Disease State Transition Probabilities Across the Spectrum of NAFLD: A Systematic Review and Meta-Analysis of Paired Biopsy or Imaging Studies

Le, Phuc; Payne, Julia Y.; Zhang, Lu; Deshpande, Abhishek; Rothberg, Michael B.; Alkhouri, Naim; Herman, William H.; Hernández, Adrian V.; Schleicher, Mary; Ye, Wen; Dasarathy, Srinivasan

doi:10.1016/j.cgh.2022.07.033

Cited by 21 publications

(10 citation statements)

References 69 publications

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“…[6][7][8] In Singh et al and Le et al, the results suggested that fibrosis progression could be dependent on fibrosis stage at baseline. 7,8 However, the impact of patients' characteristics on fibrosis progression and regression could not be assessed fully, due to lack of access to patient-level data and the chosen approach. A quantitative, model-based approach to accurately predict the future development of fibrosis and to identify factors that impact fibrosis progression on an individual patient level is still missing.…”

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 97%

“…Previous meta‐analyses have shown that people with NASH progress faster to advanced fibrosis stages than people with NAFLD 6–8 . In Singh et al and Le et al, the results suggested that fibrosis progression could be dependent on fibrosis stage at baseline 7,8 . However, the impact of patients' characteristics on fibrosis progression and regression could not be assessed fully, due to lack of access to patient‐level data and the chosen approach.…”

Section: Introductionmentioning

confidence: 99%

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A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts

Knöchel,

Bergenholm,

Ibrahim

et al. 2023

CPT Pharmacom & Syst Pharma

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Disease progression in nonalcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end‐stage liver disease and mortality. Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform a clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical nonalcoholic fatty liver disease cohort with serial biopsies over 3 decades. We evaluated covariate effects on all model parameters and performed clinical trial simulations to predict the fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibrosis. Fibrosis progression rate (FPR) was twofold higher for fibrosis stages 0 and 1 (F0‐1) compared to fibrosis stage 2 and 3 (F2‐3). A twofold increase in FPR was observed for T2D. A two‐point steatosis worsening increased the FPR 11‐fold. Predicted fibrosis progression was in good agreement with data from external clinical cohorts. Our fibrosis progression model shows that patient selection, particularly initial fibrosis stage distribution, can significantly impact fibrosis progression and as such the window for assessing drug efficacy in clinical trials. Our work highlights the increase in hepatic steatosis as the most important factor in increasing FPR, emphasizing the importance of well‐defined lifestyle advise for reducing variability in NASH progression during clinical trials.

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Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts

Knöchel,

Bergenholm,

Ibrahim

et al. 2023

CPT Pharmacom & Syst Pharma

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“…The notable placebo response rate identified in early phase studies of NASH mirrors the lack of standardized approaches to lifestyle recommendations, renders cross-trial comparisons impracticable, and hinders the assessment of novel therapeutics [ 167 ]. However, the rates of liver fibrosis progression and regression are much higher in randomized clinical trials than in observational studies [ 168 ], calling for studies to bridge the gap between clinical practice and sponsored research.…”

Section: Research Agendamentioning

confidence: 99%

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

Lonardo,

Ballestri,

Mantovani

et al. 2024

Metabolites

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This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular–kidney–metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone.

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“…Although studies have consistently shown that the fibrosis stage 2 has a stronger correlation with adverse liver-related outcomes than features of NASH, inflammation is after all the driver of fibrosis progression. 3,4 Moreover, the United States Food and Drug Administration and the European Medicines Agency accept NASH resolution with no worsening of fibrosis and/or fibrosis improvement with no worsening of NASH as key histological endpoints for conditional approval of new drugs for NASH. 5 Until the regulators accept the use of noninvasive surrogate biomarkers in place of liver biopsy, assessment of inflammation will remain central in the drug development process.…”

Section: Introductionmentioning

confidence: 99%

Non-invasive biomarkers for liver inflammation in non-alcoholic fatty liver disease: present and future

Yip¹,

Lyu²,

Lin³

et al. 2023

Clin Mol Hepatol

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Terry Yip has served as a speaker and an advisory committee member for Gilead Sciences.Vincent Wong has served as an advisory committee member for AbbVie, Allergan, Echosens, Gilead Sciences, Janssen, Perspectum Diagnostics, Pfizer and Terns, and a speaker for Bristol-Myers Squibb, Echosens, Gilead Sciences and Merck.Grace Wong has served as an advisory committee member for Gilead Sciences and Janssen, as a speaker for Abbott,

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Disease State Transition Probabilities Across the Spectrum of NAFLD: A Systematic Review and Meta-Analysis of Paired Biopsy or Imaging Studies

Cited by 21 publications

References 69 publications

A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts

A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

Non-invasive biomarkers for liver inflammation in non-alcoholic fatty liver disease: present and future

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