Reply to: “Non-invasive testing for advanced fibrosis in patients with diabetes with fatty liver disease needs further evaluation of cut-off values”

A prospective study on the prevalence of NAFLD, advanced fibrosis, cirrhosis and hepatocellular carcinoma in people with type 2 diabetesJournal of HepatologyVol. 78Issue 3PreviewThere are limited prospective data on patients with type 2 diabetes mellitus (T2DM) specifically enrolled and systematically assessed for advanced fibrosis or cirrhosis due to non-alcoholic fatty liver disease (NAFLD). Therefore, we aimed to evaluate the prevalence of advanced fibrosis and cirrhosis in a prospectively recruited cohort of adults with T2DM. Full-Text PDF Non-invasive testing for advanced fibrosis in patients with diabetes with fatty liver disease needs further evaluation of cut-off valuesJournal of HepatologyVol. 79Issue 5PreviewThe study by Ajmera et al.1 published in the March issue of the Journal establishes the significant prevalence of advanced fibrosis (14%) based on magnetic resonance elastography (MRE) or vibration-controlled transient elastography (VCTE) in a well-characterized prospective cohort of 501 patients. This is in line with previous publications except that they utilized MRE, which has the highest accuracy for detecting advanced fibrosis2 among non-invasive approaches. In this study, 303 of 501 patients were deemed biopsy eligible based on certain criteria (elevated alanine aminotransferase ≥30 U/L + MRI-estimated proton density fat fraction [MRI-PDFF] ≥5 + VCTE ≥6.9 kPa/MRE ≥2.65 kPa, or patients with MRE ≥3.63 kPa or MRI-PDFF ≥10%), 134 of whom underwent a liver biopsy. Full-Text PDF We thank Dr. Rajvanshi for his comments regarding our recently published manuscript characterizing the prevalence of non-alcoholic fatty liver disease (NAFLD), advanced fibrosis and cirrhosis in a prospectively recruited cohort of older adults with type 2 diabetes mellitus (T2DM)[1]Ajmera V. Cepin S. Tesfai K. Hofflich H. Cadman K. Lopez S. et al.A prospective study on the prevalence of NAFLD, advanced fibrosis, cirrhosis and hepatocellular carcinoma in people with type 2 diabetes.J Hepatol. 2023 Mar; 78: 471-478Google Scholar and his acknowledgement that this data contributed to a change in practice recommendations supporting screening for advanced liver disease in patients with T2DM.[2]Rinella M.E. Neuschwander-Tetri B.A. Siddiqui M.S. Abdelmalek M.F. Caldwell S. Barb D. et al.AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology, Baltimore, Md2023Google Scholar Dr. Rajvanshi and colleagues raise a few important points, which we seek to expound upon. They note that the utilization of magnetic resonance elastography (MRE), which has the highest accuracy for detecting advanced fibrosis,[3]Hsu C. Caussy C. Imajo K. Chen J. Singh S. Kaulback 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 : official Clin Pract J Am Gastroenterological Assoc. 2019; 17: 630-637.e638Google Scholar,[4]Ajmera V. Loomba R. Imaging biomarkers of NAFLD, NASH, and fibrosis.Mol Metab. 2021; 101167Google Scholar distinguished our study from prior studies evaluating the prevalence of advanced fibrosis in adults with T2DM. As it would be unethical to offer liver biopsies to patients without significant liver disease on advanced MRI imaging, the population who underwent liver biopsy had to meet pre-specified criteria suggesting underlying NAFLD, and as a result was different from the population who did not undergo liver biopsy. Dr. Rajvanshi outlines the significant opportunity to evaluate the performance of non-invasive tests (NITs) in adults with T2DM, using advanced MRI quantification of liver fat and liver stiffness as the reference standard. We agree with his assertion that patients with T2DM and steatotic liver disease, now termed metabolic dysfunction-associated steatotic liver disease (MASLD),[5]Rinella M.E. Lazarus J.V. Ratziu V. Francque S.M. Sanyal A.J. Kanwal F. et al.A multi-society Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023 Jun 20; (S0168-8278(23)00418-X)Google Scholar may differ from those with MASLD without T2DM, including recent evidence of a higher fibrosis progression rate.[6]Huang D.Q. Wilson L.A. Behling C. Kleiner D.E. Kowdley K.V. Dasarathy S. et al.Fibrosis progression rate in biopsy-proven nonalcoholic fatty liver disease among people with diabetes versus people without diabetes: a multicenter study.Gastroenterology. 2023 Aug; 165: 463-472.e5Google Scholar Importantly, emerging data demonstrate that liver stiffness on MRE is directly associated with liver-related outcomes,7Ajmera V. Nguyen K. Tamaki N. Sharpton S. Bettencourt R. Loomba R. Prognostic utility of magnetic resonance elastography and MEFIB index in predicting liver-related outcomes and mortality in individuals at risk of and with nonalcoholic fatty liver disease.Ther Adv Gastroenterol. 2022; 1517562848221093869Google Scholar, 8Kim B.K. Bergstrom J. Loomba R. Tamaki N. Izumi N. Nakajima A. et al.Magnetic resonance Elastography-Based prediction model for hepatic decompensation in NAFLD; a Multi-Center cohort study. Hepatology, Baltimore, Md2023Google Scholar, 9Ajmera V. Kim B.K. Yang K. Majzoub A.M. Nayfeh T. Tamaki N. et al.Liver stiffness on magnetic resonance elastography and the mefib index and liver-related outcomes in nonalcoholic fatty liver disease: a systematic review and meta-analysis of individual participants.Gastroenterology. 2022; 163: 1079-1089.e1075Google Scholar further supporting its use as a reference standard for NITs in T2DM. Our manuscript included multiple important findings regarding the performance characteristics of NITs in adults with T2DM. First, the FIB-4 cut-off point of 1.3 to exclude advanced fibrosis had a sensitivity of 81.6%; however, a lower FIB-4 cut-off point of 1.0 increased sensitivity to 95.9% using MRE as the reference. The FIB-4 cut-off of 1 to rule out advanced fibrosis performed similarly in the subset of patients with liver biopsy with a sensitivity of 89.5%. Second, we evaluated the diagnostic accuracy of VCTE and emerging VCTE-based scores for advanced fibrosis. Agile 3+ had a diagnostic accuracy for advanced fibrosis that was similar to VCTE alone, AUROC 0.85 vs. 0.87, p = 0.60. Agile 4 had inferior performance to VCTE, AUROC 0.67 vs. 0.86, p <0.001. The VCTE cut-off point of 8.8 kPa for advanced fibrosis had a sensitivity of 83.7% and specificity of 90.4% using MRE as the reference. Finally, in the subset of patients with liver biopsy, MRE maintained excellent diagnostic accuracy with a c-statistic of 0.91 supporting its use as an accurate biomarker of liver fibrosis in adults with T2DM. We acknowledge that additional exploration of NITs in this population will be of significant value and have ongoing research projects evaluating the diagnostic accuracy of additional NITs including the enhanced liver fibrosis score and the sequential use of NITs as outlined in AGA[10]Kanwal F. Shubrook J.H. Adams L.A. Pfotenhauer K. Wai-Sun Wong V. Wright E. et al.Clinical care pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease.Gastroenterology. 2021; 161: 1657-1669Google Scholar and AASLD guidance documents,[2]Rinella M.E. Neuschwander-Tetri B.A. Siddiqui M.S. Abdelmalek M.F. Caldwell S. Barb D. et al.AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology, Baltimore, Md2023Google Scholar which will further contribute to our management of this important at-risk population. VA is supported by NIDDK (K23DK119460). RL receives funding support from NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515), NHLBI (P01HL147835), and NIAAA (U01AA029019). RL is also supported by an Investigator initiated study sponsored by Gilead Sciences. RL serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition his institutions received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Co-founder of LipoNexus Inc. Please refer to the accompanying ICMJE disclosure forms for further details. Drafting of manuscript VA, critical revision and approval VA, RL. The following are the supplementary data to this article: Download .pdf (.14 MB) Help with pdf files Multimedia component 1