Digital pathology with artificial intelligence analyses provides greater insights into treatment-induced fibrosis regression in NASH

Naoumov, Nikolai V.; Brees, Dominique; Loeffler, Juergen; Chng, Elaine Lay Khim; Ren, Yayun; López, Patricia; Tai, Dean; Lamle, Sophie; Sanyal, Arun J.

doi:10.1016/j.jhep.2022.06.018

Cited by 57 publications

(34 citation statements)

References 50 publications

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“…In a post hoc analysis, the use of second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence (AI) analyses of the same liver biopsies showed that tropifexor treatment resulted in marked liver fat reduction (qSteatosis), which correlated well with the quantitative MRI-based evaluation of fat reduction and improvement of liver fibrosis (qFibrosis). Further insights into this analysis have been recently published 31 . While still an emerging technology, SHG/TPEF microscopy with AI analyses has the potential to reveal details of NASH pathobiology and, through its continuous scale assessment, highlight subtle interval changes from response to treatment which cannot be detected using conventional microscopy and traditional histologic scoring systems based on categorical fibrosis stage 32 , 33 .…”

Section: Discussionmentioning

confidence: 97%

Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial

Sanyal

López

Lawitz

et al. 2023

Nat Med

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The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10–90 μg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10–90-μg dose groups ranged from −10.7 to −16.5 U l−1 versus placebo (−7.8 U l−1) and tropifexor 140- and 200-μg groups were −18.0 U l−1 and −23.0 U l−1, respectively, versus placebo (−8.3 U l−1)) and % HFF (tropifexor 10–90-μg dose groups ranged from −7.48% to −15.04% versus placebo (−6.19%) and tropifexor 140- and 200-μg groups were −19.07% and −39.41%, respectively, versus placebo (−10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164

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Section: Discussionmentioning

confidence: 97%

Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial

Sanyal

López

Lawitz

et al. 2023

Nat Med

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“…However, upon diet reversal which would be expected to decrease the lipotoxic-glucotoxic load to the liver, changes were maximal in Zone 2. In a recent human trial, 18 similar changes were noted further demonstrating that the region of fibrosis improvement is not a simple reversal of the progression from stage 3 to 2 to 1, and should be considered in the context of the mechanism of action by which the disease is reversed.…”

Section: Discussionmentioning

confidence: 68%

“…In a recent treatment trial of the drug tropifexor, the majority of patients demonstrated no change in conventional fibrosis states. 18 However, based on changes in the qFPs evaluated using SHG technology, many of these patients were found to have changes suggestive of either progression or regression. Whether these findings truly reflected improving or worsening fibrosis, however, could not be ascertained because additional follow up biopsies were not available.…”

Section: Introductionmentioning

confidence: 99%

Second-Harmonic Generated Quantifiable Fibrosis Parameters Provide Signatures for Disease Progression and Regression in Nonalcoholic Fatty Liver Disease

Tai

Ren

et al. 2023

Clin Med�Insights�Pathol

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Introduction: The current ordinal fibrosis staging system for nonalcoholic steatohepatitis (NASH) has a limited dynamic range. The goal of this study was to determine if second-harmonic generated (SHG) quantifiable collagen fibrillar properties (qFP) and their derived qFibrosis score capture changes in disease progression and regression in a murine model of NASH, in which disease progression can be induced by a high fat sugar water (HFSW) diet and regression by reversal to chow diet (CD). Methods: DIAMOND mice were fed a CD or HFSW diet for 40 to 52 weeks. Regression related changes were studied in mice with diet reversal for 4 weeks after 48 to 60 weeks of a HFSW diet. Results: As expected, mice on HFSW developed steatohepatitis with stage 2 to 3 fibrosis between weeks 40 and 44. Both the collagen proportionate area and the qFibrosis score based on 15 SHG-quantified collagen fibrillar properties in humans were significantly higher in mice on HFSW for 40 to 44 weeks compared to CD fed mice. These changes were greatest in the sinusoids (Zone 2) with further increase in septal and portal fibrosis related scores between weeks 44 and 48. Diet reversal led to decrease in qFibrosis, septal thickness, and cellularity with greatest changes in Zone 2. Specific qFPs associated with progression only, regression only, or both processes were identified and categorized based on direction of fibrosis change. Conclusion: Complementing recent human studies, these findings support the concept that changes of disease progression and regression can be assessed using SHG-based image quantification of fibrosis related parameters.

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“…The width of fibrotic niche in the refence data rarely exceeded 2-3 Visium spots (55μm*2 + 45 μm distance between spots = 155μm, 55μm*3 + 2*45μm = 255μm). Reference estimates of fibrotic niche size reported in NAFLD were in the <200μm range [37, 41, 42]. Based on this prior data, we considered 165μm as maximum spot diameter.…”

Section: Methodsmentioning

confidence: 99%

Sample size calculation for a NanoString GeoMx spatial transcriptomics experiment to study predictors of fibrosis progression in non-alcoholic fatty liver disease

Ryaboshapkina

Azzu

2023

Preprint

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Sample size calculation for spatial transcriptomics is a novel and understudied research topic. Prior publications focused on powering spatial transcriptomics studies to detect specific cell populations or spatially variable expression patterns on tissue slides. However, power calculations for translational or clinical studies often relate to the difference between patient groups, and this is poorly described in the literature. Here, we present a stepwise process for sample size calculation to identify predictors of fibrosis progression in non-alcoholic fatty liver disease as a case study. We illustrate how to infer study hypothesis from prior bulk RNA-sequencing data, gather input requirements and perform a simulation study to estimate required sample size to evaluate gene expression differences between patients with stable fibrosis and fibrosis progressors with NanoString GeoMx Whole Transcriptome Atlas assay.

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Digital pathology with artificial intelligence analyses provides greater insights into treatment-induced fibrosis regression in NASH

Cited by 57 publications

References 50 publications

Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial

Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial

Second-Harmonic Generated Quantifiable Fibrosis Parameters Provide Signatures for Disease Progression and Regression in Nonalcoholic Fatty Liver Disease

Sample size calculation for a NanoString GeoMx spatial transcriptomics experiment to study predictors of fibrosis progression in non-alcoholic fatty liver disease

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