Saumya Jayakumar1, Michael S Middleton1, Eric J Lawitz2, Parvez S Mantry3, Stephen H Caldwell4, Hays Arnold5, Anna Mae Diehl6, Reem Ghalib7, Magdy Elkhashab8, Manal F Abdelmalek6, Kris V Kowdley9, C Stephen Djedjos10, Ren Xu10, Ling Han10, G Mani Subramanian10, Robert P Myers10, Zachary D Goodman11, Nezam H Afdhal12, Michael R Charlton13, Claude B Sirlin1, Rohit Loomba14. 1. University of California at San Diego, San Diego, CA, United States. 2. Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, United States. 3. The Liver Institute at Methodist Dallas, Dallas, TX, United States. 4. University of Virginia, Charlottesville, VA, United States. 5. Gastroenterology Consultants of San Antonio, San Antonio, TX, United States. 6. Duke University, Durham, NC, United States. 7. Texas Clinical Research Institute, Arlington, TX, United States. 8. Toronto Liver Centre, Toronto, Ontario, Canada. 9. Swedish Medical Center, Seattle, WA, United States. 10. Gilead Sciences, Inc., Foster City, CA, United States. 11. Inova Fairfax Hospital, Falls Church, VA, United States. 12. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. 13. University of Chicago, Chicago, IL, United States. 14. University of California at San Diego, San Diego, CA, United States. Electronic address: roloomba@ucsd.edu.
Abstract
BACKGROUND & AIMS: Non-invasive tools for monitoring treatment response and disease progression in non-alcoholic steatohepatitis (NASH) are needed. Our objective was to evaluate the utility of magnetic resonance (MR)-based hepatic imaging measures for the assessment of liver histology in patients with NASH. METHODS: We analyzed data from patients with NASH and stage 2 or 3 fibrosis enrolled in a phase II study of selonsertib. Pre- and post-treatment assessments included centrally read MR elastography (MRE)-estimated liver stiffness, MR imaging-estimated proton density fat fraction (MRI-PDFF), and liver biopsies evaluated according to the NASH Clinical Research Network classification and the non-alcoholic fatty liver disease activity score (NAS). RESULTS: Among 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24 weeks of treatment with the study drug. The area under the receiver operating characteristic curve (AUROC) of MRE-stiffness to predict fibrosis improvement was 0.62 (95% CI 0.46-0.78) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRE had 67% sensitivity, 64% specificity, 48% positive predictive value, 79% negative predictive value. Among 65 patients with MRI-PDFF and biopsies at baseline and week 24, a ≥1-grade reduction in steatosis was observed in 18 (28%). The AUROC of MRI-PDFF to predict steatosis response was 0.70 (95% CI 0.57-0.83) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRI-PDFF had 89% sensitivity and 47% specificity, 39% positive predictive value, and 92% negative predictive value. CONCLUSIONS: These preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH. LAY SUMMARY: Liver biopsy is a potentially painful and risky method to assess damage to the liver due to non-alcoholic steatohepatitis (NASH). We analyzed data from a clinical trial to determine if 2 methods of magnetic resonance imaging - 1 to measure liver fat and 1 to measure liver fibrosis (scarring) - could potentially replace liver biopsy in evaluating NASH-related liver injury. Both imaging methods were correlated with biopsy in showing the effects of NASH on the liver.
RCT Entities:
BACKGROUND & AIMS: Non-invasive tools for monitoring treatment response and disease progression in non-alcoholic steatohepatitis (NASH) are needed. Our objective was to evaluate the utility of magnetic resonance (MR)-based hepatic imaging measures for the assessment of liver histology in patients with NASH. METHODS: We analyzed data from patients with NASH and stage 2 or 3 fibrosis enrolled in a phase II study of selonsertib. Pre- and post-treatment assessments included centrally read MR elastography (MRE)-estimated liver stiffness, MR imaging-estimated proton density fat fraction (MRI-PDFF), and liver biopsies evaluated according to the NASH Clinical Research Network classification and the non-alcoholic fatty liver disease activity score (NAS). RESULTS: Among 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24 weeks of treatment with the study drug. The area under the receiver operating characteristic curve (AUROC) of MRE-stiffness to predict fibrosis improvement was 0.62 (95% CI 0.46-0.78) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRE had 67% sensitivity, 64% specificity, 48% positive predictive value, 79% negative predictive value. Among 65 patients with MRI-PDFF and biopsies at baseline and week 24, a ≥1-grade reduction in steatosis was observed in 18 (28%). The AUROC of MRI-PDFF to predict steatosis response was 0.70 (95% CI 0.57-0.83) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRI-PDFF had 89% sensitivity and 47% specificity, 39% positive predictive value, and 92% negative predictive value. CONCLUSIONS: These preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH. LAY SUMMARY: Liver biopsy is a potentially painful and risky method to assess damage to the liver due to non-alcoholic steatohepatitis (NASH). We analyzed data from a clinical trial to determine if 2 methods of magnetic resonance imaging - 1 to measure liver fat and 1 to measure liver fibrosis (scarring) - could potentially replace liver biopsy in evaluating NASH-related liver injury. Both imaging methods were correlated with biopsy in showing the effects of NASH on the liver.
Authors: Nidhi P Goyal; Mary Catherine Sawh; Patricia Ugalde-Nicalo; Jorge E Angeles; James A Proudfoot; Kimberly P Newton; Michael S Middleton; Claude B Sirlin; Jeffrey B Schwimmer Journal: J Pediatr Gastroenterol Nutr Date: 2020-01 Impact factor: 2.839
Authors: Rohit Loomba; Brent A Neuschwander-Tetri; Arun Sanyal; Naga Chalasani; Anna Mae Diehl; Norah Terrault; Kris Kowdley; Srinivasan Dasarathy; David Kleiner; Cynthia Behling; Joel Lavine; Mark Van Natta; Michael Middleton; James Tonascia; Claude Sirlin Journal: Hepatology Date: 2020-10-09 Impact factor: 17.425