Episode 008: All about MASLD/MASH from diagnosis to treatment
Guest: Dr. Scott Fung
SHOW NOTES
Vrati Mehra
Thanks so much for tuning in again to Scope Notes: A University of Toronto Division of Gastroenterology and Hepatology medical education podcast.
For any new listeners, I’m Vrati Mehra, a 1st year Internal Medicine resident at University of Toronto in Canada and I’m joined by my co-host Huaqi Li, 2nd year Internal Medicine resident at the University of Toronto. Our faculty advisor is Dr. Parul Tandon, a staff Gastroenterologist and Clinician Scientist in inflammatory bowel diseases at the University Health Network/Sinai Health in Toronto.
With Scope Notes, you can look forward to monthly episodes covering all things GI including practice guidelines, research reviews, and special career topics! So come join us from your favorite podcast streaming app! We would like also to extend a big thank you to the Division of Gastroenterology and Hepatology at the University of Toronto for their generous support of this podcast.
With all that being said, let’s get started on the episode! So in today’s episode we’re talking about Metabolic dysfunction-associated steatohepatitis and liver fibrosis.
We’re very fortunate to be joined today by a leading expert in the field, Dr. Scott Fung. Dr. Fung is an Associate Professor of Medicine in Division of Gastroenterology & Hepatology at the University of Toronto and works at the Toronto General Hospital. He is Hepatology Lead for the GI Residency Program Committee and Director of the Hepatology Fellowship Committee. He is also the Education Director for the Toronto Center for Liver Disease Steering Committee, Canadian Hepatitis B Network Education Committee and is also on the Education Board for the Royal College of Physicians and Surgeons of Canada. His academic interest is in epidemiology and treatment of chronic hepatitis B and C and Metabolic dysfunction–associated steatotic liver disease. Thank you for being here today Dr. Fung, we are so excited to have you on the show!
Huaqi Li
Hi, Dr. Fung, thank you so much for joining us on the podcast today! Before we get started on discussing today's topic on MASLD and MASH, could you tell the audience a little bit more about yourself? Where did you do your training and what made you want to specialize in hepatology?
Dr. Scott Fung
Great, thank you so much. Thank you for the kind invitation to be the guest on the podcast this evening. I'm an academic hepatologist at Toronto General Hospital. My clinical practice and research interests largely focus on chronic hepatitis B, but nowadays it's almost impossible to escape the epidemic of MASLD/MASH. It's so prevalent, as we'll soon talk about, but also is found in patients with viral hepatitis and other liver diseases. So, patients can really have more than one liver disease at one time.
But I've been in practice for, I guess, close to 19 or 20 years now, time flies really quickly. I started knowing that I liked doing some procedures, I liked having a lot of connection with internal medicine. I think that's why hepatology is so special that way. It's very close to internal medicine, and a lot of the complications we see are clearly Internal Medicine focused, like electrolyte disorders, like renal failure, certain types of tumors and infections. And so, there's a real breadth of practice in hepatology. That's what the real draw was for me. I liked things like infections and as I mentioned before, much of my practice is chronic viral hepatitis, and so it worked out well. But for those interested in internal medicine, certainly please consider GI, because there really is something for everybody in GI, from procedures to office, practice, etc.
Huaqi Li
Thank you!
Vrati Mehra
Alright, so I'll take the next question for you, Dr. Fung, will start us off by telling us, how do you define MASLD and where does MASH fit in in the definition? As well as, what's the epidemiology in Canada, and how does it compare to other chronic diseases? And then I have a few other questions, I think based on terminologies you might want to update the listeners about how terminology changed over the years.
Dr. Scott Fung
Absolutely yes, MASH or MASLD is what we used to, and so many of the colleagues around the world, are still calling non-alcohol fatty liver disease or NAFLD/NASH. That's the old terminology, and we recently updated that in 2023, many expert societies like the AASLD came up with a new nomenclature. But basically, what it means is, in the simplest terms, a patient has an ultrasound for whatever reason. Often, they're asymptomatic and often, it's done incidentally, or they have some nonspecific, right upper quadrant or abdominal pain. The family doctor may order an abdominal ultrasound. Lo and behold it comes back with fatty infiltration. And as we see most ultrasounds, it only comes in kind of a qualitative type of descriptor, either mild, moderate or severe. So that's usually the entry point for the diagnosis, basically having fat on your ultrasound. Now, because we like to define the condition as more of a positive diagnosis, like tell us what it is, rather than what it isn't. So that's what was behind a lot of the new nomenclature.
So metabolic dysfunction associated steatotic liver disease or MASLD, basically it just means that you have an ultrasound showing fat and you have at least one of the so called cardiometabolic risk factors. And I think almost everybody has a cardiometabolic risk factor nowadays, with the common things like having diabetes or dyslipidemia, hypertension, chronic kidney disease, any of the cardiovascular risk factors will be enough. Just one or more of them will fit the diagnosis of metabolic dysfunction associated steatotic liver disease, usually implies the ALT is normal in that situation, as opposed to MASH or metabolic dysfunction associated steatohepatitis, MASH, basically the same patients once their ALT becomes abnormal. So, once it becomes elevated, we think that there's some degree of inflammation going on at that point, and the patient may have a more progressive form of liver disease, which encompasses the whole spectrum of fibrosis of the liver from very mild fibrosis all the way to cirrhosis and all of its complications.
You asked also about the epidemiology, and really, MASLD/MASH is the next liver epidemic that I think is already here. We recognize it more and more now, because almost everybody has an abdominal ultrasound, or nowadays FibroScan, which we can talk a little bit about later. That’s a condition now, if you were just to go out and do ultrasounds on everybody on the corner of the street, 1/4 to 1/5 even some studies 1/3, depending on the country and the part of the world you're in, you'll find evidence of fat in the liver of the ultrasound of that person. So very, very prevalent. If we just talk about MASLD alone, in most of the epidemiology studies, about a quarter of adult population, 25%. But luckily for us, in the GI liver world, we don't see all of those patients, because many of them will have the normal ALT, non-progressive form of MASLD but almost like a quarter of a quarter around 6 or 7% in total will have the active form of MASH and progressive liver damage. And even that alone it's a very large number, particularly when we compare it to what we think is a relatively common liver disease in the Canadian population, like hepatitis C, and everybody's looking for hepatitis C to treat it and to eradicate it. And that's currently at still less than 1% of the adult population, 0.8-0.9% compared to, say, 6-7% for MASH and 25-33% for MASLD. And so, it's a huge number. We're already I think in most liver clinics at capacity. We can't really see any more of these patients. So particularly with the low-risk MASLD form, we find ways to help identify those who are at higher risk for progression of liver disease like MASH, by using various noninvasive tests. But even with that, myself and most of my colleagues are already at capacity trying to assess many of these patients. It's the number one reason for referral for consultation for most outpatient hepatology clinics.
Vrati Mehra
Thank you!
Dr. Scott Fung
Sorry that was a long answer.
Vrati Mehra
No, no I asked a lot!
Dr. Scott Fung
Anything else we wanted to talk about? The nomenclature is really almost a talk in itself! Really the whole idea behind renaming and reclassifying this condition, previously known as NAFLD/NASH, was again to focus really on the heart of the pathophysiology, which is the metabolic syndrome. And so, in that umbrella term, so called steatotic liver disease or basically fatty liver, MASLD MASH is basically the most common form of it- the metabolic dysfunction associated steatotic liver disease. And then at the other end of the spectrum, there are patients who have what is called alcohol associated liver disease, or alcohol related liver disease, not a new condition at all. But we know from the pathophysiology and from ultrasounds and even liver biopsy, if you biopsy patients who drink too much alcohol, you do see fat in the liver as well and to the pathologist that often looks the same histologically, they always ask us about the alcohol history if it’s not already provided, because it really helps to determine is this alcohol related or MASLD related, because there's a degree of overlap histologically.
Patients who clearly drink above the safe limit for men and women, say more than 20 to 50 grams per day for females or 30 to 60 grams of alcohol per day, these patients are clearly in that alcohol associated, alcohol related liver disease, or ALD is the short form now. But we've always known in this field that there are patients who are both alcohol and non-alcohol, patients who are clearly MASLD, they have cardiometabolic risk factors, they have fat on their ultrasound. But when you take the history, you find that they are probably drinking much more than they should, and they often will be very open and tell you about that. And in the past, we had no way to kind of classify these patients. We knew they had more than one liver disease going on, and so the new nomenclature really has the advantage of this. We all love terms and labels in medicine, but the new term is now MetALD, basically MASLD and increased alcohol intake, or metabolic ALD.
Even within that category there’s quite a spectrum. There are some patients who drink just a little bit, probably within the safe level of drinking, say less than a drink a day for women, or less than two drinks for men. So, they're clearly at the MASLD predominant end. And there are patients in that spectrum who are closer to the alcohol liver disease because they probably drink much higher than the usual limit, but they also have metabolic risk factors. So that's the new terminology, its MetALD. And we hear about that a lot and various review papers and in our notes from the clinic, when people talk about MetALD, this is this category of patients in between. They drink too much and they have metabolic risk factors. But the commonality is they have fat on their ultrasound.
Then there are always these other less common categories of patients who probably have some secondary form of fatty liver. And so, we always ask about, obviously, drugs and the liver sometimes can be a bad combination, but certain medications are known to deposit more fat in the liver, corticosteroids, for example, methotrexate, tamoxifen, amiodarone. These are relatively common medications we see, and that's another reason for consultation in our clinics. There are certain diseases that can masquerade and look a lot like fatty liver, particularly in younger patients, Wilson disease, for example, and various inborn errors of metabolism. Not so much now, but patients with certain genotypes of untreated HCV can also have, what we call a specific etiology associated steatotic liver disease. Then if you can't find any cause, and you've ruled everything else out we call it cryptogenic steatotic liver disease. That's the useful new categorization, MASLD/MASH and MetALD versus alcohol related liver disease.
Vrati Mehra
Thank you for that! That's very helpful.
Huaqi Li
Dr. Fung, just going back to something you mentioned earlier about the significant burden of the disease of MASLD/MASH. I think it really hit home for me recently when I was on CTU, because we had a patient coming in with liver failure NYD, fulsome workup, autoimmune, infectious, all of those things. And ultimately, after we did a liver biopsy, it was in the picture of metabolic liver disease, and now she's up for liver transplant. So that was really eye opening for me.
Dr. Scott Fung
We're seeing more and more of patients who are coming in decompensated. Sometimes it's the first presentation of MASLD/MASH, or even nowadays, our transplant team and oncology team will tell you more and more of non-cirrhotic HCC related to fatty liver. It's still not that common, and we really don't even have any guidelines on how often we should be screening for liver cancer HCC in patients without cirrhosis, but they have fatty liver, unlike how we do for, say, hepatitis B, we keep sending them for ultrasounds based on age and gender. But for MASLD the denominators are so huge, from a programmatic or policy point of view, there really are no guidelines to suggest how often these patients should be getting ultrasounds done to look at the degree of fatty infiltration or look for progression of cirrhosis or even development of HCC. That's because it's still not very common but increasing reports of liver cancer appearing in patients without cirrhosis.
Huaqi Li
And Dr. Fung, you mentioned this a little bit, and the name itself also gives us some information on the pathophysiology. But can you comment more specifically on how these diseases develop and the explicit role of metabolic?
Dr. Scott Fung
Yeah, that's a great question. We've known for many years that at the heart of the pathophysiology is probably the metabolic syndrome and really the insulin resistance. And we know diabetic patients, up to two thirds of them, even more than the general population, will have MASLD or fat on the abdominal ultrasound. And so, we know that there's a there's a huge role of insulin resistance that's at play in patients with MASLD/MASH. What we think is going on is there's more progressive deposition or infiltration of fat in the liver cell, the hepatocyte. So, some degree of lipo-toxicity. Some of that could be diet related, not all, there is a role of diet and sedentary lifestyle in there. But basically, as more and more lipid is delivered to the liver. It can be deposited intracellularly or maybe into the organelles that leads to some degree of toxicity, oxidative stress, and the liver generally only can respond in a couple of ways, and usually it’s through progressive fibrosis. You get progression from a non-cirrhotic liver to varying degrees of fibrosis to the point of cirrhosis. The lipo-toxicity will stress the liver cell and lead to number of different mechanisms that causes fibrogenesis, so activation of the stellate cells inside the liver and you get more and more deposition of fibrosis and eventually cirrhosis in these patients. It's also known there's probably more lipogenesis, or so called de novo lipogenesis, occurring in patients who have fatty liver. And so, it's a complex pathophysiology. There's probably some trigger that leads to the transition from MASLD, normal ALT, to active MASH, elevated ALT, whether it's infection or some other trigger within the portal venous blood supply, the cause of that nobody still really knows at this point. But the microbiome and other factors are probably at play here, as my researcher colleagues will tell you.
Vrati Mehra
Thank you. I feel like when you're talking about pathophysiology and you're talking about, you know, how do you define diseases? The next step is, really, how do we diagnose it? Could you walk us through the diagnostic approach for MASLD as well as, what role does history and physical play versus labs and imaging? And then, in terms of imaging, we have VCTE. We also have the role of liver biopsy, that Huaqi just mentioned, is not completely obsolete. It does come in handy every now and then. So, what are the roles of imaging versus more invasive diagnostic procedures like liver biopsy? And then, is there a way for us to identify which of our patients would be at the highest risk of progressing and worsening from their liver function perspective?
Dr. Scott Fung
Yeah, absolutely, really great questions. So the diagnosis part is probably the easiest, as we said, if a patient has an ultrasound with fat and your directed history and physical tell you that the patient has cardiometabolic risk factors, the simple things we always do, even in liver clinic, the blood pressure, the body weight of the patient, you can do waist circumference, things that might suggest, BMI is not the only indicator, but it's a quick and convenient one that we often will use in the clinic to determine if the patient is obese or overweight. So, BMI over 25 in Caucasians or over 23 in Asian patients, being overweight will point us in that direction. And if they've got other cardiometabolic risk factors and they usually come with an abdominal ultrasound that shows fat. Then, in fact, that's really all you need for the positive diagnosis.
Now, in the past, when we called it nonalcoholic fatty liver, then we would go and make sure that we rule out all the other things, make sure it's not virus, it's not autoimmunity, it's not genetic liver disease, it's not iron or copper, all these things. And we sometimes still need to do that in the right context. But I would say, because it's now more of a positive diagnosis, you don't have to go ruling out all those other secondary causes, because in most patients usually those investigations come back negative anyway, and you're left with the diagnosis of basically MASLD. But now you can make it more of a positive spin on it just by going through the history, physical, and just looking at the ultrasound of the patient usually comes referred with their initial consult to the liver clinic.
And so, when you ask about the denominator, the number of patients is huge. We can't really see all of them. We can't even assess all of them through our triage and our long list of consult patients. So, we have always had various pathways that colleagues have used around the country. The most famous ones from University of Calgary, looking at ways to pull out or identify the highest risk patients, is based on very simple blood tests that should be available and attached to every consult you see or you’re asked to see for fatty liver. But the FIB-4 score is a very simple, noninvasive test that was really designed for even primary care to use to help determine which patients have more advanced fibrosis. And really, it's the fibrosis that we mentioned before in the pathophysiology that really determines the prognosis of MASLD/MASH, in fact, for probably most liver diseases. But it's the most common one that we have to face nowadays. If the patient has an ALT, AST, platelet count, and you know what their age is. You put it into the formula, and you can see if it's a very low value, less than 1.6 then you can say that the patient could be better served in primary care and may not need to come to specialty clinics downtown or in an academic center. And so that was the way to weed out all of the low-risk patients and have those patients stay with their family doctor to have age-appropriate screening for diabetes and dyslipidemia, dietary counseling in the family doctor's office.
As opposed to the patients who had a high FIB-4 over 3.2, or in some cases 2.7 is the indeterminate range, for those patients we probably need further evaluation in your clinic because they may have advanced fibrosis. So, the second step of the noninvasive test, if the patient already has it, it’s great something called the FibroScan, or basically liver stiffness measurement or vibration control transient elastography. That's a test that is becoming more and more, available, particularly in large urban centers, as a noninvasive way to determine liver fibrosis once again, and even cirrhosis, if the patient has advanced disease. So, if the patient has had the FibroScan already, if that value suggests more than mild fibrosis or advanced fibrosis, for that matter, then those are the patients that we would preferentially want to see and focus on in subspecialty GI and liver clinics, because they may already have compensated or decompensated cirrhosis. Their monitoring schedule is going to be much more labor intensive, and they may need liver transplant assessment at some point, so they'll need specialty care, screening for clinically significant portal hypertension, screening for hepatocellular carcinoma, things that might require a little more resource in the academic center. So, we use both of those tests quite often, either or whichever one you have, or both.
There are a number of other blood based or serum-based fibrosis tests that can be used for the same purpose but really risk stratification in those patients. Imaging based techniques like transient elastography, or in a center like ours, we do have limited access, to magnetic resonance elastography, MRE, and that's also been very helpful in some cases where patients are not able to undergo the FibroScan, or there are limitations with respect to the FIB-4 mainly related to age, etc.
And so that's why we tend not to do a lot of biopsies nowadays. I think that was the question you wondered about. The more invasive way to make a diagnosis of MASLD/MASH yes would be through percutaneous liver biopsy, but I would say now that's become somewhat more of a rarity in the liver clinic. We still occasionally will biopsy patients, to confirm the diagnosis of MASH and to look for prognosis. In those cases, really where the noninvasive test don't make sense, the FIB-4 suggests one thing, but the ultrasound says there's no cirrhosis, or the FibroScan gives a value that is unacceptably high and you don't think the patient has cirrhosis. So, the liver biopsy remains the reference standard, we occasionally still have to do but we probably only do one or two liver biopsies a week in our medical day unit now. We do send some to through radiology to do liver biopsies, but again, it's not mandatory, certainly, to make the diagnosis of MASLD/MASH using a liver biopsy. Occasionally, we still need to do it in the more complicated cases, when a patient has noninvasive tests that don't concur with each other or there's some doubt in the diagnosis, they have more than one liver disease. So that type of situation, but it's not that common nowadays.
Vrati Mehra
Thank you!
Huaqi Li
Piggybacking into what you were saying about monitoring fibrosis in clinic. When would you actually consider referral to transplant hepatology, for example?
Dr. Scott Fung
You know, it's a great question, because we have so many patients who are kind of on the brink of decompensation and who have evidence of advancing liver disease. But generally, it's still based on, again, medical need, and it's very objective by looking at various parameters of liver function. So, the MELD score is probably the easiest way to go, MELD I think we're up to 3 now through 3.0 or MELD NA was 2.0, basically just looking at in the patient with cirrhosis what’s their bilirubin, their PT/INR, their creatine and sodium levels.
But generally, in transplant, we're interested in seeing them once there's evidence of advancing MELD score, worsening MELD score, usually it's always going a little bit higher. But around 14 or 15, that level, when we would start to send them for transplant, or if they had evidence of recurrent hepatocellular carcinoma, that's another avenue to have transplant assess the patient. They may have very compensated, barely cirrhotic liver disease, but should they develop recurrent HCC, they do have a higher priority on the transplant list. But I think it's not always an obvious decision. Any of these patients will have other comorbidities, as is common with metabolic syndrome, such as heart disease, chronic kidney disease, diabetes and other comorbidities that may preclude transplant. But we always like to get the formal opinion to see if the patient can proceed with the transplant work up.
Huaqi Li
Thank you so much!
Vrati Mehra
Thank you. What are some of the risk factors for HCC in these patients?
Dr. Scott Fung
So you know, we always worry about patients who go on to progressive liver disease and then develop cirrhosis. Developing cirrhosis related to MASH is still the primary risk factor for most patients who develop MASH-related, hepatocellular carcinoma. Independent to that there are probably other things, such as diabetes itself is risk factor for development of HCC. The family history is important to see as well. Not only just HCC, but it’s also well known that these patients could develop extra-hepatic tumors such as colorectal cancer is another example of that, whether that's metabolic related or the link between pancreatic cancer and diabetic patients. So, they're all kind of mainly within the GI realm of things. And the number of times that we've been screening for HCC and we find some tumor that we're not really looking for, namely pancreatic, adrenal, RCC, lymphomas, other tumors, even gastric tumors in a patient who's not yet had endoscopy or body imaging are great at picking up many other tumors outside the liver that we weren't really looking for. And so that certainly is a risk, really it's great point to mention the risk of extra-hepatic malignancy.
Vrati Mehra
Thank you.
Huaqi Li
And Dr. Fung segueing into treatment, so lifestyle modification is still a huge cornerstone of these diseases.
Dr. Scott Fung
It is Huaqi, yes!
Huaqi Li
I'm just wondering when a patient's actually in front of you in your clinic, how do you walk them through this and how do you decide how to manage them?
Dr. Scott Fung
So, despite, it's an exciting time to be in liver disease because there are more and more development of pharmacologic agents. But still, when we see these patients, the first discussion or the cornerstone still remains, really a lifestyle modification. It’s the easiest thing for us to recommend. It's not always that easy for the patient to follow through with it, but really we have a handout that we give them in terms of dietary modifications that generally follow Canada's Food Guide, and we're trying to have more ethnic specific versions of that. We now have part time dietitian working in our liver clinics who can help some of the patients in terms of counseling and how to avoid high carbohydrate diets or simple sugars and high fructose drinks.
So those things where, if you go through the patients 24hr or 48hr food records, which many of my colleagues in nutrition will do, you will find hidden sources of carbohydrate, and mainly that's where we worry most about in these patients. But going through the diet very carefully, having to work with the dietitian is often helpful if they're cirrhotic, and obviously there are things related to sodium intake and varying degrees of decompensation, but really the dietary modification is huge.
We ask about things like, obviously alcohol and alcohol consumption. Some of our MASLD/MASH patients are zero alcohol drinkers, so it's really nothing to work with in that area. But coffee consumption is still written about, a lot of the reviews, and it's not based on certainly the strongest of evidence but drinking two to three cups of probably black coffee, drip, kind of brewed coffee, is probably the best studied and that in itself may help to remove some fat from the liver and maybe it causes the patient to lose a little bit of a weight as well. Nobody knows really what the mechanism is, but these relatively simple things. If the patient's already a coffee drinker, will ask “do you add sugar to it, is it the double double? Is it like a cappuccino or something with a lot of sugar or extra carbohydrate in there that can be modified”. But many of our patients are tea drinkers, and they refuse to switch to coffee. So that's sometimes a difficult discussion to have, but I really had the cornerstone of all of it is diet modification.
And then, on the other hand, really the exercise levels are also important, and we're not really the masters of exercise and weight loss in our liver clinics, but to find out just how active the patient is. Because the amount of weight loss in many studies has been associated with not only the reversal or basically the burning up, the defatting of the liver on ultrasound or CAP score on FibroScan. But also, the more weight you lose, say if you're up to now, 5% of body weight loss may make your ultrasound look almost normal. You might go from moderate to mild or mild to no fat on the ultrasound. If you lose even a little bit more even like 7 to 10%, that has been associated with resolution or improvement in the inflammation on a liver biopsy, so the ALT will start to normalize at that time, if not already normal. And then anything more than that, more than 10% body weight loss, has been associated with reversal of fibrosis, and so it gets even better. So, had the patient been cirrhotic or had they had advanced fibrosis, with sustained weight loss, in fact, even the liver starts to remodel and there is resorption of the bands of fibrosis. Could take a long time to happen, but in these biopsy studies, they were able to show it was almost a biologic gradient, kind of a stepwise reduction, or step wise increase in body weight loss was associated with more and more histologic benefits in patients with MASH.
Huaqi Li
Thank you so much! And you mentioned earlier that some different demographics have varying cut offs for BMI, for example, there is a subset of patients who kind of fall in the category of lean MASLD/MASH. How do you navigate the care for those patients?
Dr. Scott Fung
Yeah, it's a great question. It's very, very tricky, because we tend to think about these MASLD/MASH patients as with obesity or overweight. But they're not all like that, and nobody knows why that is, and we tend to see more of it in our Asian patients, who are clearly still on the lean side. So many times, their BMI is no greater than 23 or even 21, and lo and behold, you do an ultrasound and there's still a lot of fat in there, and we never know what is at play there. Often they have other liver diseases, we see Hepatitis B and fatty liver, and we see that together. But it's harder, but there's always some room for improvement, because you may find that many of those patients are still working long hours, or they have sedentary lifestyles, and they don't have a lot of time for exercise. So now the diet part is one thing, and many are probably still consuming a lot of carbohydrate, and so there's always room for improvement in the diet and the exercise part too. So we approach the lifestyle modification in the same way, but they probably don't have a lot of room to lose like 7 or 10% of their body weight. And so my expert colleagues in Hong Kong and in other parts of the world would just downgrade that recommendation and say maybe 3 to 5% body weight loss, a very small amount of body weight loss. But the idea being you still get them to become more physically active and to pay more attention to their diet, but it's a great point. There are just different phenotypes when it comes to fatty liver, non-obese versus obese.
Vrati Mehra
Thank you! It's an exciting time because we have GLP-1 agonists and dual incretin therapies and anti-fibrotic agents. What are the role of these medications? And what do you think is the future looking like for treatment of fibrosis?
Dr. Scott Fung
Yeah, no, it's a very exciting time because we've seen so much drug development in this area. Many of these newer agents are still in phase two or three studies, but we can see on the horizon at every liver conference more and more medications in various classes. You mentioned, the incretin, GLP-1s, the GIP combos, the PPAR drugs. As well as Resmetirom, which is a little bit of a newer orphan drug, a thyroid hormone beta drug agonist. It's been already approved for use, the first drug in history to be approved for treatment of MASLD/MASH in the US, and I think, only available in the US right now. But it's an oral medication that helps to basically stimulate the thyroid gland in a good way, to help the patient probably lose a bit of weight, improve their lipid profile, and as a result they end up removing fat from the liver. You burn up some of the fat in the liver and if we use it long enough there's evidence of regression of fibrosis in those patients as well. So, all of the trials are kind of looking at these end points, which are primarily histologic at this point, but improvement in the inflammation without worsening of the fibrosis, or improvement in the fibrosis without worsening the inflammation.
So there are sometimes tricky endpoints, and they still require a number biopsies before and after treatment, but we're starting to move toward these noninvasive endpoints for many of these newer therapies that you mentioned, like semaglutide, GLP-1 or Mounjaro/Tirzepatide, as examples. But really there’s nothing's available with a label indication for fatty liver still in 2025, but as we've seen in clinic, we have we're starting to build a more and more real-world evidence for patients on GLP-1s, mainly because they're more available in Canada for treatment of diabetes, and they also happen to have fatty liver. So what happens to their ALT, what happens to their CAP scores, or Fibro scans? And we do see improvement, as the first part of the ESSENCE 3 Trial, which looked at GLP-1s, basically semaglutide in patients with stage two, three fibrosis, fatty liver, and we saw the histologic endpoint already I think after one or two years of use, they're now going on to look at improvement in cardiovascular risk factors and mortality and morbidity.
But as of yet, it's not yet Health Canada approved so that it won't say on the label indicated for treatment of fatty liver. But more and more patients we see are coming to us already on GLP-1 or have been started on those agents by primary care or by endocrinology. And we see their liver enzymes are starting to improve as the weight comes off. Sometimes they don't lose that much weight but there still is improvement in their ALT as well.
So it’ll be an exciting time. I think we'll see more and more medications become available, but the important point is you still have to, I think, focus a lot on the diet and the lifestyle that part still needs to continue. And all the diabetic patients already know that, their endocrinologists or their family doctors talk to them all the time about their diet and their exercise level, but they may just need a little bit of extra pharmacotherapy on top of it.
But MASLD/MASH is a little bit more complicated, because many of these patients, again, have either no fibrosis or very little liver fibrosis. So, we know that their prognosis is largely dictated not by their liver disease, but by their metabolic profile or cardiovascular risk factors. So many of these patients who have no fibrosis, very minimally elevated ALT, we may only see once in clinic, and say the plan is diet and lifestyle modification. Go back to your family doctor and come back to us maybe in three years or five years for repeat FibroScan to see if they progress, maybe three years, just to be a little more conservative. And then if at that time, we have agents that are approved for use in patients, I think primarily with more advanced degrees of fibrosis, I think those will be the patients who will be prioritized for treatment. But who's to say maybe later on, there will be medications that are geared or directed more towards patients with lesser degrees of fibrosis, but they have a lot of fat in there, and that's obvious on their ultrasound or on their FibroScan CAP score.
Vrati Mehra
Thank you.
Huaqi Li
That's a great point, Dr. Fung. I think that even though there's all these exciting therapies out there, that we still really need to focus on the lifestyle and the longitudinal aspect.
Dr. Scott Fung
We tend to forget about that part of it too, because we're always busy. We don't always have time to ask the patient about all the details of their diet and their exercise regimens, but it's important to the patient, and I think it helps to really validate a little bit more when we keep asking about those things. If you have the ability to have the luxury of a clinic nurse to help you, kind of to screen some of these things and see how the patient's doing, or a dietitian to help. I think it really makes a difference in a multidisciplinary type of MASLD clinic.
No, I think we talked about a lot of different things, all the way from diagnosis, pathophysiology, treatment and how to monitor these patients. I guess we should just mention again, we're maybe speaking to our internal medicine crowd here, but generally as the patient's BMI goes very, very high, that there's still a role of surgical therapy, bariatric surgery nowadays, more endo-bariatrics for many of my colleagues in therapeutic gastroenterology. Many other types of procedures that can be done to help with the patient's absorption of calories and different things that can be done in terms of endoscopy. Many of them are not that experimental, just depends on the expertise and center where your patient is at. But I think we're looking more towards endo-bariatrics for many of these patients, even before some of these medical therapies become approved. So, there'll always be a role for both medical and surgical therapy, I think for some of these patients the ultimate surgical therapy is probably transplant, for some of these patients who may also have, like a sleeve gastrectomy performed at the same time.
But patients can be complicated. They can have more than one therapy. They can have more than one liver disease. I think MASLD/MASH has been the great model to show us how all these things fit together, right from diet and lifestyle all the way to the point of liver transplant, it's really quite a spectrum disease.
Huaqi Li
Thank you so much.
Vrati Mehra
Well, that wraps up our discussion on metabolic dysfunction–associated steatohepatitis and liver fibrosis. To our listeners, thank you for tuning in! And a special thank you to Dr. Scott Fung for sharing your expertise and insights today. That’s it for this episode of Scope Notes GI. Be sure to join us next month for another update in the world of gastroenterology and hepatology!
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