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- [00:00]
Podcast Host
Welcome back to Run the List, a medical education podcast in internal medicine. As a quick disclaimer, this podcast is made for educational and informational purposes only and should not be understood as medical advice under any circumstances. Before we get to the show, a quick word on the sponsors for today's episode.
- [00:16]
Sponsor Representative
Open Evidence is the premier AI powered medical information platform for physicians and medical students. It's like ChatGPT for anyone who practices clinical medicine. Whether you have a clinical question, a question that comes up during your literature review, if you have a question that comes up when you're trying to synthesize a topic you're going to teach, you can just go to openevidence.com enter your question and it'll synthesize the answer for you while also linking to those actual articles. It's an outstanding resource.
- [00:55]
Emily Gutowski
Welcome back to Run the List. My name's Emily Gutowski and today I have with us Dr. Sam Sanders, internist at Bellevue Hospital of New York City Health and Hospitals and Assistant professor of Medicine at NYU Grossman School of Medicine. Dr. Sanders, thank you so much for joining us.
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Dr. Sam Sanders
Thanks so much for having me.
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Emily Gutowski
So today we'll be discussing a very interesting topic referred to as masthld, or Metabolic Dysfunction Associated Steatotic Liver disease, which some of our listeners might be more familiar with previously as nafld. And we'll get into some of the terminology a little bit later because there have been some changes. So Sam, can you tell us a little bit about why you feel passionate about this topic, why this is an important topic for learners to get an update on?
- [01:36]
Dr. Sam Sanders
Yeah, absolutely. So as a primary care physician, I feel like we see mildly elevated LFTs all the time in clinic and oftentimes the cause of it is masled. I work in a clinic where a lot of our patients also have other diseases that fall into this brain category of metabolic syndrome. And so there's a lot of interest in this disease area in particular. And you know, Maslow's is really an epidemic on the rise. You know, its prevalence is really increasing, especially within the United States. And it's something that as a general internist we have a lot of power to treat and to counsel our patients about. And so for all of these reasons, it's such an important topic for all general internists and really excited to talk about it today.
- [02:23]
Emily Gutowski
Here's alright, so let's get into our case. We have Mr. F. He's a 64 year old gentleman with history of type 2 diabetes, obesity, hypertension and hyperlipidemia, who presents to his PCP. For his annual visit, he's taking metformin, lisinopril and atorvastatin. He feels generally well, no real complaints. And during their visit, his PCP discusses the importance of losing weight and the role that obesity plays in his other medical conditions. He gets some basic labs drawn and they come back with an AST of 55 and ALT of 76. These were previously normal a year ago. The rest of his labs, including his CBC, are normal, including a platelet count of 260. As his PCP reviews his lab results, she takes a look at his prior imaging. He actually had an abdominal ultrasound done a couple years ago for abdominal pain at the time that showed incidental hepatic steatosis. So, Dr. Sanders, before we get into the weeds of this case, can you tell us what exactly hepatic steatosis is and how it relates to masthld, where all these different names came from?
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Dr. Sam Sanders
Yeah, absolutely. So steatosis refers to fat in the liver, and we really think about a healthy liver as having less than 5% of fat within hepatocytes, the cells of the liver. And steatosis really refers to a liver with greater than 5% of hepatocytes with fat. In terms of the progression of this disease, you start off with a healthy liver, and then as you accumulate fat in the liver, you develop steatosis. And that is really known as masles in this case, if it's related to metabolic dysfunction, and then that can further progress onward to something called mash, which is metabolic dysfunction associated stem, and then that eventually can develop into cirrhosis. And so that's really the progression from a healthy liver to liver with, you know, steatosis in this case related to masvid, and then eventually to MASH and to cirrhosis. And just breaking down the different categories of the acronyms that I was just using just to say, the old nomenclature that we used for these disease areas were nafld, which is non alcoholic fatty liver disease, now known as masld, like I said, which is metabolic dysfunction associated steatotic liver disease. And that really just refers to fat in the liver related to metabolic dysfunction. And then the old terminology for steatohepatitis related to this disease area was nash, which is non alcoholic steatohepatitis. And it's now known as mash. So it rhymes, but it's different. And that's metabolic dysfunction associated steatohepatitis. And the idea there is the earlier stage of this disease area is just having fat in the liver, which is mazzaled or steatotic liver disease. And then once you get inflammation on top of that, you get something called steatohepatitis, which is mash, and that's the metabolic dysfunction associated steatohepatitis. So you start with the normal liver, you get some fat that's mazzled, then you get some inflammation that's mash, and then eventually you develop a cirrhotic liver, unfortunately. And the reason why the terms were changed was really to focus less on the fatty element of the liver and more on the metabolic risk factors that are underpinning your development of this disease area. Our goal as general internists is really to identify MASLD and MASH in its early stages before you get to the progression of cirrhosis. Because once you progress to cirrhosis, it's really not reversible. And obviously there are so many complications with cirrhosis like hepatocellular carcinoma that we're trying to avoid here. And so our goal here is really to just catch it early and to figure out who can be treated for it before they develop cirrhosis. One thing I would say here is that the reason that I keep harping on mazzled and steatotic livers is there are a lot of different causes of steatotic liver disease. Steatotic liver disease is really an umbrella term for all liver diseases with accumulation of fat in greater than 5% of hepatocytes, the liver cells. You can also get steatotic liver disease from alcoholic liver disease, drug induced causes, genetic causes, cryptogenic causes, and there's even one entity called MET ald, which is basically masled in the setting of increased alcohol consumption. So all of this is to say steatotic liver disease takes lots of different forms, but the one that we're talking about today on this podcast is this specific entity called mazzld, where you're getting that steatosis, specifically in the setting of these metabolic risk factors and metabolic syndrome.
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Emily Gutowski
Got it. I know the terminology can be confusing. One vocabulary word that makes its way into this sequence is also fibrosis. Can you tell us a little bit about how fibrosis fits in here and what exactly it is and how we measure it?
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Dr. Sam Sanders
Yeah, absolutely. I know we just talked about stuff at a really high level. That idea of developing MAZZL with the steat and the fat, and then that developing into mash, which is that steatosis with inflammation as the natural progression of this disease. And just to say here that inflammation that you see in MASH is a precondition for fibrosis so eventually, once you've progressed to mash, which is when you have the fat plus the inflammation, you are at risk of developing fibrosis. And fibrosis is really progressive scarring within the liver parenchyma in response to this ongoing inflammation. And it is really important to talk about because it's the most important predictor of poor outcomes. And eventually, if you have extensive fibrosis, you get something called confluent fibrosis, which is cirrhosis. And so one thing to note is that there are a lot of ways to risk stratify patients that have mash, which is the steatohepatitis. The most common way is we grade them based off of their level of fibrosis. It goes from F0 to F4. If it's F0, then they don't have any fibrosis. F1 is very low levels of fibrosis. If it's F2.2 to F3. We think about the patient kind of being sort of in this in between phase. They do have fibrosis, but it hasn't gotten to what we call cirrhosis just yet. And if they have F4 fibrosis, that's somebody that has MASH and then cirrhosis as well. They have that confluent fibrosis that leads to a very fibrotic liver and a cirrhotic liver. Essentially. What I will say is that we really want to catch these patients, like I said before, they get to that F4 fibrosis, which is cirrhosis. And so that's something we think about a lot here. I will also say that fibrosis progression is really dynamic. It's variable. Some patients progress really fast once they develop mash, other patients progress more slowly. And it is reversible, which is something that we'll talk about later on in this podcast.
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Emily Gutowski
I've also heard about the scoring system called FIB4, and I know that can also help us risk stratify certain patients. Can you tell us a little bit about that score?
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Dr. Sam Sanders
Fib 4 is really what we use in a primary care setting to risk stratify. These patients basically determine who needs further workup. It's telling us, based off of everything we just talked about with fibrosis, what's the probability that this patient in front of me has significant fibrosis? And it's a validated score. You can find it on any risk calculator that uses age, ast, alt, and platelets to determine whether patients are likely to have significant fibrosis or not. We don't use it for every single patient we see in our clinic. You know, just to talk through which risk categories we think about using this score for. We would use it if we think that we've caught masled incidentally. So we think somebody has steatosis in their liver. We want to see if they progress to MASH with significant fibrosis. Then we'll definitely calculate a score. When I say catch it incidentally, I mean that group of patients that we see steatosis when we get a liver ultrasound or some other form of imaging or patients that have elevated LFTs. For those patients, we want to calculate a FIB4 because we think that they might have MASLD. We want to determine if they have significant fibrosis. There are also other groups that we search for MASLD in because these are high risk groups with high pretest probability of masld. And in terms of who, who's worth testing, Everybody with type 2 diabetes. You want to screen with a fib 4, and we'll talk about how to follow up on that. Additionally, patients who have obesity and then one additional risk factor for metabolic syndrome, and that might include elevated bmi, pre diabetes, hypertension, hypertriglyceridemia, or low hdl. For those patients with obesity and that one additional cardiometabolic risk factor, we tend to say, let's also screen them with a fib four.
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Emily Gutowski
Got it. Okay. So in our patient, I think he would definitely meet those criteria, having a history of type 2 diabetes as well as obesity and hypertension and hyperlipidemia. So in his case, we calculate his FIB4 score using his age, his AST, his ALT, and his platelets, and we get a score of 1.55. Can you interpret that for us?
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Dr. Sam Sanders
Typically, when we interpret a fib 4, its cutoff on the lower end is 1.3. So anything below 1.3 means low probability of significant fibrosis. Its cutoff on the upper end is 2.67. So anything above 2.67 means high probability of significant fibrosis. And when I say significant fibrosis, I'm really talking about F3 and F4, which are those stages of fibrosis. For a patient with MASH who have a lot of fibrosis or ultimately cirrhosis. And so if you're below 1.3, we think you're in the safe zone. If you're above 2.67, we think that you have a high probability of significant fibrosis of that F3 and F4, the space in between 1.3 and 2.67 is really an intermediate space. And so those are patients that need further evaluation. For this patient in particular, he's 64 years old. And so we can really apply this scoring. And so when we see a Fib 4 score of 1.55, we're thinking that they're in that intermediate phase and that they need more workup.
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Emily Gutowski
And any caveats to keep in mind with a patient's fib score when you get that initial number?
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Dr. Sam Sanders
Yeah, the one brief pearl I would say is that like we talked about, age is part of the scoring. And so we tend to think that if somebody is 65 years old or older, we want to use different cutoffs here. Rather than using 1.3 as our lower end, we tend to use 2.0. So if somebody has a Fib 4 score of less than 2.0, then we say there's a low probability of significant fibrosis. And that's really because fib4 increases independent of age. Similarly, if somebody is really young. So if they're less than 35 years old, there's some discussion among the hepatology community that you should think about it more closely for these patients because they're more likely to have a lower fib 4. So we don't use different cutoffs with that age group, but we just use more caution when we're interpreting it.
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Emily Gutowski
Got it. So back to our patient. His score was 1.55, which puts him in the intermediate risk category. What exactly are our next steps in working him up?
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Dr. Sam Sanders
So if they're in the intermediate risk category, we go to fibroscan next. The fibroscan is called, more formally, VCTE Vibration Controlled Transient Elastography. And fibroscan is basically a fancy ultrasound. At my hospital, the. The hepatologists and GI folks do it. It's basically an ultrasound based measurement of liver stiffness. And liver stiffness is used here as a surrogate marker for fibrosis. It's not perfect for patients with, you know, morbid obesity or a lot of hepatic congestion. It can affect the quality of the fibroscan because those are conditions that limit the ultrasound wave penetration at the abdominal wall. But it's a really good and well validated tests that can estimate essentially what the fibrosis score is, and that serves as a proxy here for the stage of fibrosis that the patient is at. So it will typically tell us if the patient is F0, F1, F2, F3, F4. There also is a second type of testing that I am not as familiar with. We don't use it as my hospital. It's called ELF testing. It's. And that's a proprietary blood test of three different components involved in matrix turnover. And that can also be used to further risk stratify an intermediate fib4. And they tend to use it a lot in rural settings where they don't have access to a fibroscan. Or sometimes you can also use it for patients with morbid obesity where the fibroscan is not as accurate.
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Emily Gutowski
Okay, just to recap, we have a patient who has mildly elevated LFTs. We think about their comorbidities. We see that they have hepatic steatosis on their imaging. So we take them through this primary risk assessment and we calculate a fib 4. And in his case it was intermediate. I don't think we touched on this yet. But if his fib score were elevated, would we go on to the secondary risk assessment and do the fibroscan for him as well?
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Dr. Sam Sanders
That's such a great question. And I would say it is definitely dependent on what your practice is and what your access to hepatology is like. But I would say in general, we really only do this secondary risk assessment in that intermediate probability of significant fibrosis. If they have a low probability, you don't have to worry about it. You'll repeat that fib four every one to three years from here on out. By contrast, if you have a high probability of significant fibrosis, so the fib 4 is telling you you basically have F3 or F4 fibrosis, you're going to straight refer them to hepatology. Typically, you don't even need that fibrous cap to do that secondary risk assessment. Then you're stuck with that middle category. For those patients with this intermediate or indeterminate risk of significant fibrosis, those are the patients that you're sending to do the fibroscan or you're sending them to do the elf. If you're in a rural setting and that's what you use. And then to break down what you see, that would make you worried enough to refer to hepatology. From there, let's say going back to our patient, you have a fib in that intermediate or indeterminate risk profile, their fib4 is 1.3 to 2.67. You send them, they get their fibroscan. If the fibroscan shows 8 to 12 kPa, which is the way that it measures liver stiffness, that is also considered intermediate oftentimes. But you want to refer those patients to hepatology because you are seeing some fibrosis on that fibroscan. If you're seeing greater than 12kpa, a lot of liver stiffness, it portends, you know, significant fibrosis. And so you're also sending those patients to hepatology. But by contrast, if you have one of these intermediate patients going back to our patient, Mr. F, they've got a fib 4 of 1.55, they do the fibroscan. The fibroscan shows less than 8.8kPa. That really demonstrates that the patient does not have significant fibrosis. They're in the F0 to F1 range of fibrosis. And so you can lump them back in with those patients who have a fib 4. That's low risk because you're seeing that this patient has a low risk of significant fibrosis. And for that sort of patient, you don't need to refer them to see a hepatologist. After you get the fibroscan, you can just continue to measure the FIB4 and calculate that every one to three years along with your other low risk patients.
- [19:40]
Emily Gutowski
And is it possible to have an elevated fib 4 score even with normal LFTs?
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Dr. Sam Sanders
Absolutely. You can have an elevated fib 4 with normal LFTs. For those patients, we really advise still using your clinical judgment. If your patient has normal LFTs, but the FIB4 is elevated, which can happen, you still should get a secondary risk assessment if the fib is in this indeterminate intermediate stage. And you should still refer to hepatology if the FIB4 is extremely elevated. What constitutes clinical suspicion is really up to you. Oftentimes, those same patients that we were discussing earlier with metabolic syndrome or diabetes, they might have masled or mashed without having elevated LFTs. And so if those patients have a fib 4 that falls into those buckets, we still recommend acting on it like normal. By contrast, one question I get asked a lot actually is what else should I be doing if a patient is coming to me with elevated LFTs, and I think that those are related to MASL, do I need to stop? And a whole big workup. If you really have a high clinical suspicion for masld, as the etiology of the elevated LFT is, you don't have to do a ton, I would say repeat the LFT is to make sure that they're actually elevated. But basically what we recommend is ordering, you know, a fibro scan if it's appropriate. You can also get hepatitis serology is an iron studies as just a very basic workup. You also might get a liver ultrasound, although, honestly, if you're getting a fibro scan anyway, that can be helpful at pinpointing whether the patient has steatosis or not. And so you can sometimes skip the liberal ultrasound if you know that the patient's going to get a fibro scan pretty quickly. And then if those elevated LFTs stay elevated for, let's say, three or six months with no clear diagnosis based off of that initial workup that you did, that's really when we recommend going to a secondary workup, which includes autoantibody studies like anti lkm, anti smooth muscle antibody, ana. You could also get a ceruloplasmin to rule out Wilson's disease. You could get an alpha one antitrypsin. And so you're just doing the broader workup at that point. The one exception I would say is that if a patient has ALT or AST that's greater than five times the upper limit of normal, you really do want to do that full workup, including the autoimmune markers right away. Masld will not cause an AST alt greater than 5 times the upper limit of normal, typically. And so if you see that, it's a reason to pause and really focus on a broader workup.
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Emily Gutowski
Okay, great. So let's say that Mr. F gets the fibroscan. His score is 11 kPa, which again, is in this intermediate risk category of 8 to 12. This tells us that he should see hepatology. We send him to hepatology. They take a look at his case, and given that he has several risk factors that could lead to fibrosis, like we spoke about before, his obesity, his hypertension, diabetes, hyperlipidemia, they think that a biopsy is not necessary for him. So Mr. F asks the hepatologist what he can do to reduce his risk of progression. Can you tell us a little bit about the treatment of masal tear?
- [23:12]
Dr. Sam Sanders
Yeah, absolutely. I would say, you know, the goal of the treatment here is really, like I said, not to sound like a broken record, but it's to prevent cirrhosis and also to prevent cardiovascular disease, because liver fibrosis and MASLD and mash, they're just one part of this broader metabolic syndrome and this broader slate of cardiometabolic disorders. And so in order to achieve those goals. Goals, the cornerstone of treatment is oftentimes non pharmacological for these patients. We really, really, really want them to lose weight. And in addition to thinking about non pharmacological ways to lose weight. There's now obviously so much on the market and so many tools that we have in our arsenal to, you know, help patients lose weight in other ways too. I really hammer home weight loss with these patients because if you have even a 5% reduction, there are proven studies that show that you have less steatosis in your liver as a result. So let's say you lose 5% of your body weight, you're going to lose fat in the liver too. And if you have 7 to 10% loss of body weight, then for patients with MASH complicated by fibrosis, we actually see a reversal of fibrosis and fibrosis reduction. And so weight loss is absolutely the cornerstone of this non pharmacologically, we tend to think about a Mediterranean diet. All of the lifestyle and dietary counseling that we tend to do around minimizing processed meats, ultra processed foods, sugar, sweetened beverages. Recommend physical activity greater than 150 minutes a week of moderate intensity physical activity or 75 minutes a week of vigorous physical activity. And we also counsel avoiding alcohol in particular. There's actually no safe level of alcohol use for the literature in these patients. So we counsel a lot around that. We use a lot of GLP1 agonists in my practice and also GLP1 GIP dual agonists. And so those are very, very exciting and more to come in that pharmacological area as well. I think we additionally tend to refer a lot of our patients for bariatric surgery if they meet criteria. At the hospital that I work at, we have a really, really strong bariatrics program. And so that can be also very helpful for this disease too, if the patient is motivated and interested in that. And then I think we'll talk about this in just a second. But there's also one FDA approved drug that I don't prescribe myself, but the hepatologists do prescribe in terms of treatment as well.
- [25:50]
Emily Gutowski
I actually just saw a commercial for this when I was at the gym recently and I had never heard of it before. So yes, please do tell us about this medication.
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Dr. Sam Sanders
Okay, that's so funny. I have yet to see a commercial on it, but I love that. I'll just say, you know, I know there's so much drug advertising out there, but this medication actually is supposed to be quite good. It's called Resmiterom. It's the first FDA approved medication for treating masled and mash. It is a THRB receptor agonist, which is a class of drugs that Basically promote fatty acid oxidation and increase mitochondrial respiration, which reduces hepatic fat accumulation. It demonstrated on studies that there was resolution of MASH and improvement in fibrosis. It's the only drug that's known to reverse fibrosis for MASH and masld. And so resmetirom is very exciting for patients in particular who have F2 or F3 fibrosis. Those are really the stages where we think it works, where the patient has enough fibrosis to qualify for resmetirom and to need that fibrotic reversal, but not so much that they've entered the stage of F4 fibrosis or cirrhosis.
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Emily Gutowski
That is very exciting. You know, this is an area that hasn't really had a lot of dedicated medications for it. So very exciting things to come there. We are nearing the end of our episode, but before this patient's appointment is over, he has two more questions for our hepatologist. The first is that he's on atorvastatin. He's heard that these statin medications can be tough on the liver, so he just wants to make sure that it's safe for him to continue staying on atorvastatin.
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Dr. Sam Sanders
Yeah, absolutely. Stay on atorvastatin like we were talking about. Masalg is just one part of this greater spectrum in this greater disease area of metabolic syndrome. And so preventing those cardiovascular events is very, very important in that population. And so definitely stay on the atorvastatin. What I will say is, again, I am not a prescriber of resmetirom. The hepatologists at my institution prescribe it. But I will just say it does have drug interactions for rosuvastatin and simvastatin. If somebody's on resmetirom concurrently, they'll cap the dose for those statins at 20 milligrams. If somebody's on pravastatin or atorvastatin, they'll typically cap the dose at 40 milligrams. And the idea there is just to prevent any drug drug interactions.
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Emily Gutowski
Got it. Makes sense. And you were starting to get at this before with regard to alcohol, but he does like to go out with his friends a couple times a week and get a few beers. What would you tell them about that?
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Dr. Sam Sanders
Yeah, what I would say is, unfortunately, there's really no safe amount of alcohol intake when it comes to MASLD and MASH. There was actually a 2010 study from Scotland that showed that alcohol intake is actually super additive to the effects of increased BMI and MASLD on a patient, and so we think that alcohol can really accelerate the risk and progression of MASLD and mash, and so definitely want to counsel against that if possible. Great.
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Emily Gutowski
Our patient is counseled on all of these things, including weight loss efforts. He actually decides to start a GLP1 and they plan to follow up again with repeat labs and imaging in around a year or so. Dr. Sanders, thank you so much for helping us take such good care of our patients in the primary care setting and learning when to refer them to hepatology.
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Dr. Sam Sanders
Such a pleasure. Thanks so much for having me on today.