Thank you so much for joining us today. My name is Dr. Cecilia Lo Wong, and I'm a professor of medicine at the University of Colorado School of Medicine in the Division of Endocrinology, Metabolism, and Diabetes. I'm also the chair of the ACE Disease State Network Oversight Committee. I'm happy to be here with you today to present the first part of our program on a MasLD and MASH, Early Identification to Decrease Associated Complications. Let's start with definitions. MASLD, or MASLD, stands for Metabolic Dysfunction Associated Steatotic Liver Disease. This was formerly known as NAFLD, or non-alcoholic fatty liver disease, and refers to the presence of excess liver fat in the setting of having at least one cardiometabolic risk factor without the significant contribution of other causes of steatotic liver disease. The specific amount is a liver fat level of 5% or greater. We also have to consider degree of alcohol consumption. So 140 grams or greater in women, or 210 grams in men or greater per week, should prompt the consideration of METLD, which is a combination of MASLD and alcoholic liver disease, or ALD. Cardiometabolic liver disease, or SLD, in a particular patient can also be due to multiple etiologies at once, such as celiac disease and or hepatitis C in addition to MASLD. So what cardiometabolic risk factors are we talking about? This chart shows the adult criteria on the left and pediatric criteria on the right. Having just one of these out of the five would meet the criterion for MASLD if there's the presence of excess liver fat and no other significant contribution to steatotic liver disease. So the risk factors are actually similar to what we think of for metabolic syndrome. An elevated BMI, dysglycemia, which includes either elevated fasting glucose, a glucose of 140 or greater during an oral glucose tolerance test, an A1C of 5.7% or greater, a history of type 2 diabetes, and or being on a glucose-lowering therapy for type 2 diabetes. The third criterion has to do with blood pressure, blood pressure of 130 over 85, or on antipertensive therapy. The last two criteria are related to insulin resistance. Fasting triglycerides of 150 or greater, or on lipid-lowering therapy, or an HDL of less than 50 in women or less than 40 in men, or on lipid-lowering therapy. A few other terms to be aware of include MASH, M-A-S-H, which was previously termed NASH or non-alcoholic steatohepatitis. This is a more advanced form of steatotic liver disease caused by MASLD with hallmarks of cellular inflammation and death, noted as ballooning on biopsy, and promotes the formation of fibrosis. Liver fibrosis refers to the evidence of scar tissue formation from hepatic inflammation and cell death. Keep in mind that there are four stages of fibrosis. Stage 1, which is perisinusoidal or periportal fibrosis, stage 2, which is both, stage 3, which is bridging fibrosis, and stage 4, which is bridging fibrosis with nodular regeneration, which is also known as cirrhosis. The diagram on this slide puts it all together really nicely. Steatotic liver disease is the umbrella term for all of these disorders. On the far left, you can see MASLD and a more advanced form of MASLD, which is MASH. In the middle, you can see the spectrum from MASLD being predominant to ALD being predominant. And this is MASLD in the presence of increased alcohol intake. On the right side, you can see alcohol-associated liver disease or ALD. And then there are certain specific etiologies for SLD, including drug-induced liver injury, monogenic diseases, and other. On the far right is cryptogenic SLD. Now let's move to screening and testing options. So who should be screened? We should think about screening using a FIB4 test, anyone who falls into one of the high-risk groups for MASLD. The high-risk groups include individuals with prediabetes, type 2 diabetes, obesity, metabolic syndrome, or polycystic ovarian syndrome. Oftentimes, patients may have incidental steatosis noted on imaging. All of these individuals that I've listed in the high-risk groups, as well as those with incidental steatosis, should be assessed for intermediate to high-risk disease using a FIB4 calculation. Liver enzyme tests and a platelet count along with age are used to calculate a FIB4 score. Your patient might have incidental steatosis found on imaging. Some examples of imaging where one might find this include the following. Ultrasound, which has a lower sensitivity and specificity when steatosis is milder, but may detect potential cirrhosis with findings of a nodular liver surface and or splenomegaly. Some patients also may have a non-contrast CT scan that shows 48 Hounsfield units or lower. This may be highly specific for moderate steatosis, as is a liver-to-spleen ratio of less than 1.2. Lastly, a patient may have an MRI that shows proton density fat fraction of 5% or greater. This is actually considered the gold standard for steatosis, but it's not used for screening because of cost. Patients in one of the high-risk groups or with incidental finding of hepatic steatosis on imaging should undergo thorough evaluation, including key elements of the history. The first is an assessment of alcohol use. A typical weekly number of alcoholic beverages consumed should be assessed. And keep in mind that there is a whole blood alcohol biomarker called PEF that can indicate harmful levels of alcohol consumption over the previous month to rule out alcohol as a potential cause of the liver disease. In addition, all patients with steatotic liver disease should be screened for hepatitis C. Keep in mind that this can occasionally present with normal liver enzymes. Next, patients should be screened for hypothyroidism, or if they have existing hypothyroidism, they should be evaluated for adequate treatment. What we do know is that inadequately treated hypothyroidism can promote progression of steatotic liver disease. Lastly, celiac disease is a comorbid condition that should be assessed, and patients should be screened, and especially if you see an abnormal CBC with a low hematocrit and or abnormal CMP, think about celiac disease. Now in terms of screening options, we should be starting with a CBC and a comprehensive metabolic panel. On the CMP, the ALT and AST are used along with a platelet count to calculate a FIB4 score. That can help to stratify patient risk. Results of the CBC or CMP might also indicate other comorbidities that should be actively managed, such as diabetes, obesity-associated conditions, renal dysfunction, or anemia. Patients with a FIB4 score of 1.3 or greater should undergo a secondary risk assessment, and advanced fibrosis is likely in patients with a FIB4 score of greater than 2.67, although at this point it would be reasonable to do further non-invasive testing. Screening with an ultrasound is considered reasonable and can indicate steatosis or provide clues of more advanced liver disease, especially signs of cirrhosis, as indicated by nodular changes or hepatosplenomegaly. Individuals who are found to have excess liver fat should be worked up for possible significant or advanced steatotic liver disease, and of course those with concerns for advanced fibrosis or cirrhosis should be referred to a specialist. Another form of screening might be performed with a FibroScan. It's a non-invasive method of measuring liver stiffness. For low-risk patients, or those with a score of less than 8, the FibroScan should be repeated every two to three years to assess for progression or improvement. Higher-risk individuals with a score of 8 or greater should be evaluated every one to two years. Some medications can induce MASL-D, so it's important that the patient's current medication list be reviewed. So the medications known to impact liver disease and cause abnormal liver function tests include glucocorticoids, tamoxifen, heart therapy, amiodarone, methotrexate, valproic acid, nifedipine, a number of chemotherapeutic agents, and atypical antipsychotics, among others. Thank you, Dr. Lo Wang. My name is Dr. Thomas Jensen. I'm an associate professor of medicine in the Department of Endocrinology, Diabetes, and Metabolism at the University of Colorado Ansche's Medical Campus. I will now start talking to you about our ability to detect MASH. So in the past, people have tried to check various non-invasive scoring algorithms and blood tests, including ones such as cytokinin-1018 and procollagen-3, as well as other scoring systems such as FIF-4, the fibrotic NASH index score, and other proprietary blends you can see that are listed. And they've shown some promise, but have not been able to reliably rule in or rule out MASH. In addition, people classically have been confused, thinking that patients with elevated liver enzymes with fatty liver disease must have MASH, but we know that these elevated enzymes have poor sensitivity and only modest specificity for identifying MASH and distinguishing it from simple steatosis. Other people have looked at combining certain type of imaging tests with biomarkers, such as the FAS score, which combines the FibroScan test with AST. The MASH score, which combines MRI lastography scores with AST. And then what's called the MEB-Fib score, which is MRI combined with FIF-4, along with looking at MRI control T1 images. And these have shown promise to detect at-risk MASH, meaning MASH with stage 2 fibrosis or higher, and these may be then useful in helping to decide which patients may be appropriate for starting certain pharmacological treatments as they become FDA approved. But currently, right now, biopsy still remains the gold standard for being able to diagnose MASH. When it comes to detecting hepatic fibrosis, we have several tests, including blood and imaging modalities, that have become very useful in being able to determine patients with more significant or advanced fibrosis versus relatively benign disease. Blood tests, including proprietary tests such as ELF or FibroSpect and FibroSure, along with the FIB-4 score, as you can see in the table there, have shown excellent ability to detect more likely for advanced fibrosis, meaning stage 3 or 4. In addition, we also have, as discussed before, ultrasound elastography, especially the FibroScan. And this has become relatively easy and available for many individuals across the country. Many guidelines are currently using with the FibroScan a score of 8 or greater to indicate that there's more likelihood for significant fibrosis, again, meaning stage 2. And in these settings, usually people recommend further evaluation by a specialist in this area. We know, though, sometimes the FibroScan has some limitations. If you have a higher BMI or things such as right heart failure, infiltrative hepatic disease like hemochromatosis, or very elevated liver enzymes or tumors, this may make the results less accurate. Also, we have MRI elastography in some centers. This is shown to be superior to ultrasound elastography, but because it's more expensive and less available, this should be only ordered or considered by specialists. And again, biopsy is still considered the gold standard for diagnosis, but frequently we're using it less except in settings of uncertainty about whether someone has another cause of their liver disease or if there is uncertainty between the non-invasive tests and wondering if the patient may have cirrhosis. Now we'll discuss management strategies for every stage of MASL. For managing MASL at any stage of disease, the foundational treatment we want to emphasize with our patients is lifestyle modifications. We know that goal weight loss of 5% to 7% or more in patients with a BMI of greater than 25, or even 3% to 5% in patients with a BMI of 23 to 25 who have what is known as lean muscle can benefit and help to reverse disease. What we want to do with our patients is assist them with their meal planning by creating a calorie plan that creates a deficit based upon their personal goals and emphasize consuming unprocessed foods, especially lean proteins and fiber, as well as healthy fats and avoiding more processed and ultra processed foods such as simple sugars, saturated fats and high fructose corn syrups while trying to respect their personal cultural and ethnic preferences as far as meal planning. Using such things as meal planning apps or calorie counters really can be very beneficial. In addition, we want to emphasize decreased alcohol consumption in patients with more mild disease, trying to ensure our patients restrict their alcohol consumption to less than 15 drinks per week for men and less than 10 drinks per week for women is a highly recommended. Also, if patients have more advanced disease such as stage three or four, then they should abstain from alcohol consumption altogether. Finally, we want to emphasize increased activity level. And I talk about with my patients trying to find what type of exercise or activity they most are going to be able to tolerate. This could be a set type of exercise activity or routine which accumulates about 150 minutes of moderate intensity exercise. Or if it's better for them to do something, say track their steps, to try to reach a goal of somewhere between eight to 10,000 steps a day. In addition, weight resistance can be very beneficial to help maintain lean muscle, especially in our patients with more advanced disease that are at risk at sarcopenia. In addition to lifestyle modifications, we know that pharmacological interventions or bariatric interventions can be quite useful in helping patients obtain weight loss that will help reverse fatty liver disease. For patients with MASL, those with a BMI of 27 or greater can be considered for weight loss medications. And we especially encourage this to be considered with patients with MASH or fibrosis, especially if there's any clinical data as we have seen with the GLP-1 or dual agonist medications that can help improve weight loss and help reverse MASH or prevent progression of fibrosis. For patients with bariatric indications such as patients with MASL, consider endoscopic interventions for patients with a BMI of 30 or greater with emerging data showing that they're benefit. And as I said before, traditional bariatric surgery in patients with a BMI of 35 or greater have shown to be greatly beneficial. Also patients with MASH or fibrosis should be strongly considered for either endoscopic or traditional bariatric procedures unless they have decompensated cirrhosis. Finally, it's important to help reduce cardiovascular disease risks, especially by managing blood pressure. And it has been thought that patients being placed on ACE or ARB medications should be considered first line. In addition, cholesterol management is highly recommended, especially statin use has been shown to help reverse cardiovascular disease risk in patients with fatty liver disease and should be prescribed appropriately based upon other risk factors including diabetes or moderate risk ASCVD scores. In addition, certain medications and randomized control trials have shown to be beneficial in certain populations who have MASH and or fibrosis. For instance, in individuals without diabetes, it's been shown that vitamin E, pioglutazone and GLP-1 receptor agonists have been beneficial. While those with diabetes, pioglutazone and GLP-1 have been shown beneficial to improve MASH but not vitamin E. Recently, we've had the approval of the first FDA medication for MASL, a medication known as resveratron which is a thyroid beta receptor agonist. And this has been shown to be beneficial in reversing MASH as well as improving fibrosis by one stage or more in patients with at-risk MASH. Finally, for special considerations for type 2 diabetes, medications including pioglutazone, GLP-1 receptor analogs or GLP-1 and glucose-dependent insulomatron polypeptide dual agonist or GIP have been shown to be beneficial along with SGLT-2 inhibitor medications. Metformin and insulin as well as DPP-4 inhibitors can be considered as well although there's less data that they have as much benefit histologically. And finally, sulfonylurea medications should be avoided if possible as they appear to have negative impact on liver outcomes. When it comes to managing cirrhosis, providers should carefully work with specialists including gastroenterologists and hepatologists to help co-manage these complex patients. Lifestyle interventions can still be considered especially to help prevent weight gain and allow for appropriate weight loss including trying to avoid those processed foods we talked about in the past. In addition, one should really focus on increased protein intake around 1.2 grams to 1.5 grams per kilogram ideal body weight to help reduce the risk of worsening sarcopenia and frailty. It can be very beneficial of course to work with a nutritionist who specializes in this area along with other people such as sports medicine and physical therapists to help maintain functional status for these individuals. Bariatric surgery can be considered for some patients but generally we would want to avoid this in patients who have clinically significant portal hypertension. And when we are considering a procedure it's probably safer to consider sleeve gastrectomy as if the patient may require a transplant later on. There is a concern though those who undergo wound-wide gastric bypass surgery may have difficulty absorbing the rejection medications. GLP-1 receptor agonists as well as dual agonists can be considered although one would maybe want to consider holding these medications if there was worsening in their liver frailty index. Apply caution of course when using pilozone in patients with decompensated cirrhosis as well as avoiding statins typically when patients are also decompensated. Finally, one would want to apply caution when using ACE or ARB medications in decompensated cirrhosis as there's an increased risk for exacerbating hepatorenal syndrome. Consider use for potassium sparing and loop diuretics for management of deuma can be helpful. And those who are found to have clinical significant portal hypertension is now recommended consideration for non-selective beta blockers to help prevent decompensation events. Finally, we will now discuss our ability to monitor response to therapies. Unfortunately, guidelines currently right now that are out in press do not have any direct information in regards to what non-invasive tests we can monitor to suggest improvement in histological outcomes. That's in part because many of the times a lot of studies have very heterogeneous outcomes based upon the modality of intervention whether it was just lifestyle modification or placebo or drug treatment. And therefore it makes it at this time uncertain how to accurately define response in individuals based upon particular treatments. Regardless, monitoring with tissue elastography including FibroScan as well as more advanced techniques such as MRI elastography and liver multi-scan to look for resolution of excess fatter fibrosis using cutoffs based upon the manufacturer recommended guidance can be encouraging for patients and to help also monitor for worsening disease. In addition, there has been some consensus about possible endpoints that may be able to be used although further studies are needed. For instance, it was found in the Flint trial a reduction of 17 points or more in ALT was shown to be associated with histological response. Another score, the FAST score, which we talked about earlier was found in a study with semaglutide that a reduction of 0.22 points or more was associated with the primary endpoint of NASH resolution without the worsening of fibrosis although there were variations in sensitivity and specificity based upon whether on treatment or not. And in addition, as regards to the FibroScan, there's been a few prospective data on looking at changes over time though more so in patients with viral hepatitis or alcohol liver disease. A study in 2018, for instance, though, did find that a change in a capscope greater than 38 decibels per meter was suggestive of a 1% absolute change in fat fraction on MRI. Also, we've noted that a greater than 20% increase in KPA, stiffness over time, has been associated with liver-related events. Several studies have also shown that MRI protein-density fat fraction with an improvement of 30% or more has been linked to histological improvements and or NASH resolution as well as when we combine it with liver enzymes that has improved on its capacity to show improvement histologically. In addition, a worsening of 15% or more on KPA has been linked to worsening fibrosis when looked at on biopsy. Finally, liver multi-scan has shown that improvements in 77 milliseconds on controlled T1 imaging has correlated with a two-point improvement in NASH scoring without worsening of fibrosis versus non-responders in three large cohort trials. Though there are no consensus guidelines on how to exactly monitor non-invasive tests based upon level of disease, the following are suggested for providers to consider. For instance, with patients with low Fib4 scores, it's suggested that you repeat the Fib4 score yearly, and if it rises above 1.3 or in the case of a patient at 65-year-old or 2.0, consider secondary non-invasive testing such as FibroScan or ELF. For patients without significant or advanced fibrosis, we suggest monitoring at least every two years if it's suspected of having NASH or every three years to monitor for worsening disease. And then finally, those patients who do have more significant or advanced fibrosis, we suggest reassessing at least every two years if it's stage two or every one year if it's stage three or four. Again, to review certain medications that have been shown to be beneficial in the treatment of Maslod, first we'll discuss Rosmetarone, which again is the first only FDA-approved medication for the management of Maslod, in particular patients with NASH with either stage two or three fibrosis. And this has been shown to help to reverse NASH and or reverse fibrosis by one stage or more. The important thing to note is that it is not necessary to start this medication based upon biopsy, but certain cutoffs which are emerging and guidelines will be coming out soon to help guide us as far as what the cutoff should be can help us decide when patients may be best to start Rosmetarone and also duration and monitoring of treatment. As we've talked about, GLP-1 receptor analogs and dual agonists have been shown to have great benefit for patients both who have failure disease with or without diabetes. This has been shown to improve fat content, reverse NASH and potentially prevent progression of fibrosis. Also, there's preliminary data that the co-agonist GLP-1 GIP has been shown in phase two trials to help reverse NASH and maybe potentially able to help reverse fibrosis, but we're waiting for their phase three trial data. Thiazolidazone, which has been used commonly to treat type two diabetes, has been shown to be beneficial to help reverse NASH in both patients with and without fibrosis. Statins, as we've discussed, reduce harmful levels of LDL cholesterol to address these higher risk of cardiovascular disease. Aspirin should be considered for secondary prevention to reduce cardiovascular disease for those at risk. And patients without diabetes may consider taking vitamin E if it's thought that they have NASH. Finally, we also want to mention that there are currently many ongoing clinical trials, especially looking at patients with NASH with either stage two or three fibrosis, but there are also even trials looking at outcomes to prevent decompensation in patients with compensated cirrhosis. So it's important as much as possible to not only find available medication and treatments, but also consider patients who might be appropriate to be referred to clinical trials, as this will better help our understanding in the management and treatment of NASL. Thank you very much for your time.

metabolic dysfunction-associated steatotic liver disease

MASLD

non-alcoholic fatty liver disease

NAFLD

liver fibrosis

cirrhosis