Diagnostic Screening and Clinical Referral

Welcome to this peer voice activity . To access the entire activity, including supporting material , go to w ww . peer voice. com slash YW G . This activity is supported by an independent medical education grad from Madrigal Pharmaceuticals. Hello, I'm Hanalay jarin and from the University of Helsinki, and I'm delighted to welcome Dr. Cyril Kaisi the University of Lyon in France . Over the next twenty minutes or so we are going to focus on the subject of MASH , metabolic associated stelto hepatitis in the endocrinology clinic, especially in patients with type two diabetes . This is a very pertinent topic given that the first two medications for treatment of mass were recently approved also for use in Europe . These medications and the non invasive tests you can use to identify patients at risk will be discussed by Dr. Kausi . I will start by discussing the current definition of metabolic associated static liver disease or masculine, its mechanistic relationship to the metabolic syndrome of type two diabetes and emphasized the importance of liver fibrosis in mass in predicting mortality . According to the current definition of masold , you first have to diagnose pterosis , which is usually done by imaging or a biopsy , but it's an incidental finding as screening is not recommended . Then the patient should have a cardiometabolic criteria which is these criteria are identical to the metabolic syndrome criteria which the endocrinologist is familiar with obesity, increased blood glucose, blood pressure , increased triglycerides and low HDL cholesterol. If you have one of these, it's sufficient to diagnose mascal. Note that the diagnosis of metabolic syndrome requires three out of five , then you need to assess alcohol consumption if it's less than twenty grams per day in women less than thirty grams per day in men the person has muscled and amongst these pati ents there are patients who have inflammation and ballooning on histology . And implies that they have mash and then mash can occur also with fibrosis . If you have F three, F four states fibrosis, you have advanced fibrosis , and if you have Form , you have cirrhosis . Then the new diagnostic criteria also include a category where alcohol consumption exceeds twenty grams, but it's less than fifty grams per day in women and or is between thirty to sixty grams per day in men. And this is a condition called muscle with moderate alcohol consumption . And if alcohol consumption is higher than that, then the person has alcohol has ALD and then we have rarer causes of steratosis, which you may need to explore if the patient does not have any cardiometabolic criteria . Now, we know that mascal is a very good obesity independent predictor of type two diabetes. There are over twenty prospective studies showing this and also predicts not surprisingly because it's closely associ ated with metabolic syndrome, cardiovascular disease . And then some patients may develop mass, advanced fibrosis, and even some may develop hepatocellular caracinoma . Now how is the metabolic syndrome type two diabetes related to this risk of liver disease . We know that the causes of why the liver becomes statotic, it's overreading and physical inactivity , leading to substrate excess, high glucose, high lipids, high amino acids , and also in these patients the adipose tissue becomes inflamed and dysfunctional and releases excess amounts of free fatty acids, which are then incorporated into triglycerides in the liver thus making the liver fatty. The fatty liver is resistant to the action of insulin to inhibit triglyceride production leading to elevated triglycerides. Also it's resistant to the action of insulin to inhibit hepatic glucose production leading to hyperglycemia . So the fat de liver is essential in an insulin resistance in the fat delivery, it's essential to explaining why patients with metabolic syndrome have hypertractus , low HDL cholesterol, high glucose and therefore have a high risk of type two diabetes and adheral thrombotic vascular disease. Now these patients who have these components of the metabolic syndrome also have a highly increased risk of major liver outcomes . If you have type two diabetes alone, the cumulative incidence of major liver outcomes over fifteen years, according to this huge swedish study was less than one percent . If you have a full blown metabolic syndrome, the incidence is closer to three percent . So metabolic syndrome and liver disease are very closely interlinked . The parameter which really predicts mortality in liver disease is fibrosis . We know that fibrosis states is a key . And here you can see that the mortality rate ratio increases to forty two if fibrosis states progresses from zero to four . The good news is that these fibros is states can be assessed fairly accurately, non invasively using elast ography as we will be discussed later . As to the question, how common is liver fibrosis then in type two diabetic patients which are the ones the endocronologist especially C . This is a prospective study of five hundred and one patients from Professor Roet Lomba's lab . And here fibrosis was assessed with a state of the art tool magnetic resonance Elastography or MRE , and it was found that about fourteen percent of type two patients had advanced fibrosis and clinically significant fibros is was observed in approximately one out of five people in type two diabetes . So this is not a very rare problem and And we need to identify these patients and treat these patients and that is why we have then the next presentation . So this is the brief was the brief introduction to muscle, its definition , its relationship to the pathogenesis of type two diabetes . And also I tried to emphasize the role of fibrosis in predicting future risk . And then I would like to ask Dr. House , whether you have some thoughts of what I just said or questions or comments , whether you agree or would like to add something . Hi everyone . Yeah, thank you, Anna. I think you really perfectly unphases the fact that we do see in our clinic as endocrinologist patients with type two diabetes and potentially those also with multiple metabolic mobilities which have a risk for advanced fibrosis . I think this is really important for endocrinologists and diabetologists to acknowledge this and also be able be more aware of the liver impact and potentially the risk of advanced fibrosis. Indeed, there are increased risk for liver outcomes such as HC for example, which can be really improved if you enter the patient in a in a screening and a surveillance. So in a nutshell, I think really this is setting the stage for just adding another complication or boxes to check when we do the annual checkup of our patient and just make sure that we are also aware of the library status of our patients. So thank you. And then I think it's time for Dr. Kalsi to move on to discuss treatment and diagnosis of MASH . Welcome back . Having focused on why we should all be identifying and referring referring patients with MASH with Dr. Hicki Yavinan. I will now take a look at the new treatment option for patient with MASH and how we can efficiently and with that I mean quite easily access at risk patient to ensure timely referral and pronoun intervention , which could actually really make a difference for our patients. So you probably already heard, we have new targeted treatment for MASH . Two therapies have been approved actually both for marsh and modern itemed fibrosis F two and F three . One is Wesmetrome. It's a normal thyroid hormone receptor bed agonist with a very selective action with minimal impact on the systemic pteroderman levels . It's been approved in Europe in august twenty twenty five . It mainly acts directly in the apaticide, reducing inflammation, reducing denomial hypogenesis with a beneficial increase in the mitochondria metabolism and this results in the decrease in the oxidative stress, inflammatory and hypotoxicity. The other one is semigratite. You are probably more familiar with it. It's an injectable GLP one receptor agonist . There is no receptor of GLP one receptor of GLP one in the ap atocyte, but the mechanism of action is mainly linked to weight reduction and reduced metabolic dysfunction overall , which also lead to reduced inflammation, hypogenesis and n regonulation of fibrosy regulated . These two therapies have been tested in a phase three randomized control trial for Resmetabron is the mastronized trial that provide inter im analysis with at fifty two weeks of therapy looking at two different endpoints. These are the classical endpoints that we assess in mash therapies, mash resolution of fibrosis improve ment at two dose riskimum eighty milligrams or one hundred milligram daily versus plac , a patient achieved significant significant higher proportion of patients achie ve mash resolution versus placebo or phagosis improvement, and we do observe also a change in LDL cholesterol in patients treated with material compared to placebo . Importantly, in the maestromash trial , there were patients enroll ed with already stable doses of GLP one receptor mainly for type two diabetes indication. And subcroup analysis has shown that the efficiency remained the same for mesh resolution of fibrosis improvement with though no differences observed based on the background GLP and receptor agony therapies. The safety profile is really we are showing. The main adverse event were diarrhea and nausea in patients treated with rhysmatic rum, these were mostly mite to moderate and did not induce a major number of discontinuation . When we look at the result of the Essence trial, which is the phase two brand m conticerol tri al that assess the efficacy of semagnitide two point four milligram weekly versus flexible . Again, a significantly higher proportion of patients achieve this two endpoint mice resolution versus plastibo or reduction of liver fibrosis of at this one stage that was ring up mash with the usual side effect observed in GLP one receptor agonist therapy such as GI , diarrhea nose abdominal pain . And we will next discuss the non invas ive test and how we can use them to identify patients who will benefit from this new liver targeted treatment. So let's back to how we can assess the risk of having mash with significant abdomen Thybrosis. It's a pretty straightforward process. I'm showing you the two step algorithm that is recommended by the European guidelines, which is which is a joint guideline between the European Society of Diabet ology, Obesity and Liver Disease . First, you start by identifying the patient at risk and of course, as we mentioned earlier with Dr. Aiki Yavin, a patient with type two diabetes, obesity with at least one cardiomabolic risk factors and there are two steps. The first line test is a FIP four score , which allows you to estimate the risk of having advanced fibrosis . If the score is below one country , there is a very low risk of having advanced fibrosis and then you can risk clatify your patient as a low risk . If it's above one point three , there is a risk and then you need to consider performing a second line test which is BCTE preferably or alternative test with a higher diagnostic accuracy andespecially a higher positive predictive value in order to further determine if your patient has a risk of advanced fibrosis. And as you can see in the guidelines, if the VCT is above eight kilopascal. The patient needs to be referred nepatology. If it's below eight kilopascal, you need to intensify the management of commobites, but there is no need to refer the patient, but make sure you reassess them. So what is FIP four? Fip four is a very simple score based on h, AST, platelet count and ALT . As I already studied mentioned, there are different cutoffs in order to assess the r isk. What you need to remember is the low cutoff one point three for patient below sixty year or below two for patient older than sixty year enable you to rule out with a very high negative predictive value the presence of advanced fibrosis. There's a higher cut off two point six seven , which is really in favor of having advanced fibrosis. And in this case, also you need to refer the patient in epithology and there's a gray area indeterminate zone where you would need to perform an additional test . This additional test could be vibration control trans and elastography , which allows you to also measure the control attenuation parameter, which can confirm the present of tatosis with different calor . And most importantly, we'll assess the liver st iffness, which is correlated with the presence of liver fibrosis. This has been well validated in large and multicenter international courts with a local of below eight kil opascal, there is a very low risk of having advanced fibrosis and then the patient can really stay in the endocrinology department and having all the management of chomobidities . If the patient has a high value grader than twelve. There is a high risk of having advanced fibrosis and between eight and twelve it's intermediate to a high risk, but the patients still need to be with her for additional worker. We did test this second shell combination and two step strategy in the multi center study at performing diabetology clinic. More than six hundred patients have been enrolled with masoD and I'm just showing you briefly the main results when we when we apply this two step strategy , the majority of our patients have a low risk of advanced fibrosis based on FIP four. You see that fifty four percent will be risk classified as having a low risk . And for the one who has an intermediate score when you perform secondary the VCTE , you you correctly risk classify your patient with a very large number of patients classify as low risk which are true truly patients that did not have any advanced hygosis and approximately fourteen percent of the population screen need to be referred in nepatology . If and the guideline says also that if obvious is not available in your clinical setting , there's an alternative which is the ELF test . The elf test is based on three blood based biomarkers that are linked to the presence of fibrosis based on the livobiopsy. It's urinoric acid, proc anterinal peptide and the tissue inhibitor of matrix methaloprotane is one . Again, to cut off, if the Earth test is below one point two, you can exclude and rule out the presence of ad vent pagosis and patient with an HELP test grade on nine point eight would need to be referred. We did also test this two step strategy in our carts. It's a reasonable alternative strategy perform a little bit less well as BCT, but still you will appropriately classify your patient . So as a summary , of course, if your FIP four is high grader than two point six seven, you need to refer. There is no need to try to perform a second line test for those with an intermediate result above one point three up to two point six seven . You can either perform a Nerd test or BCTE and refer based on the higher threshold In gastronology or hepatology clinic, it would be important to wafer because the patient will be then further testing and there will be assessment of the indication for antimash therapies. They can also potentially access to other clinical trials that are ongoing and most important ly they will enter in a follow up for a patient with cirrhosis, this is really important because they will be able to engage in HC surveillance and have appropriate care. So with that said, I think I would really love to have Dr. Hiki Yabin opinion on this strategy and the importance of potentially difficulty to access to VCT and health. And so do we really need this testing and the chronology , what about just screening for MesLi? What are your thoughts on this Dr. Kiominan ? Yeah, well thank you , Dr. Karsey, I think this presentation raised many important questions. One which I had in mind was based on the treatment trials you showed what I understand you the hepatologist doesn't have to take a libr biopsy anymore. So which threshold do you think BCTE, for example, should exceed all other things being equal when you start when you start pharmacotherapy. That's an excellent question. And indeed this is also very good news for the patient. There is no need for liver biopsy to have access to the antimash therap ies. There has been guideline released by our colleague from the U. S. that has been the first to use this treatment and based on VCTE if you have elevated livestiffness about eight or ten kilobascal, you could consider the therapy for sure. I think really the one with elevatifiness greater than ten kilopascal are those who are at higher risk of librated events . So these are mainly the ones that we would like to target, but make sure to exclude the presence of cirrhosis because there is no indication yet in patients with cirrhosis. So if this is above twenty kilopascal and this is an exclusion for treatment, but this will be very well handed by our chronic hepatologist in this case. And also , most importantly, maybe we can touch upon what if the patient have a lonely bastif and doesn't need to not qualify or is not eligible for an antimash therapy. I think it's really important to also remind our colleagues that there's many things we can do such as pharmacological and lifestyle intervention, which are key. We did not touch upon that, but it's really there's a lot of impasies in our guid elines to make sure that the patient are properly managed , tacking obesity, weight loss management, and also the optimization of medication and commorabilities. But I'm sure Anna may want to comment more on how we can further improve the cardiometabolic profile of our patients with methodology . Well, well, I think these are the patients that we tried to discuss in the presentations who are really at high risk because they have a lot of the metabolic risk factors and these patients of course should be treated anyway , but this special thing about the liver should enter the diabetologist endocrinologist mind and I think your situation in France is very good. But in many countries in Europe, including Finland this masled of mass and these liberty issues are not even mentioned in our diabetes guidelines. So that would be the first step to enter our muscled mass in the diabetes guidelines and we have a little mention in the obesity guidelines, but the diabetologists tend to read the diabetes guidelines. And if master and mas is missing, they might miss this. So that would be that would be something which probably would focus on attention on this issue. Yeah, absolutely. I think you are absolutely right. Thank you for this comment . And really to summarize, I think now that we have new and efficacious drug for MASH , which would improve also the outcome of our patient , it would really important and timely that in the chronology clinic we play our part being more aware of the risk not only for MASH but Mesoldi as you said and apply the non invasive tests that are currently available in order to make sure that those who have a risk for liver fibrosis are referred to to our colleagues. Well, I really would like to thank you, Dr. Eki Yavan, for this thoughtful discussion . Thank you for the viewer for listening . This has been an activity published by Peer Voice