Episode #389: Your Liver Enzymes Are Elevated — But It Might Not Be Your Liver

0:00 [SPEAKER_01]: before every lab draw that he remembers, he would go to the gym and work out. [SPEAKER_01]: In a survey of physicians that were given a case where a young asymptomatic man had elevated liver associated enzymes, 50-6% of those physicians failed to list exercise induced muscle damage in their differential, and over 60% listed primary liver disease as their diagnosis.

0:25 [SPEAKER_01]: Every year, thousands of healthy active individuals are told that their liver is failing based on a routine blood panel. [SPEAKER_01]: The clinician sees the labs, the patient sees the panic in the doctor's eyes, next few weeks are filled with expensive imaging, viral screenings, and the looming threat of a biopsy.

0:40 [SPEAKER_01]: Now, in medical school, we're taught that elevated transaminases, which are more correctly called liver-associated enzymes, mean liver disease, and for the fitness enthusiast, this often leads to a recommendation to stop working out or worse, misdiagnosis of drug-induced liver injury. [SPEAKER_01]: What if the very thing making the patient healthy is what's making their labs look pathological?

0:59 [SPEAKER_01]: Today, on the Barbomedicine podcast, we're breaking down a mystery case that highlights a massive blind spot in modern medicine where a completely expected lab finding is mistaken for clinical disease. [SPEAKER_01]: And help us work through this problem like a pro. [SPEAKER_01]: It's the second most handsome doctor in North America, Dr. Austin Baraki.

1:15 [SPEAKER_01]: We have a little bit of a different mystery case today. [SPEAKER_01]: It's not an emergency, but it is a big problem in medicine. [SPEAKER_01]: Many doctors apparently miss this with over half of physicians failing to include this in their differential diagnosis and every miss costs a lot of money and potentially harm to the patient.

1:33 [SPEAKER_01]: That all being said, I always guess if you're going to get this, or if you're not, you're 100% going to get this. [SPEAKER_01]: Oh, my pressure's on. [SPEAKER_01]: Okay. [SPEAKER_01]: Don't let me down. [SPEAKER_01]: But we can take the time and get our audience involved because I think they want to participate.

1:47 [SPEAKER_01]: So the question is, are you ready? [SPEAKER_01]: I am Red. [SPEAKER_01]: Let's do this doctor Baraki you are working in clinic today and your first patient of the day comes in. [SPEAKER_01]: He's a 39 year old previously healthy male. [SPEAKER_01]: He's presenting for lab follow-up. [SPEAKER_01]: Six months ago, while in Asia, he went to a clinic for some nausea and an abdominal pain.

2:05 [SPEAKER_01]: He says he checked out fine, but they told him to follow up with his doctor when he got home because of his, quote, liver. [SPEAKER_01]: He says he's been fine, but yeah, he's here to follow up on some labs. [SPEAKER_01]: Since he's been home, he subsequently went to another clinic which tested his liver again, and they said he needed a liver biopsy which freaked him out.

2:23 [SPEAKER_01]: He heard that you're the best and he wanted a second opinion. [SPEAKER_01]: So he hands you the lab read out and it's a, quote, liver panel test which I'll send you now. [SPEAKER_01]: And as you can see, the lab test from Asian nine months ago is pretty normal, other than a modestly elevated alkaline phosphatase, which is 131, and gamma glutamal transferase GGT, which is 68.

2:46 [SPEAKER_01]: Since he's been back in the States, he's had an additional set of liver tests done, that continues to show modest elevations in alkaline phosphatase and GGT. [SPEAKER_01]: But now also, it shows elevated alanine transaminase, ALT, [SPEAKER_01]: Both are one and a half to two times the upper limit of normal.

3:06 [SPEAKER_01]: Now while you're interviewing the patient, you glance at his vital signs in the chart, everything's normal. [SPEAKER_01]: Perhaps he's been paying attention to the barbell medicine vital five. [SPEAKER_01]: You also notice that he appears well without any gross abnormalities standing out to you.

3:18 [SPEAKER_01]: You're a great multitasker. [SPEAKER_01]: He takes no medications or supplements. [SPEAKER_01]: He denies any use of drugs. [SPEAKER_01]: And he says he doesn't think he has any family history of disease that he knows of. [SPEAKER_01]: Now, when you ask him about any current abdominal pain, nausea, weight loss, or recent illness, he says, nope.

3:34 [SPEAKER_01]: And then asks, hey, man, should I be worried? [SPEAKER_01]: So, Dr. Baroque, I've got three questions for you. [SPEAKER_01]: And if you're playing along at home, let's see if you can answer these questions. [SPEAKER_01]: You should pause the podcast now. [SPEAKER_01]: First question, what do you think about this patient?

3:46 [SPEAKER_01]: The second question is, can you take us through the different labs contained in a quote liver panel and explain them to the audience? [SPEAKER_01]: And a third question, what is your differential diagnosis? [SPEAKER_02]: Sure, I would be happy to. [SPEAKER_02]: So this is a pretty common situation that I'm faced with on a regular basis, a patient with abnormal, we'll say, liver chemistries.

4:07 [SPEAKER_02]: So overall, we have a pretty young, [SPEAKER_02]: abnormalities in his liver chemistries, including both abnormalities in the transaminases and in the alkaline phosphatase. [SPEAKER_02]: And this is this summary helps us with the general approach that I will kind of work through next. [SPEAKER_02]: So your second question was to review these labs and to go through them.

4:33 [SPEAKER_02]: So be happy to. [SPEAKER_02]: In general, the basic liver chemistries, [SPEAKER_02]: One are what we call hepaticellular tests, and these are lab tests that are associated with the liver cells themselves. [SPEAKER_02]: And when those cells get injured by some mechanism, [SPEAKER_02]: they essentially die and release their contents into the blood.

4:58 [SPEAKER_02]: So this is similar to what we see in a lot of other areas of the body. [SPEAKER_02]: For example, if somebody gets rabbed of myelysis from too much exercise that they're unprepared for, the muscle cells break down and release creatine kinase or CK into the blood. [SPEAKER_02]: And so that CK becomes essentially a marker of muscle injury.

5:16 [SPEAKER_02]: when somebody has a myocardial infarction or a heart attack, those muscle cells die and release a particular protein called proponent into the blood. [SPEAKER_02]: That is a marker of myocardial cell injury. [SPEAKER_02]: When liver cells or hepatocytes are injured by some mechanism that I can get into shortly with the differential, they also release into the blood their contents that include things like ALT and AST.

5:40 [SPEAKER_02]: It's important to know, though, that these enzymes, ALT and AST are also found in other areas of the body, including in muscle, especially AST is also found in muscle. [SPEAKER_02]: And so, sometimes I've seen folks get tricked when somebody actually has RAVEDO. [SPEAKER_02]: they will often also have elevations in AST.

5:58 [SPEAKER_02]: And if it's really bad RABDO, it'll also even have elevations in ALT. [SPEAKER_02]: And people will freak out and think this person's in liver failure when more often it's just that they have such severe RABDO myelysis that these enzymes that are actually involved in kind of a little bit of some Krebs cycle metabolism.

6:13 [SPEAKER_02]: I won't get that far into the weeds here. [SPEAKER_02]: But these enzymes are mostly related to liver, [SPEAKER_02]: But can also be seen, the elevations can also be seen with issues going on elsewhere in the body. [SPEAKER_02]: So that's one thing that's worth pointing out. [SPEAKER_02]: We know that ALT is a little bit more predominant in the liver than AST.

6:33 [SPEAKER_02]: And so when somebody that we can look at the pattern of elevation, so when the ALT is higher than the AST, I'm a little more concerned that maybe there's something going on. [SPEAKER_02]: with the liver when AST is greater than ALT, it can still be liver, but I might actually also be considering things elsewhere in the body, things like muscle, things like alcohol, use, et cetera.

6:54 [SPEAKER_02]: So those are the hepatacellular tests. [SPEAKER_02]: The other couple tests that we'll talk about are the alkaline phosphatase and the billi-rubin. [SPEAKER_02]: These are tests that we categorize or classify under something called colostatic labs. [SPEAKER_02]: And that refers to the generation and flow of bile out of the liver and down the bile ducts into, of course, the gallbladder and into the gut.

7:19 [SPEAKER_02]: And so when there is some problem with bile flow, like an obstruction, like there's a blockage, for example, that can essentially back up and that can lead to elevations and alkaline phosphatase as well as in elevations in Billy Rubin in the blood because rather than that Billy Rubin flowing down into the gut it backs up spills over into the blood and that can lead us to suspect.

7:42 [SPEAKER_02]: that there might be a blockage either within the liver. [SPEAKER_02]: We call that intra-hypatic colostasis, or outside of the liver, like from a gallstone that's block in the tubes of drainage, and we call that extra-hypatic colostasis. [SPEAKER_02]: There's many more causes of these things, but that's kind of a very general breakdown of these things.

7:58 [SPEAKER_02]: Similar to how I talked about how ALT and AST are very closely associated to the liver, but not perfectly associated to the liver. [SPEAKER_02]: We have the same issue here as well. [SPEAKER_02]: Alcohol and phosphatase can also be found elsewhere in the body. [SPEAKER_02]: In many other places, it can be found relating to the bone.

8:14 [SPEAKER_02]: So when people have bone fractures, [SPEAKER_02]: For example, in Boni disease, diseases of accelerated bone turnover, alkaline phosphatase can be elevated. [SPEAKER_02]: There's a placental form of alkaline phosphatase. [SPEAKER_02]: It's found, I believe, in the prostate as well. [SPEAKER_02]: There's a handful of other places where alkaline phosphatase is present.

8:30 [SPEAKER_02]: And Billy Rubin elevations, as well, can come from breakdown of hemoglobin in the blood. [SPEAKER_02]: And so there's other ways that we can try to determine is this Billy Rubin elevation due to blood issues like hemalysis or is this related to this kind of backup [SPEAKER_02]: So to summarize so far, we have the hepatosolular tests, the ST and the ALT.

8:51 [SPEAKER_02]: We have the kind of more colistatic tests, the alcoin phosphatase and the bilirubin. [SPEAKER_02]: And then the last one that I'll mention here was the albumin. [SPEAKER_02]: And albumin is a protein that our liver synthesizes. [SPEAKER_02]: And so the last kind of category of liver chemistries that I tend to look at are this group of tests that we call kind of more tests of liver synthetic function.

9:11 [SPEAKER_02]: How well is the liver doing its job to produce the things that is supposed to be producing? [SPEAKER_02]: One of those is abhuman. [SPEAKER_02]: And another way that we assess that is actually with a set of tests that are not included here, but coagulation tests, something like a Pythrombin time or PT and INR, or a few other tests that we use.

9:29 [SPEAKER_02]: So when a liver is failing acutely or chronically, and it is not able to produce clotting factors, for example, that is when we start to see the INR, for example, creep up. [SPEAKER_02]: And so that's one of the criteria for acute liver failure. [SPEAKER_02]: falls in that in that range.

9:43 [SPEAKER_02]: So we have tests that look at our liver cells actively being injured, those hepatocytostate. [SPEAKER_02]: There's is there a blockage of blood of a bile flow, those colostatic tests, and then is the liver synthesizing what it needs to synthesize, and those are things like abumin and ionar.

9:59 [SPEAKER_02]: So that's a kind of general overview of the approach to liver chemistries. [SPEAKER_02]: And patients may have a predominant element here. [SPEAKER_02]: So for example, if somebody has severe acute liver injury leading to their hepatocytes getting killed, necrosis dying, then they might have a really predominant elevation of those transaminases where they might not have as much elevation in the colostatic tests.

10:23 [SPEAKER_02]: And it might take a while before this synthetic test actually become abnormal. [SPEAKER_02]: But in practice, most of the time, there's some mixture of abnormalities and it's kind of up to us to try to identify what's the predominant abnormality here? [SPEAKER_02]: What's the most compelling, the most striking, the most unexpected, and let that lead the way?

10:41 [SPEAKER_02]: And sometimes there's not actually a very predominant feature, maybe they are all severely deranged, which is a much more concerning type of scenario. [SPEAKER_01]: Yeah, and the only other test this guy has that is abnormal, or was abnormal when he was in Asia and had that lab drill, was the GGT, the gamma-glutamel transferase.

11:00 [SPEAKER_01]: Do you use GGT in clinical practice for any other reason? [SPEAKER_02]: Yeah, yeah, definitely do occasionally. [SPEAKER_02]: It's actually not part of the standard liver chemistry panel, so it needs a dedicated separate order in most institutions. [SPEAKER_02]: And so a lot of times it's used when somebody does have, for example, an elevated [SPEAKER_02]: to try to differentiate is this more likely related to a problem with the bio flow in the liver and through the bio ducts or is this something that's more likely related to a bony problem.

11:27 [SPEAKER_02]: So that's one way to try to differentiate that is is the GGT simultaneously elevated in which case, okay, I'm much more honed in on liver and bile or is it an isolated elevation in alcohol and phosphatase in which case I might be pulled away a little bit and think in more about bony, uh, bony issues.

11:42 [SPEAKER_02]: There are also other kind of separate tests like [SPEAKER_02]: used as part of a more comprehensive liver evaluation, at least that's serology, meaning falling short of a sticking needle in and taking a liver biopsy. [SPEAKER_02]: But this is a basic overview of the kind of standard liver chemistry panel and a few associated tests like GGT and the INR.

12:03 [SPEAKER_02]: So this kind of brings me to that third question that you asked of a differential diagnosis for this patient. [SPEAKER_02]: And so the way I would characterize this is again, this young, healthy guy without past, you know, any known past medical history. [SPEAKER_02]: No meds are supplements.

12:16 [SPEAKER_02]: This is all very important kind of background for us to be keeping in mind. [SPEAKER_02]: And he had a new onset syndrome of a nausea and abdominal pain while traveling in Asia. [SPEAKER_02]: was found to have that initial abnormality on his labs of Alcoan phosphatase elevation. [SPEAKER_02]: But now we are approximately five months later, and he is having not only persistent lab abnormalities, but now new kind of evolving lab abnormalities.

12:44 [SPEAKER_02]: Characterized by a mixed pattern of both hepata cellular injury because his ALT is elevated at 96. [SPEAKER_02]: His AST is elevated at 49, but also a little bit of the colostatic pattern with a mild elevation [SPEAKER_02]: But as I mentioned, it is common for patients to have a mixture of abnormalities, meaning it's not always purely hepatocyler or purely colistatic or purely synthetic.

13:07 [SPEAKER_02]: It's common to have a mix. [SPEAKER_02]: In this situation, between those two sets of abnormalities, the hepatocylo ones actually get my attention a little bit more. [SPEAKER_02]: Having an ALT of 96 in a healthy 39 year old is something that definitely gets my attention. [SPEAKER_02]: uh both kind of have my attention, but I'm a little bit more intrigued by the uh had had a cellular uh injury.

13:32 [SPEAKER_02]: And so this is also the other important uh aspect here is the chronicity of it. [SPEAKER_02]: The fact that it has been going on for now five months and is progressive and worsening. [SPEAKER_02]: When somebody has a short term insult to the liver, if they have an acute viral infection that then gets clear, if they have a gallstone that then passes, if they take a, you know, toxic medicine drug supplement and then they stop using it, you would expect an elevation and then a resolution.

13:57 [SPEAKER_02]: But the fact that this has now persisted to progressive worsening, [SPEAKER_02]: suggests that there might be either some sort of an ongoing exposure. [SPEAKER_02]: Of course, he says he's not taking any meds or supplements. [SPEAKER_02]: Every time we've done one of these cases, where there's some concern around liver and in real life, every time I've seen this, I like grill the person every single day until finally five days later.

14:16 [SPEAKER_02]: They remember the new Chinese herbal tea that they've been drinking that they didn't think of on day one or two or three or four. [SPEAKER_02]: So I'm going to keep coming back to that question in him. [SPEAKER_02]: Is there an ongoing toxic exposure that he is ingesting [SPEAKER_02]: or is there some sort of chronic progressive process going on in his liver leading to this ongoing hepatosolular injury?

14:38 [SPEAKER_02]: What types of things can that look like? [SPEAKER_02]: The ways that our liver cells can get injured are numerous. [SPEAKER_02]: However, the fact, again, that this has been going on for five months, narrowest things down quite a bit. [SPEAKER_02]: If I have somebody who's coming in with a burrupt onset syndrome severely elevated liver enzymes into the [SPEAKER_02]: You know, 1,000s are higher.

14:58 [SPEAKER_02]: It's like, okay, this could be ischemic injury, this could be super acute toxic injury, Tylenol overdoses, things like that. [SPEAKER_02]: That does not fit this sort of a five-month-long timeline with like a modest and progressive elevation. [SPEAKER_02]: Here, I'm much more concerned again about some sort of ongoing kind of low-level exposure leading to toxicity.

15:17 [SPEAKER_02]: Again, drug supplement, something like that. [SPEAKER_02]: The other very, very, very common would be alcohol use. [SPEAKER_02]: that would fit in that exposure category, as well as things that infiltrate, get into the liver and can cause problems like adipose. [SPEAKER_02]: So fatty liver disease that can lead to these kind of very mild low-level elevations before it gets much more severe in stiato hepatitis.

15:41 [SPEAKER_02]: There are infections that can do this, hepatitis viral infections. [SPEAKER_02]: So when he was traveling in Asia, had the nausea, had the abdominal pain, did he eat something, caught a cute hep A, okay, that could happen. [SPEAKER_02]: But I wouldn't necessarily have a defined period when you get the infection and then it is cleared and those patients tend to get jaundiced.

15:58 [SPEAKER_02]: So that's a little bit less likely. [SPEAKER_02]: But there are chronic liver infections that can do this. [SPEAKER_02]: And then lastly would be some sort of autoimmune liver disease. [SPEAKER_02]: And that's kind of still at the bottom of my list right now, it can do this, but that I would want to rule out many other things first before I got down to that level.

16:13 [SPEAKER_02]: So to summarize my final summary before we move forward in this guy is I'm most concerned about some sort of an exposure. [SPEAKER_02]: medicine drug talks in like alcohol, something like that. [SPEAKER_02]: A chronic infection would be something else to look at. [SPEAKER_02]: And then, you know, obviously, I'd be assessing maybe his habitus, his level of body fat does he have fatty liver disease, something like that before pursuing something like a liver biopsy, which would need some additional serologic testing before I got to that point.

16:39 [SPEAKER_01]: Yeah. [SPEAKER_01]: That's a good summary. [SPEAKER_01]: I noticed you didn't say all you're concerned that he's eating too much protein or he's taking supplemental creatine or that he's doing too much exercise. [SPEAKER_01]: How come that's not on the differential? [SPEAKER_02]: Yeah. [SPEAKER_02]: None of those things are likely to sufficient to explain what I'm seeing here.

16:55 [SPEAKER_02]: Now taking protein would not do this unless you're taking a protein supplement that is contaminated with something that can cause this using creatine would not cause this again unless it's contaminated. [SPEAKER_02]: Exercise can contribute to elevations in these some of these tests, but again, remember that with muscle and exercise, I expect that the AST is going to be a little bit more predominant than the ALT.

17:17 [SPEAKER_02]: He has the opposite pattern here, and generally wouldn't expect it to have any significant impact on the alkaline phosphatase. [SPEAKER_02]: And so it's also kind of unclear how that would explain the trajectory. [SPEAKER_02]: It would also just be unwise and unsafe to say, ah, you're probably just [SPEAKER_01]: All right.

17:36 [SPEAKER_01]: Well, let's move on here. [SPEAKER_01]: So we move to the physical exam. [SPEAKER_01]: The patient appears well, he's sitting in gym clothes, which are a bit sweaty, but the physical exam is unremarkable, including a thorough abdominal exam. [SPEAKER_01]: He's got normal bowel sounds, no tenderness to palpation.

17:51 [SPEAKER_01]: no masses or enlargement of the liver or spleen, no jaundice. [SPEAKER_01]: And so you agree that it'd be a good idea to get some labs to see what's going on now. [SPEAKER_01]: And since the patient has no symptoms and is otherwise doing well, you're agreed to see him again next week. [SPEAKER_01]: So the patient is off to the lab to get some blood taken in.

18:07 [SPEAKER_01]: Just to be safe, let's take a picture of the liver and what's going on inside the abdomen with an abdominal ultrasound. [SPEAKER_01]: Two days later, the labs come in as does his abdominal ultrasound report. [SPEAKER_01]: So you did a lot here. [SPEAKER_01]: You ran serology for hepatitis A, B and C. These viruses, as you mentioned, are common reasons for acute spike in the transaminesis because they attack the liver cells, the hepatocytes, and it calls them to rupture.

18:34 [SPEAKER_01]: These tests were negative. [SPEAKER_01]: You also ran an electrophoresis for M proteins on antibody that has produced by specialized immune cells in a disease like multiple myeloma, for example, if the cells in the blood are producing abnormal protein fragments, they can deposit in the liver and cause damage.

18:51 [SPEAKER_01]: This was also negative. [SPEAKER_01]: For some reason, the lab also tested for antimideocondrial antibodies. [SPEAKER_01]: You didn't order that, but they tested it anyway. [SPEAKER_01]: This is a specific marker for a disease called primary, biliary colonjitis, a condition where the immune system decides to attack the small bile ducts or duct shells within the liver.

19:08 [SPEAKER_01]: This test was negative as well. [SPEAKER_01]: And the penultimate tests, the abdominal ultrasound looked for gallstones, blocking a duct, or a tumor, or significant fatty infiltration of the liver isver also normal. [SPEAKER_01]: Finally, his repeat liver labs, which I'll send to you now.

19:24 [SPEAKER_01]: So in these labs, his ALT and AST continue to be elevated. [SPEAKER_01]: His ALT is about twice the upper limit of normal. [SPEAKER_01]: His AST is more mild, but still elevated, and his GGT is also elevated. [SPEAKER_01]: So also, and again, I have three questions for you on listeners if you're playing along at home.

19:40 [SPEAKER_01]: Let's see if you can answer them in the comments. [SPEAKER_01]: So first thing, are you noticing an isolated, transaminase elevation, or is it more of a colostatic pattern that you've talked about with these labs? [SPEAKER_01]: And if so, what's the significance? [SPEAKER_01]: That's question number one.

19:54 [SPEAKER_01]: Question number two, how would you explain what's going on with this patient? [SPEAKER_01]: Two, the patient, to make sure that they have some understanding here. [SPEAKER_01]: And then three, of course, what is your new differential diagnosis? [SPEAKER_02]: Yeah, so it seems like now our ALT is essentially the same.

20:10 [SPEAKER_02]: It was previously 96 now it's 101 that's basically the same his AST was 49 now it's 59 slightly worse essentially the same and his alkaline phosphatase is about the same as well. [SPEAKER_02]: So overall we have this kind of persistent smoldering picture. [SPEAKER_02]: The directionality is slight trends towards worsening.

20:31 [SPEAKER_02]: And so this continues to have my attention of something that demands an explanation. [SPEAKER_02]: That initial evaluation, very astute clinician, would have ordered those things and it sounds like you covered a lot of the things that I had mentioned. [SPEAKER_02]: For example, some infectious possibilities, obstructive possibilities, as well as the imaging, the ultrasound, the antimideocondrial antibody getting those autoimmune causes of liver disease that I alluded to.

20:54 [SPEAKER_02]: So we've touched on a lot of things, there still remains the possibilities that I mentioned earlier of an ongoing toxic exposure, as well as fatty liver disease. [SPEAKER_02]: And so that those two remain both the most common and the things that are at the top of my list of suspicions here.

21:13 [SPEAKER_02]: There are still [SPEAKER_02]: common causes of liver disease that can develop in people. [SPEAKER_02]: So, you know, once we get sufficiently far down the rabbit hole, having ruled out more common things, we start to think more and more about, you know, types of autoimmune liver disease, deposition diseases like hemochromatosis, other other conditions like alpha 1 anti-tripsin deficiency and less and less common sorts of things.

21:38 [SPEAKER_02]: But that's still not going to be in my first pass here. [SPEAKER_02]: 2021, 2022, I think was, you know, when the initial visit to Asia happened and the subsequent follow-up, but you also provided me some labs going further back as far back as 2010. [SPEAKER_02]: And interestingly, when I look back across that whole lab trend, even back in 2010, you had an ALT in an AST level in the 40s.

22:05 [SPEAKER_02]: And one of the tricky things, this is something I come across in practice all the time, is that lab reference ranges for those transaminases are pretty [SPEAKER_02]: between institutions. [SPEAKER_02]: But real hepatology purists will say that an ALT of 40 is not normal. [SPEAKER_02]: It might be very mildly elevated on that reference range.

22:27 [SPEAKER_02]: It doesn't get my attention nearly as much as an ALT level of 1,000. [SPEAKER_02]: But that person's in acute liver failure much more likely, right? [SPEAKER_02]: But an ALT of 40 is not normal. [SPEAKER_02]: And so the true, like if you look that their professional society is called the American Association for the Study of Liver Diseases or the AASLD, and they have pretty stringent cut-offs for what normal transamination should be before you start worrying about some form of hepatocyler injury.

22:55 [SPEAKER_02]: most commonly under-recognized as fatty liver disease, even somebody with an ALT of like 28-29. [SPEAKER_02]: It might be in a territory where they're already starting to show signs of this. [SPEAKER_02]: So now, when I look all the way back to 20, this is like over a decade ago that he had some abnormalities at that point.

23:11 [SPEAKER_02]: They kind of smoldered persisted a few years later, got a little bit better, and now they're getting worse again. [SPEAKER_02]: And so with this degree of crinicity, I am much more [SPEAKER_02]: or less likely at this point some form of like autoimmune kind of disease that's like smoldering over over time that can kind of relapse and and remit.

23:31 [SPEAKER_02]: But that would be much less likely at this point without other features that I'd be looking for in in a patient like this. [SPEAKER_02]: So that's kind of my updated thought process based on the new labs you gave me and my persistent differential diagnosis that I am not wavering from at the moment.

23:47 [SPEAKER_02]: I'm sticking with my my guns at this point. [SPEAKER_02]: And so how would I talk about this with the patient? [SPEAKER_02]: Well, first I would ask him like what his understanding is of what's going on to get a sense of where is he starting from what has he been told what his is he most worried about and also by listening carefully to the way that he describes his understanding.

24:07 [SPEAKER_02]: I can also elicit and get a sense of like what's his level of health literacy, his level of education and like what level can I speak to him about or what level can I can I match him at when when speaking about this topic. [SPEAKER_02]: If he speaks to me in much more medical terms, I might you know, glean that maybe he has a background and we can speak at a different level.

24:27 [SPEAKER_02]: But ultimately my concern is that we have some sort of a long term [SPEAKER_02]: issue that has been affecting his liver and now it really seems to be declaring itself a bit more. [SPEAKER_02]: So I can see some signs of it going back over a decade ago, but it was really, really mild. [SPEAKER_02]: I wouldn't fault anybody for not making you big deal about it back then.

24:45 [SPEAKER_02]: It actually started to look a little bit better, but now it's like really starting to manifest. [SPEAKER_02]: I would say this is still not a time to panic. [SPEAKER_02]: He is not at imminent. [SPEAKER_02]: risk right now of something severe happening in the short term because that might be a big source of concern in somebody's mind.

25:01 [SPEAKER_02]: He's still we still have time to figure this out. [SPEAKER_02]: And this is something that we will get to the bottom of that. [SPEAKER_02]: I would also kind of convey that sense of confidence. [SPEAKER_02]: I can't say that I've had a scenario like this come up where it's just like, oh, you're just like never able to figure it out.

25:15 [SPEAKER_02]: There is something going on here. [SPEAKER_02]: There will be an identifiable cause that we can detect, it's just going to be a little bit of time, and fortunately we do have that time to get there. [SPEAKER_02]: So that would be the way I would talk about it with him. [SPEAKER_01]: Yeah, it seems like on the differential, you've passed the viral hepatitis, that he seems negative for that, you still have this non-alcoholic fatty liver disease or fatty liver disease on the differential, although it's less likely given his body habitus, he's very lean and appears to be active.

25:46 [SPEAKER_01]: The drug and doce liver injury still on the differential, especially if he's not really reporting all of the things that he's taking, especially in an active population, [SPEAKER_01]: particularly like Jim Ratt's, you might be suspecting a supplement that's either contaminated or even just has the risk of causing this anyway.

26:04 [SPEAKER_01]: So Sinephroening caffeine, for example, has been directly associated with severe rabidomylysis, which can cause some elevated transaminases, a fedra, which has been banned, is also linked to rabidomylysis, sometimes fatal cases. [SPEAKER_01]: many oral andabolic androgenic steroids can be hepatoxic, many herbal dietary supplements, things like hydroxycut, garsinia, Cambodia, and herbal life supplements have been associated with this, so it's still on the differential until, yeah, effectively, he's, you know, admitted and you're making sure he's not taking these, and you mentioned some of the other autoimmune conditions that we might not have evaluated for.

26:44 [SPEAKER_01]: Again, I noticed that you're still not saying exercise, although we don't have any other labs, it would be nice to have something like a creatine kinase to see like, oh, is that also elevator, like a myoglobin or lactate dehydrogenase, aldolase, something like that. [SPEAKER_01]: You would expect those two also be elevated if this was exercise, but unfortunately the lab while running your antimioticontrial antibody wants, the sample and could not do that for you.

27:10 [SPEAKER_01]: So the initial workup for this patient included the viral markers and a liver ultrasound, all of which were negative. [SPEAKER_01]: You've now ordered a third set of labs. [SPEAKER_01]: But the patient says that he has some travel so we can't get them done for a while about two months after he returns.

27:24 [SPEAKER_01]: He says he travels a lot for work, which he generally enjoys. [SPEAKER_01]: Other than the fact that he doesn't get to work out as much as he does when he's at home, [SPEAKER_01]: his new liver panel comes in and I'm going to send those to you now. [SPEAKER_01]: So yeah, the new liver panel came back or everything was normal.

27:40 [SPEAKER_01]: Normal liver associated enzymes, STNALT, normal GGT, normal ALCFOS, Bill of Ruben, you name it. [SPEAKER_01]: Okay, so it's question time for you once again, Dr. Rockie, as well as the listeners at home. [SPEAKER_01]: First question, one, how do you explain the result, liver and zymalovation, two, what is your final diagnosis?

28:00 [SPEAKER_01]: And three, again, how are you explaining this to the patient? [SPEAKER_01]: Yeah. [SPEAKER_02]: So very good news for him in that his ALT is back down now into the 40s and his alkaline phosphatases mildly improved from prior, most of the rest of the labs are in a more or less kind of similar place, but generally a trend towards improvement, which is super reassuring.

28:22 [SPEAKER_02]: And so this leaves us with a few different possibilities. [SPEAKER_02]: If there was, for example, an ongoing toxic exposure that may have been removed for long enough for things to get better, whether we ever identify or not, that's one possibility. [SPEAKER_02]: There are many other infections beyond just Hep-A, Hep-C, that can be talked, you know, injurious to the liver and those viral infections can, for example, take a while and they can ultimately be cleared and lead to improvement.

28:48 [SPEAKER_02]: I really don't think that on the barbell medicine podcast relieving me down to an esoteric, you know, hepadotropic infection that we need to get to. [SPEAKER_02]: But in real life, that would be on the, [SPEAKER_02]: list of possibilities of things that can do this. [SPEAKER_02]: Autoimmunity as we have talked about a couple times so far is classically a pathologic phenomenon that can relapse and remit and so people can have more active forms of autoimmun disease followed by periods of kind of more relative [SPEAKER_02]: But interestingly, I mean, you mentioned that he is, I think, generally quite healthy.

29:29 [SPEAKER_02]: We did not see evidence of severe, you know, fatty liver infiltration on his imaging. [SPEAKER_02]: And so with this timeline, if he did not have substantial weight loss, that would no longer be a sufficient explanation for this kind of thing. [SPEAKER_02]: Fatty liver disease, especially when you're manifesting elevations and liver enzymes does not spontaneously remit absent substantial clinically significant weight loss, at least.

29:50 [SPEAKER_02]: five plus percent and gets better, the more percent weight loss that somebody has. [SPEAKER_02]: So if that has not changed, then now I've removed that from my list of possibilities. [SPEAKER_02]: And you had mentioned, you know, that he is an avid exerciseer. [SPEAKER_02]: He traveled, maybe some changes in his exercise habits.

30:05 [SPEAKER_02]: And so that kind of brings us back to that original possibility, which we have never excluded from our list of considerations. [SPEAKER_02]: But rather said, it would be unwise to like commit to that as our diagnosis up front, [SPEAKER_02]: And so a lot of times among athletes, people who are highly active, people who pursue consultations with us or ask us this question on the forum.

30:26 [SPEAKER_02]: They're like, I had these incidentally found elevated liver tests. [SPEAKER_02]: But I train all the time and I know that it can cause it what should I do, sometimes it's just a matter of, yeah, you're might not like it, but you might need to just suck it up and take a few days off for schedule your next lab draw, you know, at least a few days after your last training session, maybe if you're trained during the week, you know, maybe reschedule your Monday session and get some labs done Tuesday morning to give yourself, I don't know, four days is maybe reasonable, but you know, people are different and you might still have some persistent elevations in that case.

30:55 [SPEAKER_02]: But you're right, that along the way, you know, I would have already, I almost always do alongside these things, check some of those other tests like in LDH like a CK, some of those other things to try to differentiate where is the potential site of pathology here and so yeah, I'm back to some sort of exposure that is no longer present and infection that was cleared that I might never actually be able to prove auto immunity that is, you know, in a remitting phase that is less likely at this point versus.

31:23 [SPEAKER_02]: the removal of the exercise stimulus that may have contributed to some elevation in his liver enzymes. [SPEAKER_02]: Which of those it is? [SPEAKER_02]: I think would still require a little bit more longitudinal follow up before you can put like a final stamp of there's absolutely nothing else here.

31:38 [SPEAKER_02]: This is just exercise, but that may be where we're headed at this point in the case. [SPEAKER_01]: Yeah, it's pretty interesting case. [SPEAKER_01]: Apparently for this particular individual before every lab draw that he remembers [SPEAKER_01]: is an AM exerciseer and so yeah, the final diagnosis they arrived at was exercise induced elevations in his liver associated tests.

32:02 [SPEAKER_01]: Now, you spell this out quite nicely that with exercise, the reason why these liver associated enzymes go up is because there's some muscular damage and subsequently there's a release of these intracellular enzymes into the blood and you pick that up on [SPEAKER_01]: blood test. [SPEAKER_01]: Now, how that happens, the strenuous exercise depletes ATP that's energy and damages some of the ion channels of the muscle cells themselves, which leads to an electrolyte imbalance.

32:32 [SPEAKER_01]: Effectively, the muscle cell now gets flooded with calcium and sodium. [SPEAKER_01]: This causes the cell to swell and together the cell swelling and the electrolytes now inside the cell break down the muscle cells membrane, which is the sarcolemma. [SPEAKER_01]: that allows the intramuscular enzymes like AST, ALT, creatine kinase, et cetera, to leak into the extracellular space and subsequently the bloodstream, which brings me to point number one.

32:58 [SPEAKER_01]: While alanine, amino transferase, and aspartate amino transferase, these are also often called liver enzymes. [SPEAKER_01]: That's kind of a misnomer. [SPEAKER_01]: they should be more appropriately termed liver associated enzymes because they're found in several tissues, particularly skeletal muscle.

33:14 [SPEAKER_01]: In this case, also the hard kidneys, ALT's less expressed in the muscle, but it's there just at a smaller or lower concentration. [SPEAKER_01]: So, when a person engages in resistance training, especially resistance training that involves a lot of eccentric loading, where the muscle produces force as it gets longer, that's a downward phase of most exercises.

33:37 [SPEAKER_01]: The muscle can experience micro trauma, which, again, increases permeability, allowing enzymes like creating kinase, AST, ALT to leak into the bloodstream. [SPEAKER_01]: This is normal physiology, not necessarily a sign of liver dysfunction, which brings me to point number two. [SPEAKER_01]: It's unavoidable.

33:53 [SPEAKER_01]: In a study of 15 healthy men who lifted weights for one hour at 70% of the 100% of participants saw bump in their deliver associated enzymes, the AST and ALT. [SPEAKER_01]: The average is about three times normal for AST with a smaller bump for ALT. [SPEAKER_01]: It seems to be more pronounced in people who are untrained or who are coming back to exercise rather than individuals who are chronic exercises or life-long exercises.

34:18 [SPEAKER_01]: But lifelong trainees cannot really avoid this entirely either. [SPEAKER_01]: It just seems to happen. [SPEAKER_01]: Just at a lower level. [SPEAKER_01]: We think the reason why it happens at a lower level or that there are smaller increases is due to a couple things. [SPEAKER_01]: One, there's reduced muscle protein breakdown in trained individuals during a workout.

34:40 [SPEAKER_01]: And that seems to be an adaptation, also one of the mechanisms by which people actually grow new muscle. [SPEAKER_01]: The muscle protein breakdown goes down enough so that the muscle protein synthesis muscle growth actually outpaces that so you get bigger muscles. [SPEAKER_01]: The other thing is you get an increase in plasma volume from training a long time effectively.

34:58 [SPEAKER_01]: If you sweat a bunch, your body adapts more fluid. [SPEAKER_01]: So there's like a little delusion of things in the blood, including liver associated enzymes. [SPEAKER_01]: And there's also it and you might find this interesting. [SPEAKER_01]: an increase in albumin production in lifelong exercises and albumin binds to calcium.

35:14 [SPEAKER_01]: I think it's like 40% of the body's calcium is in albumin, so there's less of that calcium mediated breakdown of the sarcolemma that can happen because more albumin has been produced. [SPEAKER_01]: So a little nerdy as we are known for here. [SPEAKER_00]: Use to make a podcast. [SPEAKER_01]: Yeah.

35:29 [SPEAKER_01]: The elevations tend to be higher in men, compared to women, they generally have more muscle mass and a higher baseline level of these liver associated enzymes. [SPEAKER_01]: There's also a strong genetic influence with some individuals being, quote, high responders to exercise. [SPEAKER_01]: Not in the terms of seeing gains necessarily.

35:45 [SPEAKER_01]: It's not necessarily like correlation. [SPEAKER_01]: where the higher your liver associated in times are the more gains you have, but some people just genetically will have a more robust increase in their liver associated in times. [SPEAKER_01]: We see that also with CK, there's like a condition called hyper CKemia where people just put out a ton of CK, creating kinase.

36:04 [SPEAKER_01]: They don't have rabdo, but just their genetics sort of lot that they've they've inherited. [SPEAKER_01]: and other factors like exercising and hot or humid environments, tend to produce higher levels of these liver-associated enzymes as does alcohol consumption. [SPEAKER_01]: Point number three here, it takes a while to normalize.

36:22 [SPEAKER_01]: Based on available data, AST and ALT continue to rise 48 hours post-workout, and they may take up to four to five days to peak, and they typically don't normalize until 10 to 12 days after workout. [SPEAKER_01]: Provided a person is continuing to exercise. [SPEAKER_01]: Part of this delay is structural.

36:41 [SPEAKER_01]: The muscle cells, sarcolemma, it's membrane, doesn't degrade all at once. [SPEAKER_01]: It's a gradual process, which makes some of the intra-muscular intracellular contents slowly leak out, not all at once. [SPEAKER_01]: Also ALT tends to peak later with some studies suggesting it takes as long as six to seven days to peak postwork out.

36:58 [SPEAKER_01]: Could be influenced by the longer half-life of ALT compared to AST. [SPEAKER_01]: But yeah, it's kind of up for debate right now. [SPEAKER_01]: Point number four here is that it's mostly harmless, particularly from exercise, because it's a transient benign phenomenon that represents skeletal muscle damage and repair rather than a condition that leads to long term issues of the liver.

37:19 [SPEAKER_01]: Because these enzymes leak from a sort of microtare in the skeletal muscle fibers rather than the liver itself, the liver is usually doing fine. [SPEAKER_01]: And this is true even when an athlete or a lifter appears to have sort of chronic elevation as in this case. [SPEAKER_01]: We've got like 12 years of data showing this like chronic elevation and you're like, is this a smoldering sort of disease or is this person just always exercising before every lab draw?

37:45 [SPEAKER_01]: And this exact case report that I was referred to a gastroenterologist who basically said, hey, don't work out for like a week, come back in and then we'll test again and then his labs normalized. [SPEAKER_01]: But it is a normal healthy physiological adaptation of regular training. [SPEAKER_01]: So, you know, when explaining this to a patient, probably would want to emphasize that, so they're not afraid of some unnecessary anxiety around.

38:08 [SPEAKER_01]: Well, why are my labs elevated? [SPEAKER_01]: I'm, I'm otherwise healthy. [SPEAKER_02]: Or is this exercise harming my liver? [SPEAKER_02]: Because depending on how you phrase this again, if the focus of this, [SPEAKER_02]: you know, understandably the diagnostic momentum here is oriented towards some sort of liver pathology, but if you kind of depend on how you explain it, it might convey the message implicitly that like, oh, you're harming your liver by exercise.

38:29 [SPEAKER_02]: I think which is not the case. [SPEAKER_01]: Yeah, it actually brings up an important point, you know, in a survey of physicians that were given a case where a young asymptomatic man had elevated liver associated enzymes, 56% of those physicians failed to list exercise induced muscle damage in their differential, and over 60% listed primary liver disease as their diagnosis.

38:50 [SPEAKER_01]: So why do you think clinicians often overlook exercise history in the context of screening asymptomatic young adults? [SPEAKER_02]: Yeah, I mean, I see this all the time, although it's less often in asymptomatic adults because it's more in the hospital ER setting where everybody is kind of trained to think in terms of worst case scenario, types of thinking.

39:08 [SPEAKER_02]: I think it's a combination of things, probably under emphasis in training, also that it's just not something that people see very often. [SPEAKER_02]: So if a traditional regular primary care doc is seeing, you know, a thousand patients with incidentally found elevated liver enzymes, [SPEAKER_02]: the overwhelming majority of these are going to be related to fatty liver disease and alcohol, at least in, you know, most clinics in the United States less and less likely related to maybe chronic capsii or some drug-induced issue or something else, the frequency with which they will be seeing exercise induced elevations is super, super low.

39:44 [SPEAKER_02]: And, as I said this whole time, that should not be your first assumption when you see this type of thing. [SPEAKER_02]: Even if I saw somebody who told me, I'm a regular exerciseer and I found elevated liver enzymes in them. [SPEAKER_02]: My first thought is not, oh, this is probably just exercise, but what supplement are you taking?

40:01 [SPEAKER_02]: Because again, I need to be finding the things that are more dangerous, more life-threatening, more potential for morbidity in this patient, rather than assuming the least dangerous cause of [SPEAKER_02]: Now, I might eventually get there as, of course, we did here, but I would not feel comfortable making that assumption up front.

40:19 [SPEAKER_02]: It is totally fine to tell somebody or to inquire about their exercise habits and to try to repeat the tests absent exercise. [SPEAKER_02]: But with that repeat test, I would probably still be sending a bunch of other stuff at that same time. [SPEAKER_02]: So I think it's, [SPEAKER_02]: A combination of just like how prevalent is this as a problem, how often are people seeing this in the regular practice and then what's the potential danger or risk of thinking about this first compared with thinking about actual dangerous things first and then like ending up at this later on now as to your point many of them will never get to this point.

40:53 [SPEAKER_02]: One of the more memorable cases, I think I mentioned on this podcast before, was a young patient I had who had severe rabidomyelysis and his CK was greater than 100,000. [SPEAKER_02]: So, severe severe rabdo. [SPEAKER_02]: His AST and ALT were somewhere between 3 and 4,000, which is our levels that we usually see with acute liver failure.

41:13 [SPEAKER_02]: So everybody was losing their minds. [SPEAKER_02]: He had liver enzymes. [SPEAKER_02]: They were calling for acute liver failure, even though his INR was completely normal. [SPEAKER_02]: And he's, you know, mentation. [SPEAKER_02]: He was feeling fine in that way. [SPEAKER_02]: So he didn't actually meet diagnostic criteria for that kind of thing.

41:27 [SPEAKER_02]: But again, worst case scenario, if this guy's liver shutting down for whatever reason, like that would be something that you could die from. [SPEAKER_02]: And then when I saw the CK was greater than a hundred thousand, I said, oh, this is way more likely to be muscle elevation. [SPEAKER_02]: It's just so high because of the degree of severity of his rapdo.

41:42 [SPEAKER_02]: And sure enough that ended up being the case, but it was not necessarily safe to assume that up front and I get called for admissions all the time on people with abnormal liver enzymes And they haven't checked the CK and then when I do check the CK the person ends up having rabdo and then we do the exercise history and oh, yeah, it all it all kind of fits or something like that.

42:00 [SPEAKER_02]: So [SPEAKER_02]: really common. [SPEAKER_02]: It's just a, I think it's just a matter of prevalence and training and exposure, and then we're all trained to think in terms of worst case type stuff, dangerous stuff before we assume the more benign things. [SPEAKER_01]: Yeah. [SPEAKER_01]: That all, that makes sense to me, especially considering, you know, there's some gaps, uh, when a clinician's looking at, uh, given set of labs, given, you know, history of present illness, uh, given narrative, you know, but there's just holes there.

42:24 [SPEAKER_01]: So I'm trying to create a scenario where you'd feel very confident that insane, [SPEAKER_01]: Yeah, this is definitely exercise-induced elevation of liver-associated enzymes, and so I think about a patient comes in there again. [SPEAKER_01]: They're asymptomatic, but they just have this lab abnormality, but it is accompanied by an elevated creatine kinase.

42:45 [SPEAKER_01]: It's elevated by lactate dehydrogenase that's up. [SPEAKER_01]: They say they exercise all the time. [SPEAKER_01]: They have, again, no symptoms. [SPEAKER_01]: They got a normal [SPEAKER_01]: for you. [SPEAKER_01]: Is there any scenario, you know, and it may be a normal GGT as well? [SPEAKER_01]: Is there any scenario where you can feel very confident?

43:08 [SPEAKER_01]: Like, yeah, this is exercise. [SPEAKER_01]: We don't need further testing or is it more like, you came into the medical office, now my spicy senses are tingling. [SPEAKER_02]: I don't think that there's one of these scenarios where I see that initial set of tests and I say no, there's just no need for additional testing.

43:24 [SPEAKER_02]: I would probably recommend and feel best if there was some form of repeat testing regardless. [SPEAKER_02]: It may be after a period of pausing exercise and it also depends on how much, how confident I am in my history taking from this person, how much I trust that they are not in fact using any sort of a supplement that may be contributing to it because I just see that so so often of supplement induced liver injury.

43:45 [SPEAKER_02]: That I'm going to even in an exercise or it's like it's probably more at least as common that somebody is using a supplement that's causing it as the exercise itself is causing it And I need to entertain both possibilities. [SPEAKER_02]: Yeah, just to see a one time, you know upfront snapshot elevation of ALT into the 90s and be like, Ah, nothing to nothing to repeat nothing more about I would not actually ever do that.

44:04 [SPEAKER_01]: Yeah, so that brings me to point number five, GGT is an enzyme that has been put forth this sort of this differentiator in cases like this where some have suggested that look if you have a person with an isolated elevated transaminitis, so just elevated AST and ALT, but everything else is fine, including their GGT.

44:26 [SPEAKER_01]: that effectively you could say most likely this is due to exercise. [SPEAKER_01]: And the reason why is that GGT is not in the muscle, it's absent there. [SPEAKER_01]: And it doesn't typically rise postwork out. [SPEAKER_01]: Therefore, if a patient presents with highly elevated AST and ALT, but a normal GGT, then maybe you could just write this off as exercise and do muscle damage.

44:48 [SPEAKER_01]: Now, [SPEAKER_01]: To me, that seems a bit aggressive, not knowing anything else. [SPEAKER_01]: I need to have some other assurances, like maybe a recent hepatitis serology set, for example, maybe an abdominal ultrasound. [SPEAKER_01]: But this particular patient was interesting because his GGT was elevated.

45:04 [SPEAKER_01]: And so then you're like, [SPEAKER_01]: that shouldn't happen. [SPEAKER_01]: And things aren't so simple in medicine. [SPEAKER_01]: Sometimes this does does happen. [SPEAKER_01]: This can be elevated postwork out. [SPEAKER_01]: There's been some studies suggesting up to 10% of individuals who over an half marathon that their GGT has elevated.

45:20 [SPEAKER_01]: Two potential mechanisms here. [SPEAKER_01]: One is altered. [SPEAKER_01]: liver blood flow during strenuous exercise, diverting blood away from the internal organs and towards the skeletal muscles, so this can decrease again the blood flow, and so you get some increase in permeability of the hepatocytes of the liver cells, which allows liver enzymes like GTT to leak into the bloodstream.

45:42 [SPEAKER_01]: There's also a thought that this is part of the repair process of muscular damage, which we discussed in relationship to glutathione and the damage to the muscle cells membrane the sarcolemma. [SPEAKER_01]: So GGT is thought to be involved in making amino acids available to cells for tissue repair.

45:59 [SPEAKER_01]: So those are the two mechanisms there, but yeah, this patient had an elevated GGT. [SPEAKER_01]: So like you couldn't even write that off. [SPEAKER_02]: Yes, that is part of why, you know, my answer was no, there is no scenario where I would just say no further testing needed because testing it's just never so simple, there are all tests are imperfect and there can be, you know, failure to detect things that it should detect or over detection of things that shouldn't and.

46:22 [SPEAKER_02]: you know, I think it's more people want this stuff to be simple and easy to interpret and it is just fundamentally not. [SPEAKER_02]: And once you have been doing this for long enough and you have looked at enough labs and interpreted them and correlated them to what's going on with the patient you realize, you know, the flaws and the gaps that you have to kind of mentally account for so that you don't make mistakes and you're thinking by being overconfident in your lab numbers.

46:45 [SPEAKER_01]: Yeah. [SPEAKER_01]: Oh, and speaking of an overconfident lab numbers, one thing that really bothered me about this case, the dude had an elevated alquefoss, like almost the entire time. [SPEAKER_01]: And I'm like, I cannot square this with anything that I know at this particular time relating to exercise.

47:02 [SPEAKER_01]: So down on the rabbit hole, I went. [SPEAKER_01]: Okay. [SPEAKER_01]: It turns out, alquefoss is routinely elevated post-exercise, [SPEAKER_01]: particularly in load bearing exercise, because there's some additional bone-eat terms at the time. [SPEAKER_01]: Okay. [SPEAKER_01]: It on average peaks about 20 minutes post workout and takes close to an hour to return to normal.

47:24 [SPEAKER_01]: So if this guy was going in and working out hard in the morning, then going right to the lab, that's funny. [SPEAKER_01]: The timeline makes sense to me, but yeah, when I was looking at his labs, I'm like, look. [SPEAKER_01]: Again, if it was just AST and ALT and the traditional pattern GDT was normal, no outfoss, no history of this stuff over 12 years.

47:42 [UNKNOWN]: Sure. [SPEAKER_01]: He could make a case that like, yeah, I would have picked up on exercise induced elevations earlier, but yeah, kind of threw me off the cent. [SPEAKER_02]: Yeah, that's interesting. [SPEAKER_02]: I think, you know, I'll stick by my, my position that his, a, a outcross elevation was really quite mild and actually wasn't the center of my concern.

47:59 [SPEAKER_02]: If it was significantly higher than that would have definitely drawn my attention in a, in a different direction and just to like contrast it, for example, with a [SPEAKER_02]: a patient who I spoke to, just within the past couple days, this was a woman who has, I would say, mildly elevated transaminases into, there are similar ranges to what we see here, however, her alkaline phosphatases in the 400 to 500's range.

48:24 [SPEAKER_02]: So much, much, much higher. [SPEAKER_02]: Like five times, greater than five times, kind of the upper limit of normal. [SPEAKER_02]: That is like where my attention locked in. [SPEAKER_02]: I said, oh, I'm not nearly as concerned with the transaminases. [SPEAKER_02]: but that elevation and alkaline phosphatase that has been persistent and chronic.

48:39 [SPEAKER_02]: And I'm actually quite confident that this patient has PBC, primary bilioric colonjitis, has that condition that you actually mentioned that they tested for in this case as well. [SPEAKER_02]: And so that's just a very different lab pattern that led me in a very different direction of how I was thinking about that patient.

48:54 [SPEAKER_01]: Yeah. [SPEAKER_01]: So I think this case proves that a lab value without lifestyle context can be hard, potentially costly to interpret both ways, either not enough work up, could potentially put a patient on a road to unwanted disease and unwanted outcomes. [SPEAKER_01]: And then over interpretation, [SPEAKER_01]: If this patient had a liver biopsy, that would be a bad outcome as well.

49:17 [SPEAKER_01]: But ultimately, the leakage of these enzymes, these transaminases, and even GGT from exercised muscle cells was well documented. [SPEAKER_01]: But there's a disconnect between exercise science and modern medicine. [SPEAKER_01]: To start, you kind of alluded to this, there's probably a cognitive bias stemming from calling these liver function tests, suggesting that there's like a liver only origin, which is not true, they are present in many cells, including the muscle, so not just the liver, yet because of that naming convention is hard to look past the liver, even when the patient is perfectly healthy and asymptomatic.

49:49 [SPEAKER_01]: next physicians often don't ask about exercise. [SPEAKER_01]: It's hard to come up with a solid number on this, but available data suggests that less than half of patients in the primary care setting have any documentation of their exercise habits in their chart. [SPEAKER_01]: So if we're not asking about exercise, it's hard for that to arrive on the differential.

50:07 [SPEAKER_01]: So, my thought is that as a result of being liver-focused and exercise agnostic, many clinicians, C.A. [SPEAKER_01]: slightly high ALT, the order and ultrasound, they run the hepatitis serology, and they repeat the panels all without ever asking about the patient's exercise habits. [SPEAKER_01]: The costs of this can be immense, not only financially, but also in patient stress and anxiety.

50:28 [SPEAKER_01]: Often, if you could wave a magic wand and change clinical practice overnight, [SPEAKER_01]: How would you have doctors approached this issue the next time the lab result hits their inbox, if at all? [SPEAKER_02]: Yeah, I think that I hear the point that you're making here that there is a little bit more information to be gleamed that could impact the way that people go about things.

50:49 [SPEAKER_02]: I think that there is a greater potential for harm by missing genuine liver disease than there is by nudging people to more often discount abnormalities in liver chemistry tests as being attributable to exercise. [SPEAKER_02]: Now, I think you and I both agree [SPEAKER_02]: If more clinicians took an exercise history and were willing and able to effectively counsel patients on exercise and recognize that in some situations exercise may well impact the accuracy and reliability and validity of their their tests, then it might nudge practice in a little bit of a direction to where.

51:25 [SPEAKER_02]: you know, there might be a little bit less of if you wanted to call it like diagnostic overuse in these edge situations. [SPEAKER_02]: At the same time, I think the overall population prevalence of abnormal liver chemistry is related to fatty liver disease where people are actually not exercising when they should.

51:41 [SPEAKER_02]: Even if it was right before the lab, it's like, I would rather than that is far, far higher than I think the incidence of like, let's call it diagnostic misadventures as a result of somebody exercising too close to their to their lab draw. [SPEAKER_02]: But, you know, taking a detailed comprehensive history and making sure that your the data you're getting is accurate and interpretable is a fundamental principle and in all sorts of ways not not different than if I get a lipid panel on somebody and the triglycerides are off the charts my first question is was this fasted or not because that is something that can impact triglyceride accuracy.

52:12 [SPEAKER_02]: You can make a similar case that if you see somebody who's liver, you know, associated chemistries like this are abnormal, a question that you might ask is whether there was, you know, active or vigorous exercise done shortly before the test. [SPEAKER_02]: And that might impact your confidence in the results.

52:27 [SPEAKER_02]: It should not lead you to discount them or to not repeat them. [SPEAKER_02]: but rather maybe to repeat them in a different way, similar to how I might repeat a lipid panel in a fasted state if I wanted, if I needed to get a more accurate level, fasting triglyceride level, which is not often the case anyway, but it's something that would come to mind.

52:45 [SPEAKER_02]: So those are kind of my thoughts. [SPEAKER_01]: Yeah, what I'm hearing you say is that in a new, undifferentiated patient, it would be very challenging to overlook elevation in transaminated cases and just chalk it up to exercise unless you had a ton more information. [SPEAKER_01]: And even then, you'd be kind of stretching your clinical acumen to say, okay, I feel okay about this, but you wouldn't feel great.

53:08 [SPEAKER_02]: Yeah, exactly. [SPEAKER_02]: I would probably be repeating them and I'd probably be bringing you back to really about what supplements you're taking again and make sure you're not drinking too much [SPEAKER_01]: Yeah. [SPEAKER_01]: I think the best case scenario is if you had more clinicians asking about exercise, it's highly likely they're more likely to go to counsel them on exercise and to extend that's beneficial.

53:26 [SPEAKER_01]: Yes. [SPEAKER_01]: Yeah. [SPEAKER_02]: That might do more to fix more elevated liver enzymes that are actually from fatty liver disease that would respond to more vigorous exercise. [SPEAKER_01]: Yeah. [SPEAKER_01]: Yeah. [SPEAKER_01]: Yeah. [SPEAKER_01]: Yeah. [SPEAKER_01]: Yeah. [SPEAKER_01]: That number needed to treat, I think, is what 12, the primary care physician needs to counsel 12 patients to get one person to take up and sustain exercise for a year.

53:42 [SPEAKER_01]: Pretty, pretty good numbers. [SPEAKER_01]: Um, okay, let's let's turn this on at side for a second for listeners who may be dealing with a skeptical primary care physician, not Dr. Baroque, of course. [SPEAKER_01]: There are a few strategies that I would like to put forth to help them avoid maybe unnecessary care and, you know, anxiety without a big time risk of missing a serious condition.

54:04 [SPEAKER_01]: So, [SPEAKER_01]: one you could inform your physician, hey, look, I engage in heavy resistance training and endurance exercise and I worked out shortly before my last blood draw. [SPEAKER_01]: I understand that intense exercise causes muscle micro damage, which can leak enzymes like AST and ALT into the blood that can look like liver damage.

54:23 [SPEAKER_01]: Can we follow up with some labs in a week or two after I take a break from exercise before any further imaging or specialist referrals? [SPEAKER_01]: That seemed reasonable to you. [SPEAKER_02]: Yeah, seems reasonable and tacking on a CK would be also supportive in that context as well.

54:40 [SPEAKER_02]: I think that's fair. [SPEAKER_01]: Yeah, for those who want to avoid taking a week off, I can just imagine you being counseled to take a week off. [SPEAKER_01]: On the one hand, you know, you probably would do it just to avoid any, you know, further, a curfuffle, but maybe maybe, maybe you wouldn't, maybe you push back.

54:56 [SPEAKER_01]: Look, hey. [SPEAKER_01]: Doc, can we repeat the test? [SPEAKER_01]: Can we also add a CK? [SPEAKER_01]: Can we add a lactate dehydrogenase, perhaps? [SPEAKER_01]: And if my CK is highly elevated alongside my ST and ALT, it should theoretically confirm that these enzymes are coming from my muscles rather than my liver.

55:10 [SPEAKER_01]: Would you be on board with that in isolation? [SPEAKER_01]: I suspect no. [SPEAKER_01]: But... [SPEAKER_02]: Yeah, saying confirm is a high degree of confidence there. [SPEAKER_02]: And so I think this is just a case where talking about it in the abstract is a little more challenging than having a real patient scenario in front of me to work through and see my like level of comfort.

55:28 [SPEAKER_02]: Now, if I'm confident that this patient has good access to care and follow up and they're willing to. [SPEAKER_02]: you know, we're willing and able to monitor things over time, then doing a repeat with a CK. [SPEAKER_02]: And if it's all kind of correlated, and because this is also important, is remember how I was talking about how labs can have a predominant abnormality.

55:47 [SPEAKER_02]: And so if the, you know, transaminases are much higher than the alkaline phosphatase, it's like a much more hip-hat of cellular pattern. [SPEAKER_02]: If the alkaline phosphatase and the bilirubin are much higher, it's a more colostatic pattern. [SPEAKER_02]: It could [SPEAKER_02]: So I'm imagining a scenario, for example, where somebody's transaminated says are like, you know, 180, 200, something like that.

56:06 [SPEAKER_02]: But the CK is like just very mildly elevated above the, you know, lower limit of above the limit of normal. [SPEAKER_02]: It's like, [SPEAKER_02]: I still am reluctant to chalk it up to that because the degree of abnormality is disproportionate so need to be kind of concordant in that way for me to even feel okay and I might still want to monitor it over time because what's the worst case scenario in in something like that if you are to just assume that it's exercise is instead you're you're missing.

56:32 [SPEAKER_02]: some sort of smoldering long-term process, and then years later, the person ends up developing more advanced liver disease, potentially even cirrhosis, potentially even needing a liver transplant. [SPEAKER_02]: Like, this sounds kind of crazy or catastrophic, but this... [SPEAKER_02]: truly does happen.

56:48 [SPEAKER_02]: And so like the patient that I alluded to, who I think has PBC, she has had some degree of abnormality and like chronic symptoms like itching and fatigue for the better part of a decade. [SPEAKER_02]: And a middle-aged to older woman with like chronic fatigue and itch for like a decade, I'm like, okay, this may well be PBC.

57:06 [SPEAKER_02]: And that is something that is well recognized, but the typical diagnostic delay in that condition is very long. [SPEAKER_02]: and I would prefer to not be a contributor to that degree of diagnostic delay by saying it's just your physical activity. [SPEAKER_02]: So that's kind of my hesitation.

57:20 [SPEAKER_02]: It would need to be a compelling story. [SPEAKER_02]: Good follow up. [SPEAKER_02]: Concordant results that are kind of like tracking together reliably over time. [SPEAKER_02]: again, like you quoted kind of average stats for what happens to these labs after exercise, the average time to increase, to peak, to come down.

57:35 [SPEAKER_02]: There's still a lot of variation around that. [SPEAKER_02]: I think you and I have both had our labs drawn and we have not ourselves taken prolonged time away from exercise even when we've gotten labs done. [SPEAKER_02]: And our liver chemistries, at least I know mine, are not terribly elevated.

57:50 [SPEAKER_02]: And so there actually weren't elevated at all the last time I got. [SPEAKER_02]: And so maybe there's some degree of adaptation, maybe I, you know, had a lighter session on Friday, maybe I had the weekend off and maybe I got them done Monday morning. [SPEAKER_02]: And that was just long enough for stuff to clear.

58:04 [SPEAKER_02]: But that's been my own personal experiences that it's not even the case for everyone that this always happens. [SPEAKER_02]: There's a lot of variation between people. [SPEAKER_01]: Yeah. [SPEAKER_01]: All right. [SPEAKER_01]: In the final scenario, this is for the minimalist or the person wants to do the least.

58:15 [SPEAKER_01]: Yeah. [SPEAKER_01]: I suspect you will block at this idea. [SPEAKER_01]: A doc looks. [SPEAKER_01]: And so I'm completely asymptomatic. [SPEAKER_01]: I feel fine. [SPEAKER_01]: The standard guidelines suggest that mild elevations, so less than, you know, three times the upper limit of normal, I can be safely monitored with the expectant observation.

58:32 [SPEAKER_01]: I'd prefer to watch in [SPEAKER_02]: Oh, I'm actually completely fine with that. [SPEAKER_00]: Oh, wow. [SPEAKER_02]: And the reason is the timeline that you gave me four to six weeks is not a long time. [SPEAKER_02]: If you said, I'd rather just watch and wait and recheck in like, you know, a year and a half.

58:50 [SPEAKER_02]: Uh, no, I don't feel as good about that. [SPEAKER_02]: But again, this is, this was actually part of my counseling to this hypothetical or this real patient that we walk through where I said, [SPEAKER_02]: Look, there's some elevation. [SPEAKER_02]: There's something going on here. [SPEAKER_02]: We will get to the bottom of it.

59:02 [SPEAKER_02]: But the good news is that it's not severe, life-threatening, imminently. [SPEAKER_02]: We have time to figure it out. [SPEAKER_02]: So I was kind of allaying that concern. [SPEAKER_02]: And that's also why, like, when he said, oh, I have travel, and I'm going to recheck them when I get back, I'd be like, okay, you know?

59:15 [SPEAKER_02]: There's a non-zero risk there, but I'm actually quite comfortable with it, just because the degree is not in a severe situation. [SPEAKER_02]: Somebody has, [SPEAKER_02]: Transaminationases that are actively rising 300, 400, 500, 600. [SPEAKER_02]: Like, no, no, no, no, we need to do this now.

59:30 [SPEAKER_02]: But with this degree of elevate, that's not a big deal at all. [SPEAKER_02]: That's totally fine. [SPEAKER_01]: And for we close out, hear the five things I want you to take away from today's case. [SPEAKER_01]: 1. [SPEAKER_01]: ALT and AST are liver associated enzymes. [SPEAKER_01]: They're not exclusively liver enzymes.

59:45 [SPEAKER_01]: They're found in the muscle, and exercise releases them into your bloodstream. [SPEAKER_01]: 2. [SPEAKER_01]: Resistance training can elevate them to well above the normal range, and that's completely normal physiology, especially if you're new to training. [SPEAKER_01]: 3. [SPEAKER_01]: These enzymes can stay elevated for up to 10 to 12 days after a hard workout, so timing matters [SPEAKER_01]: 4.

1:00:05 [SPEAKER_01]: Your physician might not think to ask you about your exercise habits when they see these numbers and so you may need to bring it up yourself. [SPEAKER_01]: And 5. [SPEAKER_01]: If your doctor wants imaging or a specialist referral, it is completely reasonable to request a repeat test after a week off from training first.

1:00:20 [SPEAKER_01]: That's the move. [SPEAKER_01]: Full episode is linked below and if this helped you, please leave us a 5 star review. [SPEAKER_01]: It's the single best thing you can do so that we can keep bringing you all the latest nuance and health and fitness. [SPEAKER_01]: Alright, Austin any other tips for our [SPEAKER_02]: Don't try to interpret your own labs, get some expert consultation, doing labs, interpreting labs is complex, it is challenging, even for experienced clinicians.

1:00:45 [SPEAKER_02]: I do a lot of these as part of our kind of barbell medicine consults here and there. [SPEAKER_02]: I do it with patients and I'm happy to help people through that process myself, but [SPEAKER_02]: Yeah, don't, don't try to do this on your own. [SPEAKER_01]: Who would be my main advice? [SPEAKER_01]: Yeah, that's a good advice.

1:01:02 [SPEAKER_01]: All right, so that is a wrap here on the Barbell Medicine Mystery Case, hopefully you guys took home something useful. [SPEAKER_01]: Before you guys go anywhere, please leave us a five star rating interview. [SPEAKER_01]: It really helps drive traffic to our podcast. [SPEAKER_01]: We can keep bringing you all the latest nuance and health and fitness, special shout out to Dr. Austin Barakie for joining me on the podcast.

1:01:17 [SPEAKER_01]: I'm Dr. Jordan Viagunbaum. [SPEAKER_01]: We'll catch you next week and every week right here on the Barbell Medicine podcast.