Letter: Beyond histologic improvement in MASH

To the Editor: The review by Sierra et al¹ in the May issue provides a timely overview of emerging therapies for metabolic dysfunction–associated steatohepatitis (MASH). The authors integrate data on pharmacologic, bariatric, and endoscopic metabolic interventions while highlighting the shift from lifestyle-based management toward individualized multidisciplinary strategies.

However, several factors warrant further consideration. Although semaglutide, tirzepatide, and resmetirom have shown promising histologic results, current evidence still relies largely on surrogate end points such as steatohepatitis resolution and fibrosis-stage reduction. Long-term data evaluating hard clinical outcomes, including liver-related mortality, hepatocellular carcinoma, hepatic decompensation, and liver transplantation, remain limited. Singh et al² identified fibrosis stage as the strongest predictor of liver-related and overall mortality in nonalcoholic fatty liver disease, or MASH, suggesting that histologic improvement alone may not translate into sustained clinical benefit. Furthermore, the short duration of pivotal trials such as ESSENCE (Effect of Semaglutide in Subjects With Noncirrhotic Nonalcoholic Steatohepatitis)³ and SYNERGY-NASH (A Study of Tirzepatide [LY3298176] in Participants With Non-alcoholic Steatohepatitis)⁴ limits assessment of long-term safety and durability of fibrosis regression.

Also, treatment sustainability needs greater attention. The STEP-4 (Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity) trial⁵ showed significant weight regain after semaglutide discontinuation, suggesting that prolonged therapy may be necessary to maintain metabolic and hepatic benefits. This raises concerns regarding adherence, tolerability, cost, and healthcare accessibility, particularly in resource-limited settings.

Furthermore, data on bariatric endoscopic therapies should be interpreted cautiously. Evidence for endoscopic sleeve gastroplasty and related procedures is mainly from small cohorts, surrogate markers, and short-term follow-up. Abad et al⁶ reported improved liver stiffness, but histologic evidence of fibrosis regression remains limited. Similarly, Hedjoudje et al⁷ noted favorable safety and weight loss but insufficient long-term liver outcomes. Larger multicenter randomized controlled trials with histologic outcomes are needed before routine integration into MASH management algorithms.

Not all patients with MASH are candidates for metabolic-bariatric surgery due to age, comorbidities, perioperative risk, cost, limited access, and patient preference. Even in compensated cirrhosis, risk stratification is needed. Therefore, safe, accessible, durable nonsurgical therapies are needed for broader MASH populations.

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