Echosens Webinar on Combined LSM and CAP Testing in Fatty Liver Patients

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Echosens Webinar on Combined LSM and CAP Testing in Fatty Liver Patients

good day this is Jeremy berry with echo Sims North America on behalf of Eccleston’s North America I would like to welcome everyone to our webinar on the clinical benefits of combined liver stiffness and ultrasound attenuation rate testing in fatty liver disease patients today’s webinar is brought to you by an unrestricted grant to the ASL D mikaelsons North America and provided to the AAAS LD as a courtesy from dr. Raj Babu launched a to start with I would like to talk about a recent case that I had in my clinic this is an 8 year old white man with fatty liver on ultrasound he was otherwise asymptomatic on exam he had few features of metabolic syndrome BMI was around 35 her hypertension dyslipidemia type 2 diabetes on the blood work it revealed that bilirubin was normal albumin was normal and I was normal so I got a sense that the synthetic functions the liver is preserved when I looked at his liver enzymes ast 39 and alt 43 and this is from a local lab where the aorta range in the ranges from 21 to 72 which is upper limit of normal so he was thinking liver enzymes were normal I don’t know why I’m here that was his opening introduction so this is a topic that is of interest to many people of course aslv recommends that the upper limit of a of T is 19 for a woman and 29 for a man our own institution has 45 in some labs have as high as 72 in this one hemoglobin a1c was 7.3 percent viral hepatitis was negative and platelet count was born 30 thousand so there was really no indication that patient had cirrhosis or compromised synthetic function so the questions in my mind were I know that he has none all called fatty liver disease in the United significant alcohol use but does he have nash if he does does he have advanced fibrosis should I really subject him to a liver biopsy I mean he’s 80 years old what would be the ideal non-invasive way for me to assess his liver fibrosis and how do I even follow him over time then zaimes as I said were very unimpressive and for me to follow these near normal liver enzymes may not be much help so what exactly do we mean by Naville d when I stab the fellows clinic there’s often confusion with regard to how we use this terminology the patient just has an imaging study and there is fat in the liver we use the word non-alcoholic fatty liver disease but anything below that which is natural or nash has to have a liver biopsy because these are histologic diagnoses and when the liver biopsy is done we know plain fatty liver which is natural for at least liver related outcomes it is pretty benign and if there is inflammation cell that by process then we feel that this is Nash and there is concern that if we don’t do anything about it it may progress to cirrhosis over time currently we do not have any fda-approved nash specific treatments but again as you all know there is intense research in this area there are several clinical trials phase one phase two in some phase three so it is very important moving forward that we identify patients with nash so that we may intervene with lifestyle change in addition to liver specific treatment the usual presentations or common reasons for consultation related to Napoli are either elevated liver tests with no imaging study has been done or elevated liver tests with ultrasound that most often in my experience is done for ruling out gall bladder disease shows normal girl butter and fat in the

liver more recently I am getting consults for just playing fatty liver sometimes with normal liver tests this I assume is related to more awareness about nash and definitely getting more referrals from primary care physicians with regard to fatty liver on imaging study without without elevated liver enzymes with naturally abnormal liver a test that we see are typically enzymes less than 200 for the most part Alfa’s is normal and as such we say it is hepatocellular pattern and these enzymes may fluctuate over time and that makes it even more difficult for us to use liver enzymes as their monitoring tool current challenges in managing non-alcoholic fatty liver disease it’s very common one in three that translates to about 100 million people with fatty liver liver enzymes unfortunately do not distinguish playing fatty liver or Nash Nash is a histologic diagnosis requires a liver biopsy and there are some inherent issues with liver biopsy which include sampling variability with regard to where the actual tissue was obtained observer variability which means the expertise of your local pathologists and their experience and it is at the end of the day and invasive procedure however said we think it is unfortunately there are no established non-invasive biomarkers or Nash so whenever we talk about naturally patient we have to think about these issues that often come up in our mind Naville the Naville Nash Nash without fibrosis Nash with fibrosis and if there is fibrosis is it early which is essentially F 0 F 1 clinically significant which is F 2 or greater advanced which is f3 and f4 and often we think about the biopsy or not biopsy now the recent guidelines with regard to fatty liver they recommend to think about liver biopsy in patients who have metabolic syndrome with elevated liver enzymes now an ideal non-invasive test that would help us diagnose nash should give us some degree of steatosis severity and some degree of fibrosis it has to be simple readily available reliable and cheap right now other than imaging studies that describes us with regard to degree of fibrosis we haven’t heard much until availability of CAP with regard to serologic markers for degree of fibrosis we often use these two in our practice naturally fibrosis score which is recommended by the guidelines and then fit for index these use very simple readily available blood tests for calculation and give a score based on that there is a cut-off which helps us identify other patients with advanced fibrosis or very minimal fibrosis anything in between is indeterminate as you see both the scores help in identification of advanced fibrosis with good diagnostic accuracy this is a recent paper that summarized several studies using these scores and they reported that up to 50 percent could end up with scores that are indeterminate and we wouldn’t know whether we should proceed further with a liver biopsy or not so I applied these two scores to Billy’s case these scores are available at the website G I have com this is hosted by one of our faculty members so I put in Billy’s numbers perfect for score and based on the score of two point zero one it was in determining range for Napoli fibrosis score it predicted significant fibrosis and mind you this is a patient with normal click on near normal liver enzymes and I have scores telling me two

different things so this is where we used fibrous skin we routinely obtained fibrous can with LSM and cap measurement by vibration control trends in the last ography in our clinic this is in the clinic and patient gets it during the same clinic wizard and we discuss the results right away it comes with two probe sizes medium and extra-large I apologize for any paediatric hepatologist there is a small also small probe recently approved I don’t have a picture of that but the probes differ in certain ways the extra-large probe is needed to overcome the skin to liver capsule distance but the area that the stiffness is measured is essentially the same with either probe this cylinder area that is measured and that is used to measure that they were stiffness is approximately hundred times the volume off early biopsy core so essentially there is value in decreasing the sampling error due to increased area of the liver that is being examined the basic premise in which this technology works is a vibration is generated and it passes through the liver and that’s called the shear where the ultrasound is used to measure the speed at which the shear wave is passing through the liver if there is lot of scarring in the liver the wave moves fast if there is very minimal scarring or the liver is normal the wave moves flow in based on the speed at which the shear wave moves through the liver the elastance is calculated using Young’s modulus and that constitutes the liver stiffness in measurement and that’s reported in kiloPascals now this technology has been available in Europe for more than a decade it had taken some time to come to us because of lack of extra-large probe most of the data that is in the literature is with regard to viral hepatitis and called static liver disease with a medium probe and there is emerging data with regard to the use of medium and extra-large probe for the evaluation of fatty liver as you see there are some cut-offs that helps us recognize the degree of fibrosis in a patient and these cut-offs may vary with regard to the etiology of liver disease so one should be careful in using cutoff from hepatitis B and applying it to fatty liver one of the recent papers with regard to liver fibrosis and liver stiffness measurement this is the stage of fibrosis in patients who have undergone liver biopsy for I’ll call fatty liver disease 110 patients and this is on the y-axis is the liver stiffness measurement these are box plots and there is a good variation with regard to degree of liver stiffness measurement but as you see there may be overlap and I’ll tell you how we need to overcome this issue so if we were to categorize fatty liver as clinically significant which is f2 to f4 or not which is f0 f1 and try to figure out the optimal cutoff because at the end of the day if you have a patient with Nash or Natalie and you want to know if the patient has advanced fibrosis or clinically significant fibrosis which is f2 or greater by the time it is f3 it’s probably already too late and we may have missed the boat but if you want to recognize early which is f2 or greater what would be the ideal cutoff when you have the fibrous key and these are several studies as you see many of them are with medium Pro because of the recent availability of extra large Pro don’t have much data this is the sample size of these studies and this is the percentage of the patients with f2 or greater in that sample I mean these are the cut-offs that they found with good diagnostic accuracy sensitivity and

specificity and these cut-offs range anywhere from 6.6 up to 11 this is the most recent study from Japan and again one has to recognize that these are Asian European Japanese there’s not much data from United States for example they study if you choose the lower cutoff your sensitivity increases but your specific city goes down if you choose a higher cutoff your sensitivity goes down but your specificity increases so if you have a patient with higher LS m more likely you will find advanced fibrosis this is the optimal cutoff for cirrhosis similarly several studies medium probe sample size is a percent with patients with cirrhosis in that cohort and this is the cutoff again there’s variable cut-offs that have been reported and in general if you choose the higher cutoff your sensitivity goes down but specificity increases completely different from liver stiffness measurement is controlled attenuation parameter which gives a sense of degree of fat in the liver it is simultaneous the device will acquire data with regard to stiffness and cap at the same time essentially the last of the ultrasound due to the fat in the liver is what is controlled attenuation parameter more the fat more the loss so this is the attenuation rate it is measured in decibels per meter and the range is anywhere from 100 to 400 so max is 400 decibels per meter a normal liver would have low attenuation rate and a fatty liver would have high accumulation rate for example we look at this study if there is tio dose is grade 0 or 1 the attenuation rate is lower if there is tio dose is great – or grade 3 this T the attenuation rate is higher and you realize that there is a lot of overlap here too so there has been studies comparing other non-invasive measurements of liver fat which are mr spectroscopy in this study they compared cap and mr spectroscopy in patients with biopsy proven naturally this is the histology grading which we have as grade 1 2 & 3 these are the controls with no fat and this is the cap and this is the mr spectroscopy where you fall on the report rat fraction % as you see there is a good gradation similarly we see that in mr spectroscopy so optimal cutout per cap for detection of grade 3 is around 300 decibels per meter for because and optimal cutoff for healthy patient would be 215 in this time so another potential alternative to liver biopsy for estimation of hepatic fat content is MRI by PDF of this currently is the most advanced way of looking at liberal fat proton density fat fraction by M our recent study hundred forty two patients with liver biopsy proven natural D this is the grade of steer ptosis on liver biopsy and this is the fat fraction by PDF F this is the diagnostic accuracy for each stage of patek steatosis again very nice differentiation between different stages of stay ptosis different grades of statuses and very comparable to MRI PDF f without the diagnostic accuracies sensitivity specificity and positive predictive value and negative predictive

value in another study with M probe and extra-large probe for fat fraction with MRI for 8% fat in the liver the cutoff seems to be around 267 decibels per meter for medium probe in 274 extra-large probe for 15% 16% fat seems to be around 300 decibels per meter many of the treatment trials for naphthalene ash that are at least in Phase two they are looking for patients with 15% fat or 10% fat to show improvement in the therapeutic clinical trial and this is a good way of identifying patients who would benefit from treatment trial who would have at least 15 percent or 10 percent fat based on the cap score in the clinic so fibroids can we use it in the clinic as I said it helps us with several parameters I’ll go over each one this often is done by your technician and the report is given to you for interpretation this is the cap score this is the liver stiffness measurement by vibration control transient of Laster person this is IQ IQ are generally less than 30 percent you have a reliable value if it is more than 30 percent then there’s too much variability this is the median velocity but this is converted to the cap so really we I don’t pay much attention to this number this is the progression of the shear wave through the liver in this is the skin to liver capsule distance this is the ultrasound the strength this decreases as it passes through the liver and this is the ultrasound that shows the liver so if you have a new vascular malformation you have a rave you easily see it here and if you see this amplitude not going this pattern then you know that something’s not right so Billy had the fibrous gain in the clinic and this is the report that my nurse gave to me his stiffness score was forty point five decibels per and this is kilo pascals and this is definitely in the cirrhosis range IQR was twenty seven percent reliable skin LT was less than hundred 100 so we thought this was a reasonably good scan and it was indicated of cirrhosis when you had no clue that I would be dealing with cirrhosis in him when he fought when I saw him in the clinic based on my clinical acumen his cap score was three 872 decibels per meter so this was moderate to severe steatosis in my mind I kind of classic quantify steatosis normal mild versus moderate severe and overall our diagnosis was cirrhosis nepheline – so there are many nuances in the use of fibrous cane the machine may be at a different location in the clinic done by a technician and more recently we’ve had open access like endoscopy at our institution dermatologists are ordering fibrous can because they have patients on methotrexate they’re concerned about fibrosis we have my own colleagues who manage patients inflammatory bowel disease order a fibrous can so you may not even see the patient when you have the report to interpret so it’s very important to realize the nuances and the team that supports you with regard to getting the fibrous can knows these more recently we published about the issues that go behind the fibrous key and interpretation we call it myths and mysteries of fibrous candy for evaluation of liver pie process there are things that are related to technology more recently our fibers can got upgraded with new hardware and this allows us my technician to do the tests

much faster there are issues with regard to operator experience some some leaders in the field have recommended that minimum 100 tests have to be done for your operator to be very good at doing it with minimizing all confounders then there may be some variability with regard to operators depending for depending upon their experience I’ve had some local gastroenterologist community gastroenterologist email me since the announcement of this webinar asking questions and one of the questions was patient with ascites we have unpredictable liver stiffness measurement how do I interpret definitely when there is ascites there’s a distance between the probe to the liver capsule is variable and it may not be reliable and as if patient has had liver resection then stiffness is unreliable acute hepatitis and cause elevated liver enzymes and that we pick it up by healthy more than 100 inflammation itself can affect the liver stiffness if the stiffness is performed after patient eats within two hours it can increase portal blood flow that can experience linked Rhys liver stiffness and congestive heavy toppity may affect these liver stiffness beta blockers may affect the portal slow and we still don’t know how much of an effect will it have have on the liver stiffness and if there is significant weight loss it may improve the liver fibrosis and hit me improve the liver stiffness recent alcohol news also may increase the liver stiffness so there are many confounders that could affect the liver stiffness and all these need to be taken into account when we are interpreting the LSM score so that’s why we look for alt we have a standard protocol where we request at least three hours of fasting we make sure that bilirubin and alcohols are seen before we interpret the LSM for obese people you need to have access to extra-large probe recent alcohol use right heart failure causing congestive a fatality and spurious increase in the liver stiffness and then the operator experience this is one study that looked at the effect of water intake on liver stiffness sometimes I have a patient who come to the clinic and I want to do the fibroid scan right then in there and they say they had some coffee or drank some water and I wonder if effect that they were stiffness and this is one study that looked at that this is the time after the water intake and these are the stiffness course with the degree of fibrosis but liver biopsy and this is the percent difference among these course at most three percent difference in the stiffness so we feel comfortable that water or perhaps coffee would not affect the liver stiffness this is the study that looked at effect of food on intake of liver stiffness a food intake on liver stiffness this is the time this is the stiffness and as you see the stiffness varies and comes back to the baseline at around two hours just to be sure we currently recommend three hours of fasting prior to performing a fibrous scan any diagnostic test should have good diagnostic accuracy reliability with regard to minimizing the confounders we talked about these and then reproduce ability which is very important with regard to interobserver and intra observer in this situation it would be technician doing this test currently we are looking at this issue in our through our Nash CRN this is a clinical research network with several centers we looked at firing in 11 Napa D patients across eight clinical centers they had fibrous Kian with liver stiffness and cap performed extra-large probe was required in 57 percent of the patients we generally depend in depend on the automatic probe selection tool that comes with the device that tells us

which probe B use five percent was sorry one plate one percent refused the procedure after providing informed consent and one percent had a skin to capsule distance greater than three point five centimeters and we couldn’t do the tests so overall one to two percent is the failure rate in our experience we looked at the reliability when each patient had two tests performed on the same day the correlation was point nine six which is very good mean difference between the two they were stiffness was 0.16 and with regard to cap correlation was 0.8 1 which is again very good for a human clinical trial the mean difference was around 24 decibels per meter now we looked at how far do they differ I’ll walk you through this graph this is the liver stiffness measurement to two measurements were performed the dots are the difference between the two measurements in this is the average so 95% of the values are within these two and as you see most of the dots are around zero telling us that there’s not much difference between the two measurements there are some that are outside the range we exactly don’t know how to explain this hopefully we will learn more when we analyze the predictors for this discordance but for the most part they are very concordant similarly is the case with cap overall we concluded that failure rate of 2% unreliable in two percent female gender and waist circumference were associated with failed or unreliable exam excellent interrupt server agreement for LSM and cap some other experts have proposed a two-step screening approach which is ultrasound in patients predisposed for novelty and if if there is naturally we can use serum biomarkers and transient elastography and if they kind of both indicate f2 or greater consider a liver biopsy if they don’t then continue to monitor at ru if we encounter a patient with suspected natural D we just too fibrous can we get the cap value if the stiffness is 7 or less essentially we feel that there’s mud there’s not much by process in the liver patient still could have nash but definitely not fibrosis we get a sense of degree of steatosis and degree of fibrosis and we offer lifestyle major lifestyle intervention and we could we have the option to repeat the fibrous can until there is concerned that the stiffness has increased then we considered a liver biopsy and if it is greater than 12.5 I generally use that cutoff as concerned for cirrhosis if it is not clinically obvious with trauma side Athena or imaging study showing nodular control of the liver I may subject the patient to liver biopsy but if it is obvious then I don’t see much role for liver biopsy and we also use this algorithm to identify patients who would benefit from participating in therapeutic clinical trials additional roles for fibroids can include longitudinal assessment we are just barely scratching in Napoli with regard to this powerful information which is change in LSM over time this may help us understand the natural history of natural dinesh in patients who have cirrhosis we all know there is compensated cirrhosis there is decompensated cirrhosis portal hypertension how would the progression of cirrhosis happen over time or improvement with therapeutic intervention so these are questions that we are eagerly looking forward to use

for example I had a patient recently all white woman with Nash cirrhosis who had gastric bypass in 2006 but her weight has plateaued since then our current BMI was 37 she complained of right upper quadrant pain liver enzymes have been normal there is still trembles at opinio so I really did not have much to monitor when the reliever intense had been normal since the gastric bypass she had a fibrous scan in 2014 her stiffness was 17.3 her cap score was 277 at that time so we did the fibrous skin again her stiffness was 12 point 2 which was improved from seventeen point three kilopascal her caps cold was 324 which suggests that her fat has increased potentially causing symptomatic hepatomegaly causing right upper quadrant discomfort so I was able to counsel the patient in a much more precise way giving her positive feedback with regard to improvement in the liver stiffness and at the same time telling her that fat is increasing she needs to be more with it with regard to her lifestyle measures more recently there has been some interest with regard to screening for fatty liver in patients with diabetes because these are patients at most risk for naturally nash the conclusion was it was not cost-effective possibly because there’s really no treatment that is FDA approved for treatment of nash and it requires histology and the costs related to invasive procedure with histology and compliance and the costs related to imaging but if eventually we were to redefine the way we treat naturally as naturally with clinically significant by process perhaps we may avoid all these costs or at least we do a targeted liver biopsy in patients who are at high risk for advanced fibrosis and we have new treatments that help result gnash result fibrosis liver cirrhosis then it could become cost-effective to screen for rapidly – in patients at risk there’s also role of liver stiffness measurement in patients with cirrhosis to identify at risk for viruses this is the Bobby Vivino recent conference meeting recommendations if a patient with cirrhosis has 20 kilo Pascal’s or greater at to measure – two measurements on different areas in fasting condition is high risk of them having esophageal varices and screening EDD is recommended in patients who have less than 20 kilo pascals and place it down rather than Hannam 50k they may have very low chance of having valises and potentially an awarded sting and ask so in summary fibrous can with vibration control transient elastic Rafi and cap AG website is very useful in the evaluation and management of raganuga it may help us identify early on patients at risk for clinically significant fibrosis it may help limit unnecessary liver biopsies and longitudinally it may help us assess changes in fibrosis and steatosis if we have effective treatment interventions and then it is very important to minimize confounders especially if it’s going to be an open-access fibrous game thank you very much for your time thank you talk about watching for that comprehensive presentation we have active questions coming in and just a note to all the participants please type your questions into the question field on your screen so that we can see them and present them to dr. Bob Balaji I would like to start out the question and answer period with more of a general global question dr. Paula Falacci you’re very involved in the development of new technologies in the validation of new diagnostic technologies what is your long-term view of the future of napple Dinesh biomarkers it will be increasingly

relevant and very important especially considering that we have breakthroughs with regard to therapies there will be increased emphasis on identifying patients early on and intervene in a cost-effective manner there will be increased emphasis to categorize patients with advanced fibrosis especially if the treatments are expensive we have seen that with hepatitis C with insurance asking us to identify patients with advanced fibrosis as criteria for approval of treatment we have various treatment options some may be more anti fibrotic some may be more nash specific so it may be relevant to know which patients may benefit from these treatments and also as a tool to assess response to therapy so I do think there is a lot of need for identifying Nash therefore the fibrosis non-invasively into to that point one one additional question for you if honestly you’re envisioning a combination of diagnostic tools to include both serum markers liver stiffness testing you cap continuation rate as a surrogate marvelous ears noses and of course liver imaging how do you view the integration of liver imaging and deliver stiffness and cap technologies when do you use those respective technologies it’s the availability for me fibrous Cantonese in the clinic it gives me information right away at the same time if I have a patient participating in a treatment trial where precision is very important you know we have MRI PDF f as the therapeutic end point for many phase 2 trials they are also having fibrous can with cap and LSM time will tell if this will match up but as of now for research outcomes it is MRI with PDF F but MRI for clinical use routine clinical use is going to be very expensive and for me to assess every six months or every year I think it cost may be prohibitive so I think cheap easy access and technology with the minimum confounders is very critical for use in day to day practice thank you and now I would like to pass to Danielle who would like to pose an additional question from a participant No sure so well you have a couple of questions but I’ll start with this one that I think you can probably elaborate on what you just a exact question is if the goal of fiber scan is to reduce the invasiveness of liver biopsy would you recommend cereal fiber scan annually if kilopascal is a suggestive of advanced fibrosis but not confirmation of cirrhosis as opposed to proceeding with a liver biopsy which allows for sampling error so would you recommend that this patient get fiber scan done on a regular basis as opposed to just sending them for the liver biopsy great question at the end of the day it’s all about the patient if I have a patient who undergoes a fibrous can it is indicative of advanced fibrosis or at least clinically significant fibrosis and I am looking to offer him lifestyle changes in Anning I’m looking to see what more can I do I have Weidman Yi based on the province trial we use it but that trial has been done for non-diabetic nash there is data to suggest that it would work for diabetic nash – but if i if i have a patient who is very eager and very involved and wants to participate in a treatment trial then perhaps i would do a liver biopsy and help enroll in a treatment trial because most of the phase 3 treatment trial is still the histologic endpoint so I would do a liver biopsy but if I have a patient who’s new and the new diagnosis and I

have some information from fibrous can with regard to cap and LSM and I’m counseling and he says you know what give me a change I’ll come back in six months and we can read talk about liver biopsy so sure so I think it’s end of the day discussion between the provider and the patient you know you have the next question please thank you um is there an upper limit on BMI to obtain an accurate federber scan result this is a question we get asked quite a bit yeah so the higher the BMI less chance of having a reliable and the same but I will let that device tell me your IQR will show you right away if it is less the more than 30% then it’s not gonna be any use and the way the shear wave is represented on the report so we’ve had luck generally the chance of getting reliable LSM is lower in extreme obesity if there is a significant variability and the LSM readings do you typically suggest patient to repeat the test and what are your parameters um as far as how often they come to him repeat it a longer fasting time yeah we struggle with this issue early on generally we’ve had access to the Machine without the constraints of billing in the past and we repeated every three months every six months it was free to the patient they loved it our patient satisfaction scores linka but we generally don’t see that much of variability over time perhaps if you have two measurements they may be variable but once you do the third measurement you pretty much know what’s the real LSM of the patient but you know if it is being built or a commercial insurance you have limitations with regard to how often you can perform this if there is concern for advanced fibrosis I would definitely recommend confirming with liver biopsy question please next question so I have kind of an outside question but when you were talking about water intake affecting your sores have you found that a higher caffeine intake also affects his chords and have they found that the patients lying supine for an extended period of time also affects your scores most of the times patients are in supine position for measurement of the stiffness and cap anyway they walk into the clinic and lie down on the bed and they get the stiffness measured so I’m not sure extended supine position would affect the liver stiffness measurement we have had some Hospital hospitalized patients wheeled down for stiffness measurement over time and not generally sure it’s an patient in the ambulatory setting so with regard to coffee I am not aware of any publication but a black coffee if it is just water I’m not thinking that it would affect the portal flow that much but it’s all about increased portal flow after meal intake that may affect that or stiffness Jerry do you have any more information I think there is a very good summary of what we know I do have one additional enhancement a question related to this title you mentioned in one of your slides that one of the con founders that we be careful about and liver stiffness assessment is the inflammatory component and you mentioned the use of alt is an indicator how do you integrate the alt value to shall we say interpret the liver stiffness fat yeah so you have a patient you have an alt rather than 100 fibrous cane is used

to estimate LSM and cap so here you are you have a test that’s done very well but you have an alt that is high so basically we tell that these test is not reliable because there could be potentially Falls elevation in the liver stiffness from the inflammation and that’s where we end and we take that into account if you still have a normal LSM then it’s reassuring that despite a alt elevation the LSM is normal but if you have a very high LSM you could actually say hey I’m not sure if this is truly indicator of your fibrosis because your LT is high and perhaps we could repeat this at a later time point when alt is lower and that would truly indicate the degree of fibrosis very good dan you know we have time for two more questions would you like to pose the next one sure um let’s say your eye you management algorithm appears to be entirely based upon stiffness and not cap results along those lines later stage Nash often is less fat so how does fat content help you yeah good question that’s why it just goes to the side I think it helps in understanding the degree of steatosis oftentimes patients have right upper quadrant discomfort and we tell them that it is related to fatty liver now I have a score that helps me counsel them better and also if I if I have a cap that is low I am questioning whether the elevated liver enzymes are truly related to Napa thei some of my partners and do take up much more stringently than me they may objective patient to liver biopsy with a very high cap score and normal liver stiffness because they are worried about Nash in those patients so yes my approach is mostly related to liver stiffness but the cap score is always in my mind when I am going through my algorithm and they only have time for one more well the medium probe is usually recommended if the same patient receives a fibrous can test using a medium probe and XL probe would they be expected to provide the same yo Pascal results or does the XL probe expected to result in a low or kilopascal value yeah for the same patient if you use medium and extra-large probe generally the extra-large probe LSMs are a little bit lower than medium probe but we don’t get into that situation we just stick to our protocol which is basically recommendation by the automatic probe selection tool so if the patient loses weight you know has a bariatric surgery and comes back next time you have used extra-large probe in the past know you’re using medium probe you know I don’t know how to interpret that but I just go by LSM value very good and I think we’ve consumed all of our time on behalf of all participants I’d like to thank dr. Bob launches book is very comprehensive presentation these are indeed exciting times as we have new horizons opening up floating diagnostics and therapeutics for fatty liver disease I would like to remind all participants that you will receive a follow-up email announcing how that you can access the recording of this event and also all participants will soon be receiving an announcement email of our next webinar today which will occur on may 11th and it will talk about the applications in fiber span in alcoholic liver disease thank you to everyone and thank you for purchase