#319 ‒ Peter's key takeaways on liver health, heart rate variability, AI in medicine, klotho, and lactate metabolism | Quarterly Podcast Summary #2

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Peek of the Ask Me Anything episode. Welcome to another special AMA episode of the Drive. Today's episode will be the second of what we're now calling the Quarterly Podcast Summary. We did the first episode of this back in June and the feedback was overwhelmingly positive. In fact, I don't think we've ever received more feedback on the day of a podcast release than we did for the Quarterly Podcast Summary Number one. So it's no surprise that we're going to bring this back and continue to do it, because again, people seem to really like this and quite frankly, it's a lot of fun for me. These quarterly podcast summaries will look back at recent episodes released typically over the last quarter, and I'll discuss what I learned from the interview and what I think were some of the most important insights, as well as any changes in my behavior or thinking that resulted from the interview. In today's episode, we will cover the interviews that I did with Julia Waddicharl, Joel Jamison, Zach Kohane, Dina Dubal, and George Brooks. Throughout this, we speak on topics such as liver health, heart rate variability, the emergence of AI and its potential impact on medicine, the gene and protein Clotho and its relationship to Alzheimer's disease and its potential to treat these conditions and all things related to lactate. If you are a subscriber and would like to watch the full video of this podcast, you can find it on the Show Notes page. If you're not a subscriber, you can watch a sneak peek of the video on our YouTube page. So without further delay, I hope you enjoy this special quarterly Podcast Summary AMA of the Drive.

Peter, welcome to another ama. How you doing?

Good. Thanks for having me back.

You're always welcome. So this will be the second episode that we've done like this, which is kind of our Quarterly Podcast summary. We released the first one back in June, received really positive feedback. People really liked it, wanted us to continue to do it. And so today we're going to look at previous and recent episodes of the Drive, and as we look at them, we'll kind of look at what your Key takeaways are from the episode along with anything you changed as a result, whether behavior, whether your mind, whether how you're thinking about things, anything of that nature. And so today's episode, if all goes well, we'll cover topics such as the liver, liver health, heart rate variability and training, AI in medicine, Clotho and Alzheimer's disease, lactate and and more. So with all that said, anything you want to add before we get rolling?

Only that I was so pleasantly surprised at how people took to the first episode of this quarterly summary that we did in June and said, hey, that was the single most valuable piece of content you've ever put out. And what I thought was nice that there were people who said, look, these are episodes I didn't listen to and now I just got the summary. Or these are episodes I didn't listen to and I got this summary which made me go back and listen to the actual episode. Or hey, I did listen to it, but honestly, it's just hard to remember everything. So I think when we sat here three months ago and recorded the first one, we were sort of like, well, you know, we hope people like it and if you don't like it, we certainly won't waste anyone's time doing it. But I think it might be the most emails we've ever received for a single podcast with people saying, this was fantastic, please do it more. So it's really nice to hear that and obviously it's our pleasure now to just make this a regular part of what we do each quarter.

Yeah, and you kind of hinted at there too is it's important to note these aren't replacements for listening to episodes. A lot of times they're good either refreshers, good to figure out to go back and listen to, or just to kind of put the pieces together based on what you heard. And so with that said first episode we will look at is the one with Julia Guanichero on liver health, liver disease, nafld, Mastle D, everything as it relates to the liver. So you want to kick us off?

Yeah, this was an at times technical episode. This is a classic episode of the Drive, meaning you don't expect to turn on a podcast and walk into a graduate level seminar on the liver. But if you take a step back and think about it, we kind of need to. Right. It is arguably one of the most important organs in the body. It is certainly an organ, as we discuss, for which we have no extracorporeal support, meaning if your kidneys fail, God forbid. That's very Bad. But at least you have the option of dialysis if your lungs fail, again, not a good thing. But at least you have a ventilator. Even if your heart temporarily fails. We have ways to support that outside the body. And yet, remarkably, we don't have this for the liver. If a person goes into liver failure, their only solution is a liver transplant. And what that speaks to obviously is the diversity and complexity of function in this organ. So the role that it plays. And we really talked about it in three categories. Metabolism, protein synthesis and detoxification. There simply is no parallel for those things. Now, we of course then talked about the role of alcohol. Everybody's aware, of course, that alcohol is metabolized by the liver and therefore that excess alcohol is toxic. But we talked a little bit about the how and the why. Right? And that the metabolite of ethanol known as acetaldehyde, basically causes all of the downstream problems by overwhelming the redox potential of cell in the liver. And that creates the attraction of free radicals and inflammatory cells. We did a great job, I think, really just talking about dose makes the poison here. So if a standard drink contains about 14 to 15 grams of ethanol, that will usually be found in about 12 ounces of a regular beer. Interestingly, my favorite beer, which contains like 10% alcohol, it would be you'd get that 14 grams in far less 5 ounces of wine, 1 1/2 ounces of liquor. So if you're trying to think about how much ethanol you consume, you have to be mindful of the drink. I notice that when I'm pouring a glass of wine for myself or somebody else, it's never 5 ounces, it's probably closer to 8. So I don't think it's intuitive for people to think about how many grams of ethanol they're consuming. We didn't go much further into it here because we've done so much other content which we can link to in the show, notes about the toxicity of ethanol based on how many grams per day or grams per week you're consuming. Okay, next major topic we got into was that of what is called MAZZLE D or Metabolic Dysfunction Associated Steatotic Liver Disease. That's a mouthful. Why did we bring that up? Well, because you'll always hear me and for that matter, many other people talking about NAFLD or Non Alcoholic Fatty Liver Disease. So this was an education for me as well, and I think for the listener, which is we talk about nafld and that's been something that's been talked about for the last 20 years, it's the fastest growing form of liver disease in the developed world. And it's probably poised in its long term sequelae to be the leading indication for liver transplant within the next decade. But the reason that the liver societies and the medical societies have taken on this name change is to basically be more encompassing. So again, NAFLD has the intuitive point of saying, okay, it's a fatty liver disease that does not result from the consumption of alcohol, because of course, apple D or alcoholic fatty liver disease would be the sort of sister disease. But this idea of mazzoldi, or metabolic dysfunction associated steatotic liver disease, speaks to the complete overlap of insulin resistance, metabolic syndrome, type 2 diabetes here. Now, to be clear, the overlap is so strong that I honestly think, for those of you as listeners, I don't know that it matters that much. According to Julia, 99.6% of people who meet criteria for NAFLD will also have the diagnosis of mazel D. So at that level, it's not really clear the diagnosis is based on metabolic dysfunction. So that's really the key thing when it comes to masil D is you also have to have insulin resistance, but it does not require fibrosis. It requires also that at least 5% of the hepatocytes. So hepatocytes are the liver cells. It's the functional unit of the liver. They have to contain fat. One of the things that we talked about that I used to know, and this is a great example of doing this podcast, is like, there were things I once knew and then I kind of forgot, and this was one of them was about the difference between kids and adults and the different pattern of fibrosis that they have. So in kids, it's more circulated around the portal vein. The portal vein, again, this is maybe a little more in the weeds than people want, but for me, it was very interesting. The portal vein is the vein that brings the majority of the nutrients to the liver. So the portal vein is formed by the confluence of two enormous veins in the abdomen, the superior mesenteric vein and the splenic vein. And so they merge together and run into the liver. And that's carrying just tons of nutrients into the liver. And in that sense, the liver has two blood flows that are coming into it, one through the portal vein and one through the hepatic artery. So what's the implication of this? Well, the anatomy of it notwithstanding, what's the implication is what do you see from a diagnosis perspective? And in kids, you're going to see an earlier increase in altitude, AST and ggt. Now, again, you'll often hear these things referred to as liver function tests. We talk about how we accept that as terminology, but the reality of it is they really tell us nothing about liver function. They are enzymes that are associated with liver or hepatocyte health. And when those enzymes go up, we generally understand that some sort of injury has taken place. We'll talk about that more in a moment. In adults, the fibrosis and steatosis tends to occur closer to the central vein. And as a result of that, you see a delay in the enzyme elevation. So what does that mean clinically? It means that if you're an adult and you're developing steatosis and fibrosis, it could actually be taking place for quite a while before you see it. And that's why another huge takeaway, which I'll get to in more detail in a moment, is that this reliance on elevations of the transaminases, which are the technical names for ALT and ast, and using that as your threshold for concern, might be waiting a little bit too long. Okay, so now if you look at the top three causes of liver injury in the form of steatosis and fibrosis, you have MASLD number one, followed by alcoholic liver disease, again, something we should never forget. And then finally, infections, of which hepatitis is the most common.

And real quick on that, Peter, just so people understand, is we had an older episode with Chris Sonnenday on organ transplantation, and back in that episode, y' all talked about the liver. But the fact that MASLD is now number one, is something that wasn't even close to true. 20, 30, 40 years ago, correct?

Yes. In fact, I even write about this a little bit and outlive that. I recount a story when I was got either a medical student or an intern more than 20 years ago, operating on a patient. And one of the jobs, I think it was when I was an intern, because one of the jobs of the intern is to pre op the patient. Pre op the patient means get them ready for surgery. And among those things is understanding how much alcohol they consume. Because when a patient is undergoing major abdominal surgery, as was this patient for the resection of a colon cancer, alcohol withdrawal, it's a very serious medical complication. So patients who are drinking three or four drinks a day when they're in the hospital will either need to have a continuous infusion of ethanol, or they'll have to have more benzodiazepines to cope with the withdrawal, which can actually be fatal. So point of it is, you better understand how much alcohol your patient drinks. And I'm talking to this guy the night before surgery and he's telling me he doesn't drink anything. Okay, great. Whatever I ask in a de arming way, it's not like these are questions that people typically answer without reservation. We get into the operating room to do surgery on this guy, and his liver looks like it's a piece of fat. And at the time, I think everybody just assumed, A, I was a moron for not finding this out ahead of time, and B, once they realized, yes, I did in fact ask that he was lying. And in fact, what I now realize, because we never really gave it another thought, I wish I could tell you like this led to some lifetime journey of mine to understand it. It was just, all right, let's get his col out and make sure his cancer is gone. But I now look back and realize this guy clearly had what we would have at the time called nafld. So that's a long winded way of saying you're absolutely right. 20 to 25 years ago, this was really not something that was recognized, although it was probably far more prevalent than we believed. But I would say that by, I would say 2010 to 2012, most people felt like this is an epidemic and this is going to be an enormous burden on the healthcare system. As far as liver transplantation, again, getting back to the point at the outset, which is that extracorporeal support of a dysfunctional liver is not possible. So we should spend just a second talking about Hep B and Hep C. Obviously, people have heard of those things. For Hep B, we do have a vaccine today. For Hep C, we do not. Conversely, for Hep C, we have a treatment, whereas for Hep B, we do not. So the net net is if you're someone who's coming of age today, you're a teenager today, you're probably going to have a hep B vaccination, which is going to protect you from that. And should you contract Hep C, you're going to have a treatment. However, there are many people for whom Hep B was acquired before a vaccination was prevalent. And why do we care about this? Well, we care about it for two reasons primarily. The first is the risk of liver failure and all of the things we talk about through this pathway of steatosis, fibrosis, and ultimately what is called cirrhosis, the irreversible fibrotic change of the liver. But the other thing we have to talk about here is hepatocellular carcinoma, which is a deadly type of cancer if not caught very, very early. And so the cancer risk here is a greater issue from the infectious side. So you always want to be screening patients for hep C and hep B regardless of the workup. So in other words, when we're working patients up for, usually the first thing we're seeing is this elevation in transaminases. We're also including a hep C and a hep B workup. The other thing to keep in mind here is that MASLD and alcoholic liver disease are also increasing the risk of hepatocellular carcinoma. So it's not just hep B and hep C. And as a general rule, again, this was something I learned in the podcast, either I'd forgotten it or never knew it, that as the scarring and fibrosis of any of these diseases, MAZD, alcoholic liver disease, Hep C, HepI, as the degree of scarring and fibrosis increases, so too does the risk of cancer. And by the way, I misspoke there a little bit. For hep B, that risk is regardless of disease progression. So let me just restate that. So hep B, you're going to see about a 3 to 5% per year cancer risk regardless of where you are in the disease. So fortunately, again, we have a vaccine to reduce your risk of that. But for the others, the risk of cancer goes up with the risk of disease. Okay, I think the last thing to talk about on this topic is how do you make the diagnosis? Because the gold standard for this is to do a biopsy. And it's not that a liver biopsy is as complicated as a cardiac biopsy or even a lung biopsy, but that's not a procedure you would just go and do willy nilly to stick a needle into the liver with its risk of bleeding primarily or also infection. So really what we want to do is understand how to make this diagnosis non invasively. So look again, nobody wants to do a liver biopsy. So we're really talking about blood based biomarkers and radiographic or imaging modalities. Let's start with the blood based biomarkers. If we're now going to look at blood based biomarkers, the two most common of these, the transaminases, which again are erroneously and often referred to as liver function tests, are ALT and ast. And unfortunately, we cannot diagnose masld, NAFLD with those biomarkers. Now, the reason that we see an elevation of these during fat accumulation and or fibrosis in the liver is that these are enzymes made by the parocytes that are released into plasma when the liver is stressed. So as you see more ALT and ast, that indicates more stress. But it gets a little complicated because AST is also found in muscle and therefore as you exercise, you will also see more AST increased into the plasma. And in fact, that's one of the things we use to try to understand this. My AST is always higher than my ALT. My ALT is typically in the mid to high 20s and my AST is typically in the low to mid 30s. That is the typical pattern for me and for many of our patients. And we know that that is a pattern that is pretty typical of people who are doing quite a bit of exercise. The general rule of thumb is that you would like to see an AST and alt both below about 30iu per liter. Again, I just told you that my AST is typically a little bit above that. Normal results for me might be an alt of 25 or 26 and an AST of 33 or 34. Am I concerned about that? No. I've obviously, being a curious person, done some more imaging stuff to make sure there's nothing going on. But ultimately you just have to handle each of these situations kind of clinically. There are also pharmacologic things that will raise them. So lipid lowering drugs are a very common offender and will raise AST and alt. What is the threshold at which you should be concerned? If you typically see somewhere between a one and a half and twofold persistent increase, that would really justify investigation. Even if it's in response to a drug, it would probably justify stopping that drug. For example, if you're on a statin and this is happening, that's probably reason to stop a statin. And certainly in our practice it is. Even though the guidelines might suggest you tolerate a higher level of increase when.

You kind of say stop a statin, does that mean if you're treating someone with a statin for potential CVD risk and you see the liver enzymes increase, you abandon treatment? Or are you just looking at potential other drugs to handle the cvd?

Yeah, it would be the latter. So in other words, we treat the CVD or ASCVD risk using the tools that are available. But I'm just saying that we include elevations of transaminases in the suite of things that we would view as a contraindication. So, look, I don't think any doctor out there would say, I'm going to give my patient a statin. But if they develop debilitating muscle pain, we're just going to keep hammering them with it. Of course, not 4 to 5% of patients will develop significant myopathy from a statin use. It's reversible. But obviously you're going to stop the drug and find an alternative. We would just consider a significant elevation in transaminases, a change in insulin sensitivity. Those would be the big three things we always look to get people off a statin, or at least off one statin onto another, or just off the class altogether. Let's talk about what maybe is a better test here, because I sort of just alluded to the fact that those tests don't work very well. They really lack sensitivity and specificity. So if a physician really wants to understand if their patient has MASLD and make that diagnosis, they really want to understand how much fat is present and how much fibrosis, if any, is present. And my takeaway was that the gold standard was probably magnetic resonance elastography and proton density, fat fraction, or PDFF. So that's sort of looking at Mr. Technology. So meaning an MRI to make the diagnosis. Now, the problem with this is that it's obviously costly and it's not a widely available test. You can't just go to an MRI and get that done. That's a very specific protocol. So I would say from a practical standpoint, the more common tool are ultrasound and vibration methods that are less expensive, that are easier to do in a clinic. And there's a branded version of this that we typically use called Fibroscan. So it's a vibration controlled transient elastography, and it uses both vibration and ultrasound to basically give what's called a cap score. Again, I don't know that the details of this are entirely needed. For us, it's interesting because we do these things, but basically this cap score is called controlled attenuation parameter, and we actually want to see that number. So now we're actually able to quantify the degree of fat and fibrosis in the liver. And now we have a biomarker that we're treating, because, remember, although we didn't talk about it enormously in this podcast because we've talked about it so much elsewhere, the real question here is, what are we doing when we have this information? So you've now confirmed your patient or you as the individual, have fat or fibrosis in your liver. Now what? Well, here's the thing. It's not a really clear indication for a drug per se. This is something that is going to respond most favorably to a reduction in excess adipose tissue and an improvement in insulin sensitivity. And of course, depending on the etiology or removal of the insulting agent. So, you know, I guess the way I would close this summary up would be to say that what are we doing when we see this? Well, we're getting our patients to lose weight. And again, that's not an easy thing to do. It is simple, but not easy. Right. Simple in concept, can be challenging in practice, although at times it relies on drugs like GLP1 agonists. But we're also being mindful of taking things away. So if a patient, let's say, is drinking five or six drinks a week, which would not be considered excessive, but their fibroscan score comes back showing modest steatosis and or fibrosis, well, we're going to take all alcohol out of their diet because why would you add any additional insult? So in addition to putting them on a program that's going to help them lose weight and improve insulin sensitivity, we're going to remove alcohol. The other things we're going to do, although I think we have far less data for this, are going to be remove liquid fructose from their diet. So every time a study has been attempted, to my knowledge, to look at the isocaloric impact of liquid fructose, it has been unable to discern if that is different from isocaloric glucose because the subjects usually end up losing weight even when you make an attempted isocaloric substitution for fructose to glucose in liquid form. So in other words, two things change and you can't tell. That said, we continue to abide by the idea that liquid fructose and alcohol should probably be minimized if not avoided in people with masld nafld. So it's a bit of a long summary, but it is a very important topic and I hope that either for folks who have listened to it or plan to go back to listening to it, this can sort of prime that discussion.

One follow up question on what you said. If someone is kind of curious on the state of their liver, you mentioned ultrasound might be the easiest and most widely available thing. Do you have all your patients get ultrasounds to test their liver, or is it only if you see potentially other things that are concerning that you want to see the state of it?

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