MASLD and Obesity: Mechanisms and Management

Key Takeaways

Links Between Obesity and MASLD

Obesity and MASLD (Metabolic dysfunction-Associated Steatotic Liver Disease) are closely linked global health challenges. Many people with obesity develop hepatic steatosis, and obesity accelerates progression to inflammation, fibrosis, and cirrhosis. Shared mechanisms include insulin resistance, chronic inflammation, dyslipidaemia, and disrupted adipokine signalling.

Pathophysiological Mechanisms

Adipose tissue dysfunction connects excess adiposity with liver injury. Lipid overflow, mitochondrial stress, and inflammatory cytokines drive hepatocellular damage and fibrosis. Gut-liver axis disruption and genetic variants (e.g. PNPLA3, TM6SF2) modify individual risk.

Clinical Presentation and Diagnosis

MASLD spans from steatosis to metabolic dysfunction-associated steatohepatitis (MASH). Many cases go undetected until advanced stages. Early detection through non-invasive tools such as transient elastography and fibrosis scoring is essential, particularly in those with obesity, type 2 diabetes, or cardiometabolic risk factors.

Impact and Management

Obesity worsens hepatic inflammation, fibrosis, and hepatocellular carcinoma risk, and complicates treatment planning. MASLD can progress without further weight gain if metabolic dysfunction persists. Sustained weight loss remains central to management, though often difficult to achieve. GLP-1 receptor agonists, dual incretin therapies, and bariatric surgery show promise in improving liver fat, inflammation, and fibrosis within multidisciplinary obesity care.

Future Directions and Next Steps

• Integrate obesity and liver disease management in multidisciplinary clinical pathways
• Investigate long-term liver outcomes in patients treated with obesity management medications
• Improve early detection through non-invasive diagnostics and metabolic risk profiling
• Enhance patient inclusion in MASLD clinical trials, ensuring equitable representation

Summaries are AI-generated from meeting transcripts.

Transcripts are auto generated, if you spot an error, please email enquiries@easo.org

Speaker 1
00:00 – 02:54
So, hello everyone and welcome to our new comms webinar, which will deal with metabolically associated stiato-liver disease and obesity mechanism and management. My name is Dror Dikker. I am coming from Rabin Medical Center in Tel Aviv University, Israel, and I am the co-chair of the Collaborative Centers for Obesity Management. And it’s really my honor to invite two very important speakers, Professor Rodriguez and Professor Kowsi, to give us a talk on this matter. So what we will do, we will have a 20 minute talk, and then after 40 minutes, we will have a discussion and please send your question and all what you want to know on this topic. So let’s start. So we know that we have around 1 billion people living with obesity, and from this 1 billion people, three out of four, meaning 75%, presenting muscled. And we also know that from this 70%, 75% that present muscled, 250 million are presenting MASH. We also know that these two epidemics are following each other. And we can see the prediction of the rising of the percentage of overweight and obesity parallel to the rising of the percentage of muscled. So I think the two epidemics, the two disease are really deserve a very close look and understand those two diseases and the connections. So let’s start. I want to invite really Professor Rodriguez, which is Associate Professor and Researcher at the University of Navarra, working with metabolic research laboratory at the Clinica Universita de Navarra and the CyberBorn Network. Professor Rodrigo’s research explore the endocrine, cellular and molecular mechanism linking obesity to metabolic dysfunction and related disease, including muscle. In today’s talks, she will examine the biological pathway driving the development and progression of muscle in the context of obesity and the clinical implication. So Professor Rodriguez, the floor is yours.

Speaker 2
02:56 – 04:51
– Good morning, everyone. And thank you, Professor Dicker and Yasso for the opportunity to talk about this interesting topic. So metabolic dysfunction associated with steatotic liver disease consists of a spectrum of liver disorder ranging from hepatic steatosis to a metabolic-associated osteopathetis with or without fibrosis, cirrhosis, and hepatocellular carcinoma. The current definition of muscle B consists of the presence of hepatic osteothesis together with the presence of at least one of the following cardiometabolic criteria, obesity, type 2 diabetes, hypertension, hypertriglyceridemia, or low HDL cholesterol. With this updated definition, there is a form of the disease called METZL-D that is metabolic and alcohol-associated liver, steatotype liver disease that are people with hepatic steatosis, cardiometabolic risk, and also a moderate alcohol consumption. As Professor Dicker has mentioned, METZL-D is the most common chronic liver disease and affects 38% of the population and its prevalence is increasing due to the global obesity epidemic. In this sense, people living with obesity can reach prevalence rates of 78, 75%. The pathogenesis of muscle D includes the adipocyte dysfunction and insulin resistance leading to hepatic steatosis. Adipose tissue dysfunction, and especially due to insulin resistance, is associated with an increased delivery of free fatty acids into the liver.

Speaker 3
04:52 – 04:57
In addition, dietary sugars can be used as substrates

Speaker 2
04:57 – 05:00
for the de novo lipogenesis in the liver,

Speaker 3
05:01 – 05:02
increasing hepatic osteodosis.

Speaker 2
05:04 – 08:16
This process sustained in the long-term can lead to the accumulation of toxic lipid intermediates that enhance lipid inflammation and fibrosis. In addition, we have a genetic component for muscle D. In this sense, variants in PMPL3 and other genes play crucial roles in lipid droplet remodeling, BLD secretion, and also the novel lipogenesis contributing to muscle D progression. However, the metabolic and genetic components of muscle D are different. In the metabolic component of muscle D, including obesity, we have a increased presence of substrates for the denormal lipogenesis in the liver and also a state of insulin resistance. However, in the genetic component of muscle D defined by this genetic risk score, we have a mitochondrial dysfunction that makes the liver less efficient to utilize these substrates efficiently. So mitochondria are key organelles in the onset of muscle pain. A free fatty acids delivered from the adipose tissue or from diet can enter into the mitochondria and undergo beta oxidation. And a free fatty acids can also be stored in the form of triglycerides in lipid droplets in the liver. However, at the stages of muscle D, the capacity of fatty acid removal via mitochondrial detoxification or the secretion of VLDL particles or lipopathy is impaired, leading to hepatic steatosis and also the accumulation of lipotoxic species such as ceramides or palmitic acid. During this process, mitochondria can undergo process of fusion or fission to respond to cellular energy demands. But in muscle D and particularly in patients with insulin resistance, we have an increased expression of genes involved in mitochondrial fusion, leading to the presence of elongated mitochondria. And if we observe the intersections of patients with muscle D, we will observe the presence of giant mitochondria. So regarding the role of adipose tissue in the onset of muscle D, as I have mentioned before, adipose tissue and particularly visceral adipose tissue can release fatty acids that reach the liver stimulating the renal voligogenesis. In addition, in obesity, we have had dysfunctional adipose tissue with an increased recruitment of immune cells that will secrete cytokines such as TNF-alpha or interleukin-6, and also adipocytes have a dysregulated secretion of adipokines that are pro-inflammatory

Speaker 3
08:17 – 08:19
like lentin, resistant, or bisfatting

Speaker 2
08:19 – 08:44
that impairs hepatic function. In addition to classical adipokines, the adipose tissue can also release extravaginal vesicles or exosomes that in obesity, its content is altered. These exosomes that was called by this out as obesosomes can trigger the secretion of inflammatory cytokines in macrophages.

Speaker 3
08:45 – 08:47
In addition, these exosomes secreted by

Speaker 2
08:49 – 17:11
the obese adipose tissue, the adipose tissue especially in visceral fat can impair healthier pathocytes, inducing insulin resistance and alternative metabolism. So from an adipocentric point of view, this enhanced lipolysis, the aberrant secretion of adipokines, alteric exosomes, and also the increased production of pre-inflammatory cytokines in adipose tissue, can induce steatosis, inflammation, insulin resistance, and fibrosis, contributing to muscle pain. So now moving to the mechanisms involved in the progression of steatosis to steatopatitis and fibrosis. We have seen how in the early stages of muscle death, we have an increase in the level of lipogenesis, but the chronic exposure of hepatocytes to fatty acids can lead to lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, and oxidative stress, contributing to inflammation and failure. In addition, the high fructose diets also alter intestinal permeability that is going to induce an increased presence of gut-derived inflammatory signals that will recruit and activate immune cells in the liver that will perpetuate this state of inflammation until death. In mitochondrial metabolic adaptations are lost in mass due to structural, molecular and functional adaptations. The mitochondrial respiratory chain is impaired in mice and it’s going to release, and it’s going to overproduce reactive oxygen species that will increase inflammatory pathways. In addition, mitochondria are in close contact with the endoplasmic reticulum. In muscle D, we have an increased accumulation of unfolded and misfolded proteins that we activate the unfolded protein response that is activated by canonical transducer either one alpha per ATF6. This sustained UPR is going to use mitochondrial dysfunction. And this process occur in the mitochondrial associated reticulum membranes or MAPs. that is the interaction sites between both organelles. We have seen how in early stages of mitochondria, we have elongated and large mitochondria. However, during the progression to mass, mitochondria become small and fragmented due to increased mitochondrial fission. So these fragmented mitochondria are more susceptible to mytophagy, that is the process whereby damaged mitochondria are removed. Damaged mitochondria are going to release an excess of reactive oxygen species and also mitochondrial DNA as an alarming and other signals that are inflammatory and they are going to induce the NLRP3 inflammation activation that in turn will induce the cleavage release of interleukin-1 beta stimulated the third form of pyroptosis. In obesity, we have an increase of mitochondrial dysfunction leading to inflammation activation, but also there is an overproduction of pro-inflammatory cytokines such as TNF-alpha, interleukin-1 beta, or interleukin-6, DAMS, and pumps such as lipopolysaccharide that also stimulate the inflammasome in the pathocytes and also in capillary cells. In this sense, in obesity-associated mass, we have an overproduction of NLRP3 and isofector interleukin-1 beta that will enhance the inflammatory response in these patients. So, the activation of inflammasome can induce a P-optosis, that is, an inflammatory cell cell death form depending on caspase-1 and caspase-11, but in mass we have also activated other cell death forms such as apoptosis that depends on caspases 3, 8, and 9, and is activated by TNF-alpha and cell death receptor ligands. And also there is another form of cell death that is called necroptosis that depends on the activation of the necrosomes, which in activity by TNF-alpha. In obesity, we have these ligands increasing the circulation and also in the liver. But these patients with obesity and muscle disease also have a decreased expression of the energy sensor AMPK. AMPK is an energy sensor that regulates mitochondrial homeostasis and blood sugar balance, but the reduced AMPK levels in muscle disease contributes to damage the mitochondria and also to increase inflammatory cell death. Now moving to the impact of diet in mass progression, dietary glucose, fructose, amino acids and fatty acids can be used for the de novo synthesis of triglycerides in the de novo lipogenesis, but also excess of carbohydrates will be fermented in the intestines to form short-chain fatty acids such as acetate that are beneficial, but also ethanol that is deleterious for the liver. So high-fat diets and high fructose diets can promote gut dysbiosis and this altered gut microbiome is going to show an increased production of pro-inflammatory metabolites such as ethanol and also LPS and an increased expression of short-chain fatty acids that are are beneficial, contributing to liver inflammation and fibrosis. During the progression of muscle D to mass and the severe forms of the disease, we can also observe changes in that micromutate that contribute to liver inflammation. In mass, we will have an increased expression or increased presence of clostridium or streptococcus that is deleterious for the liver and decrease presence of the microbial that is beneficial such as saccharomyces. So obesity is contributing to the development of muscle D and also mass. So it’s important in the clinical practice to identify those patients that are at risk of developing a disease. We have classic non-invasive methods for the diagnosis of advanced liver fibrosis, such as the formula FIP4, or imaging techniques such as transient clastography. In this sense, the IASL, together with the ESD and the ESL, has proposed this algorithm where to screen a muscle B in patients of developing fibrosis, fibrotic disease. So in people with type 2 diabetes, obesity with one cardiomyotabolic risk factor or persistently elevated liver enzymes, we will first check the feed for, and in case of these values, we will perform a transit elastography that if it’s over or equal E8 kilopascal, we will refer the patient to the pathologist, and in case of lower levels, lower volumes, we will intensify the management of comorbidities. In addition of these classic non-invasive methods, adipokines have been proposed as biomarkers to evaluate the risk of developing a mass

Speaker 3
17:13 – 17:13
in these patients.

Speaker 2
17:14 – 17:47
So for example, leptin and other interleukins that are released from the adipose tissue can activate hepatic acetylase cells that are the main subtype involved in the fibrogenic response. In the last years, GDF15, that is an adipokine, have been proposed as a biomarker for mass progression. GDF15 is a stress-induced factor that is produced by the macrophages within the adipose tissue.

Speaker 3
17:48 – 17:50
GDF-15 is released to the bloodstream

Speaker 2
17:51 – 20:19
and can activate in the brain its receptor GF-Bradyl producing appetite and inducing nausea, aversion and anxiety. In physiological states, GDF-15 levels are very low but they can increase in certain circumstances such as pregnancy, cancer and metabolic diseases such as obesity, type 2 diabetes and also MERS. The increase of GDF15 in mass is due to an increased recruitment of macrophages in the adipose tissue. And also, GDF15 is increased in the liver in patients with mass due to the activation of hepatocyte transcription factors related to stress. Adipokines have been also proposed as biomarkers for metal D. Alcohol consumption and thirdly, structure, the distribution and function of the adipose tissue, increasing the release of pro-inflammatory cytokines and also certain adipokines that contribute to liver inflammation and fibrosis. For example, in patients with alcoholic cirrhosis, we have an increased expression of leptin-bispatin and resistant that can be used as biomarker for the disease. Adipokines have also emerged as biomarkers of lean muscle D that is a form of the disease for those individuals with muscle D but normal body mass index. We know that BMI is not always a good marker for obesity and these patients with lean muscle D also have increased visceral adiposity. We know that during the progression of adipose tissue dysfunction, we have a decrease of adiponectin levels and also an increase of leptin levels. So as the adipose tissue becomes dysfunctional, we have a decrease of adiponectin-leptin ratio. And interestingly, in these patients with lean muscle D, their adiponectin-leptin ratio is decreased compared with normal weight control. so it can be used as a biomarker for the disease. So back to the title of this talk, we have seen how adipose tissue dysfunction, insulin resistance, lipotoxicity, mitochondrial dysfunction,

Speaker 3
20:20 – 20:22
inflammation and genetic susceptibility

Speaker 2
20:22 – 21:15
drive muscle B progression associated to obesity. So obesity is following the development of muscle B and its progression. So it’s important in the clinical practice to identify people living with obesity at risk for advanced liver disease, and we can use multi-step approaches such as PIFOR together with a transient elastograft. And finally, to conclude this talk, it’s important to state that managing obesity and exploring emerging biomarkers such as adipokines support precision medicine to prevent muscle depression and associated complications. So thank you very much for your attention. This is my group from Pamplona in the University of Navarra headed by Professor Rima Frude. And thank you very much.

Speaker 1
21:17 – 22:24
– Thank you very much, Professor Rodriguez for your outstanding really talk. And I really urge all to send questions. I’m sure you have questions on this very, very important, interesting talk. So we will discuss on and try to answer your question at the end of the next talk. So now I’m delighted to introduce Professor Causi. She is Professor of Nutrition and Endocrinologist, Diabetologist at the Lyon First University and Hospice Civil de Lyon in France. Professor Cousley leads a clinical and research program on metabolic liver disease at the Lyon Hypatology Institute, focusing on type 2 diabetes, obesity, and muscle. In this presentation, she will highlight the multidisciplinary approach to muscle management in people living with obesity, including diagnostic tool, care pathway, and opportunity to enhance clinical outcome. Professor Cousley, the floor is yours.

Speaker 4
22:25 – 45:25
Thank you very much for this introduction. I’m really happy to participate to this webinar and I will talk indeed in multidisciplinary management strategy for mazelein in people living with obesity. As you know, there is, sorry, these are my disclosures. So as you know when we are dealing with the management of patients with obesity, we are looking for many other comorbidities or maybe obesity-related complications, and today I would like to focus on the liver. It’s a really important organ that is key into the metabolism, as we just seen in the previous presentation, but it’s also a matter of finding out which patients do have a very severe liver damage. And here you have, for example, one definition that has has been proposed for clinical obesity. The point is here that we really need not only to look for steatosis, but we really need also to be able to identify those who has MASH. And as MASH is difficult to apprehend in a non-invasive way, what we are moving forward is to really looking for fibrosis. You are probably aware as well that the field has changed a little bit with a new definition, I just wanted to drive you a little bit back in how you can really make sure we are talking about Maserdi and thinking also maybe into other mixed etiology. Here you can see that the first thing is to identify stereotypic hepatic stereotosis. This is really easy to do if you perform, for example, abdominal ultrasound, you will be able to determine if the patient has stereotypical liver disease. And as a reminder, the new definition needs to also include cardiometabolic criteria. In our case, it’s very easy because we are managing patients living with obesity, so this is one of the criteria. So most of the time in my clinic, the patients do have this cardiometabolic criteria. And finally, we need also to assess alcohol consumption. This is really important. It’s a major cofactor for progression. And this also enables you to see whether your patient actually has a mixed etiology that we know called metialdi for those who drink excessive alcohol consumption greater than 20 gram per day in women and 30 gram per day in men. And if not, then your patient is suffering from mazeldi and then the goal is to determine whether he has at-risk measles such as MASH or fibrosis. How to do that? We have touched upon this on the previous talk. I would just like to really take the time to explain what is the strategy and I will for that talk more about the joint ESL/ESD/ESO guidelines that has been released last year. And you need also to know that this strategy is universally recommended in many other guidelines such as the guidelines for diabetes and also gastroenterology setting. The first step, as you heard previously, is to perform a FIP4. As a reminder for those who doesn’t know yet the FIP4, and I hope there’s not many of you, it’s very easy to do. just need to have the age, liver enzymes such as AST, ALT and the platelet count. It’s a free formula, there’s a lot of calculator online, but what I really suggest that you can do and implement in your clinical practice is to have an automatic calculation. This is something that can be implemented by the biology department and this is the case in my department, we have automatically the calculation. Another point that is very important is the threshold. If you look here, there is a low threshold and it’s very important to remember 1.3 here because this is the value where you can safely rule out the risk of advanced fibrosis. Again you see that the negative predictive value is pretty high and as long as the value of liver stiffness increases, the risk of having severe fibrosis, F3, F4, or even cirrhosis increases. And of course, if you have very high value up to 15 kilopascal, the positive predictive value increases as well. So, as a summary, then, as you’ve seen before, if you your transient elastography is about 8 kilopascal, then you need a referral to an hepatologist. If not, you can manage your patient in your daily practice and just try to provide counseling for weight loss management. As this cartoon is pretty complicated, there’s been also a global consensus led by experts in the field that just try to make it a little bit easier. Again, the screening for advanced fibrosis is recommended if you have a patient living with obesity and additional cardiometabolic risk factor and just go with an easy threshold, FIP4 greater than 1.3. And in patients with older than 60 years old, you can also use FIP4 greater than 2. And if this is the case, there is a need to move to a second like that test, such as transient elastography in order to determine the risk of fibrosis. So this cartoon is a little bit easier to remember, but the strategy remains the same. So if we have time, I just wanted to share with you our experience. I’ve been leading a prospective multicenter study performing for the Diabetology and Nutrition Department in France. And what we wanted to do is enroll patients at risk with measles, LD and type 2 diabetes and/or obesity, class 1 and 2, age between 40 and 80 years old. And the idea was that usually what we have in our hand in the department is the first-line test, the FIPRO, but we also believe that if we are equipped with liver stiffness measurement in the diabetology and nutrition department, we would be able to then perform a better screening for advanced fibrosis. And so the idea was really simple. We just move all the NITs that are actually available, such as a liver stiffness assessment using a fibroscan, but also patented tests such as the ALF test, which can be an alternative to transient elastography in some clinical setting, to be able to look at the the diagnostic performance of this strategy. You see that we were enrolled in the first publication that has been published previously this year, more than 654 participants, the majority living with obesity, 73.7. It’s a high-risk population. They have a large proportion of a patient with type 2 diabetes, 87%, but also hypertension, dyslipidemia. So it’s really a multiple risk factor population. Just to show you, if you had to perform the FIPRO in this population, the majority, 53.6, would be ruled out and would not need any further workup or assessment using a second line test. We also, as I’ve shown you, perform liver stiffness to the whole population, regardless of the FIPRO. And in this case, you’re able to rule out with obesity below than eight kilopascal, the majority, 80% of our population will be not, will not require referral in hepatology, which is reassuring. And here you can see that the rest of the 19% would have elevated liver thickness. And just to summarize this result, because I don’t have the time to go into the details, we also look at the diagnostic performance using hierarchical composite endpoint, depending on the presence of liver biopsy and magnetic resonance elastography. And what we were able to determine is that there’s actually a good performance of this two-step screening. It is not perfectly, it would not classify 100% of the population properly, but if you engage your patient in this two-step screening, you will be able to rule out with a large majority of patients, such as 81% true negative patient that you will not need to refer to a pathologist, but most importantly, you will able to narrow down the 12% patient that you will refer to a pathologist that really need to see a liver specialist in order to further engage with management. So with that said, one of the other things that you need to be aware, especially as obesity, in terms of obesity management, it’s based on our experience, but this has been also related by other teams. the grade of obesity remains an issue, especially with very severe obesity greater than 40 kilogram per meter square. These are retrospective data when we look in our center and also we have a multidisciplinary board with the hepatologist and we look at whether we were able to determine the presence of absence of advent fibrosis using the co-currency of multiple noninvasive tests and also potentially the presence of, again, liver biopsy or magnetic resonance elastography that are very accurate tools to classify the patient for advanced fibrosis. And our observation is that as you see with the greater obesity that increases the proportion of patient that remain with an indeterminate status because they have discordant value for liver stiffness but with reassuring value, for example, with a patented test such as the FIBO test is quite high and it’s not really easy to then put a diagnostic on the patient. There’s many reasons for this, potentially because it’s really difficult to also think about doing a liver biopsy in this patient, but just be aware that there’s limitation and one of those are potentially also overestimation of the liver stiffness. And that’s the reason why we also look at other solution. One of those would be to calculate another score, which called the Agile 3+. incorporate the liver stiffness assessment, but you also put into the algorithm the presence of diabetes, the gender, the age, and also AST, ALT, and platelet counts. And in that, if you apply this in patient with BMI greater than 35 with elevated liver stiffness, and you just want to make sure that it’s not only an overestimation of the liver stiffness, but really a high suspicion for advanced Maserdi or advanced fibrosis, then you can calculate the score. It’s very easy to do with an application online with the Fibroscan application, and you can be reassured you need to refer the patient in the pathology, and if the score is low below 0.45, you can actually rule out the risk of advanced fibrosis. So this is a proposition. It needs to be validated, of course, but at least it can give you some tools to move forward and really be confident in the way you analyze the liver stiffness assessment in your patient. So now it’s time to switch to GER. I will also talk about what you can do once you have identified a patient with myelody and potentially a patient with more severe stages. As you can see, again, going back to the ESL/ESL/ESDESO guidelines, weight loss management is the cornerstone for the management of myelody as well. The target is to lose more than 7 to 10 percent body weight, and these are the thresholds that actually can enable to improve MASH lesion and also induce fibrosis reduction. And we are fortunate because there’s more and more tools to achieve that. So of course, I will talk about lifetime modification, but we can also consider increting base weight loss and also consider biatric surgery. So let’s go over all of these things. Lifetime modification, I believe it’s very important. This is really true and meaningful to engage the patient in a change for their lifestyle. The goal is really to reduce calorie intakes and any mean that could achieve that would have a beneficial effect in steatosis and potentially also in margin fibrosis if you reach more than 10% weight loss. We know also that there are some type of food that we need to avoid such as sugar, sweetened beverages because they contain a lot of fructose that are not really good because they can stimulate the de novo lipogenesis. And also processed food have been consensusly linked to not only Maseldi but also more severe stages of Maseldi. And as I told you before, alcohol consumption is also very important. There is no safe threshold for alcohol consumption when patient has liver disease. This includes Maseldi. And it’s really important to encourage the patient to stop drinking. Alcohol, so in a nutshell just you need to advise your patient to quit alcohol or reduce the maximum because there is no safe amount of alcohol to drink. And then Mediterranean diet of course is really important. Here I’m showing you one of the example of the lifestyle intervention trial that has been very well conducted with biopsy before and after and as you can see A patient did have a MASH resolution and fibrosis reduction, especially those who achieved this 10% body weight loss. But unfortunately, and this is something we are usually facing in our clinical practice in obesity management, it’s difficult and only 10% of the patients that were enrolled in this intensive lifetime modification program achieved the 10% body weight loss. So, we do need something else. I think I didn’t talk about coffee because I was interrupted, but coffee is also potentially beneficial, but this is only based on very large epidemiological study, mostly retrospective, but just so you know that coffee is sometimes popping up in guidelines. It seems to be safe and also potentially beneficial. So if your patient drinks coffee, there’s no need to stop and on the contrary may be good due to potential antioxidant properties. So as I said what we need really is to encourage patient to change physical activity is also very important. Usually it’s mostly activity with resistance that is the most beneficial effect but in a practical way, we would just like to tell her the physical activity to the one that the patient can commit and sustain. And what I would like to highlight here is that really it’s a multidisciplinary care. We need dietician, we need physical educator, we need behavioral counselor and therapist in order to achieve all this goal. And this is really important. And the more we are doing it, mostly the most efficient will be the management, including when then we engage patients in therapies or in bariatric surgery. So let’s move to therapies, and I will mostly focus on the anti-obesity therapies. As you can see, the guidelines also recommend GLP-1 receptor or dual-GP-1 receptors, such such as tears appetite, but also bariatric intervention that are both options to manage patient with obesity and measles. So let’s go to the most recent results. I’m sure you probably heard of it. Semaglutide 2.4 milligram Ritley has been tested also, you know, large randomized control trial, phase three randomized control trial in MASH. This is the essence trial. As you can see, it’s a positive trial with a significant higher proportion of patient with MASH resolution, but also fibrosis improvement compared to placebo. And this led to the FDA approval of semaglutide in the indication of MASH in the US last summer. So this is really now a future therapy for MASH that we can propose to the patient, but knowing also that of course it will have a good benefit also for obesity management. He has been tested also in patients with compensated cirrhosis. It’s a negative result in terms of fibrosis improvement and MASH resolution, but what is good to know is that the safety profile was similar to what we experienced with semaglutide, nausea, diarrhea, and vomiting, but no alarm and no alteration of the liver and kidney functions. So, in this population with compensated MASH cirrhosis that was only performed for 48 weeks, we don’t expect a strong benefit in terms of liver, but at least we know that it’s safe. And if you engage patient for this treatment in order to lose weight, you will still be reassured that there’s no safety concern in compensated cirrhosis. And finally, in terms of the new generation, the dual GFGLP1 receptor agonist, Tiersepatide, it has been also tested in a phase two randomized control trial of 62 weeks, including patients with MASHF2 and F3. This is the standard design of patients with a clinical trial with MASH. Here you can see that you have a dose response with Tiersepatide in terms of MASH resolution significantly higher compared to placebo, up to 62% compared to 10%. And no dose response, but significantly higher proportion of patients with liver fibrosis improvement versus placebo. And now we need to see results of the phase three that is currently being launched. And we will have additional results of the efficacy of tirzepatide in mazodian mash in the future, but we need to wait a little bit longer than for semaglutide. Finally, biotic surgery is also an option. I know I need to catch up a little bit the time due to technical issue, but just wanted to show you that we have data showing that we are about to achieve a very strong proportion of mesh resolution. We have also a randomized control trial that have assessed bypass versus sleeve gastrectomy compared to lifestyle that demonstrate that it actually indeed induced significantly higher reduction of MASH and fibrosis improvement. But I just want to draw your attention that still, lifetime modification did improve MASH and fibrosis also, but of course, bariatric surgery performed better. And we have also long-term data. This is again the study from Francois Patou in Lille. Then even after five years, when we repeat the liver biopsy, you do see the sustained effect for MASH resolution and the effect for fibrosis improvement appears after five years, where after one year it was not so predominant. But you see that after five years, fibrosis improvement here is much better with a higher proportion of patients with F2. It is easier to improve liver fibrosis in patients with fibrosis F1 and F2, which patients with advanced fibrosis is harder, but you can still expect to achieve this improvement for 45% of them. So I will go quickly to this. We have reviewed all the potential effects of this anti-obesity medication and bariatric surgery. In this This cartoon, you can see that you are, of course, able to improve mass and fibrosis. We have evidence of improvement of major liver outcomes with bariatric surgery, and we will need to have the final result of the ongoing phase two randomized control trial with semaglutide and telzepatide in order to also say that we are going to improve liver-related outcome. But as a reminder, but I’m sure I don’t need to go over to the detail here, we also do have very strong profile and beneficial profile for many other aspects that are important in MasLD, including cardio-renal protections, obstructive sleep apnea, and of course, control of type 2 diabetes. So I just wanted to touch upon the most recent therapy that has been also approved in MASH. It doesn’t induce any weight loss in this case, but just I think it’s important that you just know that resmetirum was the first anti-MASH therapy approved two years ago in the U.S. and now is approved in Europe. And it’s a thyroid hormone receptor beta-selective agonist that actually restores the thyroid metabolites into the liver. And you see that these are the phase III randomized control trial that led to the EMA and FDA leading to a significant higher proportion of MASH resolution and fibrosis improvement with a good safety profile. Again, we are facing diarrhea and nausea with this therapy, so something we are quite already used to deal with anti-obesity medication. And with that, this is my last slide and take-home messages. There’s many things you can do once you have identified a patient with Mazeldi and also severe cases. But of course, lifestyle modification remains the roots of the management. And then, of course, you can, if needed, go for anti-obesity medication, such as GRP-1 and GRP-1 agonist, and also bariatric surgery. And I didn’t talk much about cardiovascular risk management, but please remember that this is also super important and there’s no contraindication to initiate statins in this including when they have mighty elevated events. And I would like to thank you for your attention. And we’d be very happy to take your question. Thank you so much and apologize for the technical issues.

Speaker 1
45:27 – 45:48
Thank you for Professor Koze again for an outstanding talk. And I think we have many questions. So I will read the question and you can both relate and try to answer. So the first question is, What do you think about intermittent fasting in prevention of treatment or treatment of muscle?

Speaker 4
45:49 – 47:00
Intermittent fasting and treatment. Yeah, I’m happy to start. I think it’s been shown that there’s a benefit in terms of at least non-invasive improvement and potentially steatosis. The only concern is the sustainability of this type of diet and then the risk to regain weight, which is always an issue. And that’s why I’m not really in favor and I would need to have long-term data in order to assure that this is good. And I’m not aware of very good studies that have looked at patients with liver biopsy before and after. So actually, we don’t really know if it’s improved MASH or if it’s improved liver fibrosis. So I would be cautious. And I think to be too much into this type of thing. But, well, if the patient wants to engage in that, we really need to make sure that it’s going to be for the long term and also that the quality of the diet will be improved and not only just time restrictive diets. This would be my take on this.

Speaker 1
47:03 – 47:25
Okay. There is two questions about children adolescents. So the first one, are the threshold of FIP4 the same for children? And also, do you have experience in pediatrics? Are the diagnostic tests, meaning the Fibroscan, are the same and are the cut-off values the same?

Speaker 4
47:29 – 48:17
I guess for me, again, so I’m not a pediatrician, so I don’t have any personal experience. I think FIPR would be a very bad marker because he has age. And so really in young people, this is really not the good marker. You can go with simple things like the AST/ALT ratio, for example, but I’m not really an expert in that, but really FIPR, I don’t think it’s suitable. There are some studies looking at liver stiffness that could be, I think, interesting, But it’s really difficult for me to comment on more on this because I’m not an expert in managing young children. But for sure, FIPOA is not very good. And I think there was another

Speaker 1
48:17 – 48:22
question. There was this guy. It’s the same, the cutoff.

Speaker 4
48:22 – 48:23
The cutoff, yeah.

Speaker 1
48:25 – 48:50
So Professor Rodriguez, I wanted to ask you regarding the anti-inflammation effects of the GLP-1 and GIP. So do we know much more than as Professor Koza showed us, it’s a very impressive effect on the reduction of fibrosis. So it’s anti-inflammation or what do you think?

Speaker 2
48:51 – 49:57
Yes, first it’s important to state that the liver does not express a receptor for GLP-1. So all the the effects that we are observing in those patients treated with semaglutide or other ERP or receptor agonists are indirect. So they are due to the weight loss, due to improvement of the adipose tissue function, due to the improvement of insulin sensitivity, but not due to a direct effect of the drug into the liver. So it’s important to state that because today there is no receptor for YLP1. Maybe those drugs that are also targeting glucagon receptor that is expressed in the liver, maybe they can increase this anti-inflammatory and anti-steroidic, anti-fibrotic action. But today these drugs that only target YLP1 are they are improving the liver by indirect effects. effects.

Speaker 1
49:59 – 50:20
OK. Question for Professor Fulbrek. So she is congratulates both of you on the outstanding talks and we want she want to ask Professor Kowsley, what evidence do we have about obesity management medication for muscle and mass fibrosis in the elderly? Patients.

Speaker 4
50:21 – 51:41
Very good question. Thank you. I’m afraid very few, very data indeed and I think we would need yes to same as for the using patient with obesity as a whole there’s many question about muscle functions sarcopenia and etc that we really need to we need more data I think it’s our role as academic to run this this trial and analysis and the concern is potentially also with older patients and more severe stage of myasthesia such as pre-cirrhosis or cirrhosis or advanced fibrosis, we know also that there’s a strong association with sarcopenia. So, it is really important that we provide data and safety and I think the management also, as we’re talking about multidisciplinary management, the diet would be very important, and make sure that the protein intake remain sufficient and also physical activity in order to promote and maintain muscle mass would be really important, especially in the elderly population. So thank you for this question. I think you are raising very important clinical question that we need to answer.

Speaker 1
51:42 – 52:16
– I think in general, in the elderly population, we don’t have enough studies and evidence and knowing that the adipose tissue in the elderly become much thicker, and we have to really be much more aggressive in one side than the other side, the sarcopenia and the effect on the muscle is also very important. So I join your call to do much more studies in the elderly. Professor Rodriguez, another question, when is fibrosis not reversible and how could we really clinically assess it?

Speaker 2
52:18 – 52:34
we can deactivate the cell types that are inducing fibrosis. So there are processes to deactivate hepatic esterate cells. So answering is liver fibrosis reversible?

Speaker 3
52:35 – 52:35
Yes.

Speaker 2
52:37 – 52:53
Currently we have drugs that can decrease the inflammation, maybe decrease the hepatic esterate cell activation. So maybe we don’t reverse totally the life of fibrosis, but we can improve it.

Speaker 1
52:55 – 53:16
– Okay. Thank you. And another question, very interesting question. Considering the improvement in NASH or MASH and fibrosis after lifestyle modification, do you think coffee consumption plays a direct hepatoprotective role or its effect mainly secondary to weight loss and metabolic improvement?

Speaker 4
53:17 – 54:34
Yeah, a good question. As I mentioned, the association with coffee is really mainly large epidemiological study that are mostly retrospective and there’s no intervention looking at the effect of caffeine or coffee consumption. So it’s really difficult to say. I’m not sure we really understand that. It’s just something that is constantly pop up in this retrospective studies and epidemiological studies. So, there may be a role, whether there’s confounding factors, such as diet and other things, I really cannot tell. And I don’t think we will have one day an intervention using coffee. So, we’ve been working on the update guidelines for nutrition in liver disease. And to be honest, then coffee is just not recommended. Don’t recommend someone who doesn’t drink coffee to start. I mean, this is really not something that will change something meaningfully or clinically meaningfully as a whole. And there are so many other things you can do for the diet. So don’t force someone to start coffee. And the last question for both of

Speaker 1
54:34 – 55:18
What I’m noticing in my clinical work is that the natural history of patients with MASH or MASLD is differently from those who are alcoholic-cirrhotic. I think we have much earlier deterioration in the function. So what do you think about this clinical observation or can you tell us what are the hints in those patients clinically that, you know, primary physician or internist can really look into it and start to suspect in muscle D or mesh?

Speaker 2
55:20 – 55:22
– I think what I was to make…

Speaker 1
55:23 – 55:24
– Please, please, go.

Speaker 2
55:25 – 56:16
maybe first ethanol is enhancing the inflammatory response in the hepatocytes and maybe hepatocyte ballooning is one of the pathological features that can be observed in these patients. And also, ethanol is contributing to adipose tissue dysfunction, so indirectly is leading to more inflammation that is reaching into the liver. So maybe this is why alcoholic liver disease and metabolic liver disease are different because we have an additive effect of this ethanol that is increasing the pro-inflammatory phenotype of the adipose tissue and that visceral adipose tissue is in direct contact with the liver with the portal veins.

Speaker 3
56:16 – 56:19
So we have a very strong inflammatory response

Speaker 2
56:19 – 56:45
that is impacting the liver. And also ethanol is increasing the inflammation, increasing the recruitment of immune cells and is enhancing these forms that leads to a pathosized cell death. So maybe we observe more inflammatory cell death in these patients with excessive alcohol consumption.

Speaker 1
56:48 – 56:50
– Okay, Professor Kozy, you wanted to add something?

Speaker 4
56:50 – 58:38
– No, I just wanted to add also that in the case where there’s no excessive alcohol consumption, but as the guidelines really highlight, it’s the association of multiple metabolic comorbidities that usually should trigger, like really, if you have a patient with obesity, but also hypertension or type two diabetes or dyslipidemia, these are really patient at high risk. And I agree with you, there are some different patterns, but also based on our experience, and I really want to share that in order to make you realize that once we started and I showed you data from our study when we implemented the screening in the department four or five years ago now, we really had surprises of identifying patient with compensated cirrhosis that had no symptom, very, very mildly elevated liver enzyme that I would have suspected to have cirrhosis. And we were able to really find this patient a diagnosis and no one knew, not the doctors and not the patients. So I think it’s really important just to realize that if you don’t screen and use the non-invasive test in order to verify and risk stratify your patient, you may miss patient just based on your clinical impression because it’s very difficult and most of the time the one with cirrhosis, because they have less inflammation, the liver enzymes drop. So you can be firstly reassured. So this is also really important. And, you know, I’m a strong advocate of the screening, but I really do hope this is something that would convince the audience that multiple risk factors, but then don’t just trust what you are seeing and the numbers, liver stiffness and people is useful.

Speaker 1
58:39 – 59:49
Yeah, absolutely. We see the same trend. We were very surprised to see those patients with obesity and we start to see lower numbers of platelets. And then we measure a portal hypertension and we found it. So, you start to find those patients with obesity and muscle density, rosis low platelets count. And then when you measure, you find those patients with rosis. So that’s what I alluded to. And I’m happy that you also find those patients. So I want to really thank both of you. It was really a pleasure and my honor to host you in this webinar of Yasso. And I really urge everyone to join us in the next one on the 25th of November, when we will present the first time guidelines of Yasso to treat obesity. So please, I really invite everyone to come to the next webinar. I want to thank Professor Rilges, Professor Cowsey, and all of you that you joined us today. Thank you very much.

Speaker 4
59:51 – 01:00:21
– Thank you. .