Workshop: Phosphatidylethanol: The "Hemoglobin A1c" for Alcohol Use Disorder?-Phosphatidylethanol: The "Hemoglobin A1c" for Alcohol Use Disorder?

Phosphatidylethanol: The "Hemoglobin A1c" for Alcohol Use Disorder?
Video Transcription
Okay, everyone, we'll get started. Really nice to be with you all. Thank you for coming. I'm Scott Winder. I'm a psychiatrist, a consultation liaison psychiatrist.  We've infiltrated your ranks. I'm at the University of Michigan, and I'm refraining from jumping on that bandwagon. You're trying to distract me.  We have a presentation to give, and then I'll let each of these fine gentlemen introduce themselves. But Akil Shenoy is also a CL psychiatrist, so there's double infiltration.  And then David Hathaway, the worthy replacement of Dr. Joji Suzuki, who unfortunately couldn't  travel to be with us, is an addiction psychiatrist who's heavily influenced by consultation liaison psychiatry.  So we're really grateful to be here, and I'm an admirer of addiction psychiatrists. I've benefited from many addiction psychiatrists, so it's a real honor to be here and chat  with you all. I have received some speaking fees and some consulting fees, but it's not relevant, and neither of other speakers have any disclosures.  So I will start with a case to kind of a disclaimer here. We're very medically oriented in that we're plugged into very technical medical and surgical  parts of our health systems, transplantation, hepatology, which is where PATH really took root.  But we've really taken efforts to really bring this into the forefront for a general audience. There are some great specialists here. We're aware of that.  Many of you could be giving parts of this lecture. We're aware of that. But we have intentionally tried to package this to be very off-the-shelf and practical.  We're each going to shoot to speak about 20 minutes on these topics, and then I'm sure there's going to be quite a bit of discussion, which we're looking forward to.  So we want to make sure we preserve time for that. So I'll start with the case, and then Dr. Shinoy will talk about the physiology and  the technical specifications, why we use PATH, and some of the interpretation and safety elements of it.  And then we have published a manuscript that deals a lot with not only the technical parts, but also the interpersonal parts.  This is a very powerful biomarker that brings up a lot of psychological issues, particularly in certain populations.  And so this is a room that's very aware of how to communicate with people. So we're not going to talk about it as if you don't know this, but we'd like to package  it and illustrate it in kind of granular formation for your consideration if you choose to use this marker.  And then Dr. Hathaway will finish with some more in-depth explorations about how PATH applies and is used in various populations, which is kind of the meat.  So patient Jane Doe is a 61-year-old female with decompensated alcohol and metabolic-associated steatohepatitis-related cirrhosis.  There's been a huge terminology shift in hepatology, as I'm sure you're aware. Listed for liver transplant in February of a hypothetical year at a hypothetical center,  and negative urinary ethylglucuronide and urine drug screen four times at the time of listing, and she'd not to date ever been evaluated by psychiatry.  And here you see in June later that year at an outside hospital, she had a positive ethylglucuronide, which we'll talk more about, Dr. Chinoy will, and was placed on hold.  And after a phone call, she said that she'd been swabbing her face daily with an alcohol tonic or solution for a skin condition, and you see her other labs there.  And again, this is all in the transplant hepatology phase of care. And then in July of that year, had another series of reassuring negative ethylglucuronides  at an outside hospital, and her LFTs improved from where they'd been with an AST-ALT ratio of about two to one the month before, and total bilirubin was trending downward.  And then in August, her LFTs worsened again, again with that same morphology and ratio, and then she declined to leave some toxicology.  She was unaware that they had drawn a serum path. She'd been mentioned, we explained this toxicology to our patients, but she was unaware that  that had been drawn, and you see that this is a very elevated lab value, which triggered a referral to transplantation psychiatry. And this careful, yes?  I just wanted to point out, it's pretty difficult to read those numbers. Oh, I apologize. Yeah. You're able to read out notable ones. Thank you. Yeah.  Yeah, we commented it looked like the laptop from the back of the room. I apologize. Yeah. Thank you for saying that.  So upon interview, this patient states that for years she'd been aware of fatty liver disease and she had been an avid drinker since her 30s, about two standard drinks per  day she stated. And then she'd had some persistent cravings that had been a challenge for her around the  time of stopping drinking in 2015, but she denied that alcohol had ever been a problem or an addiction or a hazard for her. And so she repeats this alcohol face wash story.  In this kind of very communal conversation environment that we tried to cultivate, we did involve the husband given all the implications.  And this was the first time he'd ever heard of this positive test, the ethyl glucuronide at the outside hospital or the PEF.  And so then they both said, well, does this mean she can't get a transplant? And then husband becomes very angry and says, you know, you really barking up the wrong tree.  This is, she doesn't drink. And we discussed the intricacies of PEF, which we'll model for you later in the talk. And then there was just repeated denying of any drinking.  And then in September later that month, we kind of understand after a disclosure, so this was the psychiatry visit, didn't come to any resolution, back to the hepatologist  and our wonderful transplant hepatologist, Jessica Mellinger, who's an amateur psychiatrist by now, I feel like, was able to receive this disclosure that she'd found her husband's  whiskey in the garage that she'd been drinking for weeks. And then there was a generally poor level of insight as we discussed this.  And then unfortunately her transplant evaluation was closed and we were able to refer her for alcohol use disorder, an invitation she did not accept.  So I hope that that models kind of how PEF all shines this really bright light all of a sudden into a patient's life and some of the problems and opportunities that are triggered  by that. And with that, I'll introduce Dr. Akhil Srinoy. Hello. Hi. Thanks, Scott. So only disclosure here is that I grew up in Michigan, so go blue, but I went to college  at UCSD and I was a biochem major. So now I live in New York, I'm at Columbia. So this is kind of, it's nice for me to kind of come back and I kind of wish my biochem  teachers were here, but they're obviously not here. They're not part of this crew, but yeah, we're kind of, you know, I've been working in transplant  for 15 years and this changed our world really. So I want to, I'm like excited to share a little bit about what PEF means to us, but really make it relevant for you. Oops.  Backwards. All right. So let's start with this and this is hopefully big enough for us to see on the laptop, but this is alcohol, our friend alcohol.  It is a tiny molecule, even from, you know, right here in the front. It's a tiny molecule. It's only two carbons big. It's got one oxygen on it and maybe a handful of hydrogen.  It's so small. It goes everywhere in the body. Goes everywhere. All it goes, the liver, all the organs just crosses the blood brain barrier, like wifi  going through walls, just flies through it. It's hydrophilic. It's hydrophobic.  It's lipophilic. It's not phobic at all. It's very philic, let's say. All right. We like it. So the interesting thing is that for, you know, we've relied on ethanol testing, which  is direct, you know, direct test of, of the, the actual molecule. Very useful, but you know, and we test this through urine and blood and, and, and breath.  And I just want to direct your attention if I can get this or it says this, and this is going to come back, the X axis here in hours, you know, and in, in minutes, right?  So this is where we are with ethanol. It really degrades and gets out of the system very, very quickly. And it has in that way, it has limited utility.  Now, there are a lot of places where this is very useful as you can imagine. And in fact, like this is useful to kind of even try to figure out, I don't know how many,  how many people try to figure out the last hour of drink using these types of tools, urine or ethanol or versus urine or blood ethanol. It's a thing that can be done actually.  You look at the ratio of the two and you can kind of tell maybe how far back the last drink was if you're in the emergency room, right?  But so, and in general, urine tends to hold on to ethanol. So we like to sort of, it sort of drags out a little bit longer than blood.  So in a way we've kind of been programmed to think about urine as this very, very valuable thing to collect when we're thinking about alcohol.  But I'm going to take you some through some different things and maybe expand your mind on this. And some of you have already heard about these things.  You know, hopefully it still goes deeper. You know, most of the alcohol that we consume gets oxidated, oxidatively metabolized, 90%  in fact, get turned into acetaldehyde from ethanol using alcohol dehydrogenase. And that's it. A lot of cells have this. The liver has a lot of this.  And then 10%, where do you think the other 10% goes after the 90% gets metabolized? Well, most of it just gets like pissed away just as ethanol.  Or you breathe it out because it's volatile.  So most of it is gone.  Tiny little amounts will, and this is where we're going to end here, these things, tiny amounts get processed in this way that we've like learned how to now collect.  But the acetaldehyde that's getting, you know, this is causing this, but also all kinds of other things that traditionally we've tried to figure out how to use those tools to see  how much alcohol is being consumed or how the burden of the alcohol use disorder. But you know, we're going to take you in the second half into this, which I think is much  more valuable with direct metabolites. So yeah, well, but I will do give you a primer on, on this stuff and then we'll, we'll end with this. Okay.  So let's start, cause this is all very familiar to everyone, AST versus ALT, right? You guys have heard about these, you guys know, there's actually a name. I didn't write it here.  There's a famous ratio, AST to ALT ratio. It's called the de Ritus ratio. I didn't, this is like old, old timey terminology, but, and these are two enzymes that are normal  hardworking functions of the, of the liver. And they process proteins and carbohydrates and they're very, very useful.  And when alcohol starts to mess around with the hepatocytes, they start to change. Now do you know where most of the AST in our body lives? Where is it? Just shout out an organ.  Most people think it's a liver, but actually it's in the muscles. Most of our AST is in our muscles and a good portions in our liver.  And the reason why we, we, we're not really testing for muscle AST is because the muscle AST stays in the muscle, doesn't leave, it's stuck in there.  Now, certainly if you're exercising quite a bit and you're doing a lot of like workout, maybe it starts to break down and start to see AST.  And that's one of the problems of, of testing AST, right? Because if someone were like big, heavy weightlifter might get some elevations in AST, but most  of the AST is in the muscle. But the reason we, we test it and it's so important to the liver is the liver is constantly leeching it as opposed to the muscle.  And most of it's in, in mitochondria. And so when there's liver damage and the mitochondria get hit, the AST gets even released in a higher clip.  And you start to see more and more AST getting leeched. So you get this ratio where more AST gets sent into the serum than ALT.  And the ratio, that deritus ratio climbs higher and higher and higher depending on how much damage from alcohol or other things. But really this, we're interested in alcohol.  So it starts to, the ratio climbs it, you know, by themselves, ALT is not very specific at all.  AST is a little bit more specific, but together it's a good, you know, it's 90% sensitive to to alcohol.  And I think that's important because I do want to make a pitch for us not only collecting  blood for when we get to a path, but for this, because we also want to study for drug induced liver injury. It's not, it's, it's not that uncommon.  And some of the medications that we do prescribe for other reasons and for alcohol use disorder, it's very, very, it's important to actually check AST and ALT.  So in that situation, if you, you know, for a drug induced liver injury, it's usually the opposite. The ALT is higher than the AST, just so you know. All right, let's keep going.  Right. So just to just to sort of reiterate, lots of false positives here. So it's not entirely specific.  GGT, more specific, more sensitive, you know, better, better tool than AST, ALT alone. Now more specific, but not very sensitive.  There's a lot of reasons for also to have false positives, false negatives. And so, but if you know the patient has alcohol use disorder and no other reason for GGT elevations,  it is an absolutely good tool to follow to see if the patient relapsed. Okay. And in fact, we have a paper coming out, a systematic review of all the randomized controlled  trials of AUD and medications. And of all the trials that we looked at, only where they tested blood before and after the trial, all but one tested GGT.  GGT is like the standard to like look to see if the person relapsed and it, you know, it only takes, you know, a few days for it to start to rise so you could tell, okay, well,  this person's, you know, started drinking again. And then after they stopped drinking, it might take about a month for it to go back to normal. So you can kind of tell there too.  It's an easy test. It's cheap. It's, it's really good to, to, to get GGT. All right. Let's keep moving. So MCV, not specific at all.  There's lots of reasons why you get elevated MCV, but yeah, right. So people say, all right, if you take the MCV and you add it to the GGT and then you  get the diuretics ratio and you add all those things together, you get really, really good, you know, sensitivity and specificity. That's true.  But, you know, I think alone it's, it's pretty useless. Percent CDT. So the last of these indirect biomarkers, probably the most robust, right? So this was standard of care.  This, this, and you know, I think, I don't know, anyone still use this percent CDT? So this is, anyone writing for this? No. So maybe 20 years ago people were writing a lot of this.  It's you know, it's involved in iron metabolism. So transferrin is this iron metabolism enzyme and it, this protein, right? It shuttles around iron and it gets messed up by alcohol.  So you can test the percent of how much it got messed up. It's another indirect tool. Much more specific, but you know, still indirect. It's a, it's a marker of damage. Okay.  So that's not as good as a direct biomarker. So we're going to get there now. So but just to summarize the old, you know, this is like 20 years ago we were talking  about percent CDT versus GGT and all these, you know, percent CDT is the best, but these numbers are going to, you're going to, we're going to blow, we're going to blow those away.  All right. But you know, I just disparage these, but any like any other ways that we could use  those indirect biomarkers in your practice, is there any, how many people collect blood from their patients? Good. I like to see that. That's positive.  You know, I think in a lot of our addiction clinics, it's like, Ooh, blood, it's icky. You know, it's, it's nice to see people raise their, you know, so we are collecting blood  and it's not just like, Oh, let the PCP do it. You know, it's important to collect blood because we want to see the impact of alcohol,  which is the thing is, which we haven't, I don't know if Coop said this today, but Dr. Coop, is he here?  Think the thing is it's the liver disease is the biggest death toll from alcohol. It's like the number one reason why people die from alcohol.  And yeah, we look at that picture of all the different ways alcohol affects the body, but it really does kill. So checking LFTs is super, super important.  So I'm glad you're getting blood, especially if you're going to order, you know, you're going to order some medications, right? How many people write for disulfiram? Good.  All right. So you should be getting LFTs. How many people write for naltrexone? Good. So you should be getting LFTs. How many people write for acamprosate? That's fine. Okay.  You can still, no, no, it's, we love acamprosate, but you just, maybe you don't need an LFT that time. All right. So let's get to ETG and ETS, right?  So some of that alcohol will wind up in one of these two ways. Very small, tiny 0.1%, 0.01% of all the ethanol in your body might get in this, in this form.  But it's really, really useful because in urine, you know, you, we had a detection window.  Sometimes we could get a week or maybe even like 10 days, but certainly three to five days, you know, pretty good sensitivity for urine ETG. Yeah, sure.  There's some bacteria in the urine issue, just like ethanol. You know, you could have E. coli running around in your urine and that could be making, and  look, there are some brands of E. coli that will create ethanol and ETG. But it's not that common. And the, and so it's pretty specific.  And the hair, which we tried for a while, I think both of us tried hair. I started, I was like a barber for a little bit, cutting people's hair, trying to get that.  And that was just, anyone try to collect hair? Oh, nice. Okay. You still? No. Okay. It's hard. It's hard to collect hair. And then I sent it off. They said it was too little.  You have to send more. And then the guy's gone. I was like, he's gone. Pencil with strands of hair. I can't, I can't go back. So ETS, similar but shorter time period.  But it's, you know, it's people were playing around with the different, different ETG versus ETS and how to be specific about the amounts of alcohol people drank.  But here we are at, at our, the reason we're here together is, well, should say it correctly, right? Should we say it together? Phosphatidyl ethanol. Okay.  Phosphatidyl ethanol. All right. Path. So there's two important moieties that you should probably know about, the 18-1 and the 18-2. That's just like the double bonds.  Like, so this is like my UCSD biochemistry. So this is the two double bonds here and this hydrocarbon, one double bond here. This is oleic acid, and this one is linoleic acid.  I don't know how to remember that, but it's just the number one is O, and the number two is L. Come up with something. So some labs will put them together and then give you  the quant for both. But often, labs will separate them out and tell you the POPATH, the phosphatidyl oleic acid, and then the PLPATH, the phosphatidyl linoleic acid.  So they'll give you two, which is nice, and I'll tell you why it might be nice to get both. But it's very specific. It only forms in the blood when ethanol is around.  And the nice thing is, we're talking about not minutes and hours, but we're talking about days and weeks. It sticks around. It attaches to the blood cells.  Right on top of the blood cell, you've got all kinds of proteins. Red blood cells, they're probably simpler than other cells, but they still  have proteins on top, and they're grabbing hold. There's an enzyme, phospholipase D, grabs onto the ethanol  and attaches it and creates a covering of these ethanol hydrocarbon moieties around it. So the nice thing about for us is it's validated in liver disease, because 50% of people  that are severe alcohol use disorder have some sort of liver damage. So everyone gets concerned, is the test going to be valid in liver disease? This one is for certain.  Yeah, ETG, ETS is also, but those other ones earlier that I was talking about have a lot of confounding. So here, you've got a very sensitive and specific tool,  even in liver disease. And the nice thing about it, the quantitative values may be correlated with different alcohol quantities. And we'll go into that a little bit in a second.  But before I get to there, just to comp with the other things, we talked about the other things. Look, it caught all the ones that ETG caught, plus all this extra.  So it's just phenomenal what it's catching. So if you look back in a week, it's 100% sensitive and specific. If you go back three weeks, four weeks,  the sensitivity drops off a little bit, because it gets degraded. But it's still close. It's like 96% sensitive and specific, even if you go back four weeks.  So I think we're onto something here. So what we do, at our center, we developed sort of cutoffs, because we were interested to know what's heavy drinking.  And we could define heavy drinking different ways. But I think for us, the standard NIAAA guidance is four drinks or more, five drinks or more. And the magic number is around here  to do this cutoff, this 200 mark. Now, some people go lower in order to make sure that they are more specific to heavy drinking.  So this will help you get more specific about heavy drinking.  If you cut off lower. It's your choice. But we want to be more sensitive as opposed to specific, because we know alcohol is already part of the dialogue.  So we just want to be sensitive about it. OK. Sensitive in more than one way. Stupid. Um.  So no, I would say the two moieties are one and two, right? Oleic acid and linoleic acid. So the interesting thing was the linoleic acid, the number two  one, kind of rises earlier and drops off. Now, this is in minutes. This is more like days. I mean, it's like thousands and thousands of minutes. But it's days, basically.  But the oleic acid doesn't rise as early, but it kind of lingers. And that's the one that we like to look at, the oleic acid.  Now, again, like I said, some labs will just combine them. And that's fine, too. You get this big hump, and that's going to be even more sensitive, which is nice.  But if you have the ability to discriminate between these two, what I like to do is, at about a week, you start to see this change, where the PO path, the oleic acid, starts  to become higher than the linoleic acid in that patient, which can kind of tell me when their last drink is. And that's very helpful for me. But again, this is kind of anecdotal,  but I'm working on it. All right, so this is my summary slide. And then I'll let these two gentlemen take over. Because I think we're building this case that  PEF, the hemoglobin A1C of alcohol use disorder, why do we say that? I mean, what is this?  Why are we making such a big deal? Number one, this is a game changer. Number two, we can use the paradigms from diabetes clinics to inform our work with alcohol use disorder.  PEF is, for patients, it's an easy conversation. PEF is on the red blood cells. It's attaching to it like barnacles on a ship. And we're telling them that just like A1C and sugar  on red blood cells, it's a residue that's left over. And it's degrading over time. And we have to watch it over time. So if it's elevated, OK, it's elevated. It's like an A1C of 10.  You're like, do you know your A1C is over 10? And you know the normal one's under 6? And they're like, OK, why are you telling me this?  Well, this is a different type of residue. But it's similar. There's a number. And the high number is concerning. And we're going to try to bring it down.  And that's the type of conversation we want to start having with patients. But we are nerding out on the numbers. So we think, in my clinical opinion,  a 400 nanograms per milliliter is about four drinks a day. So if someone tells me, oh, I only drink three or four drinks twice or three times a week,  and then they've got a 600, I'm like, BS. So that's why I'm like, one. So I think getting the number is helpful, because it gives you a sense of like,  maybe I need to call this person's spouse or something. Or let's test again. I mean, that's part of it. It's like, let's look at this number.  Look, do what you have to do, because they're going to save face. They're not going to tell you, and we're out of time. But basically, the idea is it's a nice way of saving face  and having a conversation about a number, as opposed to having a conversation about very, very shameful, difficult things, which we have to get to anyway.  But on the surface, it's a nice starter tool. OK, I'm going to get out. But I want to sort of think about this question before I hand it over.  How can we use urine ETG, which is still very valuable, which I'm sure people are ordering, with blood together, blood path? OK, but thank you.  So that was, and that's the exciting part. I think it's only exciting to doctors. It's less exciting to the patients we take care of.  And I think that's kind of what we want to dig into. And again, I think we all communicate for a living. And I would have a lot to learn from each of you.  So again, I want to reiterate that, that what some of the words I'll use and some of the style I use is me. I'm not trying to impose that on you.  But there's a spirit of kind of collaboration that this room will be familiar with. I don't think that's novel. I think what we're trying to do that's novel, if it's helpful,  would be to channel it through all this technical help that Dr. Shenoy talked us through. Because I think to use PATH well and artfully, I'm going to start this long-winded winder.  It's a thing. OK, there we go. To use this productively, we need to know the technical kinetics of the molecule, but also what to say and how not to be caught flat-footed.  The internet's also a thing. And patients will look at that. And so there's some different parts of this I would like to talk through, both on how we prepare patients  and then what we do when we're with them, and then some of the ideas afterwards. This is kind of transplant-centric, and it's kind of liver disease-centric.  But I'd submit to you that it's not that far away from so many patients that you're already taking care of with severe alcohol use disorder. In fact, we won't cite those studies.  I think Dr. Shenoy alluded to them. But so many of the patients, and this is Jay Luther's work at MGH. I don't know if anybody knows Jay Luther.  But they actually went on the addiction consult service and just went and looked for liver disease, and 40% of them had advanced liver disease.  People had no, they were not in the hospital for liver-related pathology. So it's everywhere. So I would submit to you that, yes, this  is kind of a technical thing from a transplant psychiatrist, but we really want to inform broader patterns of care. So where am I taking this from? We did not make this up.  This is ASAM guidance. And we're kind of marrying this and combining this with Dr. Jiaozi Gregoire. She's at Mayo, and these are a bunch of transplant clinicians  from around the country about how to use toxicology and transplant, where so much is on the line, and how you talk about it is so important.  And then we were able to turn this into a manuscript that we're quite proud of. And Dr. Brown at liver transplantation, the editor, was happy with what we submitted.  And I hope that it's of some worth to you as well. Again, preaching to the choir. I think you understand this. Substance use disorder patient in blue  comes forward with all sorts of things, particularly if they're sick, from fear of death to mistrust of how they've been treated in the past,  and shame about what's happening in their life, and of course, struggling to really acknowledge what's really going on. And then we're really imperfect.  And you have a transplant recipient drink again, and they swore to you they'd never drink. And you think you're a good doctor, and you will get blame. You will feel that.  I don't think it ever goes away. We just get better at managing it, and managing the cynicism that comes along with that, and of course, that counter-transference  of the patient who presents after that bad outcome. And of course, the word that we've said a lot during this conference will cloud this all up.  And so this is the landscape that a PATH discussion takes hold in. And so before the encounter, we really have to be prepared to acknowledge  that testing use of toxicology in addiction medicine and addiction psychiatry doesn't stand on its own. I think this room already knows that. And we have to have room, if we're  going to use PATH, to talk to this about people. People have really bad misunderstandings about what it does and doesn't mean. And if we don't speak to them about it,  things go off the rails quickly. The discordance is the clinical opportunity. Sometimes to our medical and surgical colleagues, that's the problem. That's the pitfall.  When things don't match up and I can't make sense of it, I think to the psychiatrist, the addiction medicine clinician, that's the opportunity to dig deep  and to understand something more. And again, transplant taught me a lot about how to balance compassion with skepticism, advocacy for the patient with the stewardship  of a precious resource like a donor liver. And PATH taught me a lot about that to hold that in mind. I think it'll develop that in all of us as we use it more.  And so we have to understand more about what's happening to the patient. And if we're making decisions like organ allocation or if this is an impaired physician with licensure  on the line, we need to have some other data supporting what it is we're doing with this number. And of course, if we're unsure, I actually went down to the toxicologist.  They actually know me by name, which I don't think is a good thing at the University of Michigan. But I call them and they're like, oh yeah, you're the Dr. Winder who always calls.  Because I was so concerned about making a recommendation or doing something based on this deceptively simple number that would impact people unfavorably.  And so consulting a toxicologist, being friends with them is a great idea. So says the CL psychiatrist. That's kind of the spirit of what we do.  Messaging with the teams is important. Teams will be very reticent, some of them, to use this because it's like don't ask, don't tell. And then others will really want to use it  because it's going to catch all these people. And so you have to really kind of balance this. If some of the members of the team, the nurse  or maybe the other psychiatrist is running their mouth about how useless PEF is on the side, it's going to destroy how it's used in the clinic.  Needs to be up front in education materials and in team procedures. And it's just going to stoke a lot of emotions. Pretty stoic people get pretty angry,  I've seen in transplant selection conferences when numbers come out because it didn't match what they saw in clinic. I've had to control myself too. I'm sure you all do too.  This is just a deeper level of objectivity that can unleash a bunch of feelings. That we're psychiatrists, we can manage that, but it's surprising how strong it can be.  And then we need to really have conversations about, yeah, I know you want to list this person, dear hepatology colleague, but this is a number that's very statistically  unlikely to be spurious.  So as I dump that all out on you, can we get some quick discussion from the room about how in your institution this might be a challenge to start looking on the red blood cells  for barnacles on a ship by the name of PEF? Just shout out some thoughts.  Cost. Yeah, so at the University of Michigan, it's about $100. We have not had any problems with insurance. There's been a couple times where we've discontinued it.  We've not had problems at a large tertiary center. Again, some of this is wrapped up inside of  transplant care and insurance companies are starting to want to see PEF in order to kind of sign off on certain things. That's fair.  Availability is kind of the next car on that train. It is more sparse. Ethylglucuronate is everywhere. I'm sure you all know that. But PEF is more isolated.  We tend to have to send people to a University of Michigan lab to get this done reliably. That's a fair point. So it's the turnaround time. Yeah, another great point.  Yes, so we were a send out to AARUP in Salt Lake City.  And it was about, from Ann Arbor to Salt Lake City is about a seven day turnaround. We ordered, there was a very loud mouth psychiatrist  at the University of Michigan who waves his hands a lot. And we eventually brought this in house. And it's now, it's batched a few times a week. It's about a two day turnaround.  So quick that it can influence treatment care for liver transplant patients, right? So it pays to be a long-winded psychiatrist sometimes. Other thoughts?  Yes, not ethanolamine. Yeah, that's a rheumatologic lab. But yes, phosphatidyl ethanol. That's the name. Yep.  The lab may not have the capacity. Dr. Shannoy was giving you a deep dive. We have it set up. You just try PEP and it'll come up. Yeah, the lab will report it separately  if they have the capacity to do so. That's a great question. Yes, sir.  Yes, Dr. Hathaway. Are you, will you be talking about that? The PEP and ETG together? Yeah, we'll cover that a little bit. Yeah, his presence in the hospital,  I think his bend on that will be helpful if we can hold that. Thank you, sir.  That was that glow in the back of the room, sir. It was you. Yeah.  Did you, you said you're using it.  And where are you?  Oh yeah, well, the wonderland of resources. Yeah.  Boston, Cleveland, Rochester. It's incredible. Yes, sir.  The red blood cells themselves. Very good, yes. So that's, it's largely unknown that we, I think we might be able to talk more about transfusions. That's pretty far in the weeds.  And again, Lisa's kind of holding us. We don't want to get too far in the weeds. If that comes up in Q&A, we can dive into that. It's an excellent point. Yes.  Are you concerned with parents  treating adolescents or over-adolescents like demanding, you know, results and then wanting certain things that are happening? Even though I've been initiated,  it can be really helpful to have a conversation. Yeah.  Yeah. Yeah, thank you for that. My own counter-transference, I'm raising two teenagers and I can feel my counter-transference just surging when you just said that.  Not being a child and adolescent psychiatrist, I will kind of mark that. But again, very fair point. I have less experience with that. Another concern I have is general skepticism  from colleagues about something new, which I've actually tried to look into step testing. First of all, I'm based in Wisconsin.  It was difficult to kind of find a lab who did it in the first place. And then like, it took me a while to get PTG, ETS  in our standard of care.  So I'm really, really excited about it. Great. Yeah, and if we can move on, I'm looking at my time. I need to keep going. But to that point, I think that transplantation,  this is an example of like the acute and most serious form is gonna kind of fertilize and change the field kind of downstream. Because more and more labs,  and that's why we were hoping that Dr. Koob would mention PEF today. I did send an email. I do think the NIAAA needs to address this and I see some of my bad habits.  So during the patient encounter,  we need to have a good alliance. Again, this is almost patronizing. I know that you're all very good at this. Again, I just want you to run your mind through these familiar trails  in the service of toxicology use. The way we talk should be plain and neutral and compassionate. We should kind of make fun of some things,  maintaining professionalism and using some humor takes the tension out of the room and normalize this. We always do this. I care about you. I don't care what comes back.  I really wanna take care of you and I wanna know. It's not that different from a diabetes lab, like Dr. Shinoy was saying. This doesn't define you. I care about you.  I'm never gonna shame you. You know that by now. And you know what? I'm proud of you. When I met you, it was 1,164 nanograms per milliliter and this last one was 66.  I'm so proud of you. I know the surgeon was a bit hard on you about that. We love our surgeons, but I'm proud of you. And I want you to know we know that  and the committee, the selection committee will know that you're working hard.  So here, dear patient, we're telling you, Dr. Shinoy did a good job of this, normalizing it, likening it. This is a medicalized population,  a lot of the patients we take care of with liver disease. So let them know why it's similar to blood pressure or the glycosylated hemoglobin in A1C.  This is our script and this is terrible, looks terrible. I apologize. The reason I included this is because I wanted you to hear what it sounded like, but because of time,  I'm not gonna read it to you. But this is in the manuscript and I really tried to listen to myself and how I've worked on this and we transferred it and edited it.  So it's in the slides, it's in the manuscript, but this is how we couch it. This is very similar to an informed consent kind of laying the platform or you're in the ER  and I might have to commit you, watch what you say type thing. It's in that spirit and I think that PEF usage requires that type of disclosure like we do for involuntary treatment,  like we do for decision-making capacity. I'd submit it to you on that level. And then we're talking about its therapeutic purposes. This is not to catch you  and this is not to make a diagnosis. We make the diagnosis looking at this together.  PEF helps us understand more about what's happening with a person's alcohol use over a few weeks to know more or less than that.  I'm actually going to skip reading all this to you, because I'm looking at my time. The manuscript that we published has scripted versions of all this,  because sometimes, as somebody who has a lot to learn still about how I communicate, I read psych journals, and I'm like, yeah, but what do you say?  You tell us to do these things, but what do you say? And we tried to give language, and so I'm going to defer on reading it to you,  to not be too tedious and time consuming, but I would invite you to look at that manuscript if you're interested in how we talk about it. And then the power of tracking this.  Dr. Hathaway will talk more about this, about the power, the psychological power, of tracking PETH and seeing it. It's almost like a biofeedback mechanism,  and so that's a way to think about this and talk to patients about it. And so we're using it, dear patient, to kind of understand you on a deeper level,  and sometimes what you say is not going to match up with what we find, and we're definitely going to listen. We're going to ask open-ended questions in the MI spirit,  and we're going to thank them when something comes up that was really difficult. We're an ALD clinic, alcohol-related liver disease clinic,  and we get indexed disclosures about childhood sexual trauma. I'm not looking away. I'm protecting that encounter. I'm with them.  I might even show some emotion, and then I'm saying, thank you for sharing that, and then they say things like, I can't believe I told you that,  and I can't believe I'm in a liver clinic, which is inside of a transplant center, talking about this. And then you know that the PETH and this whole work is doing something,  and I know you already know that, but even with these technical parameters of PETH, it never gets old when you reach somebody on this level,  and I know this audience understands that. And then when things are rough and when there's a huge PETH that is the elephant in the room,  can I share some things about this, dear patient, with you? Would it be okay to give a different point of view of how this looks to the transplant center?  You deserve a doctor who believes you, and there's some other information I'd like you to consider. Would that be okay?  Again, highly couched in that am I asked permission and sidestepping arguing. These people are pissed when they realize and they looked in their portal  and they have this value, and they had to wait 10 days to see you. Then they show up and they're angry. I thought the psychiatric emergency service at the University of Michigan  was where I was going to learn how to de-escalate situations. PETH encounters can be absolutely combustible,  and so really sidestepping arguing and building rapport and using that humor is important to get to any productive discussion about this. Postponing the tough stuff to the end.  If you know it's coming at the end and they'll give you more stuff, put the PETH at the end. Don't lead with it. Again, this is stuff that I think I'm going to just skip this.  We do use a lot of metaphor, and so we will use blood pressure. We will use hemoglobin A1c, and I think that that helps to really de-escalate.  So I'd invite you to think of helpful, simple metaphors and analogies to help people understand why this is happening  and how other parts of their life where other people can see things about them that they can't see and how that might be similar. We found that to be a very workable exercise.  And then the tough thing happens when there's a timetable. The 90-day mortality of acute alcohol-associated hepatitis is as high as 70%.  At what point do you just motivational interview people into their own demise? I meant that as a provocative statement because I think MI is like the ethanol molecule.  Everywhere. It should go everywhere. It should be everywhere. However, there is a role for confrontation, and it needs to be very compassionate,  and PEPF will precipitate confrontation, and we have to be ready for that. So afterwards, sometimes there's going to be people who their PEPF levels will tell us  what they need independent of whether they acknowledge it. Sometimes the discordance means that they need a higher level of care,  and it can be, in our opinion, an ongoing evidence-based part of alcohol care. Again, candidly, that's why we were a little bit frustrated  or confused why that wasn't more of a prominent discussion earlier today at the plenary there, the symposium. And we need to refer it.  If you've expired in what you can do with this patient, having a referral, changing the landscape with a colleague after PEPF soured everything is not a bad idea.  And if this is an impaired professional or if this is a transplant candidate and the PEPF comes back, they are incentivized to conceal.  You don't want to be skeptical or cynical, but you need to understand, as I'm sure you would, why patients would continue to deceive.  If we do a good job up front normalizing this, the rapport we have can unlock some of that and maybe even bypass some of the intention to deceive. We've seen that a lot.  We need to preserve the therapeutic alliance. I just ordered a test that got you off the liver transplant waiting list,  and you kind of hate me right now, but you need alcohol use disorder treatment, and there's not another psychiatrist who's going to take care of you.  So this salvage operation of keeping our alliance together is really worthwhile. I'll be working on it as long as we're using PEPF and as long as I'm practicing.  It's very challenging. And that we don't lose sight. We do not lose sight in our psychiatric and medical notes of alcohol pathology and the need to continue to monitor alcohol.  Again, I love my liver colleagues and I love my surgical colleagues, but alcohol disappears from their notes. And to do this well in a complicated environment,  PEPF monitoring and asking clinical interview questions needs to remain a priority. So, again, we talked about this, that if things go wrong,  and I've made so many mistakes with this, I could tell you stories about things that, you know, PEPF really creates some challenging circumstances.  So we need to individually and collectively commit to work on this. We have to maintain confidentiality. Back to the comment earlier about the daughter and the child and the parent.  We can't be caught flat-footed. If the lab comes back and we're not we make it worse. First, do no harm. If you don't understand PEPF and you're explaining a PEPF to a patient,  there's some psychological harm that could occur there. If you don't have the bandwidth, don't order PEPF. Don't order PEPF. It's better without it.  It creates a wonderland of opportunities and problems that if you don't have the bandwidth, I would caution you. That collaborative relationship with your toxicologists.  And at some point, you have to ask the medical colleagues and some of the other people in the clinic, even if you love PEPF, how is this going? Should we still be doing this?  Do we have enough people for this? You know, because our hepatology nurses are like, why the hell are we calling these patients to talk to them  about their addiction just because this is a medical lab? Fair point. Fair point. And so all the psychosocial people in the transplant center are like,  yeah, we should be calling and we do that. So checking in, because this rattles cages whenever it's used. The most commonplace that this is used at the University of Michigan  is not the transplant center. It's not the ALD clinic. It is the inpatient service, and that's exactly what the good Dr. Hathaway will talk more about. Dr. Hathaway.  That was 20 minutes almost on the dot. So thank you. All right. Let's see. I wonder if we could do a quick exercise. I've been sitting down for a while.  I'm wondering if everybody can stand up, if you could stand up.  I have two numbers. I have this side of the room number, one of the numbers, and this side of the room number, the other numbers. It's actually – okay, we'll start over here.  Can everybody over here remember the number 20? Can you just say 20, please? 20. Okay, and you can sit down. All right. And then over here, you can remember the number 200.  Okay, great. Thank you. Okay, so 20 and 200, those are the numbers. This is a very difficult presentation because I'm supposed to stick to a script  that was written by someone else, so we'll see how well I do with that. So, again, my name is David Hathaway. I'm an addiction psychiatrist at Brigham and Women's Hospital  where I work under Dr. Joji Suzuki, our division director, and I mainly consult CL psychiatrists, but I also work as a medical director of measurement-based care.  And you'll also see – it's not on the slide, but I'm the co-director for the Harvard Medical School Motivational Interviewing in Addiction Medicine  and Addiction Psychiatry elective course. So I'm supposed to ask a question here, and I ran through this presentation with my wife, who's a surgeon, before,  and she said, you should cut out that one where it says, if so, how. So we're going to cut that out because the surgeon said to cut that. But can I just see a show of hands?  Does your institution already utilize PETH testing? Okay, and it may be easier if – can I ask if you don't? Can you raise your hand if they don't?  Oh, can you raise it if you don't know? Okay, I had no idea. It looks about even, so – but I don't know if you had a better view on that. You have me. Okay.  All right, so we have four areas that we're going to look at today. And before I dive into these, I just want to say, I have kind of a different practice than my colleagues here  because I work for my patients pretty much exclusively. In other words, there's nobody – like I'm not holding the liver, right, when I go to see them.  It's not like in the consult setting, you know, I'm talking to them. I work for them, right? I go in, I'm like, hey, you know, this is what could happen.  You know, I'm talking to them with motivational interviewing, ask, tell, ask, ask permission before providing information, all those kind of things, reflections.  In the outpatient setting, you know, people don't have to get this test, and yet it's been such a hit, and I'm really excited about it.  So we're going to talk today about screening, diagnosis, monitoring, and supporting recovery. Okay, I just don't get excited about screening. I don't know.  Does anybody have that feeling? Like, you know, I feel like that's other people, they do screening.  I'm like, you know, by the time they get to me, they've already been screened, whatever. But it's actually kind of important to talk about,  and we'll see if I can make the case for that. So a lot of people drink alcohol. I checked, it's actually about two-thirds,  and it's been like the same amount for about 100 years or so. Like that's about how many people drink alcohol.  About half of those people probably drink too much alcohol in the U.S., and then a smaller percentage actually drink way too much alcohol  and have consequences, and we call that alcohol use disorder. So I care about, I really care, and this talks more about the people that have alcohol use disorder,  but also people that are at risk, that are drinking too much. And we've talked a little bit about what defines that.  There's something called screening, brief intervention, and referral to treatment. Be careful, because the takeaway for this talk  is not that everybody should get screening, brief intervention, and referral to treatment. There's actually some people that brief intervention is not good enough,  and we need to be careful about that. But I wanted to talk about this, first of all. For your primary care colleagues,  they are supposed to screen for adults age 18 or older for unhealthy alcohol use, and they're also supposed to provide behavioral counseling. So you notice I said supposed to.  Okay, then the surgeons. The surgeons must, so this is not like optional, the surgeons must do this or the hospital loses a lot of money, potentially.  And this is actually written into the guidelines that came out of 2022. So this actually has teeth to it.  They are required to screen all admitted trauma patients older than 12 for alcohol misuse.  And they have to get at least a B on this. So like 80% has to be working. And then they also have to be making referrals. They also have to be doing trauma-informed care.  I skipped over that. So how do we do this? Well, we can use self-report. That could be the end of this talk, right? We could just stop right there. Self-report, good enough, right?  Maybe not. So we use Audit C at the Brigham quite a bit. And if it's no, if the patient doesn't screen positive, right, stop there, pat on the back.  But if it's yes, then you really should ask some other questions. And if it's high-risk use, you should do a brief intervention. And if it's severe use, referral to treatment.  So from here on out, I'm not really going to talk more about this, but the point is we really want to get people channeled down.  This way, if that's appropriate. And we don't want anybody that shouldn't, that's, we don't want any false negatives.  Because we really want to, this is, I mean, I've heard one of my mentors said, you know, God gave you 10 years of heavy drinking, right? And then you're kind of shot.  So you really want to catch people and, you know, leave people with more liver function before they hit the end of the road.  So let's look at a few studies here, and they won't be too many. And I'll try to not spend too much time on this, because I really want to open up time for discussion.  So there's been some studies looking at patients in the ICU and using PEF in those settings. This one, they looked at 33 ICU patients, 51 detox patients, and 38 healthy controls.  And they found that PEF actually had very good positive predictive value and negative predictive value. Remember those ROCs? Remember from earlier back? The ROC on this one is .92.  That's higher than any of the ones from those other indirect measures earlier. So it's looking pretty good. So the conclusion from this study was,  PEF can help identify unhealthy alcohol use among critically ill patients using a cutoff of 250. So don't forget the 200, right? 200, just remember 200, you're fine.  But you'll see different numbers going through here. Another study done, also in trauma ICU. 238, so we're starting to get some bigger numbers here.  Now this is one of the key takeaways I wanted everybody to come away with. People lie. No, people might not accurately report alcohol use.  And, I mean, yeah, we can have these validated scales. We can do all these fancy things. We can throw a ton of federal tax dollars at these things.  But at the end of the day, if we don't have a good measure, maybe we don't know if we're really doing the right thing. So, again, good ROC with this as well. And this is tough.  You read some of these papers, they compare PEF to self-report. As in, like, self-report's a gold standard? Yeah, anyhow, we'll talk more about that. Here's another one.  Let's see if I can actually use this thing. Here we go. Psychiatric inpatients. Okay, so we've just moved from trauma ICU to psychiatric inpatients.  This one, PEF was obtained and audit was obtained for 177 adults. One out of five had reported no drinking but had a measurable PEF. So remember we talked about that little channel.  Are you going up the let's get this person help or let's just give them a pat on the back? Up to one in five of those patients could have been sent down the wrong road.  Think about that. In the airlines, would that be acceptable? If this was any other industry, like, oh, yeah, you know, some luggage lost,  some people lost, you know, but, you know, I'm just getting experience, you know. If you just give me a few other planes, I'll be fine, you know. ED.  We've also looked at this in the ED. I see a lot of BALs in the ED. We're starting to use Peth more in the ED as well. Now look at the N on this study, 1,160 adults.  And up to over one in ten were having heavy use. And here we go. The numbers just keep getting bigger, right? Up to one in four had a positive PEF that had a negative BAL.  So if you think that you can rely on BAL to rule out alcohol, you know, heavy use or severe use of alcohol, not so promising here. So I just cringe when I read this slide.  It says the gold standard tools such as these self-report measures, and I just, I don't know, I just feel really bad when I read that because I feel like it's fool's gold.  And they're good. I mean, like, don't get me wrong. Audit C and Peth generally correlate. They're generally.  It's just I feel bad for those patients that we're losing because we're not doing everything like we do in the rest of medicine, right?  I go to the dentist and they ask me, did you floss? And I'm like, yeah. And then they're like, and they see, like, all this bleeding, right? And they're like, no, you don't.  You know, I go to my PCP. They're like, do you exercise? Do you, you know, eat healthy stuff? And I'm like, yeah. And they look at my hemoglobin A1C and they're like, no.  And they say it in the nicest possible way, but, you know, I actually walk away from that appointment like, let's go exercise. Let's go eat better, right?  You know, like, anyhow, I could go on. But so what are these areas where we're really, really seeing some high yield uses of Peth?  I think it's really important if a patient can't talk, if we know how much alcohol they've been drinking recently. We have a case report currently.  It's almost under review, but almost out. And it's of a patient that reported drinking two Coors Lights a day.  And he was being treated for, you know, a billion-dollar workup in the ICU. And comes back, his Peth was off the charts. All of a sudden we knew we were up against DTs.  We've had other patients that have reported a lot of heavy use. Actually, I think I'm skipping ahead here. Let's see. And then the Peth comes back negative.  All of a sudden, that patient that has an alcohol use disorder, our antennas are up for whatever other substance use we should be really paying more attention to.  So anyhow, I think I am close to time. So we believe, I believe that Peth is a game changer. We have totally drunk the Kool-Aid up in Boston. It's very popular.  I mean, I've got to say, this is probably, you know, like those people that go viral, like all the fellows, they all come through me, right?  So it's like we have four fellowships come through us at the Brigham, and then plus neurology residents. So, like, I don't know. I walk around the hospital now and, like,  all these patients that I have no contact with whatsoever are now having Peth ordered on them. And it's very interesting,  and it's kind of increasingly accepted as standard of care there. And that's not even transplant settings. Similar results we found in terms of discrepancies  between self-report and actual Peth levels. And this is in a detox, right? When people are showing up requesting detox  or medically supervised withdrawal, I think I'm supposed to say now, and actually a lack of concordance, they might have a negative or zero Peth, not negative, zero Peth,  but be reporting that they need alcohol withdrawal treatment. So, okay, so that's all about monitored screening so far, which I guess I got pretty excited in diagnosis.  And, yeah, so anyhow, I'm meshing it all together here. This is the part I get excited about, and it's actually none of these things, because I don't really do any of these things.  Transplant, we hear a lot about that. Workplace testing, I mean, I know people that do that. Insurance, forensics, criminal justice, competitive sports.  Peth has been the domain of forensics for the longest time. I feel like what this talk is all about, if I had to put it in a nutshell,  is all about bring it to, you know, why can't it be for everyone? You know, like everybody that could benefit from it. Not literally anyone, but if there is an indication,  and this is where I found it super helpful. You know, we all have these guidelines we look at, right? When you have treatment-resistant depression, we're thinking,  okay, did I try SNRI? Did I try MAOI? Should I refer to ECT? TMS? You know, like I'm going through my list, and then I'm like thinking, well, could it be alcohol?  And then you check the alcohol, you check the Peth, and it's off the charts. And you're like, ah, treatment-resistant depression.  And all of a sudden, you know, it's a whole new ballgame, and you can start talking to that patient.
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