The Association of Histologic and Noninvasive Tests With Adverse Clinical and Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis

Gastroenterology. 2021 Apr;160(5):1608-1619.e13. doi: 10.1053/j.gastro.2020.12.003. Epub 2020 Dec 8.

Abstract

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).

Keywords: Abdominal Symptoms; Fatigue; Fatty Liver Disease; Physical Functioning; Vitality.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Benzamides / therapeutic use
  • Biomarkers / blood
  • Biopsy
  • Clinical Trials as Topic
  • Elasticity Imaging Techniques
  • Female
  • Humans
  • Imidazoles / therapeutic use
  • Liver Cirrhosis / diagnosis*
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / etiology
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / diagnosis*
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Patient Reported Outcome Measures*
  • Predictive Value of Tests
  • Progression-Free Survival
  • Prospective Studies
  • Pyridines / therapeutic use
  • Severity of Illness Index
  • Time Factors
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Benzamides
  • Biomarkers
  • Imidazoles
  • Pyridines
  • simtuzumab
  • selonsertib

Associated data

  • ClinicalTrials.gov/NCT03053050
  • ClinicalTrials.gov/NCT01672879
  • ClinicalTrials.gov/NCT01672866
  • ClinicalTrials.gov/NCT03053063