00:00:00: Hello everyone. Welcome to this episode of the UEG Podcast. My name is Pradeep Mundre. I am a

00:00:05: gastroenterologist from the UK. I'm a podcast host for UEG. Welcome to this another episode where we

00:00:11: cover a lot of basics on a particular topic. Today we're going to discuss about MASLD, metabolic

00:00:17: dysfunction associated steatotic liver disease. And the discussion will be centered around what

00:00:23: a general gastroenterologist or a trainee or a primary care physician or a general practitioner

00:00:29: needs to know about MASLD. And to discuss that, today we have our guest, Professor Sven Francque,

00:00:38: Professor of Gastroenterology and Heptology from Antwerp University Hospital, Belgium. Sven has

00:00:45: made a huge contribution in the field of MASLD as a clinician, researcher, and an educator. And he's

00:00:51: one of the authors for the latest ESL slash multi-society guidelines on MASLD published in

00:00:58: 2024. On behalf of UEG, welcome for this conversation, Sven.

00:01:05: Yeah, thank you. Thank you very much, Pradeep. I'm happy to join.

00:01:09: Thanks. We're going to try and do this in two parts, Sven. Part one, where we try to cover the

00:01:14: basics, the diagnosis and monitoring. And part two, we'll cover the treatment, future directions,

00:01:20: and the latest in this. So Sven, let's start with the basics in terms of prevalence. We all know that

00:01:29: the prevalence is increasing and hugely increasing compared to various other diseases. This is a modern

00:01:35: day disease. Maybe if you can shed some light on what is the scale of the increase in prevalence and

00:01:44: how would it affect us in the future of how bad it is? Well, it obviously has to do with the

00:01:50: pathophysiology of the disease, which is closely linked to mainly dysfunctional adiposity. That's

00:01:57: really one of the key. And then diabetes is also an important factor in disease progression. The

00:02:02: estimates are because I'm saying it's estimates because still the gold standard or the best standard for the

00:02:08: diagnosis specifically for the more severe subtype of steatohepatitis is based on liver biopsy. And of

00:02:14: course, we do not have population-based data with liver biopsy. But the estimates are that roughly 30,

00:02:21: 35% of the adult population has steatotic liver disease, mainly mesal-D. Luckily, it's not in all

00:02:29: those patients truly a progressive liver disease. It's a sign of being metabolically unhealthy, but not

00:02:35: necessarily an advanced liver disease. But of those 30, 35%, the estimates are that roughly 20,

00:02:44: 25% will have steatohepatitis and a risk of progression to fibrosis, which means that between

00:02:51: 5, 7% of the adult population has MASH and the percentage evolving to cirrhosis is also there within

00:03:00: about 20% that the estimates. Over time, because this disease takes long before it develops to

00:03:09: advance chronic liver disease and cirrhosis, but given the evolution over time, we will face a huge

00:03:16: burden. We're already facing the burden, but the burden will increase because of the natural history

00:03:21: of the disease. And Svet, do you see that in your own practice? You know, the kind of patients that you're

00:03:27: seeing and the amount of hepatologists you're employing in your own hospital are dealing with

00:03:32: this disease? It's clearly increasing. Of course, in the first year referral center, you're getting a

00:03:39: selection of patients. And as this is a chronically evolving disease, probably evolving more slowly

00:03:46: than, for example, viral hepatitis or alcohol-related liver disease, we start now to see an increasing

00:03:52: number of those patients. Also because it's not still that easy to know who exactly has to take

00:03:57: care of those patients. So, it has already become a quite substantial proportion of our patients. It's

00:04:03: clearly increasing. Also, when you go to the more extreme side and end-stage liver disease needing

00:04:08: liver transplantation, it's clearly increasing in terms of the proportion of patients that we see.

00:04:14: Okay, Sven. So, thanks for clarifying that. Let's move to the terminology, Sven. The guidelines are

00:04:20: very clear in this. Just for our audience, can you clarify what each of the terminology means and

00:04:27: what is the umbrella term and what do you mean by metal, mash and all those things just in brief?

00:04:34: So, in the past, we talked about non-alcoholic fatty liver disease, meaning there is fatty liver and it's

00:04:41: not alcohol. So, it was a little bit a basket term for everything that was not related to alcohol for

00:04:47: or known reasons of steatosis. It was, of course, as really in that terminology, mainly related to

00:04:54: metabolic dysfunction. But now in the new nomenclature, it's clear we start from the

00:05:00: observation that there is liver steatosis and then under that umbrella, you have a long list of causes of

00:05:06: steatosis. But the main causes in daily practice are, of course, metabolic dysfunction on the one hand and

00:05:13: the use of alcohol on the other hand. If you have alcohol consumption which is above the thresholds

00:05:20: that we use to define alcohol consumption non-alcoholic, then it's the combination of both.

00:05:25: So, even if under the umbrella, you have a long list of potential causes, the most prevalent ones are

00:05:32: metabolic or alcohol or the combination of both and that's then the MET-ALD.

00:05:36: Dr. So, what you're trying to say, Sven, is that there's this big umbrella term called steatotic

00:05:42: liver diseases and in that you have ALD, MASH, but you're also trying to say that there are other

00:05:49: causes of steatotic liver diseases, not just alcohol and Masal-D.

00:05:54: No, it can be drug-induced. You have some specific genetic mutations. Of course, genetic mutations

00:06:00: play also a role in Masal-D and in alcohol-related liver diseases, you know, but you have specific,

00:06:06: called monogenic diseases that also cause steatosis. So, I think that the advantage of the umbrella term

00:06:12: is that it forces you to think of all different risk factors for chronic liver disease that might

00:06:19: go inside in one given patient and not just saying, okay, this patient is drinking alcohol, so

00:06:25: his liver steatosis is alcohol-related liver disease. No, you have to think of all potential causes of

00:06:31: steatosis and all potential causes of chronic liver disease that can coexist. And of course,

00:06:36: some of them are more prevalent and others are more rare diseases, but at least you have that,

00:06:42: you have to have that reflex that it's not the first cause you identify is not always explaining the

00:06:48: whole picture. And in the guidelines, Sven, I think there's a really beautiful flow chart which kind of

00:06:55: guides people like me to kind of come to a conclusion and it's really, really beautifully written and I'd

00:07:01: really advise the listeners to go and look at this flow chart. It's really lovely and very succinct.

00:07:09: Yeah, and you can also find it in the EASL guidelines app which is also very practical to have it in your pocket.

00:07:15: Yes. So, let's talk about the pathophysiology. So, you have fat deposits in the hepatocytes. So, what happens,

00:07:23: you know, how, what happens eventually? What did that cause? How long does it take to progress into

00:07:29: other things such as fibrosis, cirrhosis? Just getting, just briefly delineate just so that we can

00:07:35: understand how, let's say, pharmacological treatment works. First of all, it's very important to understand

00:07:40: that this is largely driven, first of all, by, as I mentioned early on, by dysfunctional adiposity. So,

00:07:47: it's all starts there and then there is spillover to ectopic fat deposition in other organs including

00:07:54: the liver but also spillover of inflammatory mediators and other mediators that also drive

00:08:01: liver disease. And then in the liver, once you have, first of all, that lipid accumulation, you get

00:08:07: lipotoxicity, you get mitochondrial dysfunction there. A bunch of pathways that are altered directly by the

00:08:14: lipid accumulation indirectly by other mediators coming from the adipose tissue and the systemic

00:08:21: chronic inflammation. And on top of that, of course, you have all the mechanisms the liver is equipped

00:08:27: with to cope with that or the lack of. So, it's a very complex pathophysiology that both includes

00:08:34: dysfunctional adipose tissue and then all the liver pathophysiological pathways and the abilities of

00:08:41: the liver to cope with that and to defend itself. Which explains the large heterogeneity in the

00:08:47: patients where you can have metabolic risk factors and despite that no liver disease and on the other

00:08:53: hand, relatively minor metabolic risk factors and still having quite progressive liver disease.

00:08:59: On average, the evolution is slow. The estimates are that in stage, in terms of stage of fibrosis

00:09:07: progression, we usually use a classification that stages the disease from zero to four, so with

00:09:13: five stages, the estimates are that you need about six, seven years to go from one stage to the next one

00:09:21: if you have underlying steatohepatitis. If you do not have steatohepatitis, there can still be some

00:09:27: progression but it's way slower. So, it takes you 15, 20 years, sometimes 30 years or longer to evolve from

00:09:35: no fibrosis to advanced fibrosis and cirrhosis. So, on average, it's a very slowly evolving but evolving disease.

00:09:45: But do all the patients progress to, yeah, what's the roughly?

00:09:50: No, no, no. In that big group of, as I mentioned, the estimates are 30-35% of the adult population.

00:09:58: Luckily, the majority will not evolve towards steatohepatitis and not towards end-stage liver disease.

00:10:07: That's, in percentages, a relative minority. Of course, given the large numbers of patients, it still represents

00:10:14: a large number of people but it's only a few percentages that, in the end, will evolve to cirrhosis.

00:10:21: As I said, about one out of four of the patients with steatosis have steatohepatitis with a clear risk of fibrosis progression.

00:10:29: And so, is there anything within the baseline characteristics which would predict the risk of progression?

00:10:37: Are there any particular subset of patients within the MASH who are high risk of progression to cirrhosis

00:10:43: at all so that we are aware, you know, which ones to look out for?

00:10:46: Well, there are a few factors. We still are facing that heterogeneity with the patients.

00:10:52: There are the issue of difference between men and women.

00:10:56: Okay.

00:10:56: So, women are relatively protected until the menopause, but after the menopause, there is an accelerated progression of the disease.

00:11:04: Men are a little bit at risk at earlier ages, so that's one component.

00:11:11: Visceral adiposity clearly is a risk factor, so it's not just BMI, it's how the body composition is,

00:11:18: and abdominal fat accumulation is clearly more vulnerable. The presence of diabetes is for sure a risk factor,

00:11:27: a very important risk factor for more aggressive fibrosis progression.

00:11:32: Clinically, that are the most prominent factors. We have some genetic mutations that have an influence

00:11:41: on the disease progression. To date, with the limited implications, that's not something for routine

00:11:47: clinical practice, but in the future, that might also be something that helps us to better risk stratify the patients.

00:11:53: Dr. Thanks for explaining that, Sven. At least that will help us to, at least the

00:11:58: geographic physicians or general gastroenterologists to maybe monitor these patients more than the other,

00:12:05: at least risk stratify them. Based on that, one more, to the patients who were labelled as MASS-OVD

00:12:11: with a normal body mass index, so they're non-obese, different. Are there any ethnic factors to consideration

00:12:18: while sticking to this? Because, you know, I know as a trainee, for me, MASS-OVD was,

00:12:24: the obesity was the key factor in MASS-OVD, but that doesn't seem to be the case completely.

00:12:30: Dr. No, that's not completely the case. Also because, I mean, our understanding of obesity is

00:12:36: also evolving, and that's why the obesity physicians now insist on clinical obesity and on

00:12:42: dysfunctional adiposity, rather than a pure BMI-based approach. And it's not just

00:12:48: obesity. Also, people living with overweight have already a clearly increased risk. And some of the

00:12:53: people with class 3 obesity are not always as steatotic as you would expect. So, it's really

00:13:01: about dysfunctional adiposity and not so much about weight. And with this said, what we see in those,

00:13:07: what you could call lean MASS-OVD, although I do not like the terminology at all, and I think we

00:13:12: should not use it. Most of these people do have some visceral fat accumulation and some dysfunctional

00:13:19: adiposity and insulin resistance. So, they are not metabolically healthy, despite the fact that,

00:13:25: according to the criteria, they do not have overweight. It's typically something we see in

00:13:30: people from Asian descent. There, it's something that is more frequently encountered than in most of the

00:13:37: other ethnicities. But still, even if people have normal weight, according to the BMI criteria,

00:13:43: they usually have visceral adipose tissue accumulation and dysfunction and insulin resistance

00:13:49: that explains the occurrence of MASS-OVD, even if they are not overweight.

00:13:53: Dr. Swen, coming to the practical management, you know, the way I come across such patients is,

00:13:58: you know, when I'm investigating them for the diseases, they get incidentally,

00:14:03: you find transaminitis or transiently raised ALT, which is persistent. That's when I suspect.

00:14:10: Or you do a CT scan or ultrasound scan for some other reason, and that shows imaging abnormalities

00:14:17: suggestive of fatty liver. So, you suspect MASS-OVD in these patients. What's your workup like

00:14:24: normally in your practice? What do you do with such patients? Either radiological evidence of

00:14:29: steatosis or persistently raised liver enzymes in the absence, let's say, of other etiology that

00:14:36: would explain these liver enzyme abnormalities, plus in the presence of these risk factors.

00:14:41: Dr. Yeah, you're touching already on a very important point, I think,

00:14:45: Pradeed. If you have a chronically elevated transaminases, there are, of course,

00:14:50: several causes that we need to exclude. So, even if you have steatosis, you should think of excluding

00:14:57: viral hepatitis and autoimmune hepatitis, etc. But if that is done in the scenarios that you mentioned,

00:15:04: I mean, probably not in a hepatology clinic, but in a more general setting with lower prevalence of

00:15:10: advanced disease, FIB4 is a good starting test. So, it's an easy test based on AST, ALT,

00:15:15: platelets and the age of the patients. It's not reliable below the age of 35, and as age is part of it,

00:15:23: you also need to have different cut-offs when people get to the age of 65. But it's a very good

00:15:30: starting point, because it has a very high negative predictive value. The positive predictive value is

00:15:36: not good, so you cannot use it as a positive diagnostic tool, but you can use it to reliably exclude

00:15:44: the presence of significant fibrosis because that's the target which corresponds to the F2 on the 0-4 scale.

00:15:54: So, calculating the FIB4, and if it's below 1,3, then you can reassure the patient at least to say,

00:16:01: okay, you do not have or there's a very low likelihood that you have significant fibrosis. It

00:16:09: still means that you're metabolically unhealthy, so you need to work on the metabolic comorbidities,

00:16:15: for sure, but in terms of viewing it from pure liver perspective, with such a low FIB4, you can

00:16:22: reassure the patient and just make sure that there is some follow-up in the future because, of course,

00:16:27: the risk can evolve. When you have a high FIB4, which means that the threshold is 2.67,

00:16:35: then there is an increased likelihood of the presence of fibrosis, so that needs then referral,

00:16:41: at least for a second-line test to confirm or deny that first result. And if you are in between,

00:16:49: then the guideline also gives you two options. If you have still metabolic risk factors you can work on,

00:16:55: you can intensify the management of those metabolic comorbidities and then reevaluate after

00:17:01: six months or one year. Or you can also go straight ahead because you are in the gray zone to a second

00:17:07: line test. But all that applies to a setting where you have a relatively low prevalence of advanced

00:17:15: disease because there that kind of screening test works well. Okay, so that's the primary care setting?

00:17:22: Dr. Yeah, or Diabetology Clinic, Obesity Clinic. That's a perfect tool there to do a first screening.

00:17:30: Dr. Excellent. So, to summarize this one, so I see patients with hepatoxiautosis on imaging or

00:17:36: persistently raised liver enzymes. I exclude other diseases and they fit into the criteria for diagnosis.

00:17:43: So, again, I would advise the listeners to go through the guidelines. There's a good flow chart to

00:17:47: to make a diagnosis of Masal-T. I do a FIB4 test at baseline and risk stratify them based on the number

00:17:55: and then follow them up depending on the risk. So, I want to just quickly delve into the middle range,

00:18:02: the intermediate range FIB4 test. You mentioned intensified management of comorbidities. That's

00:18:08: not just a bit of dietary therapy, a bit of exercise. So, you're suggesting that you can go more into that.

00:18:15: Dr. Treatment for OBHC, medical treatment, surgical treatment and all that. Is that what you mean by

00:18:20: intensified management of comorbidities? Dr. It's a little bit of both because what is sometimes very

00:18:27: helpful is we all know that lifestyle modification is easily set but it's not so easy to implement it

00:18:35: in daily life even if patients are motivated to do so. If you know that there is a risk of having

00:18:42: more advanced liver disease with the appropriate support, people can change their lifestyle. So,

00:18:49: that already is an important step. But if that's insufficient or if that's not something that is

00:18:56: likely to be very successful, I think indeed you need to think about the management of obesity with

00:19:01: more than just lifestyle modification. There are now several drugs that are highly efficacious to treat

00:19:07: obesity. As you mentioned bariatric surgery, I think it's still something we need to include in

00:19:12: the armamentarium within the proper indications. But if there is an indication of the presence of

00:19:18: liver disease, I think it should add to the medical indication to at least consider bariatric surgery

00:19:24: in the spectrum of other options, of course.

00:19:26: Dr. Sven, let's go through the patient journey. You know, such patients come to me and I'm just doing

00:19:32: these FIB4 tests and manage them intensively. At what point do you as a specialist hepatologist

00:19:38: want to get involved? What should be the threshold for referral to the hepatologist, so to say,

00:19:44: a hepatologic clinic? Dr. Well, I think you have two possible scenarios. The first one is already when

00:19:51: you have that high FIB4, then there needs to be a confirmatory test and then it depends a little

00:19:57: bit on how the healthcare system is organized, who is going to perform or ask for that second-line test.

00:20:03: That if you have tests like liver stiffness measurements readily available, tests like ALF

00:20:09: readily available, then that can also be asked by the one who did the first screening. If that test

00:20:16: comes also back positive, I think definitely the patient needs to be seen in a hepatology clinic. In

00:20:22: other healthcare systems where the access to those second-line tests is probably a little bit more

00:20:27: limited, then they should more quickly go to the level where those second-line tests are available.

00:20:33: If you are in the intermediate category, I think that the intensification of the treatment with

00:20:39: lifestyle and as you said, mobility care is very important, but then you should make sure that you

00:20:46: re-value the risk of presence of significant fibrosis. And if on re-evaluation you're still in the gray

00:20:52: zone or even above the threshold, then that's also the patient that needs to be seen in a hepatology

00:20:59: clinic. Dr. Okay, good. And with the liver stiffness, the FIPR scan, at least wherever hospitals

00:21:06: are, we have very easy access to these. How is the access in the rest of Europe? Is it easy for

00:21:14: clinicians to access these tests? And if they don't have access, let's say, to a Fibroscan or ELF test,

00:21:20: is there any other way to get that information whether they have advanced fibrosis or not?

00:21:25: Dr. I think the situation in Europe is very different from one country to another. I think

00:21:31: the availability of Fibroscan has substantially increased in most of the countries. For ELF,

00:21:37: it's the pattern is quite diverse. Of course, Fibroscan is not the only tool we have for liver

00:21:45: stiffness measurement. There is 2D-She-Wave elastography, for example, also present, which can

00:21:51: be added to a normal classical ultrasound. Okay. We have less data in terms of validation within the

00:21:59: mesoth space, but I assume that it's an equally valid tool to assess liver stiffness. So you have that

00:22:06: as an alternative. Of course, there's also MR elastography, but there the availability is in

00:22:12: Europe, at least throughout Europe, rather limited. So I think a liver stiffness measurement and or

00:22:20: ELF are tools that we really need to develop further in places where this is still not really

00:22:27: available because they are very important to avoid the need for a liver biopsy. A liver biopsy still has

00:22:32: its place for sure, but it requires a high level of expertise for a correct interpretation and

00:22:39: obviously it's also a more risky procedure. So we need those non-invasive tools absolutely to have a

00:22:45: proper patient trajectory and only reserve that procedure for those who really need it.

00:22:50: So Sven, talking about liver biopsy, just to end the part one of this conversation, when do you use

00:22:57: liver biopsy in your practice for Maslow-D patients? Because it looks like we're moving away and we're

00:23:03: just using non-invasive tests and things and you... Yeah. And I think in routine clinical practice,

00:23:08: you can go a long way with the non-invasive tests. Of course, you will have instances where,

00:23:15: first of all, you still remain doubtful about, is this just a pure Maslow-D case or is there

00:23:22: another etiology? So some patients will have some autoantibodies that are positive or might take

00:23:28: drugs that cause theatosis. So you might be in doubt about the underlying etiology and then a liver

00:23:36: biopsy is for sure very useful. You might also have a situation where your non-invasive tests come back

00:23:43: with discordant results and then because identifying advanced hybrosis and cirrhosis has an impact on the

00:23:50: management of the patient, then you can still also argue that the liver biopsy is needed. And then,

00:23:56: of course, if patients are potential candidates for clinical trials, the clinical trials are still

00:24:02: based on the liver biopsy for phase three at this time point. So there, definitely you still need the

00:24:09: liver biopsy. Also, that is probably something that will change in the upcoming years, but for the time

00:24:15: being, that's not the case. Thanks, Sven. I think we would conclude the part one of this discussion.

00:24:21: And we discussed about the diagnosis, practical aspects of managing a patient under non-specialist,

00:24:29: and how would you monitor and when would be referral to the specialist-teptologist. Thanks once again.

00:24:36: Okay. Thank you.