Metabolic Surgery Improves Long-Term Liver Outcomes in MASH-Related Cirrhosis

Steven Nissen, MD

Credit: Cleveland Clinic

In the absence of approved medical therapies for compensated metabolic dysfunction-associated steatohepatitis (MASH)-related cirrhosis, new research is shedding light on the potential role of metabolic surgery for safely and effectively improving liver outcomes in this patient population.¹

Findings from the Surgical Procedures Eliminate Compensated Cirrhosis In Advancing Long-term (SPECCIAL) study point to a 72% reduced risk of incident major adverse liver outcomes (MALO) and an 80% reduced risk of progression to decompensation with metabolic surgery versus nonsurgical treatment in patients with compensated MASH-related cirrhosis and obesity.¹

Approved on March 14, 2024, resmetirom (Rezdiffra) is currently the only US Food and Drug Administration-approved MASH therapeutic, but it is only indicated for patients with MASH and moderate to advanced fibrosis. For those with cirrhosis, a major unmet need remains.²

“Patients with MASH-related cirrhosis have extremely limited treatment options. Currently, no therapeutic interventions have demonstrated efficacy in mitigating the risk of severe liver complications within this patient population,” Sobia Laique, MD, a transplant hepatologist and the study coinvestigator at Cleveland Clinic, said in a press release.³ “This underscores a critical unmet need for the development of effective therapies specifically targeting patients with compensated MASH-related cirrhosis.”

To address this gap in research, investigators conducted the SPECCIAL study, which was designed to examine the long-term association between metabolic surgery and the risk of progression to MALO in patients with compensated biopsy-proven MASH-related cirrhosis compared with well-balanced patients who were medically managed. Investigators defined MALO as the first occurrence of ascites, variceal hemorrhage, hepatic encephalopathy, hepatocellular carcinoma, liver transplantation, or all-cause mortality.¹

Among 36,912 patients who underwent liver biopsy at the Cleveland Clinic Health System in the United States between 1995 and 2020, 168 patients with compensated histologically proven MASH-related cirrhosis, Child-Pugh class A, Model for End-Stage Liver Disease ≤ 10, and obesity were included in the present analysis. Among the cohort, there were 62 metabolic surgery patients, including 37 Roux-en-Y gastric bypass and 25 sleeve gastrectomy, and 106 nonsurgical control patients.¹

Time to incident MALO was compared between the groups, with a mean follow-up of 10.0 ± 4.5 years. At the end of the study period in the unweighted dataset, 10 patients in the surgical group and 42 patients in the nonsurgical group progressed to MALO. The 15-year cumulative incidence of MALO was 20.9% (95% confidence interval [CI], 2.5–35.9%) in the surgical group compared with 46.4% (95% CI, 25.6–61.3%) in the nonsurgical group, with an adjusted hazard ratio of 0.28 (95% CI, 0.12–0.64; P = .003).¹

At the end of the study period in the unweighted dataset, 4 patients in the surgical group and 33 patients in the nonsurgical group progressed from compensated cirrhosis to the decompensated stage, defined as the first occurrence of ascites, variceal hemorrhage, or hepatic encephalopathy. The 15-year cumulative incidence of decompensated cirrhosis was 15.6% (95% CI, 0–31.3%) in the surgical group compared with 30.7% (95% CI, 12.9–44.8%) in the nonsurgical group, with an adjusted hazard ratio of 0.20 (95% CI, 0.06–0.68; P = .01).¹

Of note, the mean percentage of weight loss at 15 years in the surgical group was 26.6% (95% CI, 24.5–28.7%), which was significantly greater than the nonsurgical group 9.8% (95% CI, 7.8–11.8%; P <.001).¹

In the initial postoperative period, 10 (16.1%) patients had adverse events including wound-related complications (n = 5), bleeding (n = 2), intraabdominal infected hematoma requiring laparoscopic washout (n = 1), pneumonia (n = 1), and contained leak after sleeve gastrectomy requiring surgical and endoscopic management (n = 1). No deaths occurred due to metabolic surgery, and there were no hepatic decompensation events in the early postoperative period.¹

In long-term follow-up, reoperation was required in 4 (6.5%) patients; 3 had conversion of their original sleeve gastrectomy to gastric bypass, and 1 patient with a history of gastric bypass required resection of excluded stomach for a bleeding peptic ulcer.¹

“The SPECCIAL study shows that bariatric surgery is an effective treatment that can influence the trajectory of cirrhosis progression in select patients,” Steven Nissen, MD, chief academic officer of the Heart, Vascular and Thoracic Institute at Cleveland Clinic and the study’s senior investigator, said.³

References

1. ^{Aminian A, Aljabri A, Wang S, et al. Long-term liver outcomes after metabolic surgery in compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis. Nat Med. https://doi.org/10.1038/s41591-024-03480-y}
2. ^{Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed January 27, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash}
3. ^{Cleveland Clinic. Weight-loss surgery lowers risk of developing complications of liver disease in patients with cirrhosis and obesity. EurekAlert! January 27, 2025. Accessed January 27, 2025. https://www.eurekalert.org/news-releases/1071494}