Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

Warm welcome to everybody. Uh Today, we will talk about how to identify patients with MS who are at risk of increased mortality. Now, as you know, MS is part of a larger syndrome called metabolic dysfunction associated stea steatotic liver disease or ma SLD, which is characterized by the development of steatosis in the liver, which damages the liver tissue and leads to a condition called steatohepatitis, which leads to increasing inflammation and fibrosis, culminating in cirrhosis, which leads to bad liver related outcomes which without transplant lead to mortality. And even if we transplant patients frequently, the disease will recur. So our goal is to try to break this cycle by identifying individuals who have already started progressing that on their journey towards cirrhosis. And to be able to bring therapeutics to play, to stop the progression to cirrhosis or if they've already gone to cirrhosis to keep them from decompensating and uh eventually dying. Now, a good place to start. This conversation is to first discuss why this is a relevant topic. It is relevant because the global burden of M ASL D is increasing and is linked to the pandemic of obesity. As you can see on the left, the global prevalence of MSL D is projected to be almost 30% in adults. And about five, the prevalence of its more aggressive histologic phenotype steatohepatitis or MSH is about 5.3%. And even in areas where obesity is not quite as prevalent, the incidence of obesity is increasing. And in Asia, for example, up to 28% of the population has been reported to have MS. And if you look at those who are overweight or obese, almost two thirds to 70% of these patients have underlying excess fat in their liver. So when you have excess fat in the liver, it puts you at risk for this progression that we talked about. But much of this happens silently because the liver is a very forgiving organ and does not tell us that there are symptoms or there are problems going on. So the only point of contact that patients who have this condition with the health system is when they're going for their annual physicals. And so for practical reasons, most of these patients reside largely in the realm of primary care. So unless they have symptoms that somehow draw attention to the patient or unless it is discovered accidentally, currently, most patients are ignored and allowed to progress silently to hepatocellular carcinoma and endstage liver disease. And only a minority of patients actually get identified and then triaged for further care. Very important point to remember is that up to 70% of patients presenting for the first time with the first complication of cirrhosis were not actually aware they had liver disease. The liver disease had never been diagnosed and given that it takes almost 20 years or more to develop cirrhosis. That means they've had the disease for 20 plus years without anyone paying attention. And our job now is to actually increase awareness of this and to develop methodologies to identify those particularly who are well on their way to progressing to cirrhosis. So the first key takeaway point to remember is that the liver risk is linked to the severity of scarring. And there are two critical concepts when we think about MS LD, one is the concept of disease activity which reflects the injury to the liver, from the delivery of excess fat to the liver. And so it has three components. It has steatosis which reflects the metabolic perturbation, hepatocellular ballooning, which is a very specific histological feature that reflects injury. And then of course, there's the inflammatory response to having injured cells in your tissue. And this can be quantified with various activity scores. There is also something called stro hepatitis, which is a larger sort of a more global assessment of disease activity. Now, the consequence of disease activity is scarring of the liver and that results in fibrosis and is called fibrosis stage. So, fibrosis stage tells us proximity to cirrhosis cirrhosis is when you have liver outcomes. Therefore, fibrosis is a very important prognostic biomarker. And indeed, when you follow large cohorts of patients prospectively, as shown in this slide, we see that the risk of decompensation and all cause mortality are a function of fibrosis. And really the progression to cirrhosis is a milestone in this progression of the disease where as you can see in the black line that those patients who have stage four disease, which is cirrhosis have substantially higher rates of decompensation and all cause mortality. So how can we identify people who have started scarring down their liver and particularly are getting close to cirrhosis or have cirrhosis. So many years ago, a test called FIB four which is based on age ast A LT and platelets was developed to identify those who had significant scarring of their liver and patients who had HIV and Hepatitis C oh infection. So, following the development of F four for HIV HEP C coinfection in 2009, we looked at its ability to predict advanced fibrosis in patients with cirrhosis in a fatty liver disease. And that's shown on the left and you see that it has an excellent aura of 0.8. Now, if you look on the right things have moved a lot over the course of the last 10 years. So here you see data from a real world study of about 2500 patients who were followed uh longitudinally. And here we are connecting the dots between fifth four and clinical outcomes. And you see there are three, N two, numbers 1.3 and 2.6. As long as the FB four is 1.3 or less, the rates of outcomes are relatively low. But if you go to F 4/2 0.6 and then if you look at the intermediate time, uh uh range of fib four scores, you see that there is a stepwise increase in the likelihood of mortality in the incidence of liver related events and with development of mace and even hepatocellular carcinoma. So F four is a good way to get an assessment of baseline risk. Now, it is not very sensitive to change. And therefore, we often will add a secondary test to allow us to follow the patient over time. But F four alone not only gives you a handle on the likelihood of having advanced fibrosis and that number is 2.67 is the one to remember, we round it off to 2.6 because that uh the remaining 0.07 probably does not make a big clinical difference. But then we also need a test or secondary testing. Now, a lot of people criticize the F four because it includes age. But if you look at the relationship of uh F four scores versus mortality, you can see overall shape of the curve is quite similar. And with the uh data for those less than 50 years of age shifted to the right a little bit compared to the left, but the overall relationship is quite similar. So while the exact probability scores are a little bit different, but in general, rising f for even a at a younger age is associated with increased risk of outcomes. Here's another study with almost 44,000 patients or more uh from Europe that is presented. So over here, if you look at the first panel on the left and you'll see liver events, you have cardiovascular events in the middle and then you have mortality data on the right. And as you can see again, the high fib for strata based on that 2.6 threshold has a substantially higher risk of liver events. There's a progressive step up at cardiovascular events with fib four and similarly, there's a progressive increase with fib four strata in terms of all cause mortality. So we have large data sets from Europe and from the US. Now showing that fit four alone gets you very good risk stratification information that allows you to now think about how you're going to follow the patient. The other tool, the secondary tool that we follow for monitoring the patient longitudinally is liver stiffness. And this is measured most often by a test called vibration control transient elastography. The proprietary machine that that is used for this is called fibroscan. And these show that the aura for identifying increases levels of fibrosis are quite good particularly for identifying patients with cirrhosis where as you can see, the ao for stage zero versus higher stages is 0.74. And then it progressively increases to 0.93. When you're diagnosing cirrhosis. Furthermore, when you fix the sensitivity at 90% you can see you can still identify cirrhosis with a specificity of 82%. On the other hand, if you fix the specificity at 90% you have a higher cut off, but the sensitivity drops to about 0.69. But we've seen now that with af four and obesity, you uh together you can actually, I also identify patients uh risk of clinical outcomes. Now, one thing to remember when you do use fibro scan is that different day, different operator, same patient, you can get up to 35% variance. So changes in V CTE uh you know, you have to have at least a 30 to 35% change so that you can be confident that you're actually measuring a real change over time. And so where we have landed is that instead of trying to make precision uh diagnosis of risk of death, we do not yet have a, an app that tells you exactly the moment at which any one person will die. But what we can tell is the broad risk and we divide them into a safe zone, a dangerous zone and an intermediate zone. So the safe zone is when your F four is less than 1.3 as I showed you and your li and the liver stiffness is less than eight on the dangerous zone is when your fifth four exceeds 2.6 and your liver stiffness exceeds 15 because that's now in the cirrhosis zone and everything in the middle is an intermediate zone where your risk is increased but you there is no imminent threat to life. So this also allows us to link care to these risk stratification with lifestyle alone for the safe zone, lifestyle plus pharma for the intermediate zone and again, lifestyle pharma cirrhosis assessment, hepatocellular carcinoma, surveillance, et cetera for the high risk categories. Another test that has become now uh that is now approved for risk stratification is the F test or enhanced liver fibrosis test. And it is based on three parameters that give you, there's a proprietary algorithm and you get a number. So it is unitless and you just, just a plain number. So here are the data on the basis of which the F test was approved as a prognostic biomarker in NASH. So what you see is first on the top left, those with bridging fibrosis. If you're I in the in these studies, patients were followed over time and we looked at progression to cirrhosis. So using values less than 9.8 as a baseline, you can see there's a progressive increase when you get above 9.8 with a big increase above 11.3 in those who had cirrhosis. If you again, start with less than 9.8 as your baseline, you can see really see that the risk of outcomes don't change much until you get over 11.3. So the two numbers to remember are 9.8 and 11.3 particularly those above 11.3 as you can see in the capital markers on the right, have a high risk of having a clinical outcome. And for practical purposes should be considered as though they have cirrhosis. Other tools are also being developed. Two D MRI is very useful as a prognostic biomarker. These are the data that have been published but it may not be widely available and is rather expensive. So you use it if you have it and uh but you can get much of the way by just looking at F four and a fibro scan. So where would the field has moved to over the last 10 years is a much better place in terms of being able to predict future clinical events. And this is a summary of the data very recently published. Looking at both three and five year data, looking at a number of scores including the agile scores which are derived from uh liver stiffness along with the fifth four and a variety of other markers. And you can see that uh these are becoming pretty good in terms of identifying uh both liver events and mortality and the cumulative incidence of liver related events for the agile three strata are shown on the right. So the value of nit s extend beyond predicting histological severity to for predicting major adverse liver outcomes in the long term. So what can we say about this one? So we've learned that F four, both baseline and change over time can be associated but F four is not very sensitive to change. So while if a change occurs, it is associated with change outcomes, but it may or may not change the ELF test cut off below 9.8 rules out short term occurrence with a negative predictive value of 90 percent above 11.35 fold risk of developing a liver related event baseline and change in liver stiffness are independently associated with development of liver outcomes. A and two. DMR is also independently associated with occurrence of liver outcomes. Something we didn't talk about is corrected. T one which is another MRI measure also linked to presence of steatohepatitis with fibrosis and cardiovascular outcomes. So several nit s now have proven prognostic value for clinical outcomes in patients with ma sld. So some key numbers to remember is really for VST FIB four and ELF. So vic is imaging fib four and ELF are blood based. And if the liver stiffness is above 12, you are more likely to have an outcome if it is less than eight, very unlikely to have an outcome advantage is you can do it right in your clinic while you're seeing the patient 341.3 and 2.67. I usually round it off to 2.6. There's no added cost beyond whatever you're getting for routine labs. But you do need to moni adjust for age and for those above the age of 65 a higher threshold is often used around twoish and uh uh but the problem is it is very good for negative predictive value. The positive predictive value is not so great. And then you have the elf test where the number to remember is anything above 9.8 you have increased risk of uh progression and then above 11.3 increased risk of heart outcomes. But below 7.7 essentially you don't have uh significant fibrosis and the risk of outcomes is minimal up to none, but it does cost money. So, using some of these, recently, the European Society for Liver Disease and the European Diabetes Society and the European Obesity Society have just come up with their uh updated guidelines. And what you see is that in people with diabetes and cardiometabolic risk factors, we check a fib four. If it is less than 1.3 we can reassess every few years if it is more than 2.67 those patients are likely to have advanced fibrosis should go to the hepatologist. If you fall in the middle frequently, we will get secondary tests and BST is a preferred secondary test and those with a liver stiffness above eight, send them to Hepatology. So they can be further worked up and followed. And certainly those above 12 for sure, should go to Hepatology. And then if the O VS is low, then we basically, they can be managed as though they are uh low risk and they can be followed over time. So now let's talk about some tips for the more advanced practitioner. So we have been looking at some secondary scores beyond liver stiffness and comparing them to F four and the three that I'll talk to about here are the fast score, the agile three plus and agile four. So the fast was developed uh to evaluate what we call at risk match. These are patients who have MS LD with steatohepatitis with high activity and fibrosis, stage two or higher. So just for terminology sake, we call clinically significant fibrosis as stage two or higher because the risk of all cause of mortality and fibrosis starts increasing from stage two. Advanced fibrosis is stage three or four and cirrhosis is stage four. So when you see fast score, you can see the fast is very good for identifying clinically significant fibrosis but its performance declines as you move towards cirrhosis. And so while it is superior to fib four for stage two or higher, its performance for advanced fibrosis about similar and actually a little bit inferior to fib four for diagnosis of cirrhosis. So, agile three pus was developed to diagnose those who had advanced fibrosis due to NASH. And you can see over here it is very good for stage two or higher, but it's certainly even better for stage three and has a a of 0.9 for cirrhosis and agile four has very similar performances and basically was designed to identify those with cirrhosis. And you could probably use agile three and four interchangeably for advanced fibrosis, which includes cirrhosis uh because it's three and four. So they don't really distinguish between three and four because the performances here are quite similar, but they are very good for identifying those with substantial amount of fibrosis. Also, once you think somebody has advanced fibrosis and the possibility of cirrhosis is now on the table, then we have to think about whether they have portal hypertension and then how much portal hypertension. Because when your hepatic venous pressure gradient or the portal pressure increases above 10 millimeters of mercury, you are at higher risk of clinical outcomes and that is for clinically significant portal hypertension. So, noninvasive criteria have been developed to diagnose clinically significant portal hypertension and this is these are data from the anticipated study where essentially the if your liver stiffness is below 15 and your platelets are normal, you can essentially rule it out. If your liver stiffness is over 25 you can rule it in, in between. If you have a liver stiffness that's intermediate and you have thrombocytopenia, then you are more likely to be able to rule it out and the severity of thrombocytopenia. If your liver stiffness between 2025 anything below 100 and 50,000 is more relevant. If you get down to about uh liver stiffness between 15 and 20 a platelet count below 100 and 10,000. And these are also known as Bovino criteria because they were developed by consensus and Bovino and these have also led to what we call the rule of fives. And this is the good news is it can be applied to liver disease to estimate risk of decompensation and liver related death, irrespective of etiology where anything below 10 is pretty cool is not much risk from 10 to 15. The risk starts increasing above 15, you have to assume there's significant chronic liver disease. And above 25 you think there's c clinically significant po hypertension. So this gives us an idea of additional risk stratification particularly in those uh above fif uh liver stiffness of 15 or uh in those who have uh cirrhosis underlying. The next takeaway. To remember is that while we have been talking about all this liver disease, we need to remember that fixing the liver makes no sense. If they'll die of a heart attack, patients don't care what organ is involved. What they wanna know is if they're going to live or die. And uh they need to understand uh the overall risk and you need to understand the overall risk because that allows you to prioritize where you're gonna push the hardest to keep the patient alive and functional. So this brings into question the fundamental issue of whether M ASL D is a liver disease or it's part of a systemic disorder. And I think today in 2024 pretty much everybody agrees that mass LD is part of a multisystem disorder where in the liver, you can get the steatosis, steatohepatitis cirrhosis cancer. But this is closely linked through production of inflammatory products from the liver and injury products to the liver and inflammatory lipids from the liver to systemic inflammation. So, there's a bidirectional relationship between the systemic meta inflammatory and fibrotic state with the meta inflammatory fibrotic state in the liver producing MS LD in the liver, but manifesting elsewhere as vascular disease, heart disease, chronic kidney disease and a variety of cancers. So historically, we thought of hypertension, heart failure, especially with preserved ejection fraction, type two diabetes and chronic kidney disease as risk factors. But we now think of them as competing threats to life. So it is really important not only to assess risk from a liver point of view with a fib four and a fibro scan and maybe an ELF test, but also to understand the systemic threats to life in the patient. So here what we have found is that patients with ma sld have increased metabolic health outcomes as well. So patients with MS LD have a increased hazard ratio for cardiovascular disease, 1.43 hypertension diabetes, prediabetes, overall metabolic syndrome, chronic kidney disease and cancers. And so the association of course, with the hepatocellular carcinoma is of all the cancers is the highest, but that is no surprise. It is a liver disease produces chronic liver injury, inflammation and fibrosis. And then mad patients with advanced fibrosis, the risk of incident diabetes is significantly higher than in those without also the number of metabolic risk factors that a patient has increases the risk of liver related outcomes in type two diabetes. So there's this bidirectional relationship between liver outcomes and metabolic outcomes. Previously, I showed you patients with fatty liver disease have more metabolic outcomes. Now, I'm showing you that the more metabolic things that are going on, the more is the are the liver outcomes. And similarly, in this observational study from Scotland, there was an increased mortality risk for those with liver fibrosis and higher. A again, among those with both fibrosis and chronic kidney disease. So what that has led us to is to understand risk in a more holistic way where prior to the development of advanced fibrosis, the bulk of the risk is cardiometabolic and renal and cancer. But as we move into advanced fibrosis, cirrhosis, liver related mortality and liver related risks progressively become the leading cause of outcomes. So, understanding fibrosis is critical to the management of MAS LD and particularly identifying those with advanced fibrosis. IE with AF for over 2.67 liver stiffness, over 12. Certainly those above 15, for sure. Uh that is a central theme of how you assess patients with mas LD. And of course, there's a reason for doing that because as you go from uh fat to steatohepatitis to injury fibrosis and cirrhosis, there's a similar colinear increase in the blood vessels where you get fatty streaks, atheromas, stable fibrotic plaques and then an unstable plaque. So there is shared biology between mesh and other cardio metabolic risk factors. And so it is important for us hepatologists to also be aware of how this risk is assessed. So for kidney, you get a EGFR PZ straightforward, anything above 60 is good below 60 is problematic for cardiovascular risk. Historically, we have used the ASCVD calculator and this breaks it down into those who need immediate statin those where you might consider statin. And it tells us about how much risk and what is the intensity with which we pursue statin therapy. And it's very important to remember that having underlying mas LD is not a contraindication of statin. If anything, these are the patients who might benefit a lot from statins and statins are by and large safe in this population. The new a a prevent risk calculator overcome some of the deficiencies of the a CBD risk calculator. It is good for ages 39 to 95 removes race as a risk. It also includes certain social determinants of health, which is increasingly being recognized as an important predictor of outcomes and also gives us more granular detail on the risk of various types of cardiovascular outcomes. And here it, for those who are interested, this is the website that if you click on, you can get the guidelines and statements for the calculator, for the aha prevent risk calculator. So what we often will do and this is sort of my own personal practice is I think of the patient in like a target with a safe zone in the green, red zone in red for risk, high risk and orange zone in the middle. It's a little bit of a traffic light approach where I have a cardiovascular risk calculator. I follow the EGFR, I follow the A1C and I follow the F four and liver stiffness. And this allows me to assess risk, you know, organ by organ. And if you connect the dots over here, you potentially can get an idea of what the risk profile of an individual patient is and how you can proceed just watch it over time by repeating this exercise every time you see the patient. And this in our view is sort of a first step towards developing precision medicine based approaches in the assessment of risk in patients with MA SLD. So to summarize in those with metabolic risk factors. MSL D is highly prevalent. There is bidirectional relationship of hepatic and extrahepatic risks in patients with MS LD. Liver risk is driven by fibrosis. Use the tools you have at your disposal. If you're in a very risk, uh resource constrained place, just use F four, very robust relates to outcomes. Gets you 75 80% of the way there. B CT is a fantastic, excellent secondary risk assessment too. And E provides a further independent measure of risk where you do not have access to a fibro scan, but you can send a blood test off for this test. So with that I will stop. Thank you so much for your attention.