MASH Fibrosis, Not Resolution, Predicts Mortality: Zobair Younossi, MD

Fibrosis stage, not resolution of steatohepatitis, is the strongest independent predictor of mortality in metabolic dysfunction–associated steatohepatitis (MASH),¹ which should shape how clinical trials of MASH therapies define success, said Zobair Younossi, MD, MPH, professor of medicine and founding chair of the Global Center for Liver Outcomes and Policy Research at Georgetown University School of Medicine.

In part 1 of this interview with The American Journal of Managed Care^® (AJMC^®), Younossi discussed how payers are approving and monitoring MASH therapies using noninvasive tests (NITs) rather than liver biopsy, how the clinical and economic burden of the disease is projected to grow across nine countries through 2040, why he favors a societal approach to risk stratification and early treatment, and what patient-reported outcomes show about quality of life as the disease progresses.

This interview has been edited for clarity.

AJMC: At the European Association for the Study of the Liver Congress, you presented data showing that once the fibrosis stage is accounted for, MASH alone does not predict mortality.¹ Semaglutide (Wegovy; Novo Nordisk) and resmetirom (Rezdiffra; Madrigal Pharmaceuticals) were both approved on histologic end points that included improvement of fibrosis and/or MASH. What does that mean for how outcomes should be defined in clinical trials of these therapies?

Younossi: I think it’s important to recognize that historically, 2 histologic end points were basically accepted as surrogates for accelerated approval in the United States as well as Europe. One was NASH [nonalcoholic steatohepatitis] or MASH resolution, and the other was fibrosis improvement by 1 stage without worsening of steatohepatitis. These 2 are basically the end points of all the studies that are ongoing, including the 2 that were approved.^2,3

The issue is that when you look at the full approval of these drugs,^4,5 it will require improvement of outcomes like mortality improvement or cirrhosis complication improvement. The point I was making—and I’ve been making this point for a long time—is that the most important outcome for a phase 3 clinical trial should be something that predicts that long-term outcome the best. In that context, of the 2 histologic end points, only fibrosis can independently predict that outcome.

The second issue is that steatohepatitis is a histologic diagnosis, and it relies on reading of liver biopsies by pathologists. There is a great deal of variability in reading liver biopsies between pathologists, and when you take a liver biopsy, you take a small piece of a big liver. It’s a small sample of the liver, and you don’t know what’s going on in the rest of the liver.

This does not mean that MASH is not important. It is important, as it is the disease that drives fibrosis. In early phase trials, engaging the disease and a target engagement are important, and steatohepatitis should be an end point. However, for late-stage clinical trials that rely on improving long-term outcomes, the improvement of fibrosis is critical. In fact, most of the time they go together. If this is the case, why require a cumbersome end point flawed by sampling error and reader variability when you can focus only on the best end point, ie, fibrosis improvement?

What’s also important is that once you move from staging fibrosis by biopsy to determining prognostic risks with noninvasive tests [NITs], most of the noninvasive tests—the vast majority of them—are surrogates of fibrosis. Increasingly now, these NITs—the second-line NITs like transient elastography or enhanced liver fibrosis test—are also predictive of outcome.

The point here was that when we did this large data analysis of over 18,000 MASLD patients with liver biopsy and outcomes, you can see that when you do univariate analysis and look at what’s associated with adverse outcomes, both steatohepatitis, or a histologic component of steatohepatitis, and fibrosis were associated with these outcomes. But once you do what’s called multivariate analysis, which means that you need to account for confounders, the minute that you enter into the model that has steatohepatitis, histologic fibrosis stage, or an associated NIT, then steatohepatitis is no longer significant and fibrosis becomes the dominant predictor of mortality/liver events.

That was the point, and really the intention is to design clinical trials that simulate reality. In reality, nobody uses a liver biopsy in clinical practice to treat MASH or to monitor if someone is responding to treatment or not. They use NITs, and these NITs are generally “surrogates” of fibrosis and long-term outcomes. Why should clinical trials be based on an end point that is based on histology when the use of these drugs in clinical practice, once they’re approved, is based on NITs? To do this, the regulatory bodies need to align themselves with real-world practices. I’m hopeful that as we move forward, the regulatory bodies will align, and maybe they will require 2 concordant NITs to reflect treatment response. That may be what’s going to happen in the future. But the point of that our study was that when you’re looking at the outcome of mortality and events as a condition for full approval of a drug, then improvement of fibrosis is king. It’s the strongest independent predictor of these events.

AJMC: Are payers requiring liver biopsy for MASH therapies, or are they covering and monitoring treatment based on NITs?

Younossi: To the best of my knowledge, the vast majority of payers do not require liver biopsy because the approval of the new drugs did not require a liver biopsy for treatment selection or monitoring. That’s how the packaging inserts of both drugs are: the study design and regulatory approval were based on histology, but the treatment approval and monitoring in clinical practice are all based on NITs.

AJMC: You have published extensively on the economic burden of MASH. What has that research shown about how costs shift as patients progress from early fibrosis to cirrhosis, decompensation, and transplant?

Younossi: There are different types of costs that are important in assessing the economic burden of MASH. There’s the direct cost, and then there’s the indirect cost. If you’re looking at per-patient cost, the direct cost of MASH increases when the stage of liver disease becomes more severe. A patient with cirrhosis will certainly have more cost than a patient with no fibrosis. But even patients without fibrosis have significant costs when you look at total cost to society because there are so many of these early-stage patients that still require annual assessments. If you look at the United States, about 30% of the US population will have MASLD,⁶ and some of these patients would require risk stratification, which is blood testing and then monitoring over time. Even though that monitoring may be just a liver test or a liver stiffness every couple of years, that still is costly. The total cost is substantial for both advanced and early MASLD, but on a per-patient basis, the cost is more concentrated, or higher, for patients who have more advanced disease.

We estimated the economic burden of MASLD in the United States and 8 other countries using Markov modeling. In every country, we looked at 2 things. First, what happens over the next 20 years in terms of clinical outcomes? The clinical outcomes, like cirrhosis mortality, are projected to increase significantly over time. The second issue was assessment of costs, and in some countries the direct cost almost doubles in terms of billions and billions of dollars.

When you try to predict the economic outcome, the direct cost of MASH by 2040 in the US would be about $78 billion, and that’s a substantial increase from the early 2020s, which was about $45 billion to $46 billion. When you look at the additional economic loss accounted for by work productivity loss, which is actually an indirect cost; the total costs can be substantially higher. If you add the indirect costs, it’s estimated that by 2040 in the US that loss is almost $240 billion to $250 billion.

This was true for every country we looked at. We also looked at Germany, the United Kingdom, France, Italy, Spain, Brazil, Saudi Arabia, and Japan. In every one of these countries, both clinical outcomes and economic burden will increase.

AJMC: How should health plans balance the upfront costs of MASH treatments against the long-term savings of preventing cirrhosis, liver transplant, or heart attacks over a 10- to 20-year period?

Younossi: That depends on payers. In countries where the national health system is in place, it means that the government/society is responsible for paying for the management of whatever stage of liver disease the patients have. In this context, you may want to prevent the disease progression to more expensive stages and treat early so that you can prevent those patients from having cirrhosis and requiring liver transplantation. For the United States, it’s a bit different because there are so many different insurance companies and payers with different models, including Medicare. Nevertheless, if one looks at the societal perspective, appropriate risk stratification of patients with MASLD and treating those at risk is cost-effective.⁷

From a societal perspective, I think the effort should be to encourage and, even at some point, mandate risk stratification to find the patients who are at risk of developing cirrhosis or other adverse outcomes, because those are the patients who need to be treated now. Hopefully, all the payers, as well as governmental payers, can rally around the concept that—regardless of the ability of people to move from one insurance to another insurance—these patients should be risk stratified, and those who are at risk should be treated early, because then you can actually prevent the advanced liver disease and associated cost that could be absorbed by either Medicare or another payer. I think this type of policy in the United States could improve outcomes and prove to be cost-effective.

AJMC:You have helped develop patient-reported outcome tools specific to liver disease, such as the Chronic Liver Disease Questionnaire for MASH (CLDQ-MASH).⁸ What does quality-of-life data show, and what does it add that cost modeling alone might miss?

Younossi: There are 3 different types of outcomes that I look at, and I’ve already explained 2 of them. There is the clinical outcome such as cirrhosis, liver cancer, and liver transplantation. From MASLD/MASH, we are experiencing significant clinical burdens that are expected to increase over the next 20 years. The second is the economic outcome: that’s the direct costs and indirect costs. We looked at that, and that’s also increasing. The third type of outcome is patient experience based on health-related quality of life or other patient-reported outcomes. In this context, we also looked into the changes in quality of life, and as the disease becomes more severe over time, quality of life worsens.

To capture health-related quality of life, we have developed a number of instruments, such as CLDQ-NAFLD/NASH, and the more recently developed CLDQ-MASH. These studies show that MASLD, even in the early stages, negatively impacts patients’ health-related quality of life primarily through pathologic fatigue. As the disease progresses over time, the quality of life also worsens. This is an important outcome that must always be measured in clinical trials and clinical research. Although clinical endpoints such as laboratory tests are important to clinicians, patients are primarily concerned about how they feel and how the disease or its treatment affects their daily lives and experiences. This has been a major area of our research focus to always promote patient-centric research and patient-centric care.

References

1. Younossi ZM, Yu, M-L, de Avila L, et al. Liver fibrosis is the only predictor of adverse outcomes: time to remove MASH resolution as a clinical trial endpoint. Presented at: EASL 2026; May 27-30, 2026; Barcelona, Spain. Abstract OS-097.
2. Harrison SA, Bedossa P, Guy CD, et al; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509. doi:10.1056/NEJMoa2309000
3. Sanyal A, Newsome PN, Kliers I, et al; ESSENCE Study Group. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258
4. Joszt L. FDA approves resmetirom, first treatment for NASH with liver fibrosis. AJMC. March 14, 2024. Accessed October 2, 2026.https://www.ajmc.com/view/fda-approves-resmetirom-first-treatment-for-nash-with-liver-fibrosis
5. Klein HE. FDA approves semaglutide for MASH with fibrosis. AJMC. August 18, 2025. Accessed October 2, 2026.https://www.ajmc.com/view/fda-approves-semaglutide-for-mash-with-fibrosis
6. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77(4):1335-1347. doi:10.1097/HEP.0000000000000004
7. Younossi ZM, Kalligeros M, Wong VW-S, et al. Updated global consensus recommendations for risk stratification, treatment initiation, and response monitoring in metabolic dysfunction-associated steatotic liver disease. Clin Gastroenterol Hepatol. 2026;24(9):2333-2347. doi:10.1016/j.cgh.2026.03.030
8. Younossi ZM, Stepanova M, Younossi I, Racila A. Validation of the Chronic Liver Disease Questionnaire for MASH (CLDQ-MASH). JHEP Rep. 2024;7(3):101276. doi:10.1016/j.jhepr.2024.101276