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Thanks for having me. Um over the next 45 minutes, I'm gonna be talking about metabolic dysfunction as associated steatotic liver disease, which I'll call mail for short. Specifically, I'll be talking about how to anticipate and identify mas complications. Much of my emphasis is gonna be on liver disease of complications. And this is because where this is and the reason for this is um because the area of liver disease complications in Mazz is really where the thing in the field has changed over the past couple of years. This has been the focus of recently updated clinical guidelines and this is also where management of Masol is unique from other conditions. It's unique from how we manage other liver diseases and how we manage other metabolic syndrome related complications. Um Here's the main learning objectives for today and these learning objectives put together and synthesize some of the concepts that you may have heard about during the first couple of talks of this mash series. So, um my goal is that at the end of this hour, you're able to first identify patients at risk of nasal complications. Secondly, recognize clinical indicators of potential liver disease progression in nasal third understanding algorithm um to identify which patients with Masol are at high risk for liver complications and required hepatology referral. And finally, that you're able to apply this algorithm to a couple of sample cases. And these are the two sample cases we'll work through using information from this talk. The first is a 40 year old woman with signs of liver disease. She's had abnormal liver enzymes for a decade. And the second case is of a 55 year old man with type two diabetes who has no obvious signs of liver disease. He's had um normal liver enzymes consistently for as long as you've known him. So I'll come back to these um two cases in the latter half of my talk and we'll discuss how to uh use the information re review to predict which of these patients is at risk for nasal complications and what to do to reduce the risk of those nasal complications. So, let's start by reviewing some definitions. Um Let's review what is Mazz. So this is the disease that was formerly known as nonalcoholic fatty liver disease. As you know, the name was changed last year. Um a large part of the reason for why the name was changed was to fully recognize that this is the hepatic complication of metabolic syndrome. So specifically, this is a, this is a chronic liver disease, a chronic progressive liver disease. It's characterized by the presence of steatosis or triglycerides in 5% or more of hepatocytes and its root cause is obesity and insulin resistance. So, mazel is really part of a larger family of steatotic liver diseases. So, steatotic liver diseases are ones where liver injury is manifested by the presence of hepatic fat. And there's several potential causes of injury that can lead to the accumulation of steatosis in the liver. So, steatotic liver disease is further subclassify by the etiology of the liver injury that's leading to accumulation of the hepatic steatosis. So, bottom line, when you come across a patient with hepatic steatosis, you need to identify the cause of the steatosis in their liver and diagnose them accordingly. So mail is one cause probably one of the most common causes of steatotic liver disease. Um where insulin resistance or what hepatologists have decided to term metabolic dysfunction is driving the steatosis. But there's other causes for etiologies. For steatosis in liver, alcohol is another very common cause of steatosis. Um alcohol-related liver disease is one that you diagnose in patients who have a history of significant alcohol drinking for five years or more without evidence of metabolic dysfunction. There's several other causes of steatotic liver disease. Um for example, there's certain medications. Um predniSONE is one methotrexate is another. There's, there's several others. Um There's some genetic diseases like Wilson disease, all of which can uh where liver injury is expressed by the presence of steatosis in the liver. Now, the second important thing to know is that this classification system of steatotic liver diseases um recognizes that there can be dual etiologies for steatotic liver disease. So, there can be more than one thing that's causing steatosis to accumulate in the liver. So most commonly, there can be an overlap of insulin resistance or metabolic dysfunction and alcohol that are together driving the accumulation of steatosis and liver injury and liver injury. Um And this category is called called MET A LD. Recognizing the different causes of steatotic liver disease and identifying the accurate driver of steatotic liver disease is really important for understanding how to manage patients and how to anticipate complications. So, during today's talk, I'm gonna focus entirely on mazo. So that is steatosis driven by obesity and insulin resistance. So it's also important to recognize that nozzle is not associated with any specific clinical signs or symptoms. So, patients with this disease are often asymptomatic or they may have some nonspecific symptoms like fatigue, abdominal pain. They may have clinical signs of insulin resistance like acanthosis nans, but none of these are pathognomonic. By the time patients develop overt symptoms of liver disease, like variceal bleeding, jaundice, ascites, um or clinical uh exam findings like spider angioma, angiomas and splenomegaly. It means that this patient has already, their muzzle has already progressed to advanced cirrhosis. They've already progressed to a late stage irreversible stage of the disease where it's very difficult to intervene at that point. Um So our goal is really to identify patients uh who are at risk for getting to that point and doing things to reverse the process. There's some additional caveats. So, caveats specifically regarding liver enzymes. So you should know that liver enzymes are frequently normal in patients with male, particularly if they have type two diabetes. Also, liver enzymes don't correlate with the severity of someone's Mazz and they are not indicators necessarily indicators of progression of disease. So the bottom line message to take away from this is that you can't rely on patient reported symptoms, exam findings, or even liver enzymes to flag whether a patient has muzzled or whether a patient's muzzled is getting worse over time. You have to have a high level of suspicion for the disease and you have to use a different set of tools that we're gonna review uh during this talk to figure out if you're a patient with Mazz, um uh is at risk for progressing or is progressing. So, um mail is something to actively consider in three main clinical scenarios. You have to have a high level of suspicion in these three main clinical scenarios. So the first is a uh a scenario that's probably fairly um uh something you fairly you see on uh these fairly commonly and that is patients with abnormal liver enzymes, um particularly if a patient has a pato cellular pattern of abnormal liver enzymes. This is a patient to consider Mazz as a cause of liver disease. In in this patient. The second scenario to consider Mazin is a patient who presents to you who has an incidental finding of steatosis on imaging. So a common scenario, uh example of this is a patient who has some abdominal pain, you refer them for an ultrasound and an abdominal ultrasound. And incidentally, you see that they have hepatic steatosis. So the third uh clinical scenario um where you should be thinking of mail is uh a scenario that has come to our attention really in the past 1 to 2 years and has been um a clinical scenario really highlighted by recently updated guidelines. And this is um consideration of screening for higher risk muzzled in patients who have Mazz risk factors. That is patients who have prediabetes, type two diabetes, obesity, two or more metabolic syndrome criteria. This is something I'll come back to in a few slides. But the bottom line in these three scenarios is that you wanna make sure that basil is truly the diagnosis in the patient, especially the patient with abnormal liver enzymes. If you conclude that the patient has mazel or is at high risk of having Mazz, you wanna identify if this patient with Mazel is at high risk for development, developing complications from their liver disease and finally refer those patients at high risk for complications to a specialized specialist for help with co management. So here's how you make a diagnosis of NASL. So if you in a patient with evidence of hepatic steatosis, you have to determine whether they have any cardiometabolic criteria. Meaning do they have any one out of the five features of the metabolic syndrome? Um If yes, you can conclude that this patient has Mazz, they have steatosis that's entirely or in part, being driven by metabolic syndrome. Next, you have to decide whether metabolic syndrome or its metabolic dysfunction is the only driver of steatosis or whether there's an additional etiology. So this means um uh screening for uh significant alcohol drinking through a history. And if a patient has abnormal liver enzymes, testing for other etiologies of liver disease like viral hepatitis Wilson disease, et cetera. Now, if your history um finds that the patient does not have a his um uh a history of significant alcohol drinking over the years and your testing doesn't identify any additional uh cause or uh etiology for liver injury. Then you concl can conclude that this patient has um you're dealing with pure bazzle which is the focus of today's lecture. So Masol is highly prevalent. It's estimated that there's a in the general population, there's a 30% prevalence of this condition. Um The prevalence of mas more than doubles in certain populations. So populations with obesity, the prevalence is 75% in people with type two diabetes. The prevalence is as high as 65%. So this extremely high prevalence of mail in obesity and type two. Diabetes has really been the impetus to lead to new recommendations and updated guidelines to screen for Masol in these populations. And again, this is a point I'll return to in a few slides. So it's important to know if a patient has mail. And that's because having Masol is clinically significant patients with Masol are at risk for developing multiple systemic complications. They have a higher risk for the conditions listed on this slide. Compare compared to patients without Masol. The leading causes of death in patients with Masol are cardiovascular disease, malignancy and liver complications. These also constitute the causes of excess death in this in in populations with Masol. Now, most of these complications are mediated by metabolic syndrome and obesity. It's really hard to parse out whether these complications are happening and many of these uh complications are happening purely because of the Mazz or because of the underlying insulin resistance, obesity metabolic syndrome. But I'm gonna highlight two complications. Um in particular, I'm gonna focus on um on uh these two complications that represent the leading causes of death and are the most studied in mail. Um that is cardiovascular and liver related complications. So, um patients with mail are thought to uh be people who are facing competing risks from mace that is major adverse cardiovascular outcomes like ischemic heart disease, stroke, heart failure, death and from melo or major adverse liver outcomes. Um these include things like cirrhosis related decompensations like variceal bleeding, ascites, um hepatic encephalopathy, also liver failure, hepatocellular carcinoma and death from, from the from these liver related complications. So, um the risk of so patients face the highest risk from mace or um the major adverse cardiovascular outcomes. You can see here that the incidence rate of um of mace is at least three times higher than that of melo. Um there's a cumulative incidence of approximately 27% over 13 years or 24 cases per um 1000 person years. Hence, it's clinically mandatory to perform cardiovascular disease, risk assessment and manage and treat risk factors to attenuate cardiovascular disease in patients with MASL. However, currently the guidelines ask us to do this using standard risk assessment tools in the way that you would uh manage um cardiovascular risk factors and anticipate cardiovascular complications in any patient, even patients without MASL. So, guidelines recommend using tools like the Framingham risk score or a S CVD score to guide cardiovascular risk reduction and intervene on cardiovascular risk factors using standard guidelines. Um At this time, there's not um recommendations for how to anticipate cardiovascular complications or intervene them in a way that's unique speci and specific to Masol. We use guidelines that are recommended across the general population. Now, turning our attention to melo or uh major adverse liver outcomes, you can see that the incidence of melo is lower than mice um but still significant with um an incidence rate of six per uh 1000 person years. It's also important to note that not all patients with mail will develop liver complications. So the area of intense study over the past decade or so has been figuring out who are the patients with Masol that are most at risk for developing melo over time. Um And the answer to this question is it's um it depends on the degree of hepatic fibrosis. Your patient with Mazel has at the time of evaluation. Um The bottom line is patients who have severe fibrosis. That is stage two fibrosis or more at the time of evaluation are the patients who are at the highest risk of developing melo over time. Um And this is where the new guidelines, the new updated clinical guidelines most impact practice and this is where male management is unique and different from how we manage other types of liver diseases and also how we manage other types of metabolic conditions. The new guidelines provide tools and an approach to figuring out which patients with Masol are most likely to progress to melo and therefore require a referral to hepatologist and all of the guidance hinges on fibrosis management. So given the importance of understanding fibrosis, I'm gonna take a detour in the next several slides to share with you our paradigm and understanding of male pathogenesis and natural history. The reason I'm gonna do this is because understanding this is um central to understanding why guidelines stress fibrosis assessment so much. It's also central to understanding drug development for males. And the reason the drugs that are recommended at this time for treatment of Mazzo are recommended. Um, here, I've listed the two principles I'd like you to take away from the next few slides. I'm about to talk you through the fir the important principles are that first steatohepatitis drives fibrosis and fibrosis drives adverse liver outcomes. So let's dig into the pathogenesis of mail a little more. So, mail develops um the the normal liver develops steatosis because of increased fatty acid flux to the liver driven by visceral obesity and insulin resistance. Um So, having these conditions being exposed to visceral obesity and insulin resistance leads to an excess fatty acid flux to the liver and this leads to increased triglycerides stored within the liver and within the hepatocytes. And this is what we appreciate clinically a steatosis. So, in a patient who has an ultrasound that reads out as having hepatic steatosis, that's what you're seeing that the patient has some fat in their liver. No. Um about 70% of patients one second. Ok. Um About 70% of patients uh with steatosis will just remain with having simple steatosis. And it's unlikely if in patients who have simple steatosis, it's unlikely they're gonna develop, develop cirrhosis. This is um a state of the liver that's unlikely uh where fibrosis progression is very unlikely. A in about 30% of people in a subset of patients and 30%. Subset of patients, the excess fatty acid flux leads to production of lipotoxic metabolites which then inactivates inflammatory pathways and fibrogenesis. The state of toxic fat is what we term um uh uh MS or steatohepatitis. Um The only way to figure out if a patient has mash is through histology. So, the way that um we detect this um is with histology where we see something called balloon hepatocytes um on the slide which is uh encircled. Here, these patients may also have mall dank bodies. Now, approximately uh approximately 20% of people who have this toxic um state of of uh of liver fat or steatohepatitis um can have progressive fibrosis to cirrhosis. So they undergo fibrosis progression, um evolving through stages of fibrosis from uh stage 0 to 1 to 2 to 3 and ultimately to cirrhosis. And um once someone develops cirrhosis, they're then at risk for potentially developing the liver complications that we fear decompensations from portal hypertension like variceal hemorrhage and ascites um liver failure um leading to jaundice and hepatic encephalopathy and um and uh fatality related to these liver related complications. Now, I wanna talk to you a little more about fibrosis progression. Specifically what happens between um between uh steatohepatitis and developing cirrhosis. So, mass fibrosis progresses in a stepwise manner from um stage zero, which is a situation where someone might have ongoing steatohepatitis, but they have still not developed fibrosis. Um So people progress from this stage to stage four fibrosis, which is cirrhosis in a stepwise manner. Um, they'll progress from stage 0 to 1 to 2 to 3 to 4 over time. It takes approximately seven years to go between stages. Um, there are some patients who progress more quickly over an average of 2 to 3 years. There's other patients who might progress a little more slowly, but on average in patients with MS fibrosis progression, um, seems to occur at a rate of approximately one stage every seven years. Now. Um there's been a great deal of study looking into risk factors for progression of MS fibrosis. Um And all those studies have found that these are the clinical risk factors for progression uh for MS fibrosis progression, they include type two diabetes, higher BMIs, particularly BM I, more than 30 older age, um concomitant, alcohol, drinking and certain genetic uh variants. Um So, while these are well recognized to be risk factors for progression, progressive MSH fibrosis, none of these are very good for specifically predicting which of your patients with male will progress to cirrhosis. Um However, cohort studies have repeatedly shown that the presence of significant fibrosis on liver biopsy in patients with Masol is the strongest independent predictor of cirrhosis complications and mortality. So, in other, so what this graph shows what this data shows uh um are the outcomes of patients who had a liver biopsy at the time that they were uh initially diagnosed with MASL. So, what they found was that at the time of initial diagnosis, if a patient on liver biopsy already had stage two fibrosis, their risk of liver related mortality over time um increased significantly compared to patients who had stage one or less fibrosis. So the bottom line is that um so conceptually, the way to think about it is people who already have severe fibrosis at the time of initial diagnosis of their mazzo or the time of evaluation of their Mazz are at risk for continued fibrotic progression. So, the other way to think about this is um our goal when we see patients with Mazz or who are at high risk for Mazz is to figure out and identify which patients have severe fibrosis. Because again, these patients with F two or more stage two fibrosis or more at the moment that we recognize their male are most likely to de develop liver related complications over time. Whereas patients with stage one or less fibrosis are unlikely to have fibrosis progression and they're unlikely to develop liver related complications, develop cirrhosis or cirrhosis decompensations over time. Um as an aside, um steatohepatitis or mash and fibrosis are also two important histologic targets for clinical trials, testing medications for males. And that's because um in studies, it's been observed that when patients steatohepatitis resolves um their fibrosis regresses and when fibrosis progresses, people's risk of adverse liver outcomes reduces. So, um there, so therefore, mash and fibrosis are two important histologic targets for clinical trials, testing medications for mas results. And the goal is for mass medications that can lead to mash resolution and fibrosis regression. Because the thought is if you can target those two items and improve them, you reduce a patient's risk for adverse liver outcomes over time. So, um, I've highlighted how important it is to identify which of your patients with mail has severe fibrosis again. Meaning which of your patients with mas old has stage two fibrosis or more. So, how do you do this? Um Well, historically, liver biopsy has been the reference standard for evaluating fibrosis. Um That's what all the studies did um to answer the question of who progresses. And historically, we used liver biopsy to um to evaluate and quantify fibrosis in people's liver. But this is clearly an impossible thing to offer all patients. It's uncomfortable and um the prevalence of the disease is so high, it's impossible to offer. Secondly, is hopefully, um uh as I as I highlighted, liver enzymes are not reliable for um identifying the severity of Masol or identifying which patients have severe fibrosis. So you can't rely on that either. Fortunately, several what several noninvasive fibrosis tests or nits for short have been developed, that can help predict who's most likely to have severe fibrosis. Um These are a simple noninvasive bedside tests that you can do to um to predict whether the patient with Masol in front of you has severe fibrosis or not. As a note if you have a patient with measles, but this patient already has signs of portal hypertension. For example, on exam, they already have splenomegaly or their labs already show they have thrombocytopenia or if they have a history of decompensations like variceal bleeding or they look jaundice, you can already conclude that this patient has advanced cirrhosis, advanced liver disease from their muzzle and you don't need a knit, these patients need an automatic referral to a hepatologist for management of cirrhosis and management of portal hypertension. But now let's turn our attention to how to use nets to evaluate uh whether your patient has severe fibrosis and whether your patient needs a hepatology referral. So there are three nets that are recommended by clinical guidelines for use in patients in primary care patients and um uh in primary care patients. And these are tests that can again help you um help you predict whether the patient in front of you has severe fibrosis and therefore needs a referral to a hepatologist. So the first test, the first line test to use in any patient with Masol or C or any patient who's at risk for Masol is the fib four. This is a, is the fib four. This is a clinical risk score that um you can, you can Google um and you just plug in the patient's age ast A LT and platelet count and it spits out a score. A score, that's less than 1.3 is very good at ruling out the likelihood that the patient in front of you has severe fibrosis. So the way to interpret a fib four of less than 1.3 is that this patient with mail in front of you is unlikely to have significant fibrosis. And this patient um can remain in the primary care or general practitioner's office for continued care. Um uh but uh you should reassess their um fib for in 1 to 2 years, a score of more than two of more than 2.67 suggests that it's possible that this patient may have significant fibrosis. Um The positive predictive value is um not 100%. Um But this raises the possibility that there's significant fibrosis. So this is a patient. Um But the, the concern is high enough that this is a patient who should just go, you should go ahead and refer to Hepatology for further evaluation. Now, there's a subset of patients, about 30% of patients are gonna get a, have a score that falls, that's indeterminate. That means they have a fib four that falls between 1.3 and 2.67. You can't make any sort of conclusion in this patient. You can't rule it out. Um And uh the and you can't, you can't consider that they have, it's not accurate enough to consider the possibility that they have significant fibrosis. So, in these patients, you want to use a second line test and you can either use fiber scan or the enhanced liver fibrosis test. So, let's start with fiber scan. Fiber scan is essentially a form of ultrasound. It's a form of ultrasound based elastography. It's a form of ultrasound that can be used to assess what we call the stiffness of the liver. And the concept is that the more stiff, the live stiffness correlates with stage of fibrosis, the higher the stiffness, the more fibrosis the patient has. Um if a patient has a liver stiffness value of less than 8 kg pa GS, it's unlikely this patient has significant fibrosis. The negative predictive value is is, is is fairly good. So this is a patient that you could keep see watching in your primary care clinic and reassess their fib four and maybe their fiber scan again in 1 to 2 years. If a patient has a liver stiffness of 8 kg of uh eight or more kop paca, that raises the possibility of significant fibrosis and this patient should be referred to hepatology. Now, fibro scan is not a test that's that's widely available. Um So if fiber scan is not available, you could use an alternative second line test, which is this enhanced liver fibrosis test. This is a blood test um offered through labcorp. Um uh And um and it's fairly simple to use, you can just do it with your patient's next blood draw a value of less than 7.7 makes it on uh suggest it's unlikely your patient has significant fibrosis. And this is a patient you can keep managing in your primary care clinic. A value of more than seven of 7.7 or more um raises the possibility raises the concern of potential significant fibrosis. And this is a patient who to refer to the hepatologist. So, here's an algorithm that um was developed uh from the ace guidelines. The endocrinology guidelines published in 2022 that puts together these noninvasive tests to help you identify patients who are high patients with Masol, who are at high risk for adverse liver outcomes and need hepatology referral. So, the idea is that um you use these fibrosis, the these these nt noninvasive tests to assess for significant fibrosis in uh three groups of patients. So you use it in patients who have that first clinical condition. Um I mentioned people with abnormal liver enzymes, people who have steatosis on imaging, excuse me. So the first group are people with high liver enzymes. You you diagnose with basil. The second group are people who have steatosis on imaging with normal liver enzymes. And the third are people who have risk factors for basil. The idea is all of in all of these patients, you calculate a fib four. The fib four is less than 1.3. It's unlikely to have severe fibrosis. They're considered low risk for liver disease progression. This is a patient to maintain in your primary care clinic and focus on um obesity management, management, and cardiovascular disease prevention. The fib four is more than 2.67. Um they, the there is the possibility of severe significant fibrosis. Hence, these patients are considered higher risk for developing cirrhosis related complications in the future. And these patients should be referred to a hepatologist if the fib four falls between these two values of 1.3 and 2.67 it's an indeterminate value. You can't conclude one way or the other if they have significant fibrosis. So you have to order a second test, the fibro scan or the um the fibro scan that I mentioned or the enhanced liver fibrosis test and um use the um described cutoffs to decide whether or not to uh keep them in the primary care clinic for further management or refer to Hepatology. So, uh one thing to note in patients where um the fibrosis risk stratification algorithm concludes low risk. It's important to um repeat testing in one year in patients who have diabetes otherwise repeat the testing in two years. So um let's return to these two patient cases that I promised we talk about towards the um latter half of this talk. So the 40 year old woman with abnormal liver enzymes and then the 55 year old man with type two diabetes who's had normal liver enzymes forever. So let's use this information to figure out whose liver you should worry about which patient needs a hepatologist and what can be done to reduce the risk of liver related morbidity and mortality. So the 40 year old woman, if you go back, you can see her liver enzymes have been elevated and they have been this uh this way for the past 10 years. A lt of 90 ast of 60 hepatocellular enzyme elevation of 3 to 4 times upper limit of normal. Basically. So given that she has abnormal liver enzymes, um uh it's it's important to send off a se serological workup for uh a wide variety of potential causes of liver disease. So this includes viral hepatitis testing, potentially testing for hemochromatosis, autoimmune hepatitis Wilson's disease. And the ones mentioned here using these um initial uh diagnostic workup tests. It's also important if the especially if these tests come back negative to consider the possibility of drug induced liver injury. Review, a patient's chart see if they recently started any uh start any new medications in this particular patient. It's unlikely she has drug induced liver injury given that her liver enzymes have been elevated persistently for 10 years. And then it's important to look for hepatic steatosis, particularly if all of the above are negative. And um the most cost-effective way to do this is through standard B mode ultrasound or if you have access to it through fiber scan. Uh The other name is transient elastography. So um in this patient, um uh she had a negative serological workup. So everything was negative for viral hepatitis, hemochromatosis, wilsons disease, et cetera. And she had a liver ultrasound that showed steatosis. So when we look at this algorithm here, um we can conclude that this patient has Mazz with no other contributing factor to her steatosis. So, in this patient, the next step is to risk stratify her male. So now what we have in front of us is a 40 year old woman with Mazz and persistently abnormal liver enzymes. So we need to figure out whether this is a patient who's at higher risk for developing cirrhosis related complications in the future and therefore needs a hepatology referral um for intervention to prevent those complications or if this is a patient who's unlikely to develop those complications over time and therefore we can manage in the primary care clinic. So first step calculate fib four for her, her fib four was one point is 1.15 given that it's less than 1.3 you can conclude she's unlikely to have severe or significant fibrosis. This is a patient to follow in the primary care clinic and reassess the fib four in two years. Now, let's turn our attention um to uh our 55 year old gentleman with type two diabetes. So this is an example of a patient who has no signs of liver disease. He's had normal liver enzymes forever a LT 29 ast 25. Um So really, no, and this has been the case since you've known him. This is an example of that third scenario, the patient who has risk factors for mail where you want to do what we call screening or case finding. Um because the prevalence of Masol is so high in this population of patients with type two diabetes and liver enzymes are not a reliable indicator of whether or not someone has mazel and whether or not their Mazz is severe if they have it. Um So in this case, given that his enzymes are normal, you don't have to carry out a serologic liver disease workup like you did, we did for our 40 year old patient with persistently abnormal liver enzymes. Given that he has these male uh strong male risk factor, he has type two diabetes. He also has obesity with ABM I of 30 hypertension. Um I it's important to proceed directly to risk stratification. So in a way, you almost assume that this patient probably has mail, given that the prevalence of masl is 75% in people with type two diabetes. And you just go ahead and go directly to risk stratification and figure out if they have significant fibrosis or not. So, in this patient, um first step like in any, anyone is calculate a fib four. So his fib four comes back as 1.34. This is indeterminate it falls between those two numbers where you can either rule out at a fib four, less than 1.3 or consider the possibility of significant fibrosis at 2.67. You can't make a conclusion one way or the other with this fib four. So that means you have to proceed to fiber to a second line test fiber scan, which is what PCT is. Um And uh you do that, you do the fiber scan in this patient. But um in this patient, the fiber scan comes back uh and gives you unreliable, unreliable measurements. Um And this happens in about 20% of patients where you attempt an ultrasound, this um ultrasound based elastography, but the measurements are unreliable. Um This happens for a variety of reasons and it's not an uncommon scenario. Again, that means the fibro scan is not helpful in concluding one way or the other, whether this patient is at risk. So you proceed to get the alternate second line test, which is the enhanced liver fibrosis test, which comes back at 10. It's high. That means it's high than 7.7. That means this patient needs a referral to a hepatologist. It means he's someone who potentially has significant fibrosis. Therefore, he could progress to cirrhosis related complications. He may need intervention, hence, referred to a hepatologist. Um So this patient and any patient that you with mail that you refer to a hepatologist, you might be wondering what happens at the Hepatologists Office. So at the Hepatologists Office, a lot of what happens is we repeat some of what has already happened in the primary care clinic. We rule out that we go through the same uh exercise, rule out the possibility of concomitant liver disease etiologies confirm the diagnosis of Masol and we repeat many of the same noninvasive um tests um uh in patients who have indeterminant um fiber scan measures or indeterminate elf or if they have high-risk scores high-risk fiber scan findings of of more than uh uh eight Klopas or a high elf. Um A hepatologist may either use liver biopsy to confirm the presence of significant fibrosis or they may refer a patient for um Mr elastography to confirm the presence of severe fibrosis. If on that workup, we find that a patient has stage two or stage three fibrosis. These are our patients. These are the patients that we offer what we call MSH modifying treatments. These are interventions and medications that can potentially reduce steatohepatitis and therefore reduce fibrosis progression and reduce the risk of liver disease complications over time. Now, if our workup finds that this patient has cirrhosis, then things are a little bit different in these patients. We then screen for um hepatocellular carcinoma. We carry out interventions um to prevent portal hypertension complications. Uh At this time. Um Patients with uh mas cirrhosis are not targets for uh MS modifying treatments. We don't have anything that's been approved for people with MS cirrhosis. So, so again, what we're looking uh if a patient has stage two or three fibrosis on our evaluation in the Hepatology office, this is the, these are the patients that we then proceed to offer mash modifying treatments to potentially reduce the risk of uh liver disease complications. So, what are the potential mass modifying treatments? So, I've listed the four that are uh clinically available at this time. They are weight loss, pioglitazone G LP one agonists and ResMed. Um These treatments have various levels of effect on mass resolution. Um their effect on longterm outcomes. Uh Meaning reduction of of uh incidence of adverse liver outcomes like decompensations, death related to liver complications is still unknown. But what we do have data on are the effect of these various um of these four treatments on mass resolution and fibrosis regression. So, the uh recommendations to use these um these, these interventions or these treatments really comes from the data. That's that the the data related to their effects on mass resolution and fibrosis regression. The rationale being that if you reduce mash regress fibrosis in the long term, that should reduce the risk of adverse liver outcomes. So, first and foremost, weight loss is recommended among all patients with MASL, regardless of um the severity of their liver disease. Um uh weight loss is recommended, but the degree of weight loss that we recommend depends on the severity of their liver disease. And let me explain. So, um studies have found that 5% weight loss from baseline leads to reduction in steatosis, weight loss of 7% and more is more, more likely to lead to mass resolution and weight loss of 10% or more from baseline is most likely to lead to fibrosis regression. So patients who have severe fibrosis, these patients need an intervention that reduces steatohepatitis and reduces and regresses fibrosis. So, the goal in these patients um is at least 7% weight loss and ideally 10% weight loss from baseline. And that's because those thresholds of weight loss, as you can see from these graphs here are associated with the highest um a proportion of mash resolution, uh resolving of MS and fibrosis regression. Um So I'll just touch on this, but I'm not gonna go in depth um uh into interventions of weight for weight loss. So, lifestyle changes in diet and physical activity are recommended among all patients with MASL. However, it's well known that patients with Mail um do struggle patients in general struggle with weight loss. Uh So often they need more intensive support like behavioral programs to help them make these lifestyle changes, particularly patients with severe fibrosis where the need for weight loss is um I is much more urgent um in terms of the use of weight loss medication medications in bariatric surgery. Um at this time, clinical guidelines for Masol recommend using these methods for existing indications. So, if a patient happens to already, um, meet criteria for bariatric surgery, um, it, it's, it's reasonable to, um, to, uh, to consider bariatric surgery in those patients. But clinical guidelines don't specifically recommend bariatric surgery or specific weight lo loss medications for treatment of mash. Um, but on that note, it's worthwhile to uh highlight G LP one agonists, especially semaglutide, which is a G LP one agonist that's, um currently under study uh in a phase three clinical trial um for treatment of MS. So, what we have at this time, data that's been published on semaglutide are phase two clinical trial in this phase two clinical trial, it was found that patients um that use of semaglutide um uh was associated with higher rates of mash resolution resolution. 59% of patients who took 0.4 mg of semaglutide subq daily experienced mash resolution over the course of one year versus 17% with regard to fibrosis regression in this uh clinic. With this phase two clinical trial, they did not see a significant effect of semaglutide on fibrosis regression that said this was um a fairly short trial of about one year which would may have been too short of a time to see an effect on fibrosis. And again, this, this drug is under study in a phase three clinical trial um regardless um regardless of findings um of the phase three clinical trial, GG LP one agonists are most likely gonna be part of mass treatment because of its weight loss benefits. Um So in that same phase two clinical trial, you can see that um patients uh who were treated with some ide had more significant average weight loss compared to people who are treated with placebo. Um the third drug or the third intervention, th think about is pioglitazone, the name Actos. So this is an old drug used for a very long time for treatment of type two diabetes. Um in a clinical tr in a randomized clinical trial pioglitazone, uh was found to lead to mash resolution but not fibrosis regression. So people 51% of patients who were randomized to pioglitazone experience resolution of mash compared to 19% of placebo. While there there was no effect seen on fibrosis fibrosis regression was uh not significantly different in those randomized to pioglitazone versus those randomized to placebo. Um Last I'll highlight ResMed. This is a uh this is the first drug um approved for specifically approved for treatment of MS. I should just say um go back for a second pioglitazone is um is is suggested as an option in clinical guidelines for treatment of mash, but it's not labeled for treatment of mash, it's used in off label um at times for treatment of mash ResMed is the first FDA approved medication for mash. So this is a liver directed selective thyroid hormone receptor beta agonist and it's responsible for and these receptors um that it um direct its activity towards are responsible for regulating metabolic pathways in the liver. Um And it's thought that the way this drug works is by um targeting these receptors, it reduces hepatic fat through increased mitochondrial beta cell beta oxidation. So, this drug in March 2024 received conditional approval based on some uh initial uh effects um that were observed on mass resolution and fibrosis uh fibrosis regression, which I'll show you here. So, 25% of patients who were randomized to ris on 80 mg a day experienced resolution of steatohepatitis versus 10% of those who were randomized to placebo and with regard to fibrosis regression, 24% of people randomized to ResMed versus 14% experienced fibrosis regression and this was uh significantly different. So, again, it was on the basis of um these data that the FDA condi gave conditional approval. Um and the phase three clinical trial uh for this for this drug is still ongoing. Um And over the next few years, uh we anticipate um a better understanding of the effects of this drug on hard uh long term clinical outcomes. So, returning to our patients, um the 40 year old woman with abnormal liver enzymes from NASL and our 55 year old man with type two diabetes. How should we think about treatment? So, the 40 year old woman with um male and abnormal liver enzymes, if you recall had a low FB four suggesting she was low risk for severe fibrosis. So, this is a patient that you're gonna retain in the primary care clinic who at this time doesn't necessarily need co management of her liver disease with um with the hepatologist. This is a patient who um needs weight loss as I highlighted all patients with Masol um do need weight loss. Um give uh th this is a patient where you can start with um 5% weight loss to reduce the steatosis. Um We don't think she has significant fibrosis, which would require a much um much higher degree of weight loss to improve. So, uh this is a patient where I would work with her to um uh work with her to lose uh 5% of her baseline weight. Um uh This is a patient though that you can't just ignore. Um in uh in two years, you do have to reassess her fib four. because that's really gonna be the only way you can detect whether she's one of the few pa patients who is progressing despite a low fib four at baseline. So you wanna reassess her fib four in two years and all patients with masl are at potential risk for cardiovascular complications. So you want to calculate her cardiovascular risk over time and intervene using um standard of care reduction strategies. Now, turning our attention to the 55 year old man with type two diabetes who um had, you know, with normal liver enzymes for many years, if you recall his testing, um ultimately um concluded that he had a high elf score triggering a hepatology referral. So, the hepatologist then obtained a liver biopsy to confirm whether this patient has significant fibrosis. The liver biopsy shows that the patient has steatohepatitis and he does indeed have severe fibrosis. He has stage three fibrosis, meaning he's one stage away from cirrhosis. So, this patient in many ways is a much more urgent case. This is a patient who um most likely and most very well could uh progress to cirrhosis and its complications. This patient um really needs to lose 10% of his baseline weight. Um He may need some um intensive behavioral interventions to help him with that. Um uh This patient, uh I did not mention um for his diabetes, he's already on semaglutide. Um So, uh so he's already exposed to a G LP one agonist. So this is a patient where I would consider treating with ResMed that newly approved um conditionally approved medication for NASH uh given that uh in, in the trial, um the medication was associated with some fibrosis progression, about 30% of patients who took it. Um And again, like the 40 year old woman, this is a patient where you again have to focus on cardiovascular risk reduction strategies using standard of care methods to assess his risk and intervene. Um So with that, I'll conclude I just reviewed the key points from this talk. Um And this is what I hope you got uh got from this talk first. Whose liver should you worry about? So you should worry about patients who have risk factors for mail. That is type two diabetes, obesity, two or more metabolic syndrome features or who have an established diagnosis of mask, like our 40 year old woman who have findings of severe liver fibrosis. And you figure out if someone has severe liver fibrosis using noninvasive testing. Um first line applying the fib four and then if that doesn't give you the answer, then um reaching for a fiber scan or sending the patient for enhanced liver fibrosis testing. Anyone with a fib for uh more than 2.67 a fiber scan measured liver stiffness of eight or more or an elf score of 7.7 or more. Should um these patients should be referred to a hepatologist. I'll just uh say I'll just mention um because this is a question I get often, sometimes fib four is the only tool you have available. Um fiber scan may not be available. Um And E score uh referral may not be available. In that case. If a fib four is the only thing available to you, then I think it's um it's reasonable to refer any patient with a value fib four value of 1.3 or more. Um Now, if you have a patient who's high risk for adverse liver outcomes. What treatments can potentially reduce the risk of those adverse liver outcomes? So, the four available treatments are weight loss, semaglutide, pioglitazone and rised. Well, we know that all of these interventions have some uh effect on either steatohepatitis or fibrosis or both in the case of weight loss and ResMed. We don't know what the effect on hard clinical outcomes are yet. These are yet to be determined, but we assume that they can reduce um the uh likelihood of adverse clinical outcomes based on their effect on histological surrogates of steatohepatitis and fibrosis. So with that, I'll conclude and I will open up for questions.