“Beyond the Biopsy”— How NASH Therapy Will Improve When Non-Invasive Tests Become The Standard – Ep 26

The Surfers discuss the Global Liver Institute's campaign to educate and motivate key stakeholder groups on the value of non-invasive liver testing.

Donna Cryer, President and CEO of the Global Liver Institute, discusses GLI’s “Beyond the Biopsy” campaign while Stephen Harrison, Louise Campbell, and Roger Green join in with education, messages, and ideas. The “Beyond the Biopsy” campaign focuses on the importance of gaining acceptance for non-invasive liver testing. Stephen discusses why validation matters and why “H” is a magic letter. Roger discusses the history of statins and the importance of what appears on blood testing results. Louise discusses simple things that healthcare can do to diagnose and treat liver disease before it becomes deadly. An eye-opening episode!

Roger Green: For everyone with an interest in NASH or more broadly, fatty liver disease, Surf’s Up. Episode 26 of Surfing the NASH Tsunami starts now, wow.

Roger Green: By the time you hear the next episode, we will already be into autumn, this is the dog days of summer, last episode of summer. So we want to end the summer of 2020 with an inspiring topic, what life for liver patients and people who treat them be like when we are beyond the biopsy. Where we don’t have to rely on liver biopsy as a gold standard for so much of what we do. Donna, is back from having started a program by that name: Beyond the Biopsy with Global Liver Institute, at the beginning of the month, and she’ll be talking about that.

Roger Green: This week, the only folks here are us regulars, Donna, Louise, Stephen, me. So we should have plenty of time to talk slowly, think slowly, dive into this issue from several different vantage points, I think it’s a fantastic issue. Before we get started, here at “Surfing NASH”, we’re delighted that listenership for the Digital ILC episodes continues to grow. Cooler still, people who came to us through ILC or refound us after having been away for a while, have gone back and started listening to the old episodes. There are four or five old episodes that have virtually… Well, grown at least 50% listenership in the last month, month and a half, including some that we thought were pretty well-listened to in the first place.

Roger Green: At the end of this episode, I’ll ask this question again, if we have time, and I will be posting on the discussion board, two questions for all of you to come answer. One: As we plan our coverage for Digital AASLD in November, what features from ILC should we make sure to keep them and what should we change? Second, if you’ve gone back into our older episodes, which ones did you like best? If you haven’t, which ones do you remember best? Why is that? And are there any topics in the old episodes that we should revisit over the next couple of months, do another episode and say, “Well, gee, what’s going on with this?”

Roger Green: As if to anticipate that, we got a note from a listener this week that actually talked about how much he loved our coverage, but I’m going to go past the remarkably flowery prose, to touch on the two issues that I just asked. What he said he liked best was our ability to churn out daily updates throughout ILC, that were well-prepared and that covered topics accurately and where he knew exactly what he was going to get in the episode.

Roger Green: His favorite old episode is episode 12, where we discussed the implications of Intercept having received a complete response letter and that we could cover it within three or four days after news of the letter came out. So what are your thoughts? Please come to the discussion group or send us an email, let us know, and we will incorporate that into our planning. Music, we’re still staying with Jeffery Hemsdale, and the British Liver Trust because it’s such a nice, calm, placid and brilliantly talented way to go out at the end of an episode. And with that …deep breath, let’s go on to the podcast. Let’s start with personal highlights this week. Brave one, go first.

Donna Cryer: Well, I have a serious one and a light one. The serious one is that, my husband has been successfully, medically managed with having bilateral DVTs that almost scared the life out of me, to think of losing him that way. And, luckily, he is a brilliant physician and diagnosed himself and, with our care team, we got in the ER and had an amazing experience there. So kudos to Sibley Memorial Hospital, here in Washington, DC, for getting things in hand so quickly.

Donna Cryer: On the lighter note, because as if that wasn’t enough, saving both of our lives, frankly. I discovered that you can get a foam roller on a stick, you don’t have to do that crazy lay-on-your-back, over-the horrible-form-roller contortionists nonsense. You can just get one on a stick like a rolling pin and roll out your muscles, and so I consider both of those very significant successes of the week.

Roger Green: That’s funny, when I had a foam roller and I had a dog, the dog would roll on the floor with me when I was foam rolling as if we were doing it together.

Louise Campbell: I suppose mine is actually more of a professional one. Spending three days scanning in homeless people’s units, around one of the counties, and with one of the Drug and Alcohol Services, which was enlightening, educational and very engaging. So it was a thoroughly excellent three days.

Stephen Harrison: Well this is really a light note compared to the altruistic comments that Louise made, and the life-threatening situation that Donna went through. So this bit of brevity will be nice to hear, my daughter is a senior in high school. She just started her last year, two weeks ago. She’s number two in her class and is everything I wish I was in high school but didn’t do, and so now we’re looking for colleges and it’s, I guess, encouraging to note that she’s narrowed her choices down to the University of Texas, in Austin – Hook ’em – or the SMU Mustangs, in Dallas.

Stephen Harrison: That’s much to my son’s chagrin, who is a sophomore at Texas A&M, and if anybody knows anything about the state of Texas, you would have a house divided if I have a UT Longhorn and a Texas A&M Aggie at the same location. So, anyway, a bit of a challenge to come as we move forward, I’m secretly hoping she chooses SMU, so I don’t have to go through that. But I can imagine I have a tee shirt that’s half maroon and half burnt orange.

Roger Green: You can do a lot with that, Stephen, and you can make the front one and the back other or you can split it, right down in the middle, on both sides. You’re going to have alternating colors that way so it’s like a chess board, I think this might have a future.

Stephen Harrison: Lots of options, for sure, and I can’t imagine what would happen. Good thing they’re not in the same conference, in football, anymore.

Roger Green: I hope I don’t wind up regretting this later and I don’t think I will, but my personal highlight is, after not having been on an airplane since March, I’m getting on an airplane on Thursday. And I’m getting on an airplane to go to a low-risk, low-COVID environment like Texas because I want to go see my granddaughter, who I haven’t seen in two months.

Roger Green: In fact, I will be doing the podcast, next Monday, from Corpus Christi, Texas. And we’ll be there for a week and my granddaughter is beside herself, she’s shrieking on the phone that is when the dog’s not in the room, because if the dog’s in the room, everything else goes straight out the window. So we’re really excited about this.

Stephen Harrison: Just make sure there’s no tropical depression moving into the Gulf.

Roger Green: They’re coming through so fast, Stephen, I don’t know how I could plan for it, right? For an eight-day trip.

Stephen Harrison: A eight-day trip, you definitely are going to have the weather channel on, at some point.

Roger Green: That’s right.

Louise Campbell: Just take plenty of bedtime stories.

Roger Green: Yes. Well, that’s one of the things we do. We read to her by Zoom, now we’re really excited to get to read to her in person again. All right, and with that, a start that covers all the different aspects of life in one form or another, let’s go on the main topic.

Roger Green: On August 31st, Global Liver Institute kicked off a month-long campaign called “Beyond the Biopsy”. And I quote, “Dedicated to accelerating the acceptance and adoption of non-invasive diagnostics, as an alternative to biopsy.” Donna, as the CEO of Global Liver Institute, one of the leading voices for this initiative, having her on this program today is, I think, the best way one could imagine to talk about it. So, Donna, why don’t you start by just telling us a little bit about what it is, how it works, what you’re doing, what the motivation was?

Donna Cryer: Sure. Thank you so much for this opportunity and I’ll start with the motivation for it. The Global Liver Institute is very focused on looking at the entire field of liver health, and determining where the gaps are, where the opportunities are, what are the barriers to achieving best practices or best outcomes? And so when we were starting our work in NASH, it became, very clearly and quickly apparent that a dependence and a definition of the disease on liver biopsy, was the rate limiting factor for, you name it…

Donna Cryer: For patients participating in research, for studies being enrolled, for drugs being approved, for people getting access to treatment, for people getting diagnosed accurately. We spent a lot of time talking and researching and thinking about what could be done. One big thing was just awareness, particularly when we started conceptualizing this. There wasn’t a pervasive awareness that there were alternatives to liver biopsy, let alone the great diversity of innovations that we’ve seen now and were quite well-featured at EASL.

Donna Cryer: And so, when you think about the general population in particular, because when you think about a condition or a disease as prevalent as NASH’s, you really do need to start talking to the larger public.There we hit the familiar walls of low levels of liver disease, no awareness of NASH as a whole. To then hit this issue of biopsy, we really needed to shine a spotlight on the drawbacks of biopsy, one, for something that’s called a gold standard, it seems rather tarnished to me. And then the alternatives and offering an opportunity for so many who are working in so many different academic labs, government labs, companies, research networks like Stephen’s on – all these different innovations in non-invasive diagnostics, to create a platform for those discussions.

Donna Cryer: Then the second phase that we’ll move into, is really encouraging the adoption. We see that already in clinical management but encouraging the adoption in guidelines, in formal policies and payer policies. But before we get there, we really needed to just shine the spotlight and start having this conversation. So, we’ve created some materials and some questions but the heart of it really is, a radio media tour that I was so honored to do with our good friend, Mazen Noureddin, from Cedars-Sinai Fatty Liver Disease clinic. And he is well-known to those of us in the NASH field.

Donna Cryer: And we did, gosh, fourteen radio interviews in all different areas of the country, on the morning of August 31st. Luckily we were still on EASL time so it didn’t seem that early, but we launched this campaign with this radio media tour and then we are having a series of Facebook Live discussions. grounded in different localities because we wanted to understand what was available to people, in the different localities, and see how different locations might be leveraging different technologies or thinking about them in new ways.

Donna Cryer: We did one in Colorado and we had the involvement of Congressman Jason Crow, former army ranger and a member of the healthcare innovation caucus, also member of the congressional diabetes caucus, which I think is a really important collaboration for us to make. Then we’ll be going to Massachusetts, where we’ll have Ray Chung and others. Dr. Chung being the incoming AASLD president so we’re so excited to have him.

Donna Cryer: Then, in New York, Scott Friedman will lead the conversation there and then we’ll wrap up, summarizing what we’ve seen across the country and across the research and in a consortia like NIMBLE and LITMUS, with Dr. Arun Sanyal. So I’m really excited about how this has come together and the content that were being created, for everyone to be able to carry forward, to discuss why alternatives to biopsy are here to stay, are evolving, are real and really need to be what we all look forward to seeing, hopefully long before 2025, as a standard of care.

Roger Green: That’s great. So without tipping off the last episode, when you put all this together, what are you learning? What are you learning and what of it are you finding surprising?

Donna Cryer: I have often used the phrase, “Patients are very practical,” and the radio interviews that we did where… In some cases, the radio interview themselves had NASH. And so they were very like, “What are my risks? Where do I need to go? What type of doctor do I need to get to?” Those were very telling, when it became very personal, when somebody, themselves, or a member of their family had some connection to liver disease, that definitely went into one direction. But, the theme throughout the fourteen that we’ve done so far have been a sense of consternation like, “Why are we still doing this thing where you stab me in the side and wait for me to not bleed out, for a few hours? Why is this still done when we have better ways to do it?” So it tipped, for me, it wasn’t the alternatives that we had to explain the value of, to people, it was the, “Why have we ever or why would we want to continue perpetuating biopsies for a moment longer?”

Louise Campbell: I’ve got a question. And it’s more in relation to the fact that, what do you see as the biggest challenge? Is it the lack of awareness and information from within the patient groups, if you’re an endocrine patient or if you’re a cardiovascular patient, or is our biggest challenge and your biggest challenge actually healthcare, getting those disciplines to recognize, and many more, that the liver underpins a lot of the processes that make their diseases happen? So which is the biggest challenge?

Donna Cryer: To your first question about awareness, particularly within high-risk communities, I can’t really call it a challenge because there’s nothing there, there’s no awareness there, we’re going to have to build it to push. So I don’t think there will be resistance to that, it just really hasn’t been anybody’s effort, yet, and we are reaching out, as part of our overall NASH initiatives.

Donna Cryer: The challenge, I believe, is in the lack of consensus around which diagnostic to use? In what setting? And it has what value? And we interpret it. If we could go to endocrinology or primary care and say, “We, the united hepatology community, believe that this test is what you should use to screen your patients,” or, “This test is what you should use to differentiate between… Or stage them… ” Then we would get incredible receptivity. But we don’t have that clarity ourselves and so, as they say, “you cannot give what you don’t have” so it’s that lack of clarity that is stymieing the process.

Louise Campbell: That’s true.

Roger Green: So, Stephen, do you envision a circumstance under which that clarity will, at that level, become realistic in the States?

Stephen Harrison: Yeah, I do. First of all, let me congratulate Donna for her effort, I think there really is somebody that needs to be a champion, pick the baton up and run with it, and I just congratulate you on doing that. I go back to the three questions I always ask: What? So What? Now what? Well, the what is we’ve got a biopsy requirement to diagnose NASH It’s noisy, it’s a representatively smallest sample, 1/50,000th of the liver, by a lot of accounts. There’s lots of interpreting variability, we call it inter and intra-observer variability. The overall Gestalt diagnosis of NASH or you look at the individual components that make up NASH, they range from poor to good, at best.

Stephen Harrison: It’s an invasive, it’s an obtrusive test, I think Donna has even said it one time or another, on this podcast. When approached with the option of a liver biopsy, she doesn’t just run for the hills, she says, “No way,” and, “Look for alternatives to get the information you want.” So, look, I’m a hepatologist, I’ve probably done over… Well, I don’t know how many thousands of liver biopsies I’ve done; I’ve done a lot in twenty years. But I, personally, would find it challenging to have a liver biopsy done on myself.

Stephen Harrison: So I do think the “what” is liver biopsy has its inherent problems and it’s not the gold standard, as Donna mentioned. “So what? So what about it?” Well, we’ve got to find a non-invasive test, that’s a no-brainer but the issue is there’s not one-size-fits-all, right? We’ve talked about this before, also, there are three different contexts of use that I envisioned for non-invasive testing. The first is, diagnostics, “Show me the population I need to worry about.” There was another listener on the podcast that said, “Don’t show me who I need to worry about, show me who I don’t need to worry about.” Because, at the end of the day, if they’re a 100 million Americans with fatty liver, many more around the world, show me the 80% solution. The 80% solution is who you don’t need to worry about today and then we’ll focus on the 20%, once we nail down the 80%.

Stephen Harrison: You can look at it two different ways but, at the end of the day, you need a test to do that. Is that a blood test? Is it an imaging test? Well, right now, our data suggests really it’s a combination of both or a combination of multiple different wet biomarkers. The problem with all those, is that they’re not validated so the word of the day is validation, validation, validation. You have to have that to get buy-in from the agency, the payers, and everybody in between, before it becomes an acceptable surrogate.

Stephen Harrison: The second context of use is markers of therapeutic response, so as we get drugs coming on the market, how do we know they’re working? And that, I think, at least in my opinion, maybe the furthest along because pharma companies who had jumped into NASH headfirst, trying to find therapies, and boy, do we have some good ones in development, have begun to incorporate these non-invasive tests along with histology. So what we call companion diagnostics and data, which was presented at the ILC, by Rohit [Loomba] and some by myself show that we’re, at least with some drugs, able to really get after measuring therapeutic response.

Stephen Harrison: We’re not done, we still have more to go, but there’s a pretty good head start, at least in that context of use. And then, finally, long-term patient outcome measures and finding a test that I can do today, in-clinic, that I can sit down with my patient and say, “You know what? Based on the results of this test, in five years you have X% chance of having decompensating disease, progression to cirrhosis or whatnot,” will really be important. Those are also under development but I think we still have ways to go there.

Stephen Harrison: So, again, let me circle back around and say kudos to Donna and the Global Liver Institute, for really taking the mantle. I thought this would be carried by pharma once there was a drug that was approved, but knowing the challenges we’ve had with that, I think, in the intervening period, disease awareness, beginning this campaign on “Beyond the Biopsy” is really coming at a critical time because we’re realizing the challenges of liver biopsy. Really, in all of those three contexts of use that we mentioned but mainly for clinical trials, as we develop drugs for NASH and getting at a non-invasive test is absolutely critical to be able to advance the frontiers of medical science as it relates to fatty liver disease. So my hats off to you.

Donna Cryer: Thank you. Thank you so much. And thanks for that really articulate breakdown of the key areas and the key value cases.

Roger Green: Yes. Thank you, Stephen, and I’ll say this again, congratulations, Donna, on a fantastic and fantastically needed program. You made the comment that we needed to converge on a test,;I may have heard it more literally or more singularly than you meant it, but I’m wondering exactly how much clarity do patients need before they’re willing to step into doing this, how much clarity do… Not leading hepatologist but primary care and other physicians, need to trust? Is it enough to say, “Here’s step one, here’s step two, here’s step three, you have a few different options in each step?” Particularly given that Stephen points out, you’ve got three different points on the pathway that you’re looking at.

Donna Cryer: Well, even that is a huge advance over where we were starting two years ago. It was like somebody just tipped over the Scrabble board or something and it was just like, “In here, Donna, put together these letters and numbers and in some form of format, and then go call the American College of Physicians and tell them we want to do more with NASH,” it just wasn’t going to work that way. So to be able to say to them, “Yes, there are several tests that are evolving in their state of validation,” I agree that is the word of the day and the evidence generated around their use, but we are able to say and better match this test or this set of tests for this particular use, clear out the noise, this set of tests for this particular use and then this set of tests for this particular use.

Donna Cryer: That you could start putting into a clinical workflow, that you can start making sense of. It’s still not the Holy Grail of having a HbA1c test that determines it all, but it gets us a lot closer to being meaningful on the clinician side. On the patient side, it really is about the “So what” in Stephen’s progression. Any test that tells me this is how my liver is functioning and so I need to take this particular set of steps, or it tells me that I have the likelihood of this many years before I hit cirrhosis or cancer or need a transplant, is therefore meaningful. And we’re getting closer to that and that’s exciting.

Donna Cryer: And defining, I think part of this campaign, if it is successful, will help add to that clarity of defining what is meaningful, what is meaningful or useful product features for tests, for usability, all the way around? And what are meaningful results of tests or combinations of tests for people? So that we can move forward those that have that meaning and deliver that value.

Roger Green: Just one more question about the program which is, if our listeners want to catch up to the various events that are left or go back and catch earlier events, how do they do that?

Donna Cryer: They can go to our globalliver.org/beyond and we’ll have information on the shows and any contents that we have or we’ll create.

Roger Green: And then what events do you have upcoming?

Donna Cryer: So we have a Massachusetts coming up: our GLI Live episode featuring our Massachusetts contingent. And that includes Dr. Ray Chung, will be on September 16th, at noon, Eastern Daylight Time, I believe we’re still on Daylight Time, on Facebook and then we’ll post it to YouTube. On September 21st, at 11:30, Eastern Daylight Time, our New York panel will air and then on September 29th, at a very special time because everyone is very special and worth rejigging my calendar for, so that will be at 3:30 Eastern Daylight Time, on September 29th. Which is also the 26th anniversary of my liver transplant, so it is a very special day and that whole schedule is on the globalliver.org website.

Roger Green: Fantastic. Question to the team, starting whoever would like to. So, Stephen identified the three different sets of needs or value that we get from going “Beyond the Biopsy”. What do you think will be the most important shift in any of those or in each of those, either way? As we start to move “Beyond the Biopsy” and into an era when validated tests are actually driving treatment decisions a lot more simply and in ways that are easy to execute. What’s the big thing that changes first, and how does it change?

Louise Campbell: I suppose, going back to what Stephen said, from the patient comment or the comment that was received about telling the patient, “I don’t need to worry about.” I think it’s being able to get to change your primary care, that means everybody walking through the door, irrespective of age, is considered at risk. If we start with the premise that everybody’s at risk and funnel it down, because we can look at diagnostics beyond biopsy, it’s already been discussed in different categories and criteria, but some may require different ones. But we need to first identify that there is a problem and Rachel Pryke, the GP, who presented very well at the Digital Conference, was very open on the fact that most primary care physicians misinterpret liver function tests, particularly in normal liver function tests, as absence of liver disease which we know it’s not.

Louise Campbell: So I think it’s changing that paradigm, is the first way to get “Beyond the Biopsy”, from what Stephen was detailing. And I think we need to start with mechanisms where we can identify, in primary care, to make it easy to get better testing, to get better referrals into secondary care. And I think once you get better referrals, then you can get better, specific diagnostic accuracy that’s reproducible, is convenient and it’s cost-effective. And I think we’ve heard multiple times, the threat and the rise that liver disease is projecting with obesity, over the next ten to fifteen years. And liver biopsy is just not an option in the number of patients, at the rate that liver disease is increasing.

Louise Campbell: And I think the “Beyond the Biopsy” campaign is absolutely vital because if we don’t look now, at trying to isolate finding these patients, then how are we ever going to turn around the tsunami, not only NASH, but of all other areas of liver disease, globally. So that’s where I think we need to be heading, and I think we need to be looking very rapidly at how we can get these tests in. And COVID may have helped that, people are far more accepting of telehealth; they want their tests more locally, now, they don’t want to have to go to major centers. They don’t want to have to go to clinical research institutes if they can get their clinical research screening more locally, and I think Stephen would be best placed to answer that side but we need to, now, be putting in as much diagnostics in to help primary care as we can, as soon as we can. And “Beyond the Biopsy”, if it helps that in the US, then that will replicate around the world, I would hope.

Stephen Harrison: Louise, you mentioned something that reverberated with me a bit and that is, I just keep going back to the, “how simple can we make this?” How simple can we make this for everybody involved; for the patient, for the frontline physicians, for the payers, for the politicians, lobbyists, not for profit organizations, everybody involved? How do we make it simple? In the military, we have this thing called the KISS principle, “Keep It Simple Stupid”, and when you were commenting, where I went immediately to was back to Iraq in 2009, when I deployed to Tikrit.

Stephen Harrison: And I remember, over and over again, seeing many trauma evenings where boom goes the dynamite and in come the birds. And birds being the incoming Black Hawk helicopters with the trauma patients, and our trauma surgeon was very… He was an amazing surgeon, young guy, but he kept it really simple and he trained the medics, and he had them down to just a very set of simple pragmatic rules. And it was, make him naked, roll him over, chest X-ray. Every single trauma patient that came in the door got the same exact treatment. Because he had learned over the years that if you didn’t look everywhere, you could miss a bullet wound where it went in a little tiny hole, you didn’t roll him over and it came out the back, and there was a major problem that you didn’t look for. Or a pneumothorax that just wasn’t picked up right off the bat.

Stephen Harrison: Those three simple principles, basically, saved every single person’s life that came into Tikrit, at the 47th Army Combat Surgical Hospital. We did not lose a single life in seven months if they came in with a heartbeat because of him and his very simple, pragmatic set of rules that he applied. And if you take that to the US, everybody that works in the ER, my brother’s an ER physician in Jackson, Mississippi; they do FAST exams, they do ultrasounds on the abdomen, in every patient that comes in with trauma. Because they’ve learned that’s a simple tool to find something that they may not know, and identify it early and then get them to care.

Stephen Harrison: So we have to come up with some very simple set of guidelines for primary care, or a very simple set of rules for our patients to ask the right questions, and I think we’re not quite there yet. If you think about where we are, MRI’s a great tool, it’s not readily available on every street corner and not all MRIs are created equal; I learned that the hard way. Siemens, GE and Phillips all have different hardware, they all carry different software, all weren’t put into use last year so there are several that are old, they’re very expensive, and they can’t run the applications like MRI-PDFF or MR elastography, for instance, without significant upgrades and significant costs.

Stephen Harrison: But that’s a good start point, right? So we had the MRI-PDFF, it’s now the gold standard for fat; how do we develop even simpler tools that correlate with MRI-PDFF, that are handheld, that can be point-of-care test and used in the clinic? And FibroScan is a good start at that; it gives us CAP, Controlled Attenuation Parameter, that tells me, “Yes,” or, “No” for fat. It doesn’t do a good job of quantifying the fat though, and maybe we don’t need that just as a, “Yes, no.” But, again, that’s a start but is it the finish line? Can we put a FibroScan in every clinic? Probably not, based on the cost that’s associated with it, but it’s another step in the right direction.

Stephen Harrison: And I think, as long as we’re continuing to evolve these principles and these diagnostics, we will get to the simple answer. In the meantime, we’re left with, again, validating what we have so that we can develop simpler tools to use against those surrogates, that have now been validated against either biopsy or the gold standard MRI, whatever it might be.

Louise Campbell: Absolutely. I think, if I remember, you were on the paper that Phil Newsome did on SMART exam, the new upgrade to FibroScan.

Louise Campbell: It’s called SMART exam, isn’t it? Where they’re going to calculate the attenuation over something like 500 readings, rather than just those ten, because it becomes more accurate.

Stephen Harrison: That’s correct.

Louise Campbell: So do you think that is a way to go? I can get you FibroScans in every primary care if you want one. That’s my goal.

Stephen Harrison: So in the US, unfortunately, we can’t get FibroScans everywhere, just because of the cost, but I do think it’s a step forward, it’s exactly right. We evolve these tests, either through refining them internally and then testing them externally, or we identify something on the front line and it gets taken in-house, tested, and invalidated again. Or it’s a combination of something old with something new, and I think that first step we saw was taking a very old and tried-and-true biomarker, aspartate aminotransferase, or AST, and combining it with CAP and kPa and came up with FAST. Or very simply the FIB-4 and even the NAFLD fibrosis score, a large part predicated on the AST value. So AST:ALT ratio is one.

Stephen Harrison: So if I were, maybe, in Donna’s shoes, one of the things I would push for is something very simple like the AST:ALT ratio. We know this is ALT-predominant disease, when AST rises to the level of ALT, that’s bad. So, that’s something that we can at least take out to the populace and say, “Hey, are you aware of this?” I don’t know how many times I go to talk to primary care, because we do a lot of that here in San Antonio, delivering just awareness. And they always ask, “What’s something simple I can do?” I’m like, “Take your diabetics and look at the AST value, if it’s close to the ALT, red flags should be flying, spidey senses should be tingling, that patient needs to be referred. And then we’ll take it and run with it.”

Stephen Harrison: But that’s where it starts, right? And then we need to know when that happens. Doctors are very… It’s interesting, we can read New England journal, we can read annals, JAMA, Lancet, and we may not change our practice based on one double-blind, randomized, placebo-controlled trial. But you give us one anecdotal experience that we remember, it changes our practice forever.

Stephen Harrison: Educating them one at a time. The problem is you need an army to do that and, again, kudos to organizations like GLI for beginning to put that campaign together.

Donna Cryer: Thank you. But it’s only as good as this type of information and we did mention that AST:ALT ratio, as well as starting with Mazen’s paper, of course, that we discussed in a previous episode, on the cost effectiveness of screening patients with type 2 diabetes. We do want to reinforce since our starting point, amongst many physicians, is that NASH doesn’t really exist or it’s not real, or we’re just overstating or overblowing this. And so to give them a sense of success and a sense that this is real, and some momentum and traction, I think you’re absolutely right. That having something as concrete as a ratio, a blood test that they’re already taking and a diagnosis that they already have or can easily get, and using that as the first line of decision making.

Donna Cryer: I mean, I do stay up at night, always thinking about, who do we miss? Whether that’s in looking at different cutoff points of different tests. Or intermediate ranges of patients in different types of tests. But we’re at such the beginning of this field and I think, Roger, it’s great that you anchor us in thinking about what will it look like in 2025?

Donna Cryer: Because, right now, we do have to recognize that we’re still at the early stages of this field, not as early as we were, thank goodness. We’re making progress, I think, truly quickly, with so many minds on board. Whether that’s in academia or in clinical practice or in research or in the pharmaceutical companies that are different combinations and partnerships of. But we will soon, if we need to have the larger traction and the larger policymaking, and if we want to make the most of our time in the spotlight. We will need to distill things to its essential essence and to have these very simplified solutions.

Roger Green: So, Donna, let me throw one out. In the early days of cholesterol, right?

Roger Green: The first challenge was getting a cholesterol test and triglycerides, into everybody’s standard blood panel.

Roger Green: The second test was getting HDL and LDL fractions in. The third test wound up being getting LabCorp and Quest in the labs, not to define elevated as the top 5% of the population because if 80% of the population has a problem, then the top 5% just doesn’t matter, right?

Roger Green: And the reason they did that was because they knew that in primary care, whatever anybody said, most of the uptake was picked off a lab report or something that was flagged as an abnormal value. So I don’t look at other people’s bloods and I haven’t had my own taken in a while, is the AST:ALT ratio a standard, for example, on the readouts that you get when you take blood tests?

Donna Cryer: Literally reaching in my drawer right now.

Louise Campbell: I can answer that, for the UK, and the fact that it’s not standard. And maybe keeping to Stephen’s KISS analogy, and the fact that “Keep It Simple Stupid” is maybe what we do need to do.

Louise Campbell: Make that a uniform test throughout the world, just, and keep it simple.

Roger Green: That’s where I go first. I mean, Donna, the same thing might’ve have happened with diabetes. So long before you get to HbA1c, you’ve taken measures that aren’t necessarily very good but serve a purpose, and put them to that purpose. Which tends to enlighten the society on how big the issue is, as well as starting to get people treated.

Donna Cryer: Yeah. I’m looking through and I have the advantage of looking through labs assigned from a variety of specialists, here in DC area, in a relatively short span of time. Each of them do have, individually, AST, ALT and then alkaline phosphatase. But they do not have the AST: ALT ratio. They do have the albumin and globulin ratio on them, of course, and the BUN/creatinine ratio. So it’s not as if it’s a hard lift, I’m thinking-

Donna Cryer: … of the various lists I have to do. But so I think this is excellent, I love this podcast, now I have outcomes and marching orders from it. So, yes, if that is something that is helpful, I think that, that is a reasonable, achievable ask.

Roger Green: Back at KISS, any flag that’s a good flag is a good idea, right?

Donna Cryer: Yeah.

Roger Green: So, that’s great. Stephen, you’re un-muted, what did you want to say?

Stephen Harrison: Well, I was going to say the Texas Flag, obviously, is… I mean, but just to keep it light. This has been known for a long time, even back in 2008 when Beth Bryant (sp?) and others from St. Louis University, and I, published data on the different stages of NASH. And we looked at lots of variables to include ALT and AST, and AST:ALT ratio, and showed that there’s a rising AST over time. And, actually, ALT tends to plateau at stage three, and then rapidly falls as you progress into four.

Stephen Harrison: And, actually, it’s not unusual to see many patients with cirrhosis that have completely normal, same (sp?) Aminotransferases. But one interesting characteristic about the cirrhotic NASH patients. If the liver enzymes are normal, the AST will always be higher than the ALT. And, in fact, in a few cases, the alkaline phosphatase will begin to rise. We published that paper many years ago, showing that post-menopausal females with cirrhosis, it’s not uncommon for them to have normal ALT and AST, with the AST higher than ALT, and the alkaline phosphatase to be slightly high. Not in the PBC range, by any means, but 130, 140, something like that. But very pragmatically, when we develop the BARD score, which is BMI, AST:ALT ratio and diabetes which, back in the day, I was developing as a liver fellow at the same time the NAFLD fibrosis score was being developed by others.

Stephen Harrison: The AST: ALT ratio was one that came out over and over again, in multivariate logistic regression, as being an independent predictor of advanced disease. And it was down to 0.8, you didn’t have to be one, AST equaling ALT, that’s a ratio of one, but even at 0.8, it became very, very important. So I think, absolutely, if we could get that added to the lab listing through BARD or through a Quest or LabCorp or whoever, it would be very instructful. We would have to make it known, though, that normal liver enzymes don’t necessarily mean the patient is out of the woods.

Stephen Harrison: But, again, just identifying a flag, putting it red, putting an H out or something, at least to get somebody’s attention. I don’t know how many times the patient comes to me and says, “Doc, this is red, there’s an H out beside it,” and it’s really a subtype of a white blood cell, right? Maybe it’s a neutrophil or a lymphocyte. And it really has no bearing on the patient’s quality of life or even their current health, but it’s flagged as an H and so they’re worried about it, right? I think that would be helpful.

Roger Green: So, Stephen, let me ask just a couple of questions. What percentage of the population, overall, would you guess would get flagged on that, on the ratio? Say 0.8 or a one?

Stephen Harrison: That’s a good question, I would be really guessing. I would suppose maybe 5% of the population.

Roger Green: Good. The reason I asked the question is that well, that doesn’t make an exceptionally sensitive measure because an awful lot of people, more than 5% of people are challenged, but it’s a great start.

Stephen Harrison: Yeah. But listen, 5% of a 100 million .

Stephen Harrison: It’s lot of people. I don’t know how many times, even my 20-year old in college, he goes for his routine checkup and they’re wanting to test his cholesterol, they’re wanting to get an A1C, a glucose, check his blood pressure, get his lipids… But they don’t talk to them about fatty liver, at all, they don’t normally get a set of liver enzymes. In fact, just thinking back to the ILC in that paper, was it Abstract GS-08? If I remember right.

Stephen Harrison: Louise, they didn’t even have AST, they ordered ALT and AST was not even part of their routine practice.

Louise Campbell: It’s not part of the routine practice in a lot of the areas of the UK, and for the few pence that it costs. But then you get an argument, higher up the management chain, about, “It’s not coming out of my budget.” And I think this is where healthcare can become obstructive beyond belief, in its silos, as actually it’s about the person and the whole, not about the individual pieces. And I think we have to be coordinating the best set of blood tests that we can get, at every opportunity, because I’ve said it before, when somebody gives blood or any tissue, it is vitally important that we, as healthcare professionals, take and use it in the best way and the most constructive way possible. Not just repeat it or add another test because you get to a different specialist. Actually, we should be accumulating all of our best knowledge at the best times, not repeating patients coming in and in and in, and trying to do that.

Louise Campbell: And I think we do need to start doing more wholistic assessments to get where Donna wants to be, “Beyond the Biopsy”, because if you get the best way to assess a patient holistically, whether it’s cardiovascular… When I’ve worked in intensive care, we didn’t just concentrate on one organ when we hand it over, we had a system and we worked through the organs and the systems, and it was to make sure that we comprehensively handed over our patients. And I think what we don’t do in primary care and each of the specialties, is start holistically and isolate down.

Roger Green: Thanks, everybody, Louise, that will be the final word for the day and a great note on which to close. And, Donna, thanks for putting together such an inspiring program and really started to move the ball up the field, on the simple little things that are going to make a big difference if you can just get them over that line and keep pushing. Fantastic stuff. So closing question, same usual closing question, did you hear anything today that surprised you or made you think differently about this issue?

Louise Campbell: I know that Stephen has said, “Keep It Simple Stupid” before, and Stephen comes up with some very funny anecdotes every now and again. But, actually, this time I will remember it and put it in to a lot of what I look at and see and do, and see if that makes a difference because I try and make it as simple as possible, but maybe I can make it even simpler.

Donna Cryer: I will focus on the word of the day as ‘validation’, because I realized that as much as I want to simply be the advocate and as obvious as the solution or the end result is to me, I can only go as far and as fast as the science and the evidence, and the comfort level of all the stakeholders involved. And so validation is the key takeaway, at least, for me.

Stephen Harrison: I don’t know if there was a lot of surprise here for me, but there was some clarity. And that is, I spend my day, they’re long days, no doubt. And the days, for me, are spent around seeing patients, developing drugs that treat liver disease for patients, and then developing tests that helped me identify at-risk patients and whether or not they’re responding to therapy.

Stephen Harrison: And I think this podcast has helped me gain more clarity around what those navigational beacons are, what my left and right boundaries are, and it’s helped me gain a clear understanding of what true north should be. And to that end, I mean, just as an example, just focusing on AST:ALT ratio as a means to begin to foundationalize where we need to go with this, and then build on that. I think is really, really important. So I think great podcast for me to walk away from, and thanks for all the input today, I think it’s just been phenomenal.

Roger Green: And, Stephen, not a surprise but a recollection, the power of that letter H on a test, and what it motivates patients to do. But if you put that together with an AST: ALT score, and you put an H on it, all of a sudden you have patients motivated to ask a question, you’ve got doctors that have to figure out how to get an answer to the question. And that’s really about moving the reference labs, which is a different cast of characters but people who are scientific and who will benefit from doing this. So I think it has been a good hour. Anybody have anything else they want to add?

Roger Green: Okay, I’ll go to close. Go to the discussion group, the two questions that we’re asking for, what should we make sure to do at AASLD in November, and what should we make sure not to do. Are there old episodes we should be going back to and rethinking and recalibrating? And thanks again to Donna, and to GLI, for putting the program out there in the first place, it’s a great program and I look forward to this Wednesday’s episode or a version beyond that. Our special thanks for the day, Mic Wilson, our engineer, Buzzsprout, Eric, Poli, Ryan, you folks have listened to this, Louise, Donna, Stephen.

Roger Green: We will be back next week with another episode, the first autumnal episode, if you will of Surfing the NASH Tsunami, stay safe surf on, we’ll see you on the podcast, bye-bye now.