← Diabetes Core Update
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- [00:03]
A
Welcome to this special three part series of Diabetes Core Update where we will discuss metabolic associated liver disease mash. This is important because the prevalence of MASH has increased over the last 30 years. It has direct consequences on both quality of life for people and it has a range of health outcomes and it is one of the leading causes of end stage liver disease requiring transplant. I'm your host, Dr. Neal Skolnick, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. This special series of Diabetes Core Update is sponsored by Baringer Ingelheim. In the first episode, we focused on the epidemiology of mash, how it progresses and the consequences of mash, as well as screening for mash. In this second episode, we're going to home in on the diagnosis and discuss treatment. Then in the third episode, we're going to bring it all together with some cases. And joining us for today's episode, we're really privileged to have Dr. Alina Allen. Dr. Allen is an Associate professor of medicine at the Mayo Clinic in Rochester, Minnesota where she serves as the Director of Hepatology and Director of the MASL Clinic. She is a physician scientist with an NIH funded research program focused on improving outcomes in patients with metabolic dysfunction associated steatotic liver disease, nasl, and she's an associate editor of the journal Hepatology. Alina, welcome to our podcast.
- [01:50]
B
Thank you, Neil, thank you for this invitation. I am delighted to come here and have a discussion with you about this disease that is unfortunately affecting one in three adults in the United States. So, as you said, highly important and timely.
- [02:07]
A
Yeah. In the first podcast of this series, we talked with Dr. Jay Shubrook about screening. Briefly, when we think about screening, we should be screening people with obesity and one metabolic associated condition, hypertension, hyperlipidemia, glucose intolerance, et cetera. We ought to be screening everyone with type 2 diabetes and people with elevated LFTs or whom steatosis is seen on an ultrasound done for some other reason. Our goal is to identify people with MASH who have clinically significant fibrosis of F2 or higher. Alina, can you clarify for our listeners why we're focused on finding F2 and F3 fibrosis?
- [02:58]
B
Sure. Fibrosis is measured classically by histology and is graded in four stages, 1 through 4, where 1 is mild, 2, 2 to 3 is moderate to advanced, and 4 is cirrhosis. And cirrhosis is the complication we want to avoid because that's the stage of the disease that is associated with decompensating. Events, risk of liver cancer, need for liver transplantation, and until recently, an irreversible stage. It's possibly that we will be able to reverse with medications in the future. But essentially we want to not get to that stage. So we want to identify people before stage four. Why do we start at stage two? This is because several studies have shown that this is where the mortality risk increases. The, the, the most important complication in the liver is fibrosis, because that's the only one that so far has been associated with an increased risk of mortality. And the risk starts at stage four and higher and increase six potentially after that. So because of these two reasons, we want to balance the, the costs and the effort of screening and identifying the right patients to balance it with the impact of treatment. So starting at stage two through three is ideally that sweet spot so that we can prevent stage four or cirrhosis. The caveat to that is, I want to mean emphasize in the last part is that we shouldn't dismiss. If we incidentally find somebody with steatos or, you know, stage zero or stage one fibrosis, it should not be dismissed. It's just that we cannot really screen everybody and we should focus on those who are almost to that stage of cirrhosis. But mild stage 0 to 1 should also be counseled. And even though we don't have medications for that, we can prevent getting further.
- [05:02]
A
That makes sense. And we know that MASLD is a metabolic disease and those people ought to aggressively be screened for other metabolic issues and treated, whether that be prediabetes or hyperlipidemia. So it does identify a high risk people, group of people, so that our listeners have a sense. If we took everyone with masld, what used to be called fatty liver, what percent of that group group goes on to develop fibrosis?
- [05:39]
B
The epidemiologic studies show that approximately 10%, 10 to 14% of people who have steatosis go on to develop stage two or higher fibrosis. And those who reach that end stage of cirrhosis are about 2 to 3%. So minority. But we, we want to prevent getting there because again, all the reasons we, we described before.
- [06:06]
A
Yeah. And it's just helpful to have that sense of progression and that progresses over time. In our first podcast, we discussed that the recommended screening test is the fib4 and then if the value is above 1.3 or if someone's over age 65, because part of that fib4 formula is age and age drives a higher number if someone's over 65 we use a cutoff of 2.0. Then the next step is that we get either vibration elastography, most commonly the fibroscan, or as an alternative the enhanced liver fibrosis test, abbreviated as the ELF test. Let's take it from there. Can you go over how to interpret those tests and then what one does with the results of those tests? And let's start with elastography.
- [06:59]
B
Great. Yes. Elastography is our stethoscope in hepatology. We end using it, end up using it almost on a daily basis and it's really transformed our, our practice. Elastography measures really the elasticity of the liver and it is a marker of either fibrosis or inflammation. So it's a very good way of non invasively identifying the stage of liver disease. There are two types of technologies of elastography. One type is ultrasound based, the other one is Mr. Based or magnetic resonant, the ultrasound based. The most commonly used and most known is vibration controlled transient elastography, also known as fibroscan. There is another type of ultrasound based which is really embedded in a regular ultrasound machine and that's called shear wave elastography, which is less commonly used. But it is emerging in the clinical practice. The fibroscan is a point of care test that can be done in a clinical office, in not only hepatology, but maybe in a diabetes clinic or primary care. The ultrasound shear wave has to be done in a radiology suite. The other type, the magnetic resonance is called magnetic resonance elastography or mre, also done in radiology. And it is a short non contrast MRI that really just measured the elasticity of the liver. These technologies are used currently based on the availability of everyone's health system and they have different cutoffs in terms of interpretation. There's no one number that I can tell the audience to remember because it differs. But I would say for the most commonly used one for VCTE or Fibroscan, the number that we should all remember is 8kpa of liver stiffness measurement. Anything above that is high risk of having presence of fibrosis stage 2 or higher. And of course there are some nuances in cirrhosis and we can go over those too. But I'd like for people to remember that number eight for MRE, that number is 3.1 kilopascals. These are the two numbers that we determined in OR that the societies have determined that can identify candidates for treatments for mash. This is why I'm emphasizing these numbers. I'd like to also state that the elastography measures are not only a diagnostic property but also a prognosis. So we can use those numbers to identify a person's risk of developing complications in the future. They are very useful in that regard as well.
- [09:49]
A
Interesting. My sense is that we often in primary care and endocrinology will order that vibration elastography, commonly a fibroscan, and then decide what to do next. Based on that, I don't think we're as often ordering the MRI elastography as our hepatology colleagues. It's interesting when I think about it. I'm not sure there's any reason that we shouldn't. We order MRIs for everything else, but I think this is one of those areas that are just entering into practice. Is the Mr. Elastography a more accurate, accurate test than the fibroscan?
- [10:32]
B
Yes, it is because it simply measures a larger volume of liver. It measures four slices, so it has the opportunity to get more information from more tissue. VCT has a measurement of a cylinder and it can be impacted by subcutaneous tissue because the waves go through subcutaneous tissue until you get they get to the liver capsule and beyond. So there are some disadvantages. Specifically typically in patients who have central adiposity, generally at a BMI of 35 to 40, the discordance between MRE and VCTE increases with MRE being closer to the truth. So the performance of identifying earlier stages of disease. So distinguishing between stage one to two is higher in MRE versus VCTE or shear wave elastography. So MRE is a really good tool. I would encourage people to explore whether their radiologists have that opportunity. We do not have to order a full mri, which is more time consuming and more costly. There's a CPT code for a short non contrast, 10 minute MRE that can give information about presence and quantification of fat and stiffness.
- [11:50]
A
Interesting, important to know. And then a test that has emerged and I'm not sure everyone is as familiar with it, is the ELF test. In fact, I was on call this past weekend and this came up and one of my residents had a question, a very good resident, but wasn't sure what the ELF is, how to use it. Can you go over that?
- [12:13]
B
Yes. The ELF is another non invasive test that we have in our toolbox that is blood based and it stands for enhanced Liver Fibrosis score. It is a proprietary test. So something we order and it gets calculated and sent to us. Not, not something we can calculate because it has three components that are more specific markers of fibrogenesis so it has been developed as a tool to identify or to estimate fibrosis in the liver. The FDA approval for that test currently has prognostic information. It has been associated with risk of mortality, which is again important. And it's currently under evaluation for its diagnostic properties. So it is useful especially when there are no elastography techniques available in someone's institution. Or if we want to consider starting with a blood based test and then confirm that result with elastography. The cutoff where it triggers an action has slightly changed over time. I think that currently or more recently, the cutoff of 9 or higher is the number that people should remember. The current guide guidances for medication selection, and we'll talk about these later. But the current cutoff that has been selected based on previous data is 9.2. So when this test is ordered, it will come with the value and the interpretation. So if there's a higher risk, then that will trigger a need for either referral to hepatology or an order of elastography to confirm that there's truly moderate to advanced fibrosis present there.
- [14:07]
A
It seems like this is a very convenient screening test that as opposed to having to send a patient for a fibro scan or an ultrasound. And again, in primary care and endocrinology, we usually don't have the fibrous scan in the office as you do. Instead of having to send a patient for in essence another visit, which is often a half day off from work, they're getting blood drawn anyway. An ELF test is a convenient initial screen. Does that make sense as a way to think about it?
- [14:41]
B
Yes, any blood based testing is more convenient than something that requires another technology. And I think if available at someone's institution, it can be used. I don't think that at this point we can use it as a standalone test to trigger maybe treatment decisions. Unless truly there's really nothing in a radius of a few hours for a patient. But absolutely, as a first line evaluation or estimation, it's a convenient one.
- [15:12]
A
So let's go on now to treatment first, when do we think about treating Mastle Dermashe?
- [15:20]
B
So treatment of MASH currently based on FDA approval is at stage 2 to 3. Fibrosis. We do not have FDA approved medications for cirrhosis as of 2025. There are several in the pipeline and I'm confident and hopeful that in the next handful of years we will have those. Currently we don't. So moderate to advanced fibrosis is the stage that we focus on identification and all the previous tools we talked about either Illustrator pretty decent cutoffs in estimating the lower one where there's a risk of F2, F3, and a higher one where there's the risk of cirrhosis. I didn't go into this too much, but I think, you know, this is where a hepatologist can also weigh in either as a, you know, curbside or a consultation to know that if we were to consider treatment for a patient, we want to make sure that that patient does not have cirrhosis because of current lack of phase three trial data on safety and efficacy.
- [16:23]
A
That makes sense. And we were talking earlier about the importance of identifying F2 fibrosis and it relates directly to treatment because that's where all of the studies kind of have as their criteria for enrollment that F2 to F3. Is that correct?
- [16:41]
B
Correct.
- [16:43]
A
So let's move on to treatment now that's FDA approved for mash, and then we'll talk about some of the treatments that are not FDA approved, some of which have been around for a while, some of which are in various stages of development. So when we talk about patients who are eligible for liver directed therapy, what are the FDA approved treatments? And can you tell us a little bit about that?
- [17:09]
B
Yes, there are two. As of this year. The first medication approved for MASH with moderate to advanced fibrosis was Resmetirom or Resdiffra, which is a thyroid hormone receptor beta selective blocker. So this targets the thyroid hormone receptors in the liver and has been demonstrated in a phase three trial to be effective at improving steatohepatitis and fibrosis. The the proportion of those with response in fibrosis since we focused so much on fibrosis for the talk today is about 26% of those treated with the 100 milligram dose of Rezdifra compared to about 14% in those with placebo. So a placebo adjusted response rate of about 12%. The second medication that was approved just this year is Semaglutide. All the familiar to this audience, which also has been shown to have improvement in fibrosis effects. Also in MASH with moderate to advanced fibrosis stage 2 to 3, the placebo adjusted response there is comparable to resmetirom, it was about 14%. So another really good opportunity and a good medication to have in our toolbox. There are no GLP1 receptor in receptors in the liver. So this medication is acting through kind of a systemic kind of effect rather than a liver directed effect as Resmetirom has.
- [18:57]
A
Interesting. Now, with Semaglutide now available for mash. And as you suggested, it's a medicine that probably no other specialty has as much experience with as endocrinology and primary care for its use in both diabetes and obesity. Does MASH now become something that is reasonable for primary care to be treating or do you feel everyone with F2 fibrosis should see a hepatologist?
- [19:31]
B
That's a really, really important point. I think the primary care physicians, family medicine, internal medicine, endocrinology, are probably more familiar with this medication semaglutide than hepatologists. I think that absolutely they can treat and they should treat MASH knowing that a very large proportion of people with diabetes have MASH. About 66%, 65%. So two out of three people who have diabetes have steatosis in the liver. Not necessarily mash who don't have really good biopsy data in that population, but two thirds have steatosis and about one in five have fibrosis from the all comers in a diabetes clinic. That's a pretty high proportion. So really low hanging fruit for addressing that there. I think the most important part is that there should be a awareness to screen instead of just, you know, you have obesity or diabetes. Hence we treat but we don't look at the liver. I would caution to, to look at the liver specifically to identify those who may have advanced fibrosis to cirrhosis. The reason for that is, Juan, we mentioned before that in those with cirrhosis it needs to be a little bit of a, of a caution because we still, we have phase two safety data data in a semaglutide, it appears to be safe. So I wouldn't say it's contraindic. But again, caution is risk of sarcopenia because people with cirrhosis start with sarcopenia at baseline and we want to keep a close eye on that as well. But also more importantly, there is a risk of development of liver cancer. So if we don't look, we won't screen for liver cancer. And that requires screening every six months. So I would say absolutely, treat, please do treat. But remember to stage at the beginning. It's a good tool to evaluate does this patient have cirrhosis, do they need hepatology for screening of of liver cancer, esophageal varices and other things. And also a good baseline test to monitor whether the liver has improved with treatment.
- [21:42]
A
Yeah, that's such helpful advice and I like the way you put it. And we'll come back to monitoring the effect of our interventions in a little while. But it sounds like this is so common it's going to be imperative that we in primary care and endocrinology learn about it, learn where the edges are and feel comfortable moving ahead with treatment. Alina, can you go now over the meds that are not FDA approved, starting with some that have been around for a long time that many of our listeners are familiar with pioglitazone and vitamin E and then we'll go on to medicines in the pipeline. But can you tell us briefly about pioglitazone and vitamin E?
- [22:28]
B
These were studied a long time ago and they have been kind of the very few medications that have been under in our toolbox before we had this, you know, the resmetiroma and the GLP slew of medications. Pioglitazone has shown some improvement in steatosis, steatohepatitis, but not much in fibrosis. So it's not as strong as these newer FDA approved medications. Vitamin E has similar effects, not a strong antifibrotic type of, of effect. And right now because we have these FDA approved kind of the bar has really has increased that standard. Right. So if there's an indication from the diabetes standpoint to use pioglitazone I think you know, versus a glp, I think you know there, there could be some indirect benefits in the liver. Vitamin E I wouldn't recommend by itself just because we have so stronger candidates now for, for treating agents. The anti inflammatory effects or antioxidant effects of it has had been I think stronger when we did not have such potent weight loss and mash approved therapies.
- [23:44]
A
That makes sense. That's so helpful putting those in perspective. Now can you discuss there, there's a lot exciting going on in this area. Can you talk a bit about what's in the pipeline and particularly emphasizing meds that are in PH trials because those are the ones that are really most relevant for us to be aware of.
- [24:05]
B
Right. There's very exciting work in the pipeline and they're actually very highly potent medications now that are studied in phase three trials currently ongoing based on completed phase two data. So two medications that again are very familiar to this audience are Tirzepatide and retatotride. Both of these are currently in a phase three trial for MASH with moderate to advanced fibrosis and cirrhosis actually based on supportive phase two data that show a placebo adjusted response rate in fibrosis reaching higher bars than the currently FDA approved medication. So we'll see if that carries through in phase three, but we're going into the 20s to 30s difference between placebo and the treatment arm. This phase three trial just started. We will have to wait for a few years to learn more. But again, phase two data, very, very important. RETA was studied in a subset of patients with MAST celd in an obesity trial, as I'm sure you are familiar with. And some people reached a normal liver fat content, up to 90% of them or you know, almost, almost all of the patients. So very, very encouraging. The other medication to keep an eye out for is called Cervotide, which is currently under phase three study for MESH with stage two to three fibrosis and also cirrhosis to parallel studies based on strong phase two data showing fibrosis improvement in up to 65% of people. So a kind of a 39% placebo adjusted difference between those treated with the agents versus those on placebo. So again, supportive data, very, very encouraging. This is a dual GLP1 and glucagon receptor. So that glucagon receptor that is present in the livers considered to add more to that GLP effect that we are already familiar with. So very exciting data. Stay tuned. We will have a lot more agents in our toolbox in this disease in the next few years.
- [26:29]
A
Yeah, it's such an important area for us to keep up with because it's so rapidly changing and we are so fortunate to have all of this research being done because it, as we talked about earlier, is relevant for so many of our patients. My last question is with regard to follow up. So we identify someone who has mastled, we do the fib 4, we do transient elastography and we determine they have F2 or F3 fibrosis and perhaps they're started on a medicine, whether it is resmetiron or semaglutide. What then? What sort of follow up should we be aware of and should we be doing?
- [27:17]
B
Very important question and it gets back to the reason as to why should we screen for liver disease. When we consider treating these patients, maybe for a weight indication or diabetes indication, we will know based on elastography or elf. So the strongest data in terms of correlation between histologic response and non invasive testing response is with elastography. Both VCTE and MRE have good data to show that a response of at least 20% in MRE and about 30% in VCTE is a higher chance that there's histologic improvement in the liver. Now this means that we're looking for fibrosis response which doesn't happen fast. So that's the one thing I want the audience to remember or to understand that we shouldn't measure earlier than one year because we may not see these improvements. And then we may say, well, maybe there is no response. We need to wait at least a year to a year and a half to allow the liver to show some improvement in fibrosis. Fat in the liver goes down or regresses much faster and inflammation probably faster. For those we can use parameters such as CAP or mri, pdff, which can also be resulted from the MRE to know if there is an improvement in steatosis as an earlier marker. There are really I want to also emphasize for those who are interested, both resmetarom and semaglutide have guidances showing exactly these these answers. When do we start treatment? How do we monitor treatment? Both of these were published in Hepatology and they are based on experts from aasld, which is the American association for the Study of Liver Disease. They have really nice figures to really make a clear cut basis on when to start and how to monitor. The data on Semaglutide is at 96 weeks. So that's when we recommend to eat an elastography for elf. If that's the only test that somebody has in their toolbox, the decrease would be a 0.5 in an absolute value. That's the one that has some supportive data to show that it is correlation with histologic improvement in fibrosis.
- [29:47]
A
So helpful to know that sort of follow up that's recommended. This is an enormously important area where there are a lot of advances and I think a lot of us are working hard to get up to speed and how to take care of our patients with MASLD and mash. Alina, do you have any final thoughts for our listeners?
- [30:08]
B
The final thoughts are I'm really, really happy to know that there's interest from our colleagues in the diabetes space. I think we are more and more partners now more than before because we are treating essentially the same disease spectrum. We just maybe pay attention to one biomarker versus the other. So I'm just very, very excited to hear there's more interest. We are, you know, for example, at Mayo, we are a multidisciplinary clinic. I don't think there's such a good distinction now between hepatology and endocrinology or metabolic disease as maybe it was maybe 10 years ago or 20 years ago. So we are really in the same clinic even though we're not co located but we're treating the same problem.
- [30:53]
A
So, Dr. Alina Allen, thank you so much for making a complicated disease entity understandable and operationalizable for people like myself. Thank you so much for joining us.
- [31:06]
B
It's been such a pleasure to talk to you, Neil, and thank you again for inviting me and I, I look forward to future opportunities.
- [31:14]
A
And most of all, of course, thanks to our listeners. Thank you for joining us on this second of a three part series in mash. In the first episode we focused on epidemiology, how it progresses, consequences and how to screen for mash. In this episode we did a deep dive on diagnosis and treatment. And our third episode, we're going to bring it all together with some this special series of diabetes Core Update is sponsored by Baringer Ingelheim. We thank you for listening and for the American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning. Sam.