The association of histologic and noninvasive tests with adverse clinical and patient-reported outcomes in patients with advanced fibrosis due to nonalcoholic steatohepatitis
Open accessAbstract
Background & aim Fibrosis is an independent predictor of death in nonalcoholic steatohepatitis (NASH). We assessed the associations between histologic and noninvasive tests (NITs) for fibrosis with clinical and patient-reported outcomes (PROs) in advanced NASH.Methods Patients with advanced NASH (NASH Clinical Research Network stage F3 or F4) were enrolled in 4 multinational clinical trials of simtuzumab and selonsertib. Liver biopsy samples, NIT results, and PROs (Short Form-36, Chronic Liver Disease Questionnaire-NASH, EuroQol-5D, and Work Productivity and Activity Impairment) were prospectively collected.Results A total of 2154 patients with advanced NASH were included: 52.5% with F4 NASH, 40% male, 72% with type 2 diabetes, baseline liver stiffness of 24.1 ± 14.2 kPa in F4 disease and 14.6 ± 8.0 kPa in F3 disease, baseline mean Enhanced Liver Fibrosis score of 11.4 ± 1.2 in F4 disease and 10.3 ± 1.0 in F3 disease, and a median follow-up of 16 months. Of those with baseline F3 disease, 16.7% experienced disease progression to cirrhosis, whereas for those with F4 disease, 7.3% experienced clinical events (39% ascites, 24% hepatic encephalopathy); patients who progressed had higher baseline NIT scores (all P < .0001). Adjusted for baseline levels, increases in NIT scores were also associated with increased risk of disease progression in both the F3 and F4 groups (P < .01 for all NITs in F3 and for ELF, NAFLD Fibrosis Score, Fibrosis-4 (FIB-4), and liver stiffness in F4). Higher NIT scores were found to be associated with impairment in PROs: ELF, ≥10.43; Nonalcoholic Fatty Liver Disease Fibrosis Score, ≥1.80; Fibrotest score, ≥0.54; liver stiffness, ≥23.4 kPa. During treatment, patients with decreases in NIT scores experienced improvement of their PRO scores, whereas those with increase in NIT scores had their PRO scores worsen (P < .05).Conclusions Baseline NIT scores and their changes over time are predictors of adverse clinical and PROs in patients with advanced NASH. (ClinicalTrials.gov, Numbers NCT01672866, NCT01672879, NCT03053050, and NCT03053063).
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Metabolic heterogeneity of study populations, particularly T2D comorbidity, remains an unexplored source of inconsistent outcomes with omega-3 PUFA therapy.
“The metabolic heterogeneity of study populations, particularly regarding T2D comorbidity, remains an unexplored source of the inconsistent outcomes with omega-3 PUFA therapy.13,14”
Omega-3 PUFAs have recognized efficacy in lowering serum triglycerides, but their effects on other metabolic and hepatic parameters are inconsistent across studies.
“Although their efficacy in lowering serum triglycerides is widely recognized, their effects on other metabolic and hepatic parameters remain inconsistent across studies.11–13”
Retrospective analyses have provided further evidence of the potential of FIB-4, NFS and ELF to predict progression to cirrhosis and liver-related events.
“Retrospective analyses have provided further evidence of the potential of FIB-4, NFS and ELF to predict progression to cirrhosis and liver-related events. 181,182”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [181]
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“9,10 13 This inconsistency obscures the true therapeutic value of omega-3 polyunsaturated fatty acids and suggests the presence of key effect-modifying factors.”
- Authors
- Younossi, Z. M., Anstee, Q. M., Wai-Sun Wong, V., Trauner, M., Lawitz, E. J., Harrison, S. A., Camargo, M., Kersey, K., Subramanian, G. M., Myers, R. P., & Stepanova, M.
- Affiliations
- Inova Health System (US)
- National Health Service (GB)
- Medical University of Vienna (AT)
- The University of Texas at San Antonio Health Science Center (US)
- Pinnacle Clinical Research (US)
- Gilead Sciences (United States) (US)
- Center for Outcomes Research in Liver Diseases (US)
- Corresponding author
- Younossi, Zobair M.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 160
- Issue
- 5
- Pages
- 1608-1619.e13
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W3111278435
- Cited by
- 118
- References
- 43
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 19 · 2023: 28 · 2022: 19 · 2021: 11
- FWCI
- 10.42
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by-nc-nd)
- Funders
- Gilead Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Keywords
- nonalcoholic steatohepatitis, liver fibrosis, noninvasive fibrosis assessment, enhanced liver fibrosis test, NAFLD fibrosis score, Fibrosis-4 score, liver stiffness, patient-reported outcomes, hepatic encephalopathy, ascites, quality of life, selonsertib, liver biopsy histology, type 2 diabetes, Work Productivity and Activity Impairment, quality-adjusted life years
- MeSH terms
- Patient Reported Outcome Measures, Progression-Free Survival, Aged, Benzamides, Biopsy, Clinical Trials as Topic, Female, Humans, Imidazoles, Liver Cirrhosis, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Pyridines, Severity of Illness Index, Time Factors, Biomarkers, Treatment Outcome, Elasticity Imaging Techniques, Antibodies, Monoclonal, Humanized, Non-alcoholic Fatty Liver Disease
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