How I Treat MASLD/MASH

Dr Younossi reviews his approach to managing MASLD and MASH, from screening to treatment to monitoring, and how working with a multidisciplinary team provides for better outcomes.

Zobair Younossi, MD, is chairman of the Global NASH/MASH Council and Professor of Medicine and Chairman of the Global Center for Liver Outcomes and Policy Research at Georgetown University School of Medicine in Washington, DC.

Metabolic Dysfunction–Associated Steatotic Liver Disease: Noninvasive Risk Stratification and Treatment Pathway 

• MASLD risk stratification (primary care → hepatology): In patients with type 2 diabetes/prediabetes, obesity with cardiometabolic risk, or chronically elevated liver enzymes (after excluding other causes), first-line testing is FIB-4. If FIB-4 <1.3, manage in primary care (repeat annually if diabetic; every 3 years if not). If FIB-4 ≥1.3 (≥2 if age >65), proceed to second-line testing; note reduced accuracy in patients ≤35 years. Assess alcohol use via AUDIT-C or PEth.

• Second-line noninvasive tests (NITs) and thresholds: Use VCTE (liver stiffness) or ELF test. For VCTE: <8 kPa = low risk, ≥8–10 kPa = at-risk, >20 kPa = likely cirrhosis. For ELF: <9–9.2 = low risk, ≥11.3 = cirrhosis. Patients with suspected cirrhosis require standard cirrhosis management and surveillance (eg, HCC screening).

• Treatment and monitoring (noncirrhotic MASLD): Initiate intensive lifestyle therapy plus resmetirom or semaglutide (GLP-1 RA) based on cardiometabolic profile; many patients already receive GLP-1 RAs. Treatment duration ≈52–72 weeks. Monitor with NITs: response defined as ≥30% liver stiffness reduction or ≥0.5 ELF decrease. Reassess at ~6 months and 1 year; switch therapy if worsening, or continue if stable/partial response. Liver biopsy is rarely required.

Hello, I'm Zobair Younossi. I'm chairman of the Global NASH/MASH Council, as well as Professor of Medicine and Chairman of the Global Center for Liver Outcomes and Policy Research at Georgetown University School of Medicine here in Washington, DC.

It's my pleasure to be with you today and talk to you about a typical case that I see when we evaluate patients with MASLD. Now, typically as a hepatologist, I get my patients from the primary care setting or an endocrinologist where patients come in with potential risk that require risk stratification. But what are these conditions that require risk stratification from SLD? These are patients who have type 2 diabetes, sometimes even prediabetes; patients who have complicated obesity, meaning that they're obese and they actually have another cardiometabolic risk; and those who have a chronically elevated liver enzymes, and of course, in this case, you have to exclude other causes of liver disease.

In the primary care setting, the first thing that needs to be done is to do a FIB-4 test. There are other first-line noninvasive tests or NITs, but the one that's actually been used frequently is FIB-4. If the FIB-4 is less than 1.3, the primary care physician will follow those patients. If they're diabetic, they will repeat the FIB-4 every year. If they don't have any other risks, every 3 years is fine. But if the FIB-4 is 1.3 or higher, and if I have the patient that's over 65, then you use a cutoff of 2. And also remember that FIB-4 does not perform very well in very young individuals. So if you've got someone who's 30, 35 or younger, then you probably have to think about using another modality.

So once I get the patient with a FIB-4 that is on this 1.3 or higher range, then what I would do is to think about 2 things. One, I want to make sure that the patient is not consuming alcohol, even in moderation. And you can do this in 2 different ways. You can do it with simple questionnaire like AUDIT-C, or you can do it with a blood test called PEth testing. We tend to use PEth testing just because it's probably a bit more accurate.

Those that don't have alcohol-associated liver disease or even what we call MetALD, those are the patients that then will get the second-line testing. Now, we can do, of course, the second-line noninvasive testing for MetALD and ALD, but just here, we're just talking about MASLD. So for MASLD, if your VCT liver stiffness is less than an 8, then the patient goes back as low-risk to the primary care physician. If it's 8 or 10 or higher, then they're considered to be at this at-risk category and they need to be followed up.

If VCT liver stiffness is over 20, patient has probably cirrhosis until proven otherwise, and of course you have to look at clinical and laboratory tests to see if there is any evidence of cirrhosis or not. And if they do have cirrhosis and all the other things that's related to cirrhosis, including liver cancer screening or viruses screening, needs to be done.

For those patients who are within the range of treatment, then we will actually consider treatment. Now, if you don't happen to have VCTE, then we, in our practice, would use enhanced liver fibrosis test, which is a blood test. And here, if your enhanced liver fibrosis or ELF test is less than 9.2, some may say less than 9, then those patients are at low risk. If you are 11.3 or higher, then these patients have actually cirrhosis and you do the same things that we were talking about.

For those who actually are in the middle, both whether it's with liver stiffness or with ELF test, then you consider treatment with the 2 drugs that are currently available, and that's resmetirom and semaglutide. Now, it's important to remember that if you're closer to the higher numbers of VCT, closer to 20 liver stiffness or close at 11.3 with ELF tests, you probably should do another noninvasive test to make sure there is no cirrhosis.

If there is no evidence of cirrhosis by these NITs or by clinical or laboratory test, then of course the first foundational treatment is lifestyle, and lifestyle should be done in a very intense way with a multidisciplinary team that includes nutritionists, exercise specialists. And if you don't have access to those, at least you can give people guidance or patients guidance to follow these recommendations in a very strict way. And if you happen to have an endocrinologist, they can help you with management of cardiometabolic risks, and that's usually done at a metabolic clinic. If you don't happen to have a metabolic clinic, you can create this in a virtual way by having your colleagues in this field.

Now, in addition to the lifestyle, then you have 2 drugs. And which drugs do you use, semaglutide or resmetirom, is really a decision between the patient and the physician or the provider. And in this context, if the patient has multiple cardiometabolic risks, then maybe semaglutide needs to be the preferred drug of choice. But the reality is that in my practice, most of the patients come in already on a GLP1 receptor agonist for treatment of diabetes with obesity. So our options are limited in that context to just resmetirom, and we, of course, use resmetirom based on whatever dose that is appropriate for the patient.

So whether you use resmetirom alone or resmetirom, in this case, with a pre-existing GLP-1 receptor agonist, or a GLP-1 receptor agonist alone, then the treatment is approximately a year. So how do we actually monitor these patients? Well, you monitor for side effects, obviously. You don't make a decision about whether the patient is being responsive to treatment or not after at least a full duration of treatment. But if the patient ... We do a 6-months VCTE to just get an idea if patient is actually responding or not. If after a year or 52 weeks of treatment with one and 72 for the other one, then you determine using again noninvasive tests. So if liver stiffness has decreased by 30% or higher, or if ELF test has decreased by a 0.5 or more, then that patient is responding. And most of us will continue that patient, especially if there is no issue with coverage, unless there is significant weight loss and management and improvement of cardiometabolic risk or the patient doesn't want to continue on long-term treatment.

If the patient is not responding, that means that they're not responding and actually worsening, then you should consider switching to the other medication that patient is not taking. If the patient is not responding to the optimal level, if they're not actually worsening, then you have, again, a situation where you have to discuss this with the patient and decide if there is no issue in terms of coverage, patient is tolerating well and is enthusiastic to continue, then a lot of us will continue the medication on treatment because maybe there is some cardiovascular benefit if you are taking a GLP-1 receptor agonist and even resmetirom for those patients, because some of the improvement may happen in year 2 or year 3. So for those patients, we can continue to treat. At the moment, we don't have long-term data to say that these benefits will translate into heart outcome improvement, but we assume that these surrogates are surrogates of long-term improvement.

These are noninvasive tests that we are talking about, that we will continue those medications. Do we do liver biopsies in the clinical setting? Not really. Very rarely. I mean, if you have a patient that has very high autoimmune markers and has MASLD, you want to exclude superimposed autoimmune hepatitis, then you can do a liver biopsy, but most of our patients don't actually require a liver biopsy. Now there are other second-line NITs like FAST or Agile-3, Agile-4, there is mass testing. These are all a bit more sophisticated for use in clinical practice, but if your center has easy access to an MRE, then of course that would be also a test to consider a second-line treatment.

That's sort of what we do. And we are hoping that this sort of a multidisciplinary approach to treatment of MASH, creating a metabolic clinic, will help our patients ultimately to be managed by a team rather than by individuals in different silos. And I think this comprehensive integrated approach will benefit the patients the most. So this was just a summary of how we manage patients with MASLD, and I hope it's helping you and your practice. Thank you very much.