A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts
Abstract 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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-12-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13052 |
| _version_ | 1827582234402488320 |
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| author | Jane Knöchel Linnéa Bergenholm Eman Ibrahim Stergios Kechagias Sara Hansson Mathias Liljeblad Patrik Nasr Björn Carlsson Mattias Ekstedt Sebastian Ueckert |
| author_facet | Jane Knöchel Linnéa Bergenholm Eman Ibrahim Stergios Kechagias Sara Hansson Mathias Liljeblad Patrik Nasr Björn Carlsson Mattias Ekstedt Sebastian Ueckert |
| author_sort | Jane Knöchel |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-08T22:48:32Z |
| format | Article |
| id | doaj.art-bf1703e2ce564bf6916f27c82905c8b3 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-03-08T22:48:32Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-bf1703e2ce564bf6916f27c82905c8b32023-12-16T18:59:26ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-12-0112122038204910.1002/psp4.13052A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohortsJane Knöchel0Linnéa Bergenholm1Eman Ibrahim2Stergios Kechagias3Sara Hansson4Mathias Liljeblad5Patrik Nasr6Björn Carlsson7Mattias Ekstedt8Sebastian Ueckert9Clinical Pharmacology and Quantitative Pharmacology Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg SwedenDMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca Gothenburg SwedenDepartment of Pharmacy Uppsala University Uppsala SwedenDepartment of Health, Medicine, and Caring Sciences Linköping University Linköping SwedenTranslational Science and Experimental Medicine, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca Gothenburg SwedenTranslational Science and Experimental Medicine, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca Gothenburg SwedenDepartment of Health, Medicine, and Caring Sciences Linköping University Linköping SwedenTranslational Science and Experimental Medicine, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca Gothenburg SwedenDepartment of Health, Medicine, and Caring Sciences Linköping University Linköping SwedenClinical Pharmacology and Quantitative Pharmacology Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg SwedenAbstract 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.https://doi.org/10.1002/psp4.13052 |
| spellingShingle | Jane Knöchel Linnéa Bergenholm Eman Ibrahim Stergios Kechagias Sara Hansson Mathias Liljeblad Patrik Nasr Björn Carlsson Mattias Ekstedt Sebastian Ueckert A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts CPT: Pharmacometrics & Systems Pharmacology |
| title | A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts |
| title_full | A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts |
| title_fullStr | A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts |
| title_full_unstemmed | A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts |
| title_short | A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts |
| title_sort | markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts |
| url | https://doi.org/10.1002/psp4.13052 |
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