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Hello, I'm Doctor David Chasca, a hepatologist who focuses on the treatment of steatotic liver disease here at Mayo Clinic located in our Arizona campus. I'm so excited today to be part of the Mash Academy and talk about how noninvasive fibrosis tests can help us in the management of fatty liver disease as a means of level setting. I would like to start by discussing what I mean by steatotic liver disease. Histologically, steatotic liver disease is when the fat content of the liver is greater than 5% of the liver weight or when greater than 5% of the hepatocytes are full of fat globules. There are multiple potential causes of this including alcohol, medications and metabolic dysfunction, which is what we will be focusing on today. As many of you are probably aware there has recently been introduced new terminology to describe steatotic liver disease more accurately and it represents a spectrum. Additionally, the main emphasis is to differentiate steatotic liver disease from metabolic dysfunction from that of alcohol. Though it is recognized that there is overlap between the two conditions. When we're referring to mail or metabolic dysfunction, associated steatotic liver disease. There must be evidence of hepatic steatosis typically on imaging and then patients must additionally have one or more metabolic risk factors. I have put those in the bottom of the slide and they include an elevated body mass index which does need to take into account ethnicity, an elevated hemoglobin A1C or other markers of diabetes, hypertension, hypertriglyceridemia or dyslipidemia with a low HDL steatotic liver disease is a major world concern. In fact, it is the most common chronic liver condition affecting up to 25% of the world's population in some areas of the world. It may affect up to one in three patients. Data from the United States shows similar findings with anywhere from one in 4 to 1 in three persons being affected with some degree of fatty liver, 2 to 14% of Americans may have inflammation or mesh and that puts up to 2 million Americans at risk for high risk mask. Additionally, 1 million may have advanced fibrosis and may go on to need definitive therapy such as liver transplantation. Unfortunately, the prevalence of this condition is only increasing at a rate of about 1% per year. And it is worth noting that metabolic syndrome in patients with end stage liver disease requiring liver transplant has increased 10 times since the 19 eighties. With only 3% being affected with metabolic syndrome in 1987. And as recently as 20 13/30 percent, certainly that number is likely higher. Now, mash cirrhosis is a leading indication for liver transplantation in women and those over 65 years and will likely be the leading indication for liver transplant overall in the very near future. As I alluded to with the title of the last line, given the prevalence of this disease, we cannot biopsy everyone. So how do we diagnose and establish a baseline for this disease? We will talk about this over the next several slides. One place to start when trying to determine whether a patient has fatty liver or more importantly, MSH is to look simply at liver, blood tests or liver injury tests. However, it is very important to note that the reference ranges change by lab and also by the method by which the tests are performed. Traditionally and more recent guidance documents have been based on the standard laboratory methods which suggest that a normal alt for an adult male is approximately 30 units per liter and normal reference range alt for an adult female is 19 units per liter. As you can see, depending on the method used to perform the test, the reference ranges may change. However, studies have shown that when the alt increases above 30 there is an increased risk in liver related outcomes, liver injury tests or biochemistries are clearly insufficient to rule in or rule out a diagnosis of mail D or mash. And based on the new definitions of mas D, an imaging diagnosis is also required imaging. Absolutely can aid in the diagnosis of fatty liver. An ultrasound is a great initial screening test due to low cost and wide availability. It has good sensitivity and specificity to detect moderate and severe degrees of steatosis. However, it may miss lesser degrees of steatosis when liver fat content is less than 20%. Other imaging modalities may also be helpful such as unenhanced CT scan, which allows comparison of liver density with that of the spleen. As represented in this image. A hypodense liver indicates fatty infiltration and you can see here that it appears darker than the spleen. This is important to note because contrast enhancement will affect the relative densities of the liver and spleen. MRI estimated proton density fat for action or MRI PDF F is arguably the gold standard for noninvasive assessment of fatty liver disease is accurate, precise and reproducible. And unlike some other imaging modalities or non invasive fibrosis measures, it allows for global assessment of the liver. There are report caveats. MRI may be influenced by fibrosis and iron overload. However, PDF F is excellent for the detection of any fat greater than 5% within the liver with 96% sensitivity and 100% specificity. Now that we have discussed imaging to help aid in the diagnosis of excess fat within the liver. The next thing that we need to focus on is accurately staging the degree of liver fibrosis as this of course, has the most significant clinical implications with regards to adverse liver related events, death or need for transplant. Why do we care about inflammation and fibrosis? Well, that is because they drive disease progression in the setting of mail D fibrosis progression can occur in the absence of significant fla inflammation in mass D. And it is thought that mass D progresses approximately one fibrosis stage every 14 years. The inflammatory condition of mass progresses more rapidly by one fibrosis stage, approximately every seven years. So certainly there are rapid progressors when we are thinking about ways to stage the fibrosis. The questions we need to ask are, what exactly are we looking at? Is this to address a clinical question for a patient in front of us? Are we looking at a research study where we could use larger data sets and look at noninvasive testing such as the fib four score. What is the overall risk for advanced fibrosis in this particular patient population? And for instance, I provide here on the slide information about the overall prevalence of mail D in patients with diabetes. As you can see patients with type one diabetes have approximately 9% risk of having masal. Whereas the risk in a patient with type two diabetes could be anywhere from 60 to 75%. And it is also important to know that patients with type two diabetes have a high prevalence of high risk MSH, meaning mesh with more advanced fibrosis. Approximately 20% of patients with type two diabetes may be at risk. The other thing that we need to consider is the availability and costs of testing. Blood based fibrosis assessments are incredibly attractive tests because they're easy to implement in clinical practice and serve as a point of care assessment. They also tend to be fairly cost conscious when based on routine laboratory tests. Two examples include the fib four score and the NAFLD fibrosis score both perform fairly well with area under the curve of 0.7 to 0.8. I will focus mostly on the fib four score as that appears more prominently in several guidance documents. It is important to note that the fib four score is made up of routine liver biochemistries such as AST and A LT markers of liver function such as platelet count and age. It was first developed in patients in a middle age range and may be slightly less accurate on the extreme ends of the age spectrum. There are particular cutoffs to exclude the presence of advanced fibrosis and also to increase the probability of advanced fibrosis to exclude advanced fibrosis. A score less than 1.3 is considered though in patients over the age of 65 years, a score of less than 2.0 may accurately exclude advanced fibrosis. The important caveats are that fibrosis may be underestimated in patients less than 35 years old. And even with the adjusted cut off level, there is decreased diagnostic accuracy in patients over the age of 65. A more novel test is the enhanced liver fibrosis score, which is a blood based test but does not rely on routine liver biochemistries. Instead, it looks at markers of matrix turnover. The elf score is excellent at diagnosing advanced fibrosis with an area under the receiver operating curve. Greater than 0.8. A cutoff value of greater than 9.8 is highly sensitive for the presence of advanced fibrosis. Caveats include extra hepatic inflammatory states or fibrotic diseases which could lead to false positive results. Another issue is that this blood based test is relatively expensive and thus may be a good option as a secondary test. If one of these first tests indicates a high likelihood of advanced fibrosis. In addition to blood based fibrosis tests, there are also imaging based fibrosis tests. I would like to spend some time talking about ultrasound based fibrosis assessments. There are several options including vibration controlled transient elastography, acoustic radiation force, impulse point shear wave elastography and two dimensional shear wave elastography. Many of these are attractive because when combined with ultrasound, they serve as point of care testing and can be completed as the patient is also undergoing diagnostic imaging. However, in clinical practice guidelines, typically, vibration controlled trans elastography is used most often and is also in concluded in the Bino classifications to determine risk of clinically significant portal hypertension. And as such, I will focus on that modality VCT E or fiber scan is highly accurate for the detection of advanced fibrosis and cirrhosis with an area under the receiver operating curve near 0.9 is also useful because it provides information on the degree of hepatic steatosis. The broad categories for steatosis are S zero or less than 6%. S one which roughly is 6 to 30%. S 230 to 60% and S3 which would be 60% or greater again with excellent area under the curves as I alluded to they scoring system is used in the Bovino classification to rule out or rule in the likelihood of clinically significant advanced chronic liver disease and clinically significant portal hypertension. Though in real world experience, the cutoffs may be slightly different and also depend on the cutoffs as determined by the manufacturer. I've included on this slide, an image of a fiber scan report from our hospital system. And you will note that there are two scores that are given. One is the orange score, which is the stiffness reported in kopas gals. And that is used to determine the likelihood and the degree of fibrosis. The other score is the C score which helps give the steatosis. Great. You'll also note that an interquartile range is given and an accurate exam is one in which the I QR is less than 30 MRI again comes out on top as the most accurate means to noninvasively assess fibrosis. This is because it offers a comprehensive assessment of the liver and can assess the degree of fibrosis in multiple areas of the liver. During one examination, it has excellent area under the curves for detection of F two and F three fibrosis. And also the presence of F four or cirrhosis proposed cutoffs for significant fibrosis are 3.66 kopas GS with a sensitivity of 79% and specificity of 81% with a cutoff of 4.11 Klaas gals. Uh for detection of advanced fibrosis, the sensitivity is 85 and specificity likewise 85%. And for detection of cirrhosis, a cut off of 4.71 yields a sensitivity of 91% and a specificity of 81%. It is important to note that there are limitations including availability as not all centers have access to this technology and cost. And I mentioned cost specifically when this imaging technique is combined with a contrast enhanced abdominal MRI. The cost can increase quite significantly. It is important to note as well that like other noninvasive fibrosis assessments such as VCT E, this is not a direct measurement of liver fibrosis, but it is a measure of liver stiffness and things like congestion of the liver from cardiac disease can affect the results. All that said for patients who have this as an option, it is arguably the best and most accurate test to detect significant changes in liver stiffness and fibrosis and liver fat content. There are also several scoring systems that combine both blood based tests and noninvasive fibrosis imaging techniques. I've included on this slide. Some examples including the agile three plus, the agile four, the me FB score, fast score and safe score. This is by no means a comprehensive list but just to give the audience the opportunity to hear about some of these tests and we will talk about a couple of these on subsequent slides. The components of the agile three plus include ast A LT ratio, platelet count, diabetes status, sex age and liver stiffness assessment. In a study of over 600 patients with biopsy proven fatty liver disease. The agile three performed quite well and it had a higher area under the receiver operating curve then fib four at 0.88 for detection of advanced fibrosis. Importantly, it also had a smaller intermediate or indeterminant area in the test. Whereas in this patient population, 25% had an indeterminant fib four score. Approximately 8.3% had an indeterminate score for the agile three. The score also performed well with respect to prediction of liver related adverse events. As you can see in the graphic, the score performed similarly to the liver stiffness measurements and superiorly to the fib four score. The safe score is another score which is based on clinical risk factors and also routine lab testing. The data were derived from patients that had biopsy, proven fatty liver in the NASH Clinical Research Network which includes over 600 patients logistic regression was used in combination with machine learning models to construct a prediction model to distinguish high risk fatty liver and fibrosis F two or greater from F zero or F one. This model was then applied to a large data set, the National Health and Nutrition Examination Survey or N Haines three, which includes almost 12,000 patients to correlate with long term mortality. The model yielded excellent area under the curve for distinguishing F zero F one fibrosis from F two or greater at 0.8 and consistently outperformed the fib four and NAFLD fibrosis scores. The negative predictive value for ruling out F two with a low safe score of zero was 88% uh to 92%. And patients that had a safe score of less than zero found survival probability s cone consistent or equivalent to those without steatosis. Whereas increasing safe scores correlated with shorter term survival. This can be seen in the curve here with the lowest survival probability in patients with high safe scores and similar scores or survival seen in patients with low safe score or no fatty liver disease. I would light to transition during this next section to talk more about how we apply these specific tests into a clinical algorithm for thoroughly evaluating and risk stratifying patients with masal D. There is by no means one finite way to evaluate a patient with a nasty. And I would like to share with you the way that I approach these patients utilizing both the resources available at my center and best clinical guidance documents. First, I draw your attention to the middle section and the figure the job we have initially is to identify patients that are at risk, things that we may be looking for in the primary care setting, which may prompt further referral or evaluation for the presence of fatty liver disease. Include first and foremost, the presence of diabetes, especially type two diabetes, metabolic syndrome, obesity, patients with moderate alcohol use, who may otherwise be at risk for metabolic related fatty liver disease, a family history, especially a first degree relative with fatty liver disease in patients with elevated liver injury tests. Further, it is common for patients to have imaging for unrelated symptoms and incidentally be identified as having hepatic steatosis. Once any of these criteria are met, a patient should be considered for further evaluation and mass D or mass should be suspected. The next step would be to perform routine blood tests such as a CBC and liver injury tests if they have not previously been performed. And this would allow for a calculation of the fib four score. Again, as stated there are other scoring systems, but this is what I use in my clinical practice depending on the fib four score that determines the potential risk for the patient. Low risk patients with a score, less than 1.3 can likely be managed by their primary care doctor with repeated assessments of the F four score perhaps every year with their annual physical exam or even less often every 2 to 3 years. Again, the risk of progression takes anywhere from 7 to 14 years in most patients. So there is time to detect the risk of advancing to more advanced fibrosis. Now, in patients with the opposite end of the spectrum, with high risk fib four scores, those patients should really skip additional testing and be referred to Hepatology who can hopefully provide the best input for the best way to evaluate their their condition. In many cases. If available, proceeding with Mr elastogram would make sense to confirm the degree of advanced fibrosis to screen for liver cancer and to accurately quantify fat and fibrosis. Then there is a middle area. Those patients with an indeterminate score somewhere between 1.3 and 3.25. These patients need a second line test and as we discussed VCT E or ELF score are great secondary tests. One study did show that patients that are on the higher end of the indeterminate range, greater than 2.67 for a fib four score may benefit from going directly to MRE as it is cost saving as they have a potentially higher risk of having advanced fibrosis present. These patients may need at least a one time consultation with a hepatologist to help determine a surveillance plan and if they indeed have advanced fibrosis, specific treatment tailored to their individual needs. As one additional. Aside, I do think it is important to assess all patients for the presence of alcohol use to ensure that we are dealing with metabolic related liver disease and not alcohol related liver disease or potentially met ald. Further, all patients should be screened for hepatitis C. And I do recommend that testing upfront further testing for other causes of liver disease or potentially coexistent liver disease may often be deferred to the hepatologist but should at least be considered if clinical risk factors are present. We know that in many patients, mail d may progress over time. And as such, it is important to have a monitoring or surveillance plan in place. And on the next slides, we'll talk a little bit about the data for this and how best to proceed based on the patient population. Well, we probably cannot rely solely on liver injury tests in the blood. I would not completely discount them either. And I show an example here of a study that was done in Children who we're separated into groups based on diet. One group was placed in a diet low in added sugar, which meant less than 3% of daily calories from sugar. And the other group was placed in a regular diet which includes a recommendation for less than 5 to 10% of added sugar. Well, you can see in the low sugar diet group in these patients with fatty liver is that by changing their diet, their liver injury tests did improve in many instances. And this correlated with improvement in the hepatic fat fraction. So it is a useful test. And I do think that there is utility when we see a patient with an elevated alt normalize their alt, this may be sufficient screening in a patient that is otherwise low risk or has cured their metabolic syndrome through lifestyle modifications. While inflammation is certainly a driver of disease progression and can be monitored or surveyed with liver injury tests, fibrosis is also a major driver of disease progression and arguably is what we are most concerned about as fibrosis progression may end in cirrhosis including liver related complications from clinically significant portal hypertension. Potentially the need for liver transplant or death. As a reminder, this is a relatively slowly progressive condition, mass LD in the absence of cea hepatitis. However, may progress approximately one fibrosis stage every 14 years. Whereas MS progresses faster at a rate of one fibrosis stage every seven years. There are certainly risk factors in patients that may progress faster than this and some that may not progress at all. These are the best available data from currently available trials. As we talked about, there are several methods for staging fibrosis, including the F four score VC TEM R, elastography or liver biopsy. I do think it is important to include the potential costs of these surveillance tests. I have included the relative cost in us dollars for the fib four score which is approximately 100 and $45 B CT ea $140. Mr Elastography, $250. So the caveat here is that it is much higher in cost uh potentially in the thousands of dollars if combined with contrast enhanced Mr abdominal imaging and then liver biopsy is well over $1000 as well. And as we have discussed, is not practical for routine surveillance of most patients. I wanted to point out one important caveat in these tests. Specifically comparing VCT E and Mr elastography, both report results in kopas but the results are not interchangeable. And I have included the cutoff values in the slide here. For instance, trans elastography yielding a score of less than 8 kg paca, essentially excludes the presence of advanced fibrosis. However, if we look at Mr Elastography, a score of 5 kg pascals is 95% specific for the diagnosis of cirrhosis. So it is very important to know the cutoff values. And these are often included in the report for clinician reference. Even in the absence of noninvasive elastography testing, fib four and serial fib four measurements can help predict outcomes in patients with fatty liver disease. In this large study, which ended up including over 40,000 patients who had two fib four score tests within a period of five years. It was noted that patients with advancement in their fib four score by even one unit had an increased risk of severe liver disease with a hazard ratio of 1.81. Furthermore, transitioning for from a low or intermediate risk to a high risk group was associated with an increased risk of severe liver disease with hazard ratios of 7.99 and 8.64. And even more concerning were patients that were identified as high risk initially and remained high risk had very high risks of severe liver disease hazard ratio. 17, all that said it makes sense that higher scores will pretend worse prognoses. But when they looked at the co the number of adverse events, almost half of events occurred in those consistently in the low group suggesting that it fib four is not a perfect test, but again, does serve as a good test in settings where it is available for you and where other tests may not be readily available. In a study of looking at noninvasive liver stiffness measurements and change over time. It was found that baseline liver stiffness measurements can predict adverse outcomes including liver decompensation. And this was shown comparing patients with a baseline liver stiffness score of less than or greater than 21 kopas gals. And what you can see is there was a significant difference between those with higher scores which pretended a worse prognosis or increased likelihood of hepatic decompensation, uh or other adverse outcomes versus those with lower scores. Additionally, change in liver stiffness correlated with an increased risk of adverse events including hepatic decompensation. Overall mortality and development of liver cancer D study. It is important to note, chose a cutoff of greater than 20% change to account for normal variations in readings. And these smaller graphics here show that those patients with higher changes or higher percentage changes are those that were at increased risk of having liver related adverse events. Liver stiffness assessment can also be used to help direct screening and this is not specific to fatty liver disease. But I thought important to point out the Bino criteria propose that with the combination of liver stiffness assessment based on VCT scores combined with platelet scores can help to determine the probability of clinically significant advanced chronic liver disease and also whether there is clinically significant portal hypertension. And it should be noted that patients with high platelet counts and relatively lower liver stiffness measurements may be able to avoid endoscopy for variceal screening even if they do technically fit within the cut off criteria for cirrhosis. Not unsurprisingly, similar studies have been carried out using the modality of Mr elastography. In this particular study, patients who had had repeat MRE examinations over a median of 3.4 years were evaluated. And it is interesting to note that almost 60% of patients with fatty liver disease remained stable and did not progress. 27% actually had a decrease in their liver stiffness measurements and 13% ultimately progressed to more severe fibrosis, liver stiffness and progression of liver stiffness can predict mortality, baseline liver stiffness can predict three year risk of decompensation and scores less than five were associated with a decompensation risk of 1.6%. Whereas those greater than five were as high as 17. And when the score exceeded eight kopas gals, the risk of decompensation was 19%. Furthermore, increases in liver stiffness measurements greater than 19% were associated with the risk of development of cirrhosis decompensation and death. And those patients with mashed cirrhosis who progressed in their liver stiffness measurements were 19 fold more likely to decompensate or die compared with those patients whose liver stiffness remained stable or regressed. We have discussed in the previous sections using noninvasive testing to diagnose fatty liver and also stage fibrosis. We have shown how these noninvasive tests can also predict the risk of adverse events including the development of cirrhosis decompensation and death. We will now discuss using these tests to assess treatment response. But first, we have to understand what we're talking about. When we discuss treatment response. There are two main endpoints in clinical studies. Typically, when we are talking about fatty liver, we are talking about resolution of fatty liver without worsening of fibrosis as the primary endpoint, an additional primary endpoint can be fibrosis improvement by at least one stage without worsening of steatohepatitis. I would like to take you through two cases now, of how we can implement what we have learned and also use noninvasive testing to help monitor treatment response. I would like to take you through the case of a relatively healthy young patient. He's a 43 year old who presents to clinic with a BMI of 37. He has hyperlipidemia and hypertension and is noted to have an alt of 67 and ast of 46 he recalls being told he had elevated liver injury tests for the past 10 years but does not recall the levels or the testing that has been done at age 30 years. He notes weighing approximately 127 kg, which was his max weight and notes being as low as 91 later the same year after he lost weight to go skydiving over the last three years, his weight has ranged 100 and 13 to 100 and 22 kg. Today, he is again at his maximum weight at 100 and 27 kg. He has successfully lost weight for other events such as his wedding and currently he attributes his weight gain to stress. Ultrasound. Five years earlier had shown severe hepatic steatosis when looking at this patient, massel D and mash have to rise high on the differential as he has multiple metabolic risk factors. Fortunately, in this particular patient, diabetes is absent as a part of his clinical evaluation. A repeat CBC and liver injury tests are performed. This allows for the calculation of the F four score which comes out to 0.7 suggesting a low likelihood of advanced fibrosis. However, a VCT E is prescheduled as part of his consultation and this reveals potentially F two fibrosis with AC score consistent with S3 steatosis. The patient opts to proceed with intensive lifestyle modification but also given his past successes but failure to maintain those successes wishes to initiate antiobesity treatment. He does make clinical indications for the use of teret for the treatment of overweight and obesity. This is titrated over several months to a maintenance dose of 10 mg administered subcutaneously once weekly at the time of follow up in Hepatology clinic. He has lost 9% total body weight. His alt has declined from 67 to 46 overall suggesting a good treatment response. Given the discrepancy between the prior fib four score and the trans elastography score suggesting perhaps an intermediate degree of fibrosis and with the interval approval of resmetirom for the treatment of MS with advanced fibrosis. An MRE is pursued, this reveals the absence of advanced fibrosis and near normalization of the hepatic fat content consistent with the clinical response based on his BMI and also liver injury tests. This next case is arguably a little more complex as it involves a post liver transplant patient. And I should note a caveat that while VCT is routinely used in transplant patients in our institution. The data that were used to derive the cutoff values were not made in patients that had had liver transplants. A 54 year old gentleman with a history of liver transplant seven years ago, for MS cirrhosis exacerbated by Alpha One. Antitrypsin presented to clinic for routine annual follow up and was noted to have uncontrolled type two diabetes type two. He additionally had a BMI of 33 and stage two chronic kidney disease. Further, he was noted to have elevated transaminases in investigating these liver abnormalities. It was noted that he had had serial liver imaging which five years out from transplant showed F four fibrosis on V CTE with a cap score consistent with S3 steatosis clinically. However, there was no evidence of cirrhosis and so the patient was monitored with noninvasive tests with a plan to repeat the testing the following year. Unfortunately, that following year VCT E again showed F four fibrosis with a higher score this time of 21 kopas gals with a persistently elevated C score consistent with S3 steatosis. Given these findings as well as an alt of 74 the patient was referred for a liver biopsy and in a complex patient such as this, it is sometimes necessary to rule out potentially coexistent or alternate differential diagnoses most notably in a post transplant patient, allograft rejection. Indeed, that was the case. The patient did have a mild rejection. Um ra I score three of nine but most notably had active steatohepatitis with 35% macrosteatosis and F three fibrosis. This patient additionally had an MRE which was also concerning for the possibility of F four fibrosis, possibly cirrhosis II will point out interestingly, the MRE underestimated the fat content of the liver compared to the liver biopsy. Unfortunately, the patient underwent supervised pharmacotherapy and intensive lifestyle modifications but was unable to sustain meaningful weight loss. An interdisciplinary discussion was had and he was not felt to be a surgical candidate for bariatric surgery. Given the finding of portal hypertension. Once his cirrhosis was suspected, he did undergo a repeat endoscopy which showed the presence of gastric varices. As you can see in panel A, here's his starting liver biopsy with significant fibrosis and steatohepatitis. Panel B shows the gastric varices which prevented traditional surgical weight loss therapies, an interdisciplinary discussion and to meet the patient's needs. He was referred to interventional radiology. As you can see in panel C and D and ultimately, panel E, he underwent embolization of gastric varices, repeated endoscopy, confirmed near obliteration of the varices. And in discussion with our therapeutic endoscopy team, it was felt safe to proceed with endoscopic gastric sleeve. The patient underwent this therapy successfully, as you can see in panel G and subsequently had significant improvement. He lost approximately 21% of his total body weight. His metabolic derangements improved including the cessation of most of his hyperglycemic agents and subsequent liver biopsy seven months after showed improvement in his macrosteatosis from 35 to 5%. He was also showing still residual F three fibrosis at that time. However, his MRE had improved even more and was now showing approximately F two to F three fibrosis. Again, I think we were benefitted by the fact that we had a geographic assessment of the liver and we're not limited by a small sample size on the specific biopsy. The hepatic fat fraction was consistent with the liver biopsy. However, subsequently, a year later, he had a repeat um evaluation. His alt had improved down from 74 where we started to 43 and his Mr showed F one to F two fibrosis with a fat fraction of 7% and the patient continued to benefit from ongoing weight loss interventions. I hope that these cases illustrate that multiple modalities can be used to evaluate and longitudinally follow patients with steatotic liver disease. In some cases, it may be necessary to proceed with multiple modalities. And I think it is always important to be cost conscious and determine the upfront potential risk of advanced fibrosis in our patients. I'd like to thank you again for the opportunity to spend time with you today and look forward to any questions. Thank you.