Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis.

Abstract

BACKGROUND AND AIMS:

Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis.

APPROACH AND RESULTS:

Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events.

CONCLUSIONS:

In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis.

• Authors: Arun J Sanyal, Quentin M Anstee, Michael Trauner, Eric J Lawitz, Manal F Abdelmalek, Dora Ding, Ling Han, Catherine Jia, Ryan S Huss, Chuhan Chung, Vincent Wai-Sun Wong, Takeshi Okanoue, Manuel Romero-Gomez, Andrew J Muir, Nezam H Afdhal, Jaime Bosch, Zachary Goodman, Stephen A Harrison, Zobair M Younossi, Robert P Myers
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 75 Issue 5 Pg. 1235-1246 (05 2022) ISSN: 1527-3350 [Electronic] United States
• PMID: 34662449 (Publication Type: Controlled Clinical Trial, Journal Article)
• Copyright: © 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Chemical References

• Collagen

Topics

• Collagen (metabolism)
• Fibrosis
• Humans
• Liver (pathology)
• Liver Cirrhosis (drug therapy, etiology)
• Non-alcoholic Fatty Liver Disease (complications, drug therapy, metabolism)