hey Paul this morning Siri said don't call me Shirley all right I guess I accidentally left my phone in airplane mode that's good I thought you would like that my favores yeah yeah it's I mean as you know we're doing a liver episode and I've been I struggling to find any liver puns and I'm going to refer our listeners to pia.com liver puns because they are the most baffling things I've ever read in my entire life so I'm going to give you just a taste Matt if your liver starts singing you might want to get it checked out it could be a sign of liver Kara Oasis I don't know what that is no if hold let me find one more my liver took up salsa dancing it loves a good liver twist this is I don't know if this is AI or if this is translated from another language but this is my new favorite website so I'll save some for later I one for yall so my liver started exercising it joined the Bates class Bates class so like Pilates but I'm trying to I'm trying to the same website could be the curbsiders podcast is for entertainment education and information purposes only and the topics discussed should not be used Solly diagnos treat cure or prevent any diseases or conditions for the more that St Express on this podcast are SOL and should not be interpreted for official policy or position of any entity aside from possibly cash more and affiliate Outreach programs if indeed there are any in fact there are none pretty much we are responsible if you screw up you should always do your own homework and let know welcome back to the curbsiders I'm Dr Matthew Frank wad still thinking about that last Pond I'm here with America's primary care physician maybe even the primary care physician Dr Paul Nelson Williams hi Paul hi Matt yeah that one's gonna haunt my dreams I think so today we are talking about just bear with me metabolic dysfunction associated steatotic liver disease formerly known as fatty liver disease uh with the great returning guest Dr Elliot Tapper everyone's favorite hepatologist and Paul before we tell we introduce our co-host and tell everybody about Dr Tapper what is it that we do on curbsiders thanks for asking Matt as a reminder we are the internal medicine podcast we use expert interviews to bring your clinical pearls and practice changing knowledge as you alluded to we have another co-host with us we have the excellent Dr Sai ACH did I pronounce that okay Sai you're good excellent I'm not sure I'm convinced but good uh s is a neologist out of Houston Texas and the producer for this episode Sai how are things I'm good how are y'all you know anytime we have a great episode like this I'm always doing very well Sai you are a nefrologist we appreciate you taking some interest in the liver uh because you're you're that tells me you're a great doctor because you're just you're interested in all of it uh so we appreciate you for that uh but we tell us about our guest a hepatologist Dr Tapper oh for sure and I'm G to say that the liver and GI in general kind of scares me so I'm always happy to learn so we have a fantastic conversation with our guest Dr Elliot Tapper Dr Tapper is a chief of hepatology at the University of Michigan where he spends his day seeing people with liver disease and working with an amazing team on research projects He makes uh his kids listen to the curbsiders on the to the Toledo Zoo um how do you feel about that I mean it's probably child abuse in some states if we're being honest but okay s what is he what do we talk about on this episode um no he's going to teach us how to define naff mold and how can we form a framework in our mind to approach and treat these patients so without further Ado let's get to it a reminder that this and most episodes will be available for CME for all health professionals through VCU Health at curbsiders dovc health.org and if you haven't done so yet please check out our patreon at patreon.com curbsiders where you can get twice monthly bonus episodes adree episodes whole bunch of other cool stuff patreon.com curbsiders Elliot so glad to have you back we we saw you at ACP and we were like we have to have him back on the show I was telling you ahead of time the liver test episode was just a huge episode because people have so many questions about the liver and we're going to get all into that but first they want to know what are you up to these days like what are the Hobbies or interests that you have well it's it's great to be back I've been waiting for the call super excited to to be with you you guys uh you know what's exciting for me is uh we just got back from London my my kids's first trip across the Atlantic and uh we've been getting out and about doing fun stuff now that the students are gone from Ann Arbor we we went fishing for the first time and we we had a blast wait but not fishing in London right no no okay weird thing Elliot I I don't know how old your kids are but if they're like if they're less than 10 fishing with the kids means you're just untangling fishing rods like nonstop in my experience that's pretty much how it went but the Highlight was when I I had my seven-year-old grab a slimy trout and I was able to get a great picture of it yeah if you don't get excited catching a fish then something's wrong with you Paul would you agree with this no not necessarily it's fine but have you ever caught a fish Paul yeah okay how dare you I don't even know trying toly here I feel like I feel like this is some comment on who I am as a person I don't think I like it but yes I a fish my my reason for the followup question is because you you didn't seem like you care that much catching a fish it's always it's always feels great to catch a fish okay something wrong with you all right I knew it anything anything else we want to ask Elliot before we get on to the this gigantic topic that we're about to about to go into Paul no this went down a dark path let's let's just talk about the liver Paul and I might be uh breaking up as podcast coach all right well uh let's go to a case from cash laac Sai would you would you do the honors and and read our first case of course let's do it so we have a 28-year-old man who says he doesn't have any prior medical history who's coming back to follow up with you after his initial visit to your clinic at the first visit he recently moved to the area and hadn't had any symptoms apart from some fatigue due to the move you had ordered some initial labs and at this visit his vitals were temperature of 98 degrees Fahrenheit blood pressure of 110 by 80 heart rate of 60 BMI of 35 and his lobs are significant for an elevation of his alt at 31 and his a at 44 so I think right off the bat I would like to ask whenever I see a patient who has abnormal liver functions I just don't know where to go honestly so if you wouldn't mind just kind of breaking down how would you approach uh this case and where do we kind of start well thanks for bringing this up because you know this is this is a a super common situation it's almost like like we were looking for uh something to do for this gentleman who didn't have any specific complaints and we went hunting uh for things getting these liver enzymes and now that we found them uh we we often feel feel stuck and the way that I would guide our ourselves forward is thinking about the epidemiology of abnormal liver enzymes and so the most common thing that's going to impact a dude like this is going to be metabolic dysfun F associated stattic liver disease which is the new word that we have for fatty liver disease it's a it's a person first phrasing a new new new language the second thing is alcohol and then after that you're going to find smattering things like viral hepatitis but before we get into like teasing it apart for him let's just say like off like what are my first reactions one 28y old man two BMI 35 and three that that as is 44 and it is higher than the alt of 31 so these are mildly abnormal and the ratio has the as being higher than the alt and this tips me off two concerns where my concern about this young man is is immediately greater than it would be had that ratio been reversed because now I'm starting to think about one Chron IC alcohol use or two curosis because in fact as the liver disease progresses that as can rise uh and uh so I'm a little bit more worried about this guy than I than I would be for the average person AG 28 with abnormal liver incidence Elliot the the alt of 31 a lot of labs wouldn't even flag that as red so what what should we use as our cut offs I think we've said in the past like 20 we've heard 20 for a woman 30 for a man do you what what roughly do you use that's perfect so sometimes I laugh when I see the lab uh normal the lab normals are often derived from population medians and and sometimes the population that that lab sees has a lot of liver disease and I have seen a normal being anything uh less than 70 in some laps and that is that is not that is not good okay so that's 3x normal so the numbers that you came up with 20 for a woman uh 30 for a man that is that is perfect for determining abnormal Paul you're kind of our naming expert mainly for trials but let's apply it to liver disease here what do you think about mled instead of naffed I mean they're they're both a mouthful though I I Elliot I could actually use some guidances because I I remember reading I think the guidance document about these name changes is something like 3,000 pages long plus or minus but like it's a lot but can you sort of as an internist just so I can sound just smart enough to talk to hepatologist can you just sort of talk us through what what the new terminology is and and why why you being patient first because that matters but can you can you talk us through the rest of it yeah so I I'll say the good parts about this are that it is it's not a negative definition you're not saying a nonalcoholic fatty liver disease you're you're assigning a positive diagnosis to a person that this is associated with metabolic dysfunction which is true and then it also call calls up a broader family of disorders that all relate to the accumulation of fat in the liver stattic liver disease and underneath that umbrella you have this metabolic dysfunction which we would otherwise calls called naff and you also have alcohol related liver disease and you can have drug uh induced uh fatty liver setic liver disease so I think it is useful in that regard but it breaks down when you talk to patients who might not want to hear the word stattic and so I just try to tailor it to what I think the patient would be most open to hearing and and some patients really don't want to hear the word fatty and and their health uh inter interlined and so I'll use stattic but most of them come to me saying fat in the liver or fatty liver so in practice behind closed doors I'm not using this word that frequently but I think from a society perspective it's the right thing to do moving forward yeah I mean when when explaining it to a patient it's hard to explain whether you call it fatty liver or you call it mled MLB it seems hard to explain it without saying there's extra fat stored in the liver you know yeah and and yeah so it's like the word stattic is not is needs definition and then you you just say fat sometimes uh you know you people want an understanding of why them you know why their liver and I'll say things like liver diabetes or I'll I'll talk about insulin resistance and and and fat depending on how much health education the patient has at the end of the day I'm creating a definition or a set of words that I think will play for that patient and help them understand their own health condition but a as a member of uh liver land uh we're we're Mass all massel all the time now I don't know when I'm when I'm talking to patients about this and I still struggle in terms of telling them why they should care which we we can get to but I do emphasize the inflammation part of it more almost in the fatty part of it like you know we caught this because the labs show that there's some sort of irritation in the liver itself like I think that seems like a more helpful end point to discuss than just the presence of fat you know what I means does that I I wonder if that doesn't help normalize the conversation a little bit so far it hasn't worked for me but I yeah you know so the other day when I was seeing patients in the outpatient reward at cash lagac I had a patient who told me that when they had a scan and they learn they read the report and it said that there was fat in the liver that was the first thing that encouraged them to want to lose weight and stop drinking and so it's hard to figure out what is going to motivate a patient in my experience I agree with you 100% that it is these blood-based biomarkers that really matter to them that there's heat in their liver inflammation alt or if you happen to check a fertin that was elevated with that inflammation that they have something that they can track and use to reinforce the positive changes that they have over time people want to know am I making a difference and it's kind of hard to do that if you're anchoring on the fat in the liver but for some people understanding that there's fat in liver makes them feel like they're sicker than they are and that they they want to make changes to address it and uh you just have to figure that out Case by case so how how do you answer the question when patients are asking you how much time do I have what does this mean for my liver some of the prognostic you know just kind of telling them like do you give them percentages this many percent will progress to therosis or over this many years H how does that conversation go yeah so this is the most important question when someone presents with abnormal liver enzymes at plus or minus fat steatosis seen on ultrasound they need two things one they need a specific diagnosis and we should get into the differential at some point and they need a prognosis and that can be provided irrespective of what is actually causing the fat and inflammation in the liver and the way that we do this is we assess the risk for fibrosis in the liver it turns out that whether or not a patient has fat in their liver or whether or not they have inflammation whether or not it's Nash or mesh that doesn't govern their long-term outc comes in the same way that the burden of fibrosis in the liver is so I'm very quick to explain that the reason why this inflammation matters is because if you burn yourself your skin is red it's inflamed and eventually that inflammation will give way to a scar and the same thing is happening in the liver over the course of years and it will disrupt the architecture the shape of the liver it will bend it out of shape and ultimately with enough Scar Tissue it could turn into sosis we need to fix figure out if a person is on their way to therosis and the there are ways that we should do that then we and once I do those tests I can tell somebody about the risk that they could develop therosis in the next year or or three but I can't tell someone about their probability you've got 10 years to therosis I need to use tests in a dynamic serial fashion to figure out what path this person is walking down okay that's that's great we're going to get into those tests so the prognosis and the and the other part of it the diagnosis the differential what's that like or is this in order to get into that discussion do we have to talk about the testing that you're going to order yeah so I I'm doing these things simultaneously right I'm figuring out prognosis and and diagnosis and when it comes to fat in the liver like the 99% of it is going to be caused by this metabolic dysfunction liver diabetes insulin resistance alcohol the combination of the two and then rarely you'll have like some medications like tamoxifen that can cause steatosis in the liver and so to that end the most important test that I can order is one that will be very specific for the for the presence of alcohol use disorder or excess alcohol consumption I'm of course going to ask a patient how much do you drink and and I do so in a way that allows me to readily quantify that so I'm not saying how many drinks do you have I'll say what do you drink what quantity do you buy it how often do you go to the store and this allows me to back calculate how many drinks that they're having in a in a given day or or or week but I'm also going to tell them that because this is so important because it is alcohol that can chew through a liver so much faster than any other condition that causes fat to accumulate in it that because I want nothing more than to help them I'm I'm going to check their blood uh for the presence of alcohol use by using a test called phospha tidal ethanol it's effectively the A1C of alcohol tells you about blood exposure to alcohol over the last few weeks and yeah I always tell patients I'm going to check it even if they've told me that they're not drinking because I tell them that uh I have to be certain and that I want to keep an open door not to be judgmental but to say because this is so important to one's Health long term we have to be as specific as possible and I have never had anyone refuse to have that test even someone who just told me that they never drink they they all uh allow me to go ahead and order it and they proceed to the lab for it that's great I like the way you counsel them about it before you order the test it's it seems like you kind of you're heading off some problems because you're being transparent you're telling them why you're ordering it ahead of time any other tests that you're ordering for alcohol like I saw ethyl glucuronide is one if you're not using anything else can you talk about why this is such a good test the characteristics of of path yeah so ethylglucuronide is a good test it's a urine metabolite of ethanol metabolism and it will capture alcohol consumption within the last like three to five days uh it's also a urine test so if I'm I'm not frequently doing Ur testin liver clinic so uh it's like uh it's just easier to do do a blood test and then the path it gives me a longer duration of alcohol exposure and it's so it's just so good so if a if someone is drinking every day to excess it's going to be very high if they are drinking every day one or two drinks is going to be something on the order of 20 to 50 or so but you're never going to miss somebody with alcohol use disorder unless they stop drinking 3 to four weeks ago and uh just caught them at a really good good time and you're never going to overdiagnose uh severe alcohol use disorder like there are the false positives for this are effectively case reportable whereby you know if a patient got blood transfusions from people that happen to be drinking a lot of alcohol the day before they could have a weekly positive phosphole ethanol when you when you checked it but they're not going to have a 500 and that's why uh this test is check so good right and it cut off of 20 is that for the lower limit of normal is yeah okay yeah you know I don't really know how people came up with these cuto offs like what's the gold standard in this case but 20 is is widely considered something that is going to capture significant alcohol use if someone tells you well I'm having one or two drinks every other day or so and they come back at a 50 that's probably that's probably accurate Paul as America's primary care physician and someone who practices a lot of addiction medicine this seems like it could go wrong if you didn't approach it as thoughtfully as Elliot is but do you have any concerns or comments no I I obviously think Elliot's approach is great like you know an addiction medicine clinic the patient is not surprised that you're doing testing for alcohol use like that is that's not that's not going to be shocking to them so the conversation is not nearly so thorny I think as someone for whom you suspect um massal or whatever the whatever the abbreviation is but yeah I just I to to emphasize the point again like I just don't think it's the type of thing you should order and then confront the patient with without discussing testing them for it first that's unal also will just erode trust almost immediately right but I would like to say actually in classic herb cider's form we actually got right to the Laboratory Testing and diagnosis without talking to the patient um so I did want to just back up a little bit so we we're I think well we'll check the path but I guess for someone who La presents in your clinic like this or someone who would present probably more likely in our Clinic other than asking about alcohol use what other exposures what what are things should we ask about to kind of get a better sense of who this is and make sure that we're working towards the right diagnosis yeah so here's the thing about the communicable liver disease or other heritable liver disease is that the history can be useful but it is less useful than the testing so you know I often when I when I'll have residents join me they'll they'll ask about all of the risk factors for Hepatitis C did you get a tattoo this and it's like at the end of the day like you know like CDC is recommending that we screen everybody for this and so we're just checking it okay and I don't really care how how they got it and if they do have it I'm just going to cure it and uh I might I might ask them to refer their friends if they happen to be using drugs so I can cure all of everybody that they know with hepatitis C uh so I'm not asking too many questions uh about that about that sort of thing now if I identify somebody with a liver disease that like Hepatitis B I'm definitely asking questions about sexual contacts and drug use because I want to protect other people I'm not sure that beyond the risk factors for metabolic dysfunction and alcohol use I'm not sure there's too much in the way of history that is going to clue you in of course I'm I'm leaving out drug induced liver injury where you have to grill a patient several times about everything that they're eating and buying if you want to diagnose drug induced liver injury because there's tons of supplements people forget that they're taking but outside of that there's tests these tests are there for recent and you mentioned tamoxifen any other drugs I think I saw am amone is another another one but any other drugs that you think of as potentially contributing to fatty liver I know in one of the trials we might talk about later they excluded patients who were had taken drugs that could cause fatty liver disease yeah so tamoxifen is a classic uh amiodarone that is a stereotypical kind of uh uh fatty liver but uh I think you could probably see some in cortico steroids I mean it just if you think more broadly about the differential diagnosis of people with elevated liver enzymes there are a ton more you know medications that can do this but in terms of ones that have a specific uh fatty liver injury I'm I'm blanking on those but that's okay because if you are worried that a medication could be causing it you should do exactly what I do when I meet a patient and I'm considering that maybe a drug could be causing their liver injury I Google it I go to liver to.gov liver to.gov which is maintained by the NIH it is a exhaustive compendium of all medications known to man and their pattern of whether or not liver injury has been reported and the pattern of liver injury associated with there's only so many things I can keep in my head fantastic yeah well that that is a great website I believe it's been plugged on the show before and I've used it it's very easy to use so we could we could definitely do that as internist Paul we are good at blaming problems on medications and looking at the medication list to for potential problems at least that that's my thought oh yeah totally yeah it's my favorite thing to do okay so we've we've taken our History exam findings that you feel we should be looking for anything high yield there yeah so I mean the main thing that I'd be looking at a patient to understand is is to is to assess their risk of advanced liver disease every now and then you can make a diagnosis of curosis in clinic before you do any other testing so if a person has spider angomas then that has a likelihood ratio for the presence of sosis of something like seven to nine if they have capit that DOA aites very rarely will someone get diagnosed with AES for the first time in liver clinic but it has happened palmer aemma but beyond that most people who are presenting with uh Mash uh and elevated liver enzymes are going to have absolutely benign unremarkable examinations I know there's there's a bunch of potential things Paul does does this satisfy you as our physical exam nerd uh res physical exam nerd yeah it's fine Paul probably prob probably spends 30 minutes looking at the hands and that's I do a fundoscopic exam on all my new patients just just so they they know who they're messing with not because I expect to see anything so yeah it takes me a while okay so we've talked about a little bit of the prognosis we're going to be trying to assess prognosis we're we're looking for the diagnosis so most of the time this is going to be metabolic dysfunction associated steatotic liver disease which is abbreviated masl it's quite a mouthful Paul but we we have to ask about alcohol we're going to be checking a pest level uh which tells us if they've really been drinking the past two to three weeks or so and we said that we'll we'll look at the med list of course we're going to test and cure hepatitis C if it's present we are now screening for Hepatitis B and we have another episode that we talked all about that so people can check that out can't cure that one yet but uh that's hopefully someday yeah so we're using livertox for the med list we doing the physical exam looking for spider angas anything else that we need to think about here are we ready to talk about staging the liver once we're thinking that this could be masl massel what how are we pronouncing this massel massel massel okay yeah so let's get into it let's uh let's talk about prognosis what we recommend particularly when a patient is seen in primary care and by we this is a test that is endorsed by my Professional Organization the aasld the American gastron neurology Association and the American Association for clinical Endocrinology is to use the fib4 so fib4 is a freeo use algorithm based on age platelet count and the ratio of alt to as you Google fib4 you put in these numbers and if that patient has a fib4 greater than 2.67 and you don't have to remember that number all the websites will will tell you then that is a person who is at higher risk of having significant fibrosis uh in their liver if that number is less than 1.3 then their risk of fibrosis is super low and because age is part of the algorithm the older you are the higher your fib4 the websites like MD Cal will remind you that for people over the age of uh 65 the cut off is should be less than two not not less than 1.3 so you're not just referring everybody who with a F4 of two because they're 60 uh to uh to liver clinic and if you use this you can very safely rule out the risk of of advanced fibrosis and even people who go on to have a diagnosis of therosis but they have a low FIB four those people are much more stable they're less likely to ever get into liver trouble like developing a liver cancer so even if you misdiagnose something someone the fact that they have a low fib4 is a good uh prognostic sign in and of itself so if that person comes to you and has a low FIB four then there's a good chance you could just work on you know the underlying condition without uh worrying about the presence of advanced liver disease like significant fibrosis we can handle a fib four Paul right that's I feel good about that yeah yeah so we order a fib 4 I guess we didn't talk about this or we might have skipped over this part but Elliot you wrote a paper in 2017 or you and with along with some friends do we just go order all the tests or do we order just some targeted liver tests along with this so you talked about hepb he C what what tests can we maybe omit from that giant panel that's going to come up when people look look up in their in their resource yeah so just to be clear the most important test when considering liver disease is is going to be that platelet count that forms the the core the F four because it informs you about the prognosis the presence of advanced fibrosis which is the most important thing after that it's the pth and then hep C and hepb because we have treatments and vaccines or uh for for for these conditions and we did a whole podcast together about the pitfalls of ordering fiant I would say a lot of people are ordering fiant and what people need to know if they're going to order this test is that the most common cause of an elevated feragen in the United States is not hemocromatosis but it is MLD and so it's elevated because the liver is inflate so what I tend to do is I will come up with the most likely diagnosis based on the history in the presentation I will check the hep C and the hepb because we should be and the CDC recommends it and there's excellent treatments for that and there after we'll focus on the most important things getting rid of the alcohol and and changing lifestyle in such a way that we can drain the fat from the liver and if I still have elevated liver enzymes when I see them in followup then I'll start to think about well could there be uh hemocromatosis I'm only going to think about things like Wilson disease and somebody who I've excluded these other conditions who's in ano appropriate age younger I'm thinking about Autumn imune hepatitis for sure if I don't have the uh the other the more likely diagnosis and if and particularly if I see the alt climbing you can have an ALT of 200 and that's caused by the masl it can happen but I'm not going to I'm not going to rest on that so here this guy who is very restrictive in the kinds of tests that I'm ordering I'm very much thinking about autoimmune hepatitis and I'm ordering Ana anti-smooth muscle IGG when I meet somebody that has an ALT of 250 uh are those tests perfect no but if they're very positive I'll think about doing a biopsy earlier in the evaluation and followup that's really helpful yeah because I I think sometimes in the past before I knew as much a you know from from talking with you and I would order more of these tests and then I found sometimes I wasn't knowing what to do with the results and it's causing worry in the patients and a lot of the time it would end up just being masl anyway so I've kind of scaled back Paul what as America's primary care physician how do you are have you scaled back testing are you still like to go for the the full oh I never did your order set you order lime lime disease panel whatever the panel is yeah that's exactly right no I I I don't think I've ever I may have accidentally ordered cop plasm one time it was next to something that I needed but otherwise like I'm these are not things that I'm chasing down routinely yeah I think the audience they should be happy that you're telling them not to order more testing it it makes their job easier they and and you've given us very clear ways to interpret the test that you are telling us to order so I think we're in this this is all good news Paul I'm I'm saying this is all good news yes agreed when when would you pull the trigger on on Imaging Elliott so it's yeah I feel like if that you saw like a high FIB for I feel like that's a fairly obvious one or any other C ances or do you do it for everybody what is what guides when you do an ultrasound elastography or something like that first question is well what's the role of just a plain old ultrasound and sometimes this can be useful for if you're still unclear about the diagnosis and you're thinking they also have abdominal pain could this be like some stones or something like that but oftentimes it's done as a way of establishing a positive diagnosis of fat in the liver because on ultrasound a fatty liver stattic liver will be brighter than the kidney relatively they'll say echogenic liver and then this gives you a diagnosis of of stattic liver disease I don't think that that's necessary uh but it's Common Place the most important thing to remember when it comes to Imaging is if that FIB four is positive if it's elevated you cannot make a diagnosis of therosis based on that it's just not good as good of a test and to begin with the pre-test probability that your patient had therosis even if they have diabetes walking into your clinic is no more than three or so percent so we need sequential tests we need to do two test at least to get up to place where the posterior probabilities approximate some degree of clinical certainty and the next best test is going to be called fibros scan or vibration control transient LS phography and this is the most validated way of determining the stiffness of the liver and it has for all intents and purposes replaced liver biopsy for the diagnosis of advanced fibrosis and curosis so we're not doing transion listography willy-nilly we're doing it in people in whom that fib4 is positive or there's something else that's cluing us into the probability of advanced liver disease this can be ordered Open Access in many places but usually it's sort of warehoused within a GI clinic and it's a test that has very good negative predictive value but it has a a midling positive predictive value because a few things can make the liver stiff that's what it's measuring it's measuring the stiffness of the liver which you know a cerotic liver is very stiff but so is the liver of somebody with right heart dysfunction and congestion someone with an ALT of 200 is going to have a stiff liver just because of the inflammation somebody who ate a Big Mac and Fries uh is going to be have a stiff liver so you just the like whether or not they were eating a lot beforehand they should be fasting for a few hours so you have to interpret it with some caution by selecting the patients appropriately positive fib4 and making sure that you you don't think that they have other things that be could be causing that elevator liver stiffness that is helpful and I'm not sure I'm ordering this as much as I I probably should be um I I mean I think the algorithm that you're proposing you know that we talked about the testing just there you you talk about calculating a fib four and if they're low risk you know we we wouldn't necessarily proceed to this test that would be probably a waste of resources but if they're would you say if they're intermediate or high- risk we should get a liver stiffness measurement with this elastography and uh elastography can be either the ultrasound or an MRI or Mr I guess they call it m magnetic resonance elastography can you talk about like when you order that test yeah so you so you're asking two very good questions one is to just clarify that uh we're we're you're basically applying this test to people with non low FIB four so a young young person with a fib four greater than 1.3 or an older person with a fib four greater than 2.0 and then you know here I am talking about this specific ver version of elastography vibration control transi elastography because that's the most valid but the truth is that often you can get a good result from ultrasound based elastography so the usual ultrasound machines you can buy add-ons that and they're called sheer wave elastography the problem is that the quality control on some of these scans uh is not is not the best so that's why I shy away from it and uh sometimes I'm doing these uh trans listography test to confirm that and one of the problems with transi listography is that it assesses the liver at a fixed depth from the skin which for people with a lot of central osity makes that test uh ineffective so as the BMI rises above 40 the failure rate of this test starts de Cline and that's that's when we reach for magnetic resonance elastography this test is um it has different unit units of measure effectively and we should talk a little bit about the the the numbers that I'm looking for on these Fiers scan tests so the number you get on an m is like a third to a quarter lower than the number you get on the other elastographic test so you have to be careful how you interpret it because Normal on a Fiers scan is five but five on an m is is very very stiff that is curosis the data for m is uh is pretty limited and it's really from a couple of centers hasn't been validated outside of that and it's it's OB it's an MRI so it's like the most expensive thing that you can do in this case but we will reach for that if a patient has a high BMI and we and we don't think that biopsy would otherwise be useful okay we've talked about that there's a couple different types of elastography the fibros scan is the transient elastography correct and then there we talked about the magnetic resonance elastography for people with BMI over 40 and the values may differ if we're if we're if those are the two primary tests we're going to be potentially interpreting how would we interpret these what sort of numbers might we see and what what's important yeah so the kinds of values that you get from sheer wve listography and transient listography are are basically interchangeable and um there if you Google it you might get trapped in older data where we were focused on cut offs that would go down to the second decimal point but we have simplified things now and it's very helpful for for teaching in clinic to patients so most of these scanners can get up to a liver stiffness of 75 and the higher you go the stiffer you are the sicker your liver can be or or could become a five is Stone Cold normal 10 is someone who is there's a probability about a 40% chance they have advanced fibrosis so they could have therosis but many of them do not 15 the likelihood of therosis is very high it 20 the likelihood of therosis is nearly definite and 25 the patient probably has portal hypertension there's a two and three chance that this person could have vyses or enough pressure in their liver to develop vyses in the short term and these numbers are so solid that we will now make decisions based on them like you you know that for people with sorosis we're do endoscopy to screen for veres but our professional societies now recommend using these liver stiffness measures as a way of avoiding endoscopy entirely so if you have a liver stiffness measure less than 20 and a PL count greater than 150 you don't need to have an endoscopy because the probability you have vares is so low conversely if that liver stiffness is greater than 25 we can just have a conversation in clinic about starting beta blockers to treat portal hypertension and VAR es without an endoscopy because the probability is so high so rule ofes uh live by it okay and then for the uh M I imagine we're not going to be interpreting too much of that but those those values are different it's a different uh yeah rating system yeah so um something like 3.6 that's when you start to worry five is largely considered like that person has therosis uh after that it's pretty hard to know like we just don't there's just not enough data and long-term followup prospectively for patients to understand what these what these values mean so I'm not making too many clinical decisions based on an M result in in isolation but fiber vibration control transi listography yes yeah that is a very useful test all right Paul are we satisfied on that it's making a lot of sense now I never heard the rule of fives before so I wouldn't have known what to deal with the numbers I don't know about you Paul no that that's helpful I was just thinking you know if if I'm ordering a m for a patient they're probably already in trouble the numbers numbers don't really matter so much but if I pull the trigger on that something's not going well um I did want to ask because the Temptation since we're already doing blood work on these patients is to maybe do like a a serologic test for fibrosis I think there's like trade names like fibrosure I think is one that that that might be a breakfast cereal but can you talk to me about what like how those are used if at all are sort of what what you think about their their clinical utility Paul that was a good joke thank you appreciate that yeah I I I agree so so there's there's many serologic tests and what they tend to be are they're fit for that's basically what they have and then they'll have a couple of other measures usually included in these things there's a proprietary algorithm that also involves markers of fibrosis like n type procollagen 3 or other measures of of fibrogenesis so yeah they're probably better they're more accurate than fib4 uh by a little bit they might be as good as uh transient listography and so I'm not using it because there's a transient listography machine in my office right now that I can use at any time but if I was practicing uh away from a medical center with an ultrasound machine that could do listography I would definitely think about using these and the good thing about them is even though they're more expensive is that they'll come back with a report that tells you how to interpret it so you don't it's not something you have to try to study or go through PubMed to understand so uh there's a there's one test that was recommended in the guidelines for mash for my Professional Organization and it was the enhanced liver fibrosis test this hasn't been as well validated in in this population but a number like 9.8 or 11.3 is considered high worrisome uh for therosis it's FDA approved for the purpose of prognosis but not necessarily diagnosis but I I bring it up because it's the one that's mentioned specifically in a guideline document I'm thinking anybody with you know with a high liver stiffness measurement or maybe even like a really high FIB four score I probably would do the liver stiffness measurement before I referred to hepatology but when do you think is the good time to refer yeah I think ideally the hepatologist have helped you by making a available the access to to an elastographic test uh I think that's really the best thing to do now I will definitely see people in clinic that have an elevated fip4 and we'll do the transin listography at that time but if it is available to you to do those tests uh I think that you're saving your patient a lot of cost and time and also resolving their their situation a lot faster because there's a delay before they see a a hepatologist and if you've got them concerned about their liver and you have in your grasp a tool to uh either confirm your worries or put them to rest in a timely fashion I think you should use it ell I've worked in institutions that actually have fatty liver clinics though maybe they've evolved the name since that point too that actually there's a lot of wild enthusiasm for patients where the the diagnosis has made so I guess this is like the patented Paul Williams two-point question I guess the first part is that becoming more and more common is that sort the way this is headed and then this might be a time to transition into what they would actually do for the patient and sort of start us talking about what treatment actually looks like yeah so I think there's these things come in a variety of different types one is that there's somebody in that Center that wants to do research and they want to enroll patients and Bank their blood and others where they're actually providing a value to that patient by colocalizing in one Clinic the tools to provide a prognosis and then also manage the condition so that the patient they might have to wait for that visit but they can simultaneously see someone like a a dietician or a health psychologist and occasionally you'll see clinics like this where they there there will also be a use for uh for expanded use of phical therapies for for weight loss I'm not sure there's much value in a fatty liver stattic liver disease clinic that does not provide those things uh and unfortunately that's rare uh compared uh to the uh the usual uh but when it happens uh and and it's it's wonderful for a patient to be able to see all these different specialists in the care of their condition simultaneously is now a good time to talk about your general lifestyle counseling that you provide as a hepatologist or how do you talk to patients about what changes they need to make I mean we're this is this is a big part of what I do every day every day is primary care because most people are suffering from metabolic syndrome of one sort or another but how how do you approach it yeah so like I I've said this to you guys earlier I have a little bit of impostor syndrome talking about lifestyle Counseling in front of America's primary care doctor but uh like in the I what we do in clinic is to try to focus on what we know are the easiest wins for diet change and it's it's carb reduction you'll hear people talk about the Mediterranean diet which I has always confused me because it's just not available to most of our patients uh with liver disease who either because of time or finances it's just not it's not going to happen but what I do know is I can get people to stop drinking Mountain do or focus on what kind of snacks that they're having uh uh and uh and provide useful substitutions so I just try to go through like a 24-hour diet recall what did you have for breakfast what did you have for lunch it takes me like 30 to 60 seconds and then I provide alternatives for them as a template so I can just get things moving and if they're drinking Coke or Pepsi uh and putting a bunch of sugar in their coffee that is like the best because I know we're going to win right I know we're going to make a huge difference I'm definitely referring to nutritionist but while I have them in my grasp that's definitely what I'm going after and then I try to get them to exercise uh explaining exercise for me I think is pretty tough I just try to make sure that they know they should be huffing and puffing I've try to focus on encouraging resistance exercise but if if they'll walk I'll they'll I get them to walk what do you guys do Paul no it's actually ell it doesn't look all that different from what you do I do talk about it in the larger framework sort of using motivational interviewing because I I don't think using the absolute number of the weight is all that helpful for a lot of people even though you'll often be asked exactly what should my weight be but instead sort of circling back to why is it important for you to lose weight and what is useful to you and often it will come up I'm just tired of losing my breath you know walking to get with the mailbox or sometimes sometimes it's it's cosmetic and I don't think that is invalid at all and then sometimes it is concerned about future health and then start to use that to leverage towards what their goals would be but it's it doesn't look all that different I'm in the middle of Turkey Hill iced tea country and that's an easy one just if I just get that out of the diet I think I would prevent um 20% of the diabetes happen in the middle of central Pennsylvania um but yeah the simple carbohydrates and and like focusing on a diet that isort of higher in protein lower and fats higher and vegetables and really broad Strokes because I think you know I think people want a very specific diet plan but I can tell you that the diet plan I would give them they would not want specifically like if I told them the very specific foods to eat they would not be terribly happy about that so instead I I start in Broad terms not for for a greater education if they want it and then we can certainly go down the pathway of medications and stuff that comes up but I I I start with very straightforward very broad um diet recommendations in the framework of what their own personal goals are regarding their health and then kind of take things from there yeah Michelle mcmackin uh from she's a doctor from I believe she's still at NYU but she gave us this list of like superfoods that she gives out and it has all sorts of like fruits and vegetables nuts and seeds and things like that on there she talks about like kind of crowding out the bad food rather than specifically but I I do I just do find that I have to at least mention like if someone's drinking a six-pack of Coca-Cola a day you know it's just it is such an easy win um yeah yeah I I was talking to a guy not so long ago that his his A1C was 6.6% and I was like you know and he we had had multiple tests I was like you you have type two diabetes it's very mild it's probably reversible at this point and he goes I probably should just stop drinking soda and I was like yes like that will definitely fix this problem like if you're drinking a bunch of soda every day that will fix it so I agree with I agree with you yeah so I think we're all on the same same page with this what one funny story is H we we we studied um sugar sweetened Beverages and the impact on the liver using the anhan database the national nationally representative data and it showed that Sugar sweet beverages like sodas were the most potent Association with fat in the liver particularly for young people and we we we published this we got a little bit of press and I was uh invited to on a DriveTime radio show to to talk about it and and and the guy asked me like what I do and in in clinic I try to come up with Alternatives people don't want to just drink water they want some flavor so i' say get the flavor drops try diet soda and he interrupted me immediately to say he cannot allow his listeners to hear somebody Endor diet soda and uh it was it was like the end of the interview oh my gosh yeah it was that was that that was the end of my my radio spot but uh I think like in this case it's like I mean maybe diet soda is not as good as water but it's the harm reduction concept that this person has a problem related to Sugar consumption and whatever I can do in the short term to get them off of that so that they can feel better their sleep you gets better as their setic liver disease and their fertin and their alt come down then I'm okay with it's diet soda okay I can I can live with that yeah I mean if you if you someone's used to drinking the sweetest drinks on Earth and then you just try to switch them over to plain club soda they're they're not going to necessarily tolerate it right away yeah they got to weed themselves off most people do anyway but there there's a lot of drinks nowadays Paul that are healthier options than even if you're talking about alcoholic stuff and so I think there's there's a lot of good options for people out there now right which I mean this is not a new point but the sustainability is a key I think everyone can eat a miserable rabbit food diet with water for like a week um but it's just it's not going to be sustainable in the long term so I think you need to make changes they're actually acceptable to all parties and you can maintain over time just to add I think the other thing is to know that it's like a journey as opposed to like I got to get all this weight off tomorrow type of thing you know so I think it's like if you're drinking like days a week like soda or something it's like you can substitute one day and have like a healthier option so it's kind of just reiterating that it's a journey and it's like working together for a common goal love it yeah very good point well s we've covered a lot of stuff I think we probably have some more management questions but anything that you wanted to ask next like where did you want to go with this um I know we have a couple things left a couple topics left to cover yeah no I think just in terms of the whole realm of with uh weight reduction and uh more of a conservative management what are your thoughts about with the emergence of sgt2 Inhibitors glp1 agonists when do you kind of reach for those uh in Your Arsenal and are there any medications that are coming on the horizon for Naf and mold okay so great question and the first part of the answer is to remind people about what weight loss does to the liver so it's been worked out in a robust fashion that 5% body weight loss is sufficient to reduce steatosis in the liver around seven 7.5% is when you start to shut off the inflammation you resolve the Nash the mash and around 10% is when you start to resolve the fibrosis that the fibrosis actually improves and so sglt2 Inhibitors are not bad for the liver and in epidemi logic type studies they're they they look good but there's no evidence that they that they help in a in a direct way there are randomized trials now of gp1 receptor Agonist that show that you can resolve Nash uh with weight loss and so these drugs are probably best positioned for the person who doesn't have therosis yet all right the person who has a low fit4 or a low to medium range liver stiffness measure the main goal there is weight loss and so semaglutide triy to improve uh outcomes for people with mash and narrowly missed its end point peptide uh met its endpoint which was recently reported and then some of the newer uh medications that have more I think I think it might have to do with more of that Gip because these are combination Agonist drugs Sur is is one example I'm sorry what Cotati or covati was this was recently reported yeah I'm I'm not sure Paul I'm not sure that that I've seen that one yet either so it's I'm sure these are all coming like there's so many yeah I read some review recently they looked at 14 different glp1 Agonist I did not even know there were that many oh no yeah yeah so there's still a few in development and and the reason why it's worth mentioning is because a few of them are actually going after liver related indications and so these are making hits in like phase two and you'll see how it plays out in in larger studies the the way that these drugs get approved for uh liver disease the the bar is that they have to improve histology that that's what the FDA says and that means that they can resolve Nash without worsening fibrosis and um that's like a a double aim that they have to hit uh that means the patient has to do two biopsy so these P these trials are are kind of hard to do and probably takes a long time to fully resolve fibrosis so when you're doing a trial after 20 after after a year it's it's very rare in fact there's really only been a couple of drugs that have ever resolved fibrosis more than Placebo and uh one of them just got an FDA approval and the others are like these ones that you that haven't been approved yet that I just mentioned that are coming out with their smaller studies you mentioned the weight loss 5% you know that decreases the fat 7% or so turns off the inflammation 10% or so can help reverse fibrosis what I thought what caught my mind about this this new FDA drug that got approved res was it Retron or R retam it's not easy to pronounce but if you could talk about that a little bit and I noticed that it did not really change weight but it did hit the liver end points which is what really caught my eye about it yeah so res metam is the name of it and what it is is it's it's a basically a thyroid mimetic and the the exciting thing about this drug is that it was the first drug to hit that bar that the FDA set where it reduced fibrosis more so than Placebo in a phase three trial and it did so without without weight loss so it would get back to when do you think about these drugs so if I have a patient without fi is who has obesity or diabetes I'm definitely going straight to glp1 but if I have a patient who has F3 fibrosis who has a elevated liver stiffness 12.5 15 that is a person who is on the clock for liver related events and weight loss is pro is is probably helpful but I do want to resolve that fibrosis so I understand why this drug will have have a specific role although I haven't yet uh prescribed it and uptake is limited based on insurance approval there is a there is probably a there's there's probably a case to be made to use this drug for about a year in patients with significant fibrosis yeah this was an interim analys Paul of the Maestro Nash trial by the way Paul I mean fine depends on what Maestro stands for I think it's just a cool word they chose I tried to look it up I couldn't really figure out where they got it from it it is a great name for a trial so this is a trial that enrolled people that had F2 and F3 fibrosis on a biopsy so that they don't have therosis F4 uh and uh and it's people with F3 those are the ones that are at risk of developing therosis and therosis complications over the next five or 10 years so we agree that these are the right people to help and you know Placebo helped you know about 10% but but the drug was significantly more likely to reduce fibrosis the the problem with this medication is is one cost to some insurers for example I practice partially in the VA and the VA is currently requiring that you get a liver biopsy before we use it and and for that reason uptake will be limited and then number three is it's it's it's the stopping rules are unclear so if it's really working right do you have to continue it you've already brought that person back from The Edge and if it's not working how do you figure that out are you going to do a BMC after so I'm waiting to see what the early adopters you know tell us about their experience with it as well as the patients like how they feel when they're taking it uh so it's obviously very exciting to have a medication U it's just it's just a little bit less clear when to use it what is clear is that earlier in the disease course your goal is to resolve the fat and inflammation in the liver through weight loss can you remind me of the utility of some of the old standbys like metformin in the absence of um imper glucose tolerance or Statin therapy um if we would like is there is that something that should trigger us to to prescribe these medications or in all likelihood will they already be on them but just or even vitamins I feel like vitamin E I see thr these patients sometimes too like what about some of the older the oldies but goodies are there evidence or utility in those okay so meformin is not bad at all it's probably good and so uh most of us are are are not are making sure that metformin is not stopped if uh if people are worried that it could be causing liver disease you asked about statins we are super sensitive about stats because they get stopped for elevated liver enzymes all the time but the elevated liver enzymes are probably related to the stoic liver disease in the first place and so we're really like we are we really want you not stopping statins and people who have indications for it and then you asked about vitamin E so you like trial names so here's the trial name that gave us vitamin E it's called PIV it's called what Pivens p i v NS Pi is pitzone vitamin E ve and then NS nothing special the placebo Paul they were big entourage fans I was yeah that was the jok's right there yeah all right so so this is a this is a trial that showed that both pitzone and vitamin E reduced inflammation reduced n she was an NIH sponsored uh trial so most people are like pyone is probably not as bad as people say it is but but it causes some weight gain most people don't use it but it's probably good okay and vitamin E it's actually remarkable so we'll only really use this for biopsy proven St steatosis steatohepatitis and my experience with it is fantastic it will reduce the alt substantially and patients love it and it gets them very much engaged in the overall process of lifestyle change when they see some improvements so I I will use vitamin E you know the vitamin E is is associated with a small increase in the risk of intracranial hemorrage particularly for women so we counsel people about that but it's it's a very rare risk so often what I will do is I I will use it for like six months to make sure that it's working and if it's working I'll use it for about a year or or a year to three and long-term followup from Piven studies show that the longer you used it those people who were using it were less likely to get into liver trouble so it is probably an antifibrotic medication vitamin E interesting yeah because I I know there was something about vitamin E while why like people that were on really high dose vitamin E they stopped using it um and I want to say it was some sort of cancer risk or something I I can't think of it off the top you might be on vitamin A Matt because that vitamin A anyway it's not we I think associated with the lung cancer increase because there was the US pstf recommendation about vitamin supplementation in general and part of the considerations for vitamin A which had increased cancer risk and then vitamin E was the bleeding risk so those were the ones that they actually specifically recommended I think again just for just just for patients without specific indications for them which is a little bit of a different patient population than we're talking about here yeah yeah so the dose of vitamin used to treat Nash or Mash is 800 international units and I wouldn't just throw it around willly like I would be deliberate about it and and we really reserve it for people where we're certain that that's what we're dealing with and that we have discussed a plan about the things that will affect their cardiovascular health and so forth in the long run okay just two more quick things by the way so actually we were just talking about you speaking of trial Nam so um just chat out the pickles trial one more time um and I just found out I was just tagged on Twitter completely unrelated anything that we're talking about but just in terms of trial names Matt there is a tailored Swift trial having to do with artificial intelligence organization realization of estimated discharge was suppored weekend so it sounds like they used AI to figure out when they're going to discharge patients but they did they put in the work like they actually every single letter spells out Taylor Swift so congratulations to the authors of that very important paper okay well should we go back way back to our 28-year-old man and and try to resolve this case so what do we what do we want to say happens to this guy remember he had an ALT of 31 and a of 44 let's say he didn't have he B he C his path was negative we're very confident he wasn't drinking alcohol and let's say he had a favorable liver stiffness measurement and his FIB four was like intermediate so we we just we sort of said to him let's let's try to lose weight and he stopped drinking all the sodas and uh we had a happy ending does that does that sound okay I don't know if we need s is that how you saw this going or was he going to get sicker no no we always have a good ending here okay anything else that we Paul or Sai before we get our take-home points is there anything else that we are leaving on the table I mean obviously we could talk about the liver forever but we got to let Elliot go at some point nothing for me I think we did it okay yeah all right Elliot then if you would uh one or two take-home points that you really want the audience to remember or or or two or three if you if you need okay so there are two main responsibilities when you are faced with somebody who likely has fat in their liver and elevated liver enzymes the first is to provide them a specific diagnosis which includes excluding alcohol use disorder and two a prognosis through the sequential application of tests that can identify a risk for advanced fibrosis and the ones that you use are the FIB 4 fib4 and then most likely illas ography usually through transan listography or failing that a serologic test like the enhanced liver fibrosis test I think we can do this Paul we've we've got this this is you know some of the patients are going to end up getting seeing Elliott but I think we can do a lot of work before they get to him yeah for sure we can get them started I feel great about this all right Elliot thank you so much as always people should check out the pickles trial I believe it's spelled p i ccle it's one of the greatest Trials of all time and uh Elliot thank you thank you as always thank you guys good to see [Music] you this has been another episode of the curbsiders bringing you a little knowledge food for your brain hole yummy still hungry for more gener patreon get all of our episodes at free plus twice monthly bonus episodes at articles guidelines and news in Internal Medicine and we're committed to high value practice changing knowledge and we want your feedback so please email us at ask curbsiders gmail.com a reminder that this and most episodes are available for CME credit for all health professionals through VCU Health at curbsiders dobc health.org a special thanks to our writer and producers for this episode Dr Sai Ai and Prem Patel and to our whole curbsiders team our technical production is done by the team at podast Elizabeth Proto does our social media Jen W runs our patreon Chris The chw Man chew moderates our Discord steuart bam composes our theme music and with all that until next time I've been Dr Matthew Frank W this is saii and as always R me and Dr Paul Nelson Williams thank you and goodbye [Music] [Applause]