicating more severe disease). Results: A total of 446 adults (mean [SD] age, 47 [11] years; 294 [65.9%] women) with NAFLD (NAFL, 86 [19.3%]), borderline NASH (84 [18.8%]), and definite NASH (276 [61.9%]) were studied. Over a mean (SD) interval of 4.9 (2.8) years between biopsies, NAFL resolved in 11 patients (12.8%) and progressed to steatohepatitis in 36 patients (41.9%). Steatohepatitis resolved in 24 (28.6%) of the patients with borderline NASH and 61 (22.1%) of those with definite NASH. Fibrosis progression or regression by at least 1 stage occurred in 132 (30%) and 151 [34%] participants, respectively. Metabolic syndrome (20 [95%] vs 108 [72%]; P = .03), baseline NAS (mean [SD], 5.0 [1.4] vs 4.3 [1.6]; P = .005), and smaller reduction in NAS (-0.2 [2] vs -0.9 [2]; P < .001) were associated with progression to advanced (stage 3-4) fibrosis vs those without progression to stage 3 to 4 fibrosis. Fibrosis regression was associated with lower baseline insulin level (20 vs 33 μU/mL; P = .02) and decrease in all NAS components (steatosis grade -0.8 [0.1] vs -0.3 [0.9]; P < .001; lobular inflammation -0.5 [0.8] vs -0.2 [0.9]; P < .001; ballooning -0.7 [1.1] vs -0.1 [0.9]; P < .001). Only baseline aspartate aminotransferase (AST) levels were associated with fibrosis regression vs no change and progression vs no change on multivariable regression: baseline AST (regression: conditional odds ratio [cOR], 0.6 per 10 U/L AST; 95% CI, 0.4-0.7; P < .001; progression: cOR, 1.3; 95% CI, 1.1-1.5; P = .002). Changes in the AST level, alanine aminotransferase (ALT) level, and NAS were also associated with fibrosis regression and progression (ΔAST level: regression, cOR, 0.9; 95% CI, 0.6-1.2; P = .47; progression, cOR, 1.3; 95% CI, 1.0-1.6; P = .02; ΔALT level: regression, cOR, 0.7 per 10 U/L AST; 95% CI, 0.5-0.9; P = .002; progression, cOR, 1.0 per 10 U/L AST; 95% CI, 0.9-1.2; P = .93; ΔNAS: regression, cOR, 0.7; 95% CI, 0.6-0.9; P = .001; progression, cOR, 1.3; 95% CI, 1.1-1.5; P = .01). Conclusions and Relevance: Improvement or worsening of disease activity may be associated with fibrosis regression or progression, respectively, in NAFLD.Item Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease(Elsevier, 2023) Sanyal, Arun J.; Williams, Stephen A.; Lavine, Joel E.; Neuschwander-Tetri, Brent A.; Alexander, Leigh; Ostroff, Rachel; Biegel, Hannah; Kowdley, Kris V.; Chalasani, Naga; Dasarathy, Srinivasan; Diehl, Anna Mae; Loomba, Rohit; Hameed, Bilal; Behling, Cynthia; Kleiner, David E.; Karpen, Saul J.; Williams, Jessica; Jia, Yi; Yates, Katherine P.; Tonascia, James; Medicine, School of MedicineBackground & aims: Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD. Methods: Using modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models to identify clinically relevant severities of steatosis (grade 0 vs. 1-3), hepatocellular ballooning (0 vs. 1 or 2), lobular inflammation (0-1 vs. 2-3) and fibrosis (stages 0-1 vs. 2-4). Results: The AUCs of the four protein models, based on 37 analytes (18 not previously linked to NAFLD), for the diagnosis of their respective components (at a clinically relevant severity) in training/paired validation sets were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at-risk NASH, defined as steatohepatitis with NAFLD activity score ≥4 (with a score of at least 1 for each of its components) and fibrosis stage ≥2, was predicted by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid. Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and obeticholic acid were identified. Conclusions: Serum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD.Item Design of a multicenter randomized clinical trial for treatment of Alcohol-Associated Hepatitis(Elsevier, 2023-01-18) Tu, Wanzhu; Gawrieh, Samer; Dasarathy, Srinivasan; Mitchell, Mack C.; Simonetto, Douglas A.; Patidar, Kavish R.; McClain, Craig J.; Bataller, Ramon; Szabo, Gyongyi; Tang, Qing; Barton, Bruce A.; Radaeva, Svetlana; Sanyal, Arun J.; Shah, Vijay; Alcoholic Hepatitis Network (AlcHepNet) Investigators; Biostatistics, School of Public HealthBackground: Mortality is high for severe alcohol-associated hepatitis (AH). Corticosteroids are the standard of care for patients without contraindications. Recent data showed that interleukin-1β receptor antagonist anakinra attenuated inflammation and liver damage. We designed a multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of anakinra compared to prednisone. Methods: Patients meeting the clinical and biochemical criteria for severe AH with MELD scores between 20 and 35 were recruited at eight clinical sites. Eligible patients enrolled in the study were randomized to anakinra, 100 mg subcutaneous injection for 14 days, plus zinc sulfate 220 mg for 90 days, vs. prednisone 40 mg PO daily for 30 days. Matching placebos for anakinra, zinc, and prednisone were provided to mask the treatment. Participants were followed for 180 days. The primary outcome was overall survival at 90 days. An unadjusted log-rank test was used to compare the survival of the two treatments in the first 90 days. Between July 10, 2020, and March 4, 2022, we screened 1082 patients with severe AH, and 147 eligible patients were enrolled and randomized. The average baseline MELD score was 25 [range 20-35], Maddrey discriminant function (MDF) was 59.4 [range 20.2-197.5]. The mean aspartate transaminase (AST)-to-alanine transaminase (ALT) ratio was 3.5. The baseline characteristics were not statistically different between the two treatment groups. Conclusions: The study provided a direct comparison of the survival benefits and safety profiles of anakinra plus zinc vs. prednisone in patients with severe AH.Item Fibrosis Progression Rate in Biopsy-Proven Nonalcoholic Fatty Liver Disease Among People With Diabetes Versus People Without Diabetes: A Multicenter Study(Elsevier, 2023-08) Huang, Daniel Q.; Wilson, Laura A.; Behling, Cynthia; Kleiner, David E.; Kowdley, Kris V.; Dasarathy, Srinivasan; Amangurbanova, Maral; Terrault, Norah A.; Diehl, Anna Mae; Chalasani, Naga; Neuschwander-Tetri, Brent A.; Sanyal, Arun J.; Tonascia, James; Loomba, Rohit; Medicine, School of MedicineBackground & Aims There are limited data regarding fibrosis progression in biopsy-proven nonalcoholic fatty liver disease (NAFLD) in people with type 2 diabetes mellitus (T2DM) compared with people without T2DM. We assessed the time to fibrosis progression in people with T2DM compared with people without T2DM in a large, multicenter, study of people with NAFLD who had paired liver biopsies. Methods This study included 447 adult participants (64% were female) with NAFLD who had paired liver biopsies more than 1 year apart. Liver histology was systematically assessed by a central pathology committee blinded to clinical data. The primary outcome was the cumulative incidence of a ≥1-stage increase in fibrosis in participants with T2DM compared with participants without T2DM. Results The mean (SD) age and body mass index (calculated as weight in kilograms divided by the square of the height in meters) were 50.9 (11.5) years and 34.7 (6.3), respectively. The median time between biopsies was 3.3 years (interquartile range, 1.8–6.1 years). Participants with T2DM had a significantly higher cumulative incidence of fibrosis progression at 4 years (24% vs 20%), 8 years (60% vs 50%), and 12 years (93% vs 76%) (P = .005). Using a multivariable Cox proportional hazards model adjusted for multiple confounders, T2DM remained an independent predictor of fibrosis progression (adjusted hazard ratio, 1.69; 95% CI, 1.17–2.43; P = .005). The cumulative incidence of fibrosis regression by ≥1 stage was similar in participants with T2DM compared with participants without T2DM (P = .24). Conclusions In this large, multicenter cohort study of well-characterized participants with NAFLD and paired liver biopsies, we found that fibrosis progressed faster in participants with T2DM compared with participants without T2DM. These data have important implications for clinical practice and trial design.Item Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels(Wolters Kluwer, 2019-10-01) Gawrieh, Samer; Wilson, Laura A.; Cummings, Oscar W.; Clark, Jeanne M.; Loomba, Rohit; Hameed, Bilal; Abdelmalek, Manal F.; Dasarathy, Srinivasan; Neuschwander-Tetri, Brent A.; Kowdley, Kris; Kleiner, David; Doo, Edward; Tonascia, James; Sanyal, Arun; Chalasani, Naga; Network and the NASH Clinical Research; Medicine, School of MedicineBackground and aims: Patients with nonalcoholic fatty liver disease (NAFLD) and normal aminotransferase levels may have advanced liver histology. We conducted a study to characterize the prevalence of and factors associated with advanced liver histology in patients with histologically characterized NAFLD and normal aminotransferase levels. Methods: We evaluated 534 adults with biopsy-proven NAFLD and ALT and AST < 40 U/L within 3 months of their liver biopsy. Histological phenotypes of primary interest were NASH with stage 2-3 fibrosis (NASH F2-3) and cirrhosis. Using multiple logistic regression models with Akaike’s Information Criteria (AIC), we identified variables associated with these histological phenotypes. We developed and internally validated their clinical prediction models. Results: The prevalence of NASH F2-F3 and cirrhosis were 19% and 7%, respectively. The best multiple regression AIC model for NASH F2-3 consisted of type 2 diabetes, White race, lower LDL, lower platelet count, higher AST/ALT ratio, higher serum triglycerides, and hypertension. The best AIC model for cirrhosis consisted of lower platelet count, lower AST/ALT ratio, higher BMI, and female sex. The area under the receiver operator curves of the prediction models were 0.70 (95% CI: 0.65-0.76) for detecting NASH-F2-3 and 0.85 (95% CI: 0.77-0.92) for detecting cirrhosis. When models were fixed at maximum Youden’s index, their positive and negative predictive values were 35% and 88% for NASH F2-F3 and 30% and 98% for cirrhosis, respectively. Conclusion: Clinically significant histological phenotypes are observed in patients with NAFLD and normal aminotransferase levels. Our models can assist the clinicians in excluding advanced liver histology in NAFLD patients with normal aminotransferase levels.Item Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease(Massachusetts Medical Society, 2021) Sanyal, Arun J.; Van Natta, Mark L.; Clark, Jeanne; Neuschwander-Tetri, Brent A.; Diehl, AnnaMae; Dasarathy, Srinivasan; Loomba, Rohit; Chalasani, Naga; Kowdley, Kris; Hameed, Bilal; Wilson, Laura A.; Yates, Katherine P.; Belt, Patricia; Lazo, Mariana; Kleiner, David E.; Behling, Cynthia; Tonascia, James; NASH Clinical Research Network (CRN); Medicine, School of MedicineBackground: The prognoses with respect to mortality and hepatic and nonhepatic outcomes across the histologic spectrum of nonalcoholic fatty liver disease (NAFLD) are not well defined. Methods: We prospectively followed a multicenter patient population that included the full histologic spectrum of NAFLD. The incidences of death and other outcomes were compared across baseline histologic characteristics. Results: A total of 1773 adults with NAFLD were followed for a median of 4 years. All-cause mortality increased with increasing fibrosis stages (0.32 deaths per 100 person-years for stage F0 to F2 [no, mild, or moderate fibrosis], 0.89 deaths per 100 persons-years for stage F3 [bridging fibrosis], and 1.76 deaths per 100 person-years for stage F4 [cirrhosis]). The incidence of liver-related complications per 100 person-years increased with fibrosis stage (F0 to F2 vs. F3 vs. F4) as follows: variceal hemorrhage (0.00 vs. 0.06 vs. 0.70), ascites (0.04 vs. 0.52 vs. 1.20), encephalopathy (0.02 vs. 0.75 vs. 2.39), and hepatocellular cancer (0.04 vs. 0.34 vs. 0.14). As compared with patients with stage F0 to F2 fibrosis, patients with stage F4 fibrosis also had a higher incidence of type 2 diabetes (7.53 vs. 4.45 events per 100 person-years) and a decrease of more than 40% in the estimated glomerular filtration rate (2.98 vs. 0.97 events per 100 person-years). The incidence of cardiac events and nonhepatic cancers were similar across fibrosis stages. After adjustment for age, sex, race, diabetes status, and baseline histologic severity, the incidence of any hepatic decompensation event (variceal hemorrhage, ascites, or encephalopathy) was associated with increased all-cause mortality (adjusted hazard ratio, 6.8; 95% confidence interval, 2.2 to 21.3). Conclusions: In this prospective study involving patients with NAFLD, fibrosis stages F3 and F4 were associated with increased risks of liver-related complications and death.Item Randomized placebo-controlled trial of losartan for pediatric NAFLD(Wiley, 2022) Vos, Miriam B.; Van Natta, Mark L.; Blondet, Niviann M.; Dasarathy, Srinivasan; Fishbein, Mark; Hertel, Paula; Jain, Ajay K.; Karpen, Saul J.; Lavine, Joel E.; Mohammad, Saeed; Miriel, Laura A.; Molleston, Jean P.; Mouzaki, Marialena; Sanyal, Arun; Sharkey, Emily P.; Schwimmer, Jeffrey B.; Tonascia, James; Wilson, Laura A.; Xanthakos, Stavra A.; NASH Clinical Research Network; Pediatrics, School of MedicineBackground and aims: To date, no pharmacotherapy exists for pediatric NAFLD. Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its antifibrotic effects. Approach and results: The Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double-masked, placebo-controlled, randomized clinical trial in children with histologically confirmed NAFLD at 10 sites (September 2018 to April 2020). Inclusion criteria were age 8-17 years, histologic NAFLD activity score ≥ 3, and serum alanine aminotransferase (ALT) ≥ 50 U/l. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks, and the preset sample size was n = 110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. Eighty-three participants (81% male, 80% Hispanic) were randomized to losartan (n = 43) or placebo (n = 40). During an enrollment pause, necessitated by the 2019 coronavirus pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; 95% CI = -30.6, 32.7; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: -23.4 U/l; 95% CI = -41.5, -5.3; p = 0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: -7.5 mm Hg; 95% CI = -12.2, -2.8; p = 0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group. Conclusions: Losartan did not significantly reduce ALT in children with NAFLD when compared with placebo.Item Relationship Between Three Commonly Used Non-invasive Fibrosis Biomarkers and Improvement in Fibrosis Stage in Patients With NASH(Wiley, 2019-02-21) Chalasani, Naga; Abdelmalek, Manal F.; Loomba, Rohit; Kowdley, Kris V.; McCullough, Arthur J.; Dasarathy, Srinivasan; Neuschwander-Tetri, Brent A.; Terrault, Norah; Ferguson, Beatrice; Shringarpure, Reshma; Shapiro, David; Sanyal, Arun J.; Medicine, School of MedicineNon-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement. Methods In the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index, and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72, and 96. Liver biopsies were obtained at baseline and 72 weeks. Results In patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4, and 4% for NFS. Reductions in APRI (p=0.015) and FIB-4 (p=0.036), but not NFS (p=0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (p=0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (p<0.0001); NFS (p<0.05)]. Conclusions Readily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate end points in NASH clinical trials.Item Validation of the accuracy of the FAST™ score for detecting patients with at-risk nonalcoholic steatohepatitis (NASH) in a North American cohort and comparison to other non-invasive algorithms(PLOS, 2022) Woreta, Tinsay A.; Van Natta, Mark L.; Lazo, Mariana; Krishnan, Arunkumar; Neuschwander-Tetri, Brent A.; Loomba, Rohit; Diehl, Anna Mae; Abdelmalek, Manal F.; Chalasani, Naga; Gawrieh, Samer; Dasarathy, Srinivasan; Vuppalanchi, Raj; Siddiqui, Mohammad S.; Kowdley, Kris V.; McCullough, Arthur; Terrault, Norah A.; Behling, Cynthia; Kleiner, David E.; Fishbein, Mark; Hertel, Paula; Wilson, Laura A.; Mitchell, Emily P.; Miriel, Laura A.; Clark, Jeanne M.; Tonascia, James; Sanyal, Arun J.; NASH Clinical Research Network; Medicine, School of MedicineBackground and aims: Management of patients with NASH who are at elevated risk of progressing to complications of cirrhosis (at-risk NASH) would be enhanced by an accurate, noninvasive diagnostic test. The new FAST™ score, a combination of FibroScan® parameters liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) and aspartate aminotransferase (AST), has shown good diagnostic accuracy for at-risk NASH (area-under-the-Receiver-Operating-Characteristic [AUROC] = 0.80) in European cohorts. We aimed to validate the FAST™ score in a North American cohort and show how its diagnostic accuracy might vary by patient mix. We also compared the diagnostic performance of FAST™ to other non-invasive algorithms for the diagnosis of at-risk NASH. Methods: We studied adults with biopsy-proven non-alcoholic fatty liver disease (NAFLD) from the multicenter NASH Clinical Research Network (CRN) Adult Database 2 (DB2) cohort study. At-risk-NASH was histologically defined as definite NASH with a NAFLD Activity Score (NAS) ≥ 4 with at least 1 point in each category and a fibrosis stage ≥ 2. We used the Echosens® formula for FAST™ from LSM (kPa), CAP (dB/m), and AST (U/L), and the FAST™-based Rule-Out (FAST™ ≤ 0.35, sensitivity = 90%) and Rule-In (FAST™ ≥ 0.67, specificity = 90%) zones. We determined the following diagnostic performance measures: AUROC, sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV); these were calculated for the total sample and by subgroups of patients and by FibroScan® exam features. We also compared the at-risk NASH diagnostic performance of FAST™ to other non-invasive algorithms: NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, and AST to platelet ratio index (APRI). Results: The NASH CRN population of 585 patients was 62% female, 79% white, 14% Hispanic, and 73% obese; the mean age was 51 years. The mean (SD) AST and ALT were 50 (37) U/L and 66 (45) U/L, respectively. 214 (37%) had at-risk NASH. The AUROC of FAST™ for at-risk NASH in the NASH CRN study population was 0.81 (95% CI: 0.77, 0.84. Using FAST™-based cut-offs, 35% of patients were ruled-out with corresponding NPV = 0.90 and 27% of patients were ruled-in with corresponding PPV = 0.69. The diagnostic accuracy of FAST™ was higher in non-whites vs. whites (AUROC: 0.91 vs 0.78; p = 0.001), and in patients with a normal BMI vs. BMI > 35 kg/m2 (AUROC: 0.94 vs 0.78, p = 0.008). No differences were observed by other patient characteristics or FibroScan® exam features. The FAST™ score had higher diagnostic accuracy than other non-invasive algorithms for the diagnosis of at-risk NASH (AUROC for NFS, FIB-4, and APRI 0.67, 0.73, 0.74, respectively). Conclusion: We validated the FAST™ score for the diagnosis of at-risk NASH in a large, multi-racial population in North America, with a prevalence of at-risk NASH of 37%. Diagnostic performance varies by subgroups of NASH patients defined by race and obesity. FAST™ performed better than other non-invasive algorithms for the diagnosis of at-risk NASH.Item Vibration-controlled Transient Elastography to Assess Fibrosis and Steatosis in Patients With Nonalcoholic Fatty Liver Disease(Elsevier, 2018) Siddiqui, Mohammad S.; Vuppalanchi, Raj; Van Natta, Mark L.; Hallinan, Erin; Kowdley, Kris V.; Abdelmalek, Manal; Neuschwander-Tetri, Brent A.; Loomba, Rohit; Dasarathy, Srinivasan; Brandman, Danielle; Doo, Edward; Tonascia, James A.; Kleiner, David E.; Chalasani, Naga; Sanyal, Arun J.; Medicine, School of MedicineBackground & Aims Vibration-controlled transient elastography (VCTE), which measures liver stiffness, has become an important tool for evaluating patients with nonalcoholic fatty liver disease (NAFLD). We aimed to determine the diagnostic accuracy of VCTE in detection of NAFLD in a multicenter cohort of patients. Methods We performed a prospective study of 393 adults with NAFLD who underwent VCTE within 1 year of liver histology analysis (median time, 49 days; interquartile range, 25–78 days), from July 1, 2014 through July 31, 2017. Liver stiffness measurement (LSM) cutoffs for pairwise fibrosis stage and controlled attenuation parameter (CAP) cutoffs for pairwise steatosis grade were determined using cross-validated area under the receiver operating characteristics curve (AUROC) analyses. Diagnostic statistics were computed at sensitivity fixed at 90% and specificity fixed at 90%. Results LSM identified patients with advanced fibrosis with an AUROC of 0.83 (95% CI, 0.79– 0.87) and patients with cirrhosis with an AUROC of 0.93 (95% CI, 0.90–0.97). At fixed sensitivity, a cutoff LSM of 6.5 kPa excluded advanced fibrosis with a negative predictive value of 0.91; a cut-off LSM of 12.1 kPa excluded cirrhosis with a negative predictive value of 0.99. At fixed specificity, LSM identified patients with advanced fibrosis with a positive predictive 0.71 and patients with cirrhosis with a positive predictive value of 0.41. CAP analysis detected steatosis with an AUROC of 0.76 (95% CI, 0.64–0.87). In contrast, the VCTE was less accurate in distinguishing lower fibrosis stages, higher steatosis grades, or presence of NASH. Conclusion In a prospective study of adults with NAFLD, we found VCTE to accurately distinguish advanced vs earlier stages of fibrosis, using liver histology as the reference standard.