Resolving MASH Without Worsening Fibrosis Improves Post-Bariatric Surgery Survival

Resolution of metabolic dysfunction-associated steatohepatitis (MASH) without worsening of patient fibrosis may be a reliable surrogate endpoint for bariatric surgery, according to new findings.¹

In a first-of-its-kind trial presented at The Liver Meeting 2023 from the American Association for the Study of Liver Diseases (AASLD) in Boston this weekend, a multinational team of investigators reported findings showing that resolution of MASH without worsening of fibrosis improved the 15-year survival rate of patients with MASH to an extent comparable to patients without MASH, following bariatric surgery.

Adversely, the findings additionally showed that patients with persistent MASH or worsened fibrosis had significantly lower 15-year survival rates following the procedure.

Presented by study author Guillaume Lassailly, of the Centre Hospitalier Universitaire de Lille in France, investigators sought to examine the effects of histological MASH and fibrosis progression on patients’ long-term survival after bariatric surgery. Lassailly emphasized the need for efficient MASH intervention strategies at a both patient and public health scale; the prior BRAVES trial indicated bariatric surgery was linked to a 70% MASH resolution rate in patients, without worsening of fibrosis.²

“Bariatric surgery reduces liver fibrosis, overall mortality and cardiovascular events,” Lassailly said. “It also has been shown to reduce liver-related events and mortality in MASH patients. Although bariatric surgery effectively reduces mortality, there are no surrogate markers to predict this event.”

Lassailly additionally noted the US Food and Drug Administration (FDA), among other experts, have endorsed MASH resolution without worsening nor improving fibrosis as acceptable surrogate endpoints for assessing prevention of cirrhosis and liver-related mortality.

“These surrogate endpoints have been chosen to perform therapeutic studies without using liver-related mortality as a primary outcome,” Lassailly said. “However, their significance in the natural history of MASH, their with mortality, and their use in the context of MASH treatment, metabolic syndrome and therefore bariatric surgery are warranted.”

The investigators’ cohort from the Lille Bariatric Cohort (1994 – 2021) included patients aged 18 – 65 years old, with body mass index (BMI) scores of either ≥35 kg/m² plus cardiovascular or cardiometabolic comorbidities, or ≥40 kg/m² without such comorbidities. Included patients were additionally undergoing their first bariatric procedure.¹

Among the 2682 baseline population, 232 patients were diagnosed with MASH and 267 were diagnosed with F2 – F4 fibrosis. During the AASLD 2023 presentation, 2522 patients included 1-year follow-up data; among them, 746 had consecutive liver biopsies conducted.

Of the 746 consecutive liver biopsies, 732 had MASH status available. And of that population, 594 had quality data suitable for the trial’s MASH and fibrosis assessment.

Lassailly and colleagues sought a primary outcome of effects of MASH resolution without worsening fibrosis on 15-year survival, as well as secondary outcomes including MASH resolution regardless of fibrosis status and fibrosis improvement from F2 – F4 stages to F0 – F1 over 15 years.

Mean patient age was 49.9 years old; 74.1% of patients were female, and mean BMI was 45.7 kg/m².

Baseline MASH was associated with a more than 2-fold risk of 15-year mortality (hazard ratio [HR], 2.21; 95% CI, 1.17 – 4.15), or a 8.8 percentage point-lowered odds of survival at 15 years among the cohort (92.7% [95% CI, 91.1 – 94.3] vs 83.9% [95% CI, 77.1 – 90.8]; P <.001).

Baseline fibrosis scores of ≥F2 were linked to a more than 3-fold risk of 15-year mortality (HR, 3.37; 95% CI, 1.85 -6.16).

For the primary outcome of resolution of MASH without worsening of fibrosis after bariatric surgery, investigators observed a nearly 4-fold improved survival likelihood at 15 years versus patients with persistent MASH or worsened fibrosis after surgery (HR, 3.84; 95% CI, 1.06 – 13.9; P = .009). The rate of 15-year survival among patients with resolved MASH and no worsened fibrosis (88.4%; 95% CI, 79.3 – 97.5) was similar to that observed among patients without baseline MASH (92.9%; 95% CI, 90.3 – 95.4).

For the secondary outcome, investigators observed a more than 4-fold greater risk of 15-year mortality for patients with persistent MASH versus those who achieved MASH resolution regardless of fibrosis (HR, 4.53; 95% CI, 1.16 – 17.00; P = .002). The team additionally observed an association between improved fibrosis to F0 – F1 and longer 15-year survival.

Among patients with and without MASH, the leading causes of death were fairly consistent, save for liver failure, respectively:

• Cardiovascular event (27.77% vs 28.30%)
• Cancer (16.67% vs 16.98%)
• Liver failure (27.77% vs 11.32%)

Lassailly and colleagues concluded their analysis was the first to show resolving MASH without worsening of fibrosis is a “reliable surrogate endpoint in the context of bariatric surgery.”

“After the study from Aminian et al demonstrating the positive impact of bariatric surgery in MASH patients, our work emphasizes the importance of the histological response to predict the outcome,” he said. “In addition, for fibrosis progression, our data may suggest that a survival benefit could be obtained only after a significant reduction in liver fibrosis, reaching mild fibrosis stage.”

^Reference

1. ^{Lassailly G, Calazzo R, Goemans A, Labreuche J, et al. MASH RESOLUTION WITHOUT FIBROSIS WORSENING AFTER BARIATRIC SURGERY IMPROVES LONG-TERM SURVIVAL. Paper presented at: The Liver Meeting. Boston, MA. November 10 - 14, 2023.}
2. ^{Verrastro O et al. Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): A multicentre, open-label, randomised trial. Lancet 2023 Apr 20; [e-pub]. https://doi.org/10.1016/S0140-6736(23)00634-7}