Real-World Data Show MASH Progresses Faster Than Trials Suggest

Patients with metabolic dysfunction–associated steatohepatitis (MASH) and significant or advanced fibrosis progressed to cirrhosis far faster than earlier clinical trial data have suggested, with 17% of those with stage F2 to F3 fibrosis advancing to cirrhosis in a median follow-up time of just 16 months, according to a real-world analysis of the TARGET-NASH (NCT02815891) cohort published in Hepatology Communications.¹

Current guidelines recognize the importance of noninvasive testing (NIT) for screening and risk stratification, but how these tests are used in the real world is not well known. Furthermore, studies that focus on disease progression in MASH are based on clinical trials or small studies that are not representative of the general population and may overestimate disease progression.

“By estimating disease progression to cirrhosis, decompensation, and mortality in TARGET-NASH, we expected to enhance disease understanding beyond clinical trial evidence and existing literature, ultimately informing clinical guidelines and future clinical trial planning,” the authors explained.

The study followed 1964 adults with MASH and at least stage F2 fibrosis for a median of nearly 65 months and found steep downstream risks once cirrhosis developed: 46% of patients with compensated cirrhosis experienced some form of disease progression (decompensation, hepatocellular carcinoma, or death), and those who progressed to decompensated cirrhosis died at rates 7 to 20 times higher than patients who remained in earlier fibrosis stages.

How Does Real-World Progression Compare With Clinical Trial Data?

The previous STELLAR trials found that 13% of patients with F3 fibrosis progressed to cirrhosis over 4 years, while the TARGET-NASH analysis found a similar proportion of patients progressing in roughly a quarter of that time.

Among the 794 patients with compensated cirrhosis at baseline, 29.7% progressed to a new decompensation event, and 13.1% died over a median follow-up of 66 months; the presence of clinically significant portal hypertension further stratified risk, with 35% of those patients progressing to decompensation compared with 20% of those without it. Among the 394 patients who entered the study with decompensated cirrhosis, 29.4% died, and 9.6% underwent liver transplant over a median of 62 months.

Which Biomarkers Best Predict Disease Progression?

A central theme of the analysis was the prognostic value of biomarkers already collected in routine care. Each one-unit increase in the Fibrosis-4 (FIB-4) score was associated with a 14% increased hazard of progression to cirrhosis among patients with F2 to F3 fibrosis, and elevated FIB-4 also predicted decompensation and mortality among those with cirrhosis. Type 2 diabetes, current smoking status, higher Aspartate Aminotransferase-to-Platelet Ratio Index scores, and a non-alcoholic fatty liver disease fibrosis score above 1.455 were likewise tied to a greater likelihood of progressing to cirrhosis.

Despite FIB-4's utility, only 79% of patients in the TARGET-NASH cohort had the lab values—aspartate aminotransferase, alanine aminotransferase, and platelet count—needed to calculate it. Just 36% had a FibroScan measurement and 29% had undergone liver biopsy, underscoring what the study authors described as a persistent gap between the tools available for risk stratification and their actual uptake in practice. The data align with broader reporting on metabolic dysfunction–associated steatotic liver disease (MASLD) and MASH care, which has noted that noninvasive composite indices such as FIB-4, FAST, and Agile scores have expanded risk stratification options but still require broader validation and adoption across multicenter and primary care settings.²

Why Are Researchers Rethinking Fibrosis as the Primary End Point?

The TARGET-NASH findings echo a broader shift in how MASH researchers are thinking about which markers actually predict patient outcomes, which Zobair Younossi, MD, MPH, chairman of the Global NASH/MASH Council, has examined in his own work comparing steatohepatitis activity with fibrosis stage as predictors of mortality.

According to Younossi, steatohepatitis, which is diagnosed by the presence of steatosis, lobular inflammation, and hepatocyte ballooning on biopsy, is closely tied to the biological processes that drive fibrosis, but it loses its independent predictive power for mortality once the fibrosis stage is accounted for.

"It is still associated with mortality until you introduce the model stage of fibrosis," he told The American Journal of Managed Care® in an interview. "Once you do this, then steatohepatitis as an independent predictor of mortality goes away. It's actually fibrosis stage that determines mortality."

That distinction, Younossi explained, has direct implications for how NITs should be used and interpreted. Because most NITs in development, including transient elastography and the enhanced liver fibrosis test, are built to estimate fibrosis stage rather than steatohepatitis activity, they may be better positioned to forecast long-term outcomes.

"More and more, we show that these tests predict outcomes," he said, adding that substituting a noninvasive fibrosis surrogate for biopsy-confirmed fibrosis stage in his own analyses produced similar predictive results. "You can actually use fibrosis as your primary end point, and in fact you can even jump and say, ‘I'm going to use noninvasive surrogates of fibrosis,’...and they also can predict outcome."

Younossi argued this reasoning should inform how clinical trials are designed going forward, with fibrosis stage, potentially measured noninvasively, serving as the primary end point and steatohepatitis activity retained as a secondary one. He suggested the change could ease enrollment burdens, since trials would no longer need to confirm every component of steatohepatitis at baseline and could eventually allow noninvasive fibrosis biomarkers to substitute for liver biopsy altogether.

"The change that will come would be to make the field a little bit easier to enroll," he said, "[and] you would get a noninvasive testing at some point to replace liver biopsy."

Translating the MASH Clinical Trial Evolution

Taken together, the TARGET-NASH findings and Younossi's perspective point toward the same conclusion: the infrastructure for identifying high-risk MASH patients already exists but is inconsistently applied. The study authors called for automating FIB-4 calculation within electronic health records and expanding FibroScan access beyond academic liver centers, particularly given that the FDA recently accepted a proposal to treat vibration-controlled transient elastography as a reasonably likely surrogate end point for clinical trials in non-cirrhotic MASH with moderate-to-advanced fibrosis.³

With median progression to cirrhosis occurring in just 16 months among higher-risk patients, the authors argued that closing this detection gap—particularly in primary care, where most patients with metabolic risk factors are first seen—will be essential to identifying and intervening before disease reaches advanced, harder-to-treat stages.¹

“This evidence can provide additional rationale and justification in clinical trial design, including enrollment criteria, trial duration, and the choice of endpoints,” the authors concluded. “It also serves to inform health care providers and patients who are typically unaware of how MASH is interconnected with obesity, diabetes, and other metabolic diseases, or which MASH subpopulations may be more at risk of experiencing health outcomes.”

References

1. Newsome PN, Sartini C, Morris HL, et al; on behalf of the TARGET-NASH Investigators. Progression of MASH to cirrhosis, decompensation, and mortality, and the utility of NITs for detection and risk stratification. Hepatol Commun. 2026;10:e0962. doi:10.1097/HC9.0000000000000962

2. Jeremias S. Advances in MASLD and MASH care highlight progress and persistent gaps. AJMC^®. February 10, 2026. Accessed July 1, 2026. https://www.ajmc.com/view/advances-in-masld-and-mash-care-highlight-progress-and-persistent-gaps

3. FDA accepts proposal for reasonably likely surrogate endpoint for ‘MASH’ all-cause mortality or liver-related events. News release. FDA. August 27, 2025. Accessed July 1, 2026. https://www.fda.gov/drugs/drug-alerts-and-statements/fda-accepts-proposal-reasonably-likely-surrogate-endpoint-mash-all-cause-mortality-or-liver-related