Browsing by Author "Neuschwander-Tetri, Brent A."
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Item Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-assigned Steatosis Grades of Liver Biopsies from Adults with Nonalcoholic Steatohepatitis(Elsevier, 2017) Middleton, Michael S.; Heba, Elhamy R.; Hooker, Catherine A.; Bashir, Mustafa R.; Fowler, Kathryn J.; Sandrasegaran, Kumar; Brunt, Elizabeth M.; Kleiner, David E.; Doo, Edward; Van Natta, Mark L.; Tonascia, James; Lavine, Joel E.; Neuschwander-Tetri, Brent A.; Sanyal, Arun; Loomba, Rohit; Sirlin, Claude B.; Department of Radiology and Imaging Sciences, IU School of MedicineBackground & Aims We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference. Methods We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed. Results At baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%±3.7%, 18.1%±4.3%, and 30.1%±8.1%. PDFF classified steatosis grade 0–1 vs 2–3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91–0.98), and grade 0–2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93–0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2–3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%±8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%±6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%±6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71–0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63–0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity. Conclusions Based on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference.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 Current and Future Therapeutic Regimens for Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)(Wiley, 2018) Younossi, Zobair M.; Loomba, Rohit; Rinella, Mary E.; Bugianesi, Elisabetta; Marchesini, Giulio; Neuschwander-Tetri, Brent A.; Serfaty, Lawrence; Negro, Francesco; Caldwell, Stephen H.; Ratziu, Vlad; Corey, Kathleen E.; Friedman, Scott L.; Abdelmalek, Manal F.; Harrison, Stephen A.; Sanyal, Arun J.; Lavine, Joel E.; Mathurin, Philippe; Charlton, Michael R.; Chalasani, Naga P.; Anstee, Quentin M.; Kowdley, Kris V.; George, Jacob; Goodman, Zachary D.; Lindor, Keith; Medicine, School of MedicineNASH/NAFLD is rapidly becoming one of top causes of cirrhosis, hepatocellular carcinoma and indication for liver transplantation. Except for life style modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is hard to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD and has been shown to improve liver histology. In order to have approved regimens for treatment of NASH/NAFLD, a number of issues that must be addressed. First, all stakeholders must agree on the most appropriate clinical trial endpoints for NASH. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced stage of fibrosis, it is not an independent predictor of long term mortality. In contrast, there is significant data to suggest that stage of fibrosis is the only robust and independent predictor of liver-related mortality. In addition to the primary endpoints, a number of important secondary endpoints, including non-invasive biomarkers, long term outcomes, and patient reported outcomes, must be considered. In 2017, a few phase 3 clinical trials for treatment of NASH are in progress. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH enriches the pipeline of emerging therapies. Conclusion: Over the next 5 years, some of these regimens are expected to provide potential new treatment options for patients with NASH/NAFLD.Item Diagnostic Modalities for Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH) and Associated Fibrosis(Wiley, 2018) Younossi, Zobair M.; Loomba, Rohit; Anstee, Quentin M.; Rinella, Mary E.; Bugianesi, Elisabetta; Marchesini, Giulio; Neuschwander-Tetri, Brent A.; Serfaty, Lawrence; Negro, Francesco; Caldwell, Stephen H.; Ratziu, Vlad; Corey, Kathleen E.; Friedman, Scott L.; Abdelmalek, Manal F.; Harrison, Stephen A.; Sanyal, Arun J.; Lavine, Joel E.; Mathurin, Philippe; Charlton, Michael R.; Goodman, Zachary D.; Chalasani, Naga P.; Kowdley, Kris V.; George, Jacob; Lindor, Keith; Medicine, School of MedicineNAFLD is a spectrum comprised of isolated steatosis, NASH, advanced fibrosis, and cirrhosis. The majority of NAFLD subjects do not have NASH and don't carry a significant risk for adverse outcomes (cirrhosis and mortality). Globally, the prevalence of NAFLD is approximately 25%. In Asia, a gradient of high prevalence rates to low rates are noted from urban to rural areas. Given the prevalence of NAFLD, the clinical and economic burden of NAFLD and NASH can be substantial. With increasing recognition as an important liver disease, the diagnosis of NASH still requires a liver biopsy which is suboptimal. Although liver biopsy is the most accurate modality to diagnose and stage the severity of NASH, it suffers from being invasive, costly, associated with potential complications, and plagued with interobserver variability of individual pathologic features. A number of non-invasive modalities to diagnose NASH and stage liver fibrosis are being developed. These include predictive models (NAFLD fibrosis score) and serum biomarkers such as Enhanced Liver Fibrosis, (ELF). Other tests are based on radiologic techniques such as transient or MR elastography (MRE) which are used to estimate liver stiffness as a potential surrogate of hepatic fibrosis. Although a dynamic field of research, most of these diagnostic modalities have AUROC between 0.76 to 0.90% with MRE having the best predictive performance. In summary, developing accurate, safe and easily accessible non-invasive modalities to accurately diagnose and monitor NASH and associated fibrosis is of utmost importance in clinical practice and clinical research. These tests are not only important to risk stratify subjects at the greatest risk for progressive liver disease but to serve as appropriate surrogate endpoints for therapeutic clinical trials of NASH.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 Performance Characteristics of Vibration-Controlled Transient Elastography for Evaluation of Non-Alcoholic Fatty Liver Disease(Wiley, 2017) Vuppalanchi, Raj; Siddiqui, Mohammad S.; Van Natta, Mark L.; Hallinan, Erin; Brandman, Danielle; Kowdley, Kris; Neuschwander-Tetri, Brent A.; Loomba, Rohit; Dasarathy, Srinivas; Abdelmalek, Manal; Doo, Edward; Tonascia, James A.; Kleiner, David E.; Sanyal, Arun J.; Chalasani, Naga; Department of Medicine, School of MedicineBackground: Vibration-controlled transient elastography (VCTE) estimates liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) which are noninvasive assessments of hepatic fibrosis and steatosis respectively. However, prior VCTE studies reported high failure rate in patients with non-alcoholic fatty liver disease (NAFLD). Aim: To examine the performance characteristics of Fibroscan 502 Touch with two probes, medium (M+) and extra-large (XL+), in patients with NAFLD in a multicenter setting. Methods: A total of 1696 exams were attempted in 992 patients (BMI: 33.6 ± 6.5 kg/m2) with histologically confirmed NAFLD. Simultaneous assessment of LSM and CAP was performed using Fibroscan 502 Touch with an automatic probe selection tool. Testing was conducted twice in patients by either a single operator (88%) or two operators (12%). Failure was defined as the inability to obtain a valid examination. An examination was considered unreliable if LSM IQR/median was >30%. Significant disagreement between two readings was defined as greater than >95% limits of agreement between two readings. Results: A total of 1641 examinations yielded valid results with a failure rate of 3.2% (55/1696). The proportion of unreliable scans for LSM was 2.4%. The proportion of unreliable scans with operator experience in the top quartile (≥ 59 procedures) was significantly lower than lower three quarters combined (1.6% vs.4.7%, p=0.01 by Fisher's Exact test). The significant disagreement between first and second readings for LSM and CAP when obtained back to back was 18% and 11% respectively. Conclusion: VCTE for estimation of LSM and CAP can be successfully deployed in a multicenter setting with low failure (3.2%) and high reliability (>95%) rates and high reproducibility.Item Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease(Elsevier, 2014-12) Vuppalanchi, Raj; Jain, Ajay K.; Deppe, Ross; Yates, Katherine; Comerford, Megan; Masuoka, Howard C.; Neuschwander-Tetri, Brent A.; Loomba, Rohit; Brunt, Elizabeth M.; Kleiner, David E.; Molleston, Jean P.; Schwimmer, Jeffrey B.; Lavine, Joel E.; Tonascia, James; Chalasani, Naga; Department of Medicine, IU School of MedicineBACKGROUND & AIMS: Cross-sectional studies have associated serum levels of the keratin 18 (K18) fragment with histologic features of liver in individuals with nonalcoholic fatty liver disease (NAFLD). We investigated the relationship between changes in serum levels of K18 and changes in liver histology in adults and children with NAFLD. METHODS: We measured levels of K18 in stored serum samples collected at baseline and various time points from 231 adults with nonalcoholic steatohepatitis and 152 children with NAFLD who participated in 2 separate prospective randomized clinical trials. Liver biopsy specimens collected at baseline and week 96 were reviewed centrally. RESULTS: There were greater decreases in serum levels of K18 in adults with histologic improvement at week 96 than in those without histologic improvement at week 16 (decrease, 193 ± 293 vs 139 ± 467 U/L; P < .001), week 48 (decrease, 232 ± 360 vs 113 ± 425 U/L; P < .001), or week 96 (decrease, 269 ± 368 vs 97 ± 400 U/L; P < .001). There were greater decreases in serum levels of K18 in children with histologic improvements than in those without histologic improvements at week 48 (decrease, 197 ± 467 vs 47 ± 350 U/L; P = .005) and week 96 (decrease, 206 ± 432 vs 2 ± 474 U/L; P < .001). However, reductions in serum levels of K18 were not better than reductions in levels of alanine aminotransferase in identifying adults with histologic improvement (area under the receiver operator characteristic [AUROC], 0.71; 95% confidence interval [CI], 0.63-0.80; vs AUROC, 0.68; 95% CI, 0.61-0.79; P = .34) or children (AUROC, 0.72; 95% CI, 0.63-0.81; vs AUROC, 0.79; 95% CI, 0.70-0.87; P = .42). CONCLUSIONS: Decreases in serum levels of K18 are associated strongly with improved liver histologies in adults or children with NAFLD. However, reductions in K18 do not perform better than those in alanine aminotransferase level in identifying histologic changes in NAFLD.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 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.