Dr. Michael Ruscio, DC is a clinician, Naturopathic Practitioner, clinical researcher, author, and adjunct professor at the University of Bridgeport. His work has been published in peer-reviewed medical journals and he speaks at conferences around the globe.
Which GI Functional Markers Are Valid (and Which Are Useless)?
A GI functional marker test, or test of gut function, can be very useful to detect some gut conditions. It can help diagnose inflammatory bowel disease (IBD), predict pancreatic insufficiency (or need for digestive enzymes), and potentially detect leaky gut. However, patients should beware of paying attention to markers like secretory IgA, fecal lysozyme, chymotrypsin and beta-glucuronidase that are problematic or unvalidated. Also—because lab testing processes vary and markers can be difficult to filter even for clinicians—it’s important that patients work with an experienced clinician in order to properly interpret their results.
Dr. Michael Ruscio, DC: Hey everyone, welcome back to Dr. Ruscio Radio. I am here with second-time guest, Dr. Ilana Gurevich. We had a fantastic conversation a few months ago about some of the new methods of parasite testing. And from that conversation, I could tell that she is one of a small handful of people I really value the opinion of. I can tell that she is an experienced clinician who really has her head on straight. I think that was clearly evidenced by our conversation. So I’m very happy to have you back on the show today, Ilana, to talk about functional markers for assessing gut health.
Offline a moment ago, you were giving me a quick snapshot in terms of why you decided to do this review of functional markers. Do you just want to start with that and then we’ll go from there?
Dr. Ilana Gurevich, ND: Yep. So I’ve been really specializing for over a decade in the GI tract. In the history of my career, I would use a lot of functional GI tests. In the beginning, I was using the GI health panel a lot by Diagnostics, mainly because my mentors were using that when I was going through school. I was using it and getting relatively good clinical efficacy. And tests come on the market and they go off the market. But these tests are getting relatively expensive.
What Is a GI Functional Marker Test?
DrMR: Let me chime in one thing, just for members of our audience who maybe aren’t familiar with GI functional marker tests. These are certain things that can tell you if you have leaky gut, if you have inflammation in your stool, or maybe too much estrogen in your stool. These are what will tell you how things are functioning. These aren’t tests for infection per se, but more for functional markers. So if you’re new to the conversation, just to get you up to speed, that’s what we mean by GI functional markers.
DrIG: So I was looking, and I realized that I personally was ordering these tests left and right, but I myself had never done a literature review on if the tests had any validity. If I—with my amount of specialization—was ordering these tests, I knew that a lot of new functional medicine and naturopathic physicians were also running the tests, and they also had no idea if there was any value to them or not.
I did a look at the literature, and based on what I saw, I decided that some of these are actually pretty useful and some of them have no clinical efficacy. And for some of them (which was probably the most disappointing thing to me), the labs that I called didn’t even know what they were running. So they’re asking us to make clinical decisions based on these tests, and they don’t even know what tests they’re running, which is pretty important.
DrMR: Yeah. Well, as I’ve said many a time in functional medicine, while it’s great on the one hand that we’re trying to be progressive and have new answers, new solutions, and new tests for patients, we also have to bridle that a bit. We need to make sure that we’re not doing things that have not been validated, and really are more of a bell and whistle than something that has been shown to be accurate, studied, and something that we can say is actionable. Because you can have a piece of paper that says you are positive for XYZ, and that XYZ could be totally bogus. That’s why I’m glad that you’ve done this review.
Useful (and Useless) Functional Markers
Let’s start with the high-level summary. You were kind enough to send me a PowerPoint presentation where you recently presented this. I just want to give your summary and then let you maybe make a few comments on the summary. And then we can go through these markers point by point. Your summary has “good” tests: fecal calprotectin, fecal lactoferrin, zonulin, elastase, and steatocrit. Your “bad” tests are secretory IgA, fecal lysozyme, beta-glucuronidase and chymotrypsin. Anything you want to chime in there on the big-level summary?
DrIG: I feel like the ones that are the most validated are the ones that we’re seeing in our standard medical counterparts. They’re using those tests also. The fecal calprotectin and the lactoferrin are extraordinarily well-validated in the standard inflammatory bowel disease world. Those don’t even have a question, because they’d been so extensively validated. On the other side, for the fecal lysozyme and beta-glucuronidase, there was so little that I could find because they were so poorly validated.
DrMR: I think it’s important to echo that, because sometimes—depending on what philosophical circle you are in—in integrative and alternative functional and natural medicine, there can be this little bit of, “Well, the conventional markers are not helpful. They’re not sensitive enough, they’re not useful enough.” That sometimes may be true, but there are certainly a lot of markers in the conventional medicine paradigm that, as you just said, have been very well-vetted and we know have a large degree of clinical utility. So it’s just important for everyone to check your bias at the door. And let’s say you’re not too happy with your conventional gastroenterologist… they still may be running some tests that are highly valid and tell you some very important information. Now, their suggested treatment may not be a treatment option that you love, but some of these markers are very well-validated.
DrIG: I love the fact that you say that because the other thing that I have in my subset of IBD people is a lot of hormonal tests. And actually, it’s one of my pet peeves how quickly functional medicine and naturopathic doctors are jumping through like, the salivary estradiol and the urinary progesterone. When I look at the literature, I don’t see any validation on any of those. But they’re saying that blood isn’t accurate. Really, it’s a little bit surprising to me how quickly people throw away the older tests because they’re looking for something new and cutting-edge. When really, it’s a little bit dangerous for patients sometimes when you’re not laying a foundation of validating your results.
DrMR: Right, I fully agree. I also think this is important for both patients and providers, but in some cases more so for patients. I remember a case from about maybe four years ago and she was so upset that I didn’t comment on her elevated chymotrypsin. “Well, what about the chymotrypsin? Aren’t we going to treat that?”
And I said, “Well, it’s not really a very validated marker. And while it is included in this panel, it’s not something that I’m purposefully including in the panel. Nor do I think it’s highly actionable.” This patient had such a hard time conceiving of the fact that there was a positive on the piece of paper in front of her that didn’t actually mean anything.
So for the patients out there, yes, this can happen. And actually in functional medicine, what I tell my patients is—any time they ask for lab results from our office—I say, “Please, do not read these labs and try to interpret them without me, because you will invariably come away thinking that things are far worse than they are if you Google every one of these markers.” You definitely have to pick and choose which markers to put weight on and which ones to dismiss as not really being beneficial. If you’re asking yourself as a patient, “Well, why don’t the doctors just order the ones that are beneficial?” it’s not always that easy. Oftentimes, these come as part of panels and we just can’t remove whatever we want out of the panels.
DrIG: If we did remove out of the panels, the tests would become seven times more expensive. Because they’re grouping them all together. I think for us providers, what we need to do is start talking to our labs and asking them to validate why they’re putting some of these ridiculous tests on. Like beta-glucuronidase. That was one of the tests that made me the most angry because it has no standardization. It’s only positive for women of a certain age who are not pregnant. It’s not accurate for men. It’s not accurate if you change your diet. It has no accuracy at all. But that is one of the markers I see going through the roof astronomically and really scaring patients.
DrMR: Yep. I want to dig into that one, but let’s come back to that. That one is a marker, loosely termed, of your estrogen detox status.
Zonulin: the Leaky Gut Marker
But let’s start with the marker of leaky gut, zonulin. This is the only marker from your list that I’ve really gone through a comprehensive review of literature on.
DrIG: It was a very good document. I just wanted to say that was so organized.
DrMR: Thank you. Yeah, I mean, we literally went through every study. Man, I did this at the wrong time, during my winter vacation, and I should have been spending more time with my family, but I was at the local Dunkin’ Donuts (for all the East Coasters out there, you know there’s not nearly as many Starbucks and Peet’s Coffees and rather Dunkin’ Donuts).
I had to sneak out of the house for the first two hours every day before I played with my niece and nephew because it was so much data to go through. And I was like, “God, this is kind of a pain in the butt,” but I’m so glad that I got it done.
I think this is the one area where we may have a slight difference in terms of our opinion. I’m kind of on the fence regarding zonulin. I lean more against it than I do for it. You’re, I think, leaning the other way. So I thought maybe we could air our rationales. And I’m not trying to convince you, I don’t think you’re trying to convince me. I think we’re looking at the data set. There is definitely room for interpretation there, I don’t think the data set is definitive. But I think it would be helpful for our audience if we each share our rationales for why we either support or slightly don’t support this test.
DrIG: Okay. Let me explain what the test is first, so people know what we’re looking at. What we’re looking at is a tight junction marker. If there is intestinal permeability within the intestine, this tight junction marker of zonulin will increase within the stool or within the blood. It is a signaling pathway that lets us know that there is chronic tight junction deterioration within the bowel. It is the only protein that’s known to be reversibly regulated by intestinal permeability. So it is the thing that modulates the tight junctions.
Where I was a little bit wary about this test in particular is, it was one researcher who was doing most of the publishing. And it was discovered in his lab… Fasano, I think, was his name. So it is really a tight junction marker. You can run it in the blood or you can run it in the stool. I am almost exclusively doing it through stool. It is also only a small intestine marker. It doesn’t show anything about large bowel deterioration.
Zonulin & Quercetin in the Clinic
So the history of me trying to understand this marker and starting to use it was, early on, I was just switching the functional GI panel that I was running over the GI-MAP test. This was an add-on marker that I didn’t know very much about. At that point, I hadn’t looked at the literature. I started running it and I started seeing it being elevated in patients that had inflammatory bowel disease, celiac disease, bacterial overgrowth, parasitic infections. I was seeing it a lot, but not ubiquitously. I had one patient come into my office at the time who was a celiac patient. And he didn’t have typical GI celiac presentation. He just had headaches. So he knew he’d got some kind of celiac exposure by getting these chronic headaches.
We ran the GI map on him and the only things that came up were the zonulin was elevated and he had some dysbiotic markers. No pathogens, no worms, no fungus. Just a slight increase in some of those either autoimmune, dysbiotic markers. So I didn’t quite know what to do with him. At the same time, I was working on a presentation where I was talking about my top 10 supplements that I use to re-heal the intestinal lining. One of the things that I stumbled on at the time was using uber high-dose quercetin… all of the really, really interesting literature on how quercetin had been used in the past by a lot of our herbalists and a lot of our earlier naturopaths, and what we know about using quercetin in autoimmune disease.
There wasn’t very much going on with him, so I put him on probably a high-dose class-one probiotic. I also started him on these uber high-doses of quercetin. And those doses were a little bit closer to what the animal studies were using as opposed to the human studies. At that point, I started using quercetin at 2000 milligrams, three times a day. What I noticed—and then I continued to use this protocol—is that when somebody’s zonulin is elevated, quercetin might be the most pinpoint supplement to help heal up those tight junctions. And A, the zonulin falls, but B, symptomatically, they really go into a significant improvement of their symptoms that are systemic, but also gastrointestinal.
So ever since I started running this test, I started giving people these high doses of quercetin. That just helps me pinpoint who I’m going to give this dose to and who I’m not. Because quercetin is expensive for one, especially at the doses that I’m using it at, and two, quercetin has been shown by one study to affect thyroid conversion. So I’m trying to really pinpoint who’s gonna get what supplement. And the zonulin is how I pinpoint who’s going to get that high dose of quercetin.
DrMR: Certainly if you’re seeing something clinically, that may be ahead of what’s been published, I think we should pay attention to that. I’m in absolute agreement. It’s something that I’ve been tinkering now with some patients, giving them higher dose quercetin to support their leaky gut. I don’t believe there is a study—and correct me if I’m wrong here—that has shown quercetin will lower zonulin in humans. I think there’s some mechanism that’s suggestive, but there hasn’t been an outcome study. Correct?
DrIG: Definitely not. I have never actually even seen anybody look for it, if we’re honest.
DrMR: I’m cross-referencing our table here. So, here’s my rationale on zonulin. And I’m totally open to using quercetin, as I just said, and I’m actually starting to experiment with using it more specifically when someone has a non-responsive GI condition or symptoms.
But we know there are a number of things that can support leaky gut, and there are some trials that do show a pre-/post-improvement in zonulin after using various gut-healing agents. There’ve been two probiotic trials. There have been two dietary trials, one colostrum trial, using various groupings. So there are definitely some data showing that probiotics, things like zeolite, colostrum, or diet, can improve zonulin. What’s paradoxical is there are more trials showing, with diet specifically, that after putting people on a healthier diet and seeing these patients have improved symptoms, their zonulin doesn’t change or in some cases can get worse.
There’s also at least three, as I’m counting here, four probiotic trials showing no change in zonulin post-intervention. This is why I’m a little bit tenuous about zonulin. I’m open to it, but I wouldn’t hang my hat too heavily on it. Now, what we found to give the high-level summary is—irrespective of it being a blood zonulin test or a stool zonulin test—there does seem to be pretty good agreement that those who have various illnesses tend to have higher zonulin. So the correlation to disease does seem to be present.
DrIG: Well, generally, diseases that have some kind of effect on the GI, like diabetes, Crohn’s, celiac.
DrMR: Right. We could even make the argument that, what disease can we not maybe tie back to the gut? Looking through here, oftentimes these are in various inflammatory conditions as you mentioned, but sometimes it’s just in overweight populations. Again, overweight could come back to the GI, coronary artery disease, or type 2 diabetes. So there does seem to be some pretty good data there. One study in Parkinson’s, showing that the group with Parkinson’s had higher zonulin than the control.
DrIG: More and more we’re starting to think that Parkinson’s is now stemming from the GI.
DrMR: Right. Back to my point of how many things come back to the gut. So many. It does seem there’s pretty good agreement that diseases do display higher zonulin when compared to non-diseased control cohorts. But where the zonulin function breaks down is when looking at what happens to these cohorts after they’re treated.
When you look at all the data from a bird’s eye view is, diet seems to be the most paradoxical. Meaning there are a number of studies showing that when people go on a healthier diet—and that varies from study to study, sometimes it’s a Nordic diet, sometimes it’s Paleo, sometimes it’s low-carb—the zonulin either stays the same or gets worse, even though the participants exhibit vastly improved health by whatever marker is being tracked. There are better data showing that zonulin tracks with treatment when you’re using things like probiotics or fiber or colostrum or what have you. But even that is mixed.
So that’s why I think there’s not a right or a wrong way to interpret this. But it makes me a little bit more cautious with how much I would say, “Okay, you have X, Y or Z condition or symptom, we’re going to do a zonulin pre-/post- and expect that to be a tight corollary to how your gut is functioning.”
DrIG: I think I agree, in the fact that I don’t know if there is any single functional test—because I feel like I can totally hang my hat on a calprotectin or a lactoferrin—out there that looks at the GI, where I would say, “This is the end-all and be-all test, this is the only thing that I’m going to use to make my clinical decision.”
I feel like whenever you’re working on a patient, you need to look at the entirety of their picture. You need to look at the functionality of the pancreas, how are they absorbing fats, inflammatory markers, and everything that has to do with the GI. In my world, the zonulin is definitely part of that picture. Mainly because if I’m going to be asking somebody to spend 60 bucks a month out of pocket, I want to choose a nutrient that I know is going to, in my clinical experience, bring them into a better GI condition.
DrMR: Totally agree.
DrIG: So I totally agree. I just think that I’m using it a lot more than you are, because I feel like it helps me narrow in. The beautiful thing about the medicine that we do is, we truly do individualized medicine. The problem with individualized medicine is, it’s really nice to have an algorithm to say, if A then B. For me, I try to make those algorithms wherever I can, while still keeping things very individualized, and zonulin is one of the ways that I do that.
DrMR: I think there’s something really important in what you just said. And this is more a reflection for the audience. Clearly, you’re not dogmatic on this. That to me displays that you’re someone who’s thoughtful and you’re not unwilling to see both sides of a case. I think that’s just such a laudable mentality to have. Usually I find that people who are a bit more open-minded, or willing and able to see both sides, tend to really be better clinicians because they’re not dogmatic. They’re willing to look at both sides of the evidence and evolve their opinion. So just a quick commendation for your perspective.
DrIG: I just spent all morning finishing up this huge, huge presentation on inflammatory bowel disease and looking at all of the ways that we treat inflammatory bowel disease in standard medicine (as opposed to what we do naturopathically). But I remember when I started, I was so, so opposed to the biologic agents. I was so opposed to Remicade or Humira, and then I was opposed to combination therapy.
As you treat more complicated people, you start seeing, wow, there really is a time and a place for these medications. I don’t think it’s right when they get diagnosed. I don’t think it’s at the initiation of care. But there are lots of people who, thank goodness, have access to these really, really impressively powerful and sometimes dangerous medications, because if they didn’t, they’d probably be dead.
DrMR: Yep, well said. That’s just, I think, a degree of realism. Over time, I think we go from being idealistic, which is thinking natural medicine can cure the world…. I think every student has a degree of that, as you should. You’re excited about the field that you’re going into.
DrIG: I also think it can cure the world.
DrMR: Yeah, and agreed. But there is always a severity of disease presentation and some people are being given much harder hands than others. For some people—and this is something I often say to my patients in the clinic—just preventing you from having a part of your intestinal tract cut out is a victory, if you’re on the very severe end of inflammatory bowel disease.
DrIG: Because the reality is, especially if you have Crohn’s disease, the minute they cut out a piece of your intestine, it’s probably about two and a half years until they cut out another one.
DrMR: Right. Okay, so we’re in agreement.
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Calprotectin & Lactoferrin: Validated IBD Markers
So, let’s talk now about calprotectin and lactoferrin. Maybe just define how they’re used and go from there.
DrIG: So both of these are looking at neutrophils within the intestine. Basically, both of them are extremely stable tests. The calprotectin is looking especially at the amount of neutrophils that are in the large bowel. It is a little bit of a question mark. Let me back up. This is a really, really good test for differentiating inflammatory bowel disease from IBS. We have a couple of these really, really well-validated tests. A calprotectin will also go elevated if you’re having an acute gastroenteritis, either parasitic, bacterial, or fungal. But generally speaking, this is a marker that allows us to track inflammatory bowel disease, especially in the large bowel.
In the large bowel, it’s probably something like 95% predictive. In the small bowel, it’s somewhere between 30% and 80% predictive, which is a huge range. And then if you have small bowel and large bowel disease, it’s about 70% predictive. So this is the one that I use the most. Whenever I see an inflammatory bowel disease patient, before I do any treatments, immediately, that day, they run me a calprotectin, we send it off to the lab.
Caution… Results Vary Between Labs
This is one of the tests where I find grossly differing results, if I send them to a standard lab, like Quest or LabCorp, as opposed to a functional lab. Oftentimes, I have patients who have the same stool sample, they’ll collect and drop one off at Quest or LabCorp and the other one to one of my functional labs, and I’m seeing grossly different markers.
DrMR: Yes. Now, let’s dig into that. This is something we’ve been discussing in our clinicians’ newsletter, and I’ve been also discussing offline with a few clinicians, that they feel, and I share this. But I’m really curious—as someone who’s highly specialized in inflammatory bowel disease as you are—what your perspective is. It seems that when using the GI-MAP test, you will sometimes see a calprotectin that is elevated and it doesn’t really match the clinical picture. So, are you suspicious that you’re getting false positives with the Diagnostic Solutions GI-MAP, or…?
DrIG: I wish it was only Diagnostic Solutions. I am suspicious of every functional GI test.
DrMR: So, many of them. That in and of itself is worth this recording, because that is something that I’ve seen enough cases where it just doesn’t seem to match. In some cases where we will run, in parallel, a LabCorp request next to a Doctor’s Data or a GI-MAP, it does seem that I’m just discounting this elevated calprotectin, which you would never really do with a conventional lab. But I think that’s because the correlation to symptoms seems to be there with the conventional labs. And with the progressive functional medicine labs, I’m seeing so many that just would seem like a false positive. That’s disconcerting.
This is one of the things that came up with Dr. Robert Abbott. He said, am I now tied to the legal standard of needing to work this patient up for inflammatory bowel disease? Will I be considered negligent if I don’t go through a more robust, expensive and what can be somewhat invasive analysis for inflammatory bowel disease? My remark to him was, unofficially, I would say no, because I have a strong suspicion that he suffers from false positives. So I’m so glad to hear you say that.
DrIG: So the only thing that I can come up with is, when my patients drop off their stool at Quest or LabCorp, they immediately freeze it. They drop off the sample, they immediately freeze it and they send it off to the lab. I know as a fact, none of the functional lab tests are doing it. When I look at the literature, it seems like calprotectin should be stable at a refrigerated temperature for seven days. So I have no idea why I’m having these grossly different markers. What I am doing to cover my butt legally is, if I see an elevated calprotectin and there are other things, I’ll treat the other things. If there’s nothing else, I’ll reflex it to a standard lab.
DrMR: I think that’s a fantastic way of navigating this. Treat them. If the symptoms go away, then there’s less to worry about. If they’re somewhat recalcitrant, then you can cross-reference that with a LabCorp or a Quest. That seems very reasonable. So, again, I can’t say enough for clinicians how important I think that distinction is. Because there are a number of patients who, again, if you do a functional medicine stool lab, will go on the internet and read up about calprotectin and they will think that they have inflammatory bowel disease. If you are mishandling that conversation, you could lead someone to think that they have a disease when they don’t. This happens way more than I think it should in functional medicine, in a multitude of areas. So, that’s one area where we want to be a little bit bridled.
Now, contrastingly, that marker from a conventional lab is highly accurate. The other thing that I think is exciting about calprotectin and lactoferrin is, to differing degrees, they tend to be able to predict relapse and also track very tightly with disease severity. So, with someone who has, let’s say, inflammatory bowel disease of whatever sort in remission, are you doing every…
DrIG: Four months.
DrMR: Four months, we’re doing a repeat, to know? I think this can be helpful, because, let’s say someone has inflammatory bowel disease or Crohn’s, and they’re feeling well. And now they’re saying, “Well, can I open up my diet a little bit?” I think we all want to say yes. But it’s also helpful if we can see a crash coming. And this is where I think we have the most benefit for inflammatory bowel disease, if someone’s repeating this at least for a term while they’re figuring out how much dietary latitude that they have. You may say, “Wow, your calprotectin just jumped a fair measure and we may want to throttle back some of the drinking that you may be doing,” or whatever it is. So, is that kind of how you’re looking at this?
DrIG: So, yes, for ulcerative colitis.
Prometheus Monitr Test for Crohn’s
I have just recently changed my protocol for Crohn’s disease. Have you heard about that new Prometheus Monitr test, the Crohn’s score?
DrMR: I have. I’d love for you to tell us more about that, because I haven’t looked into it beyond just hearing about it, looking at it quickly, and being interested.
DrIG: So, it’s really, really interesting. They’re using 13 different blood biomarkers, and they can come up with a very predictive score of if the patient is in remission or if the patient is in a flare. So based on the 13 biomarkers, there’s, like, interleukin , TGF alpha, CRP. There are a bunch that I don’t even know about, but it’s this 13-panel blood test.
At this exact moment, Prometheus has made a clinical cash pay charge. So no matter what insurance pays, the patient will not be responsible for anything over $75 plus the processing fee (which in my office is 20 bucks). It is very, very predictive for Crohn’s. It’s not an ulcerative colitis test, mainly because the calprotectin is so predictive for ulcerative colitis. So what we’re doing now is, if a patient has small bowel Crohn’s or if a patient, to be frank, is just fed up with carrying their poop around in their purse, which is fair, we’ll run this blood test. You run it first thing, it’s a three-day turnaround, and then we’ll initiate whatever treatment we’re going to initiate. Then we can monitor how responsive the patient is based on that test.
DrMR: Awesome. Is that something that you have to bring a specialty vial to a phlebotomist for, or can you tack this onto a LabCorp, a Quest, or something like that?
DrIG: So, it’s tricky. If you run phlebotomy in your office, then they will control the costs of that lab. The out-of-pocket max is going to be 75 bucks. If you bring it to a LabCorp or a Quest, they can absolutely run the top of the panel, I think it’s a really simple one-vial blood draw, but then they can charge whatever they want to charge for their processing fees. And that’s where things become really expensive.
DrMR: So, you have to have the kits in office essentially…
DrMR: Okay. Gotcha.
DrIG: That’s what we’ve been doing. So that’s what I’m doing now for my Crohn’s patients. It’s roughly the same cost out-of-pocket. So it’s really, really worth it for them to not have to deal with poop, I think.
DrMR: Yep. People don’t like collecting poop. It’s something I’ve learned over the years. I’ve gotten plenty of dirty looks when giving patients a stool testing kit. Their least favorite thing to collect.
DrIG: Which is fair.
DrMR: So, calprotectin, lactoferrin, for those with inflammatory bowel disease, are good markers. They’re validated markers. Be cautious with the functional medicine labs. Also consider Prometheus as a more cutting-edge version of assessment for Crohn’s disease. Before we leave those two, anything else you want to add?
DrIG: Nope. That’s pretty much the best summary ever.
Now, coming to elastase and steatocrit. These are the last of the markers that you give your endorsement to… Let’s go over elastase first.
DrIG: Okay. So, honestly, I think these are best used in conjunction. Fecal elastase-1 was validated against the gold standard test for pancreatic insufficiency. The gold standard is basically this IV test where they’re collecting duodenal juices every 15 minutes while administering IV secretin. They’re checking to see the amount of elastase and they’re looking to see how much the pancreas is working. This test alone is really good at predicting moderate to severe pancreatic insufficiency. But if you take it in combination with steatocrit, then it’s pretty good at predicting mild pancreatic insufficiency. Pancreatic insufficiency is basically that you’re lacking digestive enzymes to help you break down your food. That’s 95% of pancreatic exocrine function.
DrMR: Right. So, for practical parlance here—and please correct me if you think there’s a different nuance here—if someone needs to be on a digestive enzyme, this can give you a predictive marker of, “Yes, you should use these,” or “No, you shouldn’t.”
DrIG: Also, the dose that you should be using them. Because, I will tell you, I had this great conversation with Heather Zwickey. Do you know who she is?
DrMR: I think I do.
DrIG: She was at the naturopathic college in Portland and she used to run the Helfgott Research Institute. She was a Yale graduate immunologist. So she knows how to look at and read studies. I’ve been realizing that I was underdosing supplements for so long, and she was like, “In animal studies, they use these astronomical doses, and then we bring them over to humans and we’re giving, like, a tenth of the dose.” So that’s the other place where this would come in handy. Because sometimes you need people on, like, 10 pancreatic enzyme pills to see clinical efficacy. That’s much more likely to be the case if they have fecal elastase that’s too low or steatocrit that’s too high.
DrMR: Super helpful. So is there maybe a between-X-and-Y range where you use this dose? Are there maybe two or three dose ranges that skew with the lab results that you could offer people?
DrIG: Okay. So I’m looking at these markers in conjunction. A normal range on the GI-MAP, which is who I’m using, is like 200 to 1000, maybe. So, if they’re in the 200, 300, low normal, or if they’re frankly deficient, and if their steatocrit is really high (which means there’s a lot of fat in their stool) I’ll probably have them take six pills with meals for a short amount of time just to give them some digestive rest, like four to six weeks. And then have them bring it down with meals.
If the elastase is normal but the steatocrit is elevated, then probably I’ll have them use two to four with meals. And then, really, I just have them titrate up and down to see where they feel the best. I’ll usually start higher and have them bring it down, because if they feel a difference, they know what they’re looking for. As opposed to, if you start too low, you’re going to say “No, it didn’t work for me.”
DrMR: That’s fantastic actually too. Now, I want to juxtapose that just briefly with HCl, where I’m a little bit cautious about that. Keep taking HCl until you feel burning. And let me stick a pin in that for a moment, to make sure we come back to it. So, give us that dosing one more time. So, you’re looking at both elastase and steatocrit.
DrIG: Elastase and steatocrit. If the elastase is low normal, like 400 or below, and the steatocrit is elevated, then I’m going to give the digestive enzymes … The one that I use, which I think Integrative Therapeutics is gonna pull from the market, is Pro-Gest. That’s the one I use right now. I think that they’re going to pull the physician brand, but they’re going to leave the Enzymatic Therapy. I think that one’s still going to be available to patients.
DrMR: Like Zenpep. Are you ever using a prescription like that or do you not like that?
DrIG: No, I’m not. Should I be?
DrMR: We actually looked at just a typical nutraceutical enzyme and we compared it to Zenpep. The nutraceutical formula actually had a higher dose per pill than the Zenpep did. I wanted to check that just to make sure. Because again, I never assume that a natural version of something is better than a pharmaceutical. So I like to check if there’s also a prescription version, which version is better, has better efficacy, has a better dose. It seemed like just your standard nutraceutical enzyme had more pancreatic enzymes in it than did the prescription Zenpep.
So, if you see the elastase in the steatocrit, is six enzyme capsules per meal what you’re doing across the board for this initial evaluation?
DrIG: That would be my high dosing. So if the picture is looking like they’re a mild to moderate pancreatic insufficiency, then I’m starting really, really high for like two weeks. And then trying to bring them down.
DrMR: Is that the six per meal?
DrIG: Six per meal, yeah. That would be the highest dose. I had one patient come in years ago, and we ran a fecal fat test… Okay, so can I tell you what a steatocrit is? Because it’s going to come full circle.
DrMR: Yeah, please.
DrIG: Basically, before we had steatocrits, we had this test—which is still considered the gold standard—which is a fecal fat, right? So a patient would collect their stool over the course of an entire day, a 24-hour period. They wouldn’t be able to leave the house. They’d have to be doing constant collections. They would bring this tub of stool into the lab. The poor lab tech would have to dig through the stool, take it out, weigh it, spin it down, and then try to figure out the concentration of fat that was within that stool. That was the old gold standard.
Now they have this thing called a steatocrit, which is taking a lipid layer off of the stool. It’s actually fairly well-validated to a fecal fat. And it’s a lot less stool for a lab tech to deal with. I had this patient for whom, back then, I ran a fecal fat. Her chief complaint was, she would have, like, oil spills on the top of her stool and she would have rectal leakage. So we worked her up. I finally got to the fecal fat, and giving her that uber high dose of Pro-Gest completely resolved the problem. She was taking it incessantly, I think, for a six-month period. Then the body just reset itself and she no longer worries about that anymore.
DrIG: That’s how I came up with that dose.
DrMR: Did she notice within the first two weeks?
DrIG: Oh, yeah.
DrMR: Is that an adequate time? Because what would be great for people is if we could say, “Okay, you take the enzymes at whatever dose for X number of weeks. If you’re not noticing anything after X number of weeks, it’s probably not the right treatment.” Is there a time interval that you would offer?
DrIG: Well, I feel like you will notice it. I feel like, give it two weeks, but you should be noticing a difference within three or four days.
DrMR: Gotcha. Okay, just making a quick note here for our audience, so that everything is nice and easily summarized in the fast facts. Great. Now, what about SIBO? Or let’s say someone’s non-celiac gluten-sensitive and they’re eating gluten, or they have SIBO, or they have maybe H. pylori through some type of down-the-line cascade? Are you finding other issues in the gut can lead to these imbalances in elastase and steatocrit, that can then be fixed after an intervention?
DrIG: Yes, I do feel like when I’m working somebody up for all of the things at the same time, there are times when I’ll find one condition and the other. I will usually treat both simultaneously, because my thought process is, treating the pancreatic insufficiency will definitely help you be more effective with your SIBO treatments.
I think maybe the only asterisk that I say about that is, I don’t do anything while they’re taking antimicrobials, because I want things to be bad so that I have something to actually kill with antimicrobials. But as soon as they’re on the motility phase of treatment and the dietary phase of treatment, then I’ll put in all of the pancreatic supports, so that we can just get the system to function as normally as we possibly can, while they’re going through healing their intestinal lumen.
DrMR: So you’re starting with treating dysbiosis and infection first. Yeah, I think that actually makes a lot of sense. Now, for the audience, there’s a couple reasons why I like that recommendation. One, I’m assuming—and I could be wrong, correct me if I am—that for something like a steatocrit, like a fat in the stool, knowing that SIBO can interfere with how bile functions, you may see that falsely positive. You may see someone have more fat in their stool if they have SIBO. So if you treat the SIBO, then you wouldn’t necessarily need to use some type of enzyme to help you digest fat. So, I like it from that perspective, where we’re consolidating the variables. And then also, you’ll likely be able to better get a symptomatic read for how effective is the enzyme if you’re getting dysbiosis or infection out of the way first.
DrIG: Yep. Totally.
DrMR: Great. All right, so those are our positive markers. Hopefully for the audience, that helps you navigate. Yes, there are some markers that can be helpful, and we also want to be a little bit bridled. We want to maybe be a little bit careful with some zonulin, right? If you’re feeling super healthy and you have a high zonulin, my opinion would be not to freak out. Because, again, it’s not a perfect marker, but it can be helpful.
The calprotectin, the lactoferrin also can be very helpful, but you have to be careful what lab you’re getting that from. And then the fecal elastase and steatocrit can also be helpful and predict if you need something like an enzyme. I’m sure many people are wondering, “Do I need this enzyme? Yes or no?” You’ve probably read something about how they’re good for you, but how do you contextualize whether or not you need that? So hopefully this part of the conversation has been helpful. Before we leave this, anything that you want to add?
DrIG: Don’t ever freak out. Everything is treatable. It’s going to be okay. We’ll go one step at a time.
DrMR: Haha, yes. Agreed.
Secretory IgA: an Immune Marker with Poor Testing
Okay, now we get into the markers that you’re not super keen on.
DrIG: I actually became angry.
DrMR: Okay, good. And I think that’s worthwhile. We have secretory IgA, which tells us the amount of mucus in your mucus membrane. We have beta-glucuronidase which tells you, loosely said, estrogen clearance, and lysozyme and chymotrypsin, which are more enzymatic function. So, let’s go through these one at a time. Which one do you want to start with?
DrIG: Let’s start with secretory IgA. So, secretory IgA is an immune system modulator and 74% of your secretory IgA should be bound to a bacteria. You’ve got a lot of bacteria in your GI lumen. So 26% should be free, theoretically, depending on how much you have of it. If you have more that are bound than your mucin level (which is the level between the enterocytes and where the bacteria live)… if a lot of those are bound, that mucin level should be a little bit smaller, because your immune system is doing a really good job modulating the bacteria that’s in there. If the secretory IgA is low, then that mucin level is expected to be a little bit thicker because the enterocytes are seeming attacked, right? So, really interesting. God, wouldn’t that be a great marker to know?
We called four separate functional labs, all of the big ones. I called Diagnostic Solutions, Diagnostics, Doctor’s Data, and Genova. None of them knew if they were running a free, a total, or a bound. Nobody knew what they were running. If you don’t know what test you’re running, this test has no value. This is a test that is ubiquitously on every single functional lab test and I have never personally seen this test available through the standard labs. Have you?
DrMR: No, I have not. And I’ve looked.
DrIG: Yep. So, for this one, if somebody could tell me what the hell they’re running, then maybe I can make some kind of clinical decision based on that. But the fact that I had to call the labs and nobody knew, it takes all of my will to not throw the baby out with the bathwater and say, these guys have no idea what they’re doing.
DrMR: Yeah. I’m assuming that the reference range that you use is heavily contingent upon the fraction that you’re measuring.
DrMR: This also may be a point of defense, if you ever read about secretory IgA and came to believe that that was a very important test based on what you read, then went to your gastroenterologist and said, “Why won’t you order this for me?” Again, this is why we should be a little bit tempered in how quickly we assign blame or get angry at people when it comes to lab testing, because there’s a lot of nuance here. There are a lot of claims that can’t always be supported. So this may be an area where, if your regular gastro didn’t want to run this marker, they may not have been really trying to disservice you in any way. They may have actually been doing you a favor.
DrIG: Yep. I agree.
DrMR: All right. So that is one test. I think many a patient will benefit from not ruminating over what that level says. So, great. I’m so glad you looked into that because again, the more turmoil we can save people, the better. That’s definitely a part of this equation. I see many patients who, again, read their lab test and they get really stressed out. Hopefully this will be an antidote to some of that stress.
DrIG: Also, I can’t believe it took me a decade to do this work, because so many of us are relying on these tests as if they mean something and having patients spend money to support the immune system. I mean, I agree with supporting the immune system, especially in autoimmune patients, but this is not the marker that you need to be running to see if your treatment isn’t working.
DrMR: This hearkens back to a concept that I’ve shared many a time: there are so many cases where we can simply employ the treatment and we don’t need a lab marker to guide us. Now, regarding secretory IgA, you can make an argument that for something like our Intestinal Repair Formula, which is an immunoglobulin cocktail, you would need to do some tests to say that you need to use that supplement. But in actuality, that’s not how it’s ever been used in any of the research.
We are seeing phenomenal results, both in the clinic and now with the audience here through the website, using this immunoglobulin cocktail, irrespective of what their “levels” are in the gut. So there are certainly examples that we can point to, or you can use many a treatment without needing some type of lab marker to guide it.
DrIG: Yep. I agree.
Beta-glucuronidase: a Meaningless Enzyme Marker
DrMR: So, beta-glucuronidase. Let’s talk about that.
DrIG: Beta-glucuronidase is really, at this point, just silly. So, beta-glucuronidase is an enzyme that lots of bacteria in the intestines produce: E. coli, Clostridium, Bacteroides, lots of different bacteria produce it. It’s found in the liver, the kidney, and the spleen, intestines, endocrine. It’s found everywhere. Here is the thing: it is normal. It is normal to have an elevated beta-glucuronidase, if you’re outside of the ages of 25 and 60. If you have a low-calorie vegetarian diet for a day, this will drop your beta-glucuronidase. If you change your diet, this will change your beta-glucuronidase. If you’re a man, it’s increased just by nature of you being a man. If you’re pregnant, it’s increased just by the nature of you being pregnant. It’s ridiculous. It’s a ridiculous test. It is a rate-limiting step in a lot of functions of how herbs affect bacteria, they’re working on that beta-glucuronidase enzymatic step, but that doesn’t mean anything, because no matter what herbs you’re going to give, they’re going to be working on the same step.
In your PowerPoint, I’m going to include an angry smiley face with a thumbs down for these few markers. I think that does a great job of depicting how you feel about some of those. Okay, so highly variable depending upon age, gender, medical status. So not one we should use.
Fecal Lysozyme: an Unvalidated Marker
Let’s move onto the fecal lysozyme.
DrIG: Okay, this is another one that is a neutrophil-based test. The calprotectin was a neutrophil-based test, the lactoferrin was a neutrophil-based test. It makes sense that, wow, this is another neutrophil-based test, let’s run it. So, one of the reasons why we’re using the other neutrophil-based test is because we’re trying to differentiate, “Is this organic disease, like inflammatory bowel disease, or is this a functional disorder like IBS?”
The more we learn about IBS, we know that there is some organic involvement in IBS. But generally, it’s not going to be as severe or you’re not going to have deterioration of the intestinal lining. So this is another one of those tests. But this test unfortunately has not been validated at all and it’s highly, highly, highly variable. It does not seem to offer us a difference between IBD and IBS patients.
DrMR: Okay. So really, not much that you can do with that at all.
DrIG: No, it kind of just tells me you’re having diarrhea. I could have told you you were having diarrhea. You told me just 10 minutes ago.
Chymotrypsin: Another Unvalidated Marker
DrMR: Right, haha. Chymotrypsin, I believe, is similar, but a little bit different.
DrIG: For chymotrypsin, I actually couldn’t even find any studies on it. I looked and the only time I would find any literature about chymotrypsin was in relationship to some of these other markers like a calprotectin or lactoferrin, basically saying this marker is not validated. So, I couldn’t even find anything on chymotrypsin.
Work with a Trusted Clinician to Vet Results
DrMR: All right. There’s a lot there that we just went through. Again, I think the biggest concept from a high level for people to take away is that functional medicine testing is not perfect. There are some markers that are helpful and there are some markers that are not helpful. And you can order one of the better functional medicine stool tests right now and you will have a mixture of both these helpful and these unhelpful markers. Even on some of the better tests, we have to contend with filtering out what is meaningful and what is not meaningful. So keep that in mind.
“Here it is folks the BEST and WORST of the gut function tests. Check out this episode with Dr. Ilanna Gurevich and learn which markers are worth looking at and which ones have little to no validity.”
Also, this is another reason why I fairly strongly believe that you as a healthcare consumer should not be ordering your own lab testing. Because if an experienced clinician, as Dr. Gurevich is, hasn’t had a chance to do this for years and years of her practice life, how can we expect you as a healthcare consumer—who has another job, other vocations and other stuff to do—to be doing this, right? It’s totally unrealistic to expect you to be able to vet these markers, when it’s even hard for the clinician to vet somebody.
So, I would say definitely let the clinician order the testing and steer the ship. Because I see a heartbreaking number of patients who spend years, literally, treating some of these markers that they will only later come to find were totally invalid. So, yes, testing can be helpful. It’s definitely not the end-all be-all.
DrIG: Yeah. Also, the other thing that I want to plug about working with somebody is, we pretend that we’re only talking about your GI tract and all that matters is your GI, but really, people have a hormonal system, a neurological system, an endocrine system. When you’re looking at a patient, you are looking at all of those things together.
And when you’re a patient in the patient’s body, you become micro-focused on every little symptom. You’re responding to the fact that you had one day that this was bad, and one day that this was good, so everything must work on the day that it’s good and everything is crap on the day that it’s bad. When you’re working with a clinician, there’s a way to pace a treatment and give treatments time to work, so that everything’s not this big emergency.
DrMR: Again, I couldn’t agree with that more. One of the things that I have to coach my patients on in their followup visits is not giving me the day-by-day play by play, because there’s a variability there. We all have some good days and some not-so-great days. Even those of us who are exceptionally healthy have a fluctuation in how good we feel. And if you’re not feeling well, there’s going to be the up, down, up, down, up, down.
And the day-to-day, moment-to-moment, up-down is not as important as looking at the last three, four weeks and aggregating. Do those three to four weeks tend to be better than your baseline or worse than your baseline? It’s much harder to do that if you’re in the day-to-day. Which is why it’s so helpful to have someone else who you can report to, who can look at all this and help steer the ship and know, “Yes, we’re moving in the right direction.”
Just one other thing here. It’s actually great, but shocking how quickly people forget how bad they felt, once they start feeling better. But if you’re a clinician and you’re taking good chart notes, you can see the evolution over three months, six months. “Wow. This person was reporting so much more bloating, so much more constipation, whatever it is. Now, they’re still complaining about a little bit of constipation, but is infinitesimally small compared to where they were six months ago.”
We can use that to help remind the person like, “Hey, you’re actually doing pretty great. We know it’s annoying if you every once in a while miss a day of moving your bowels. But remember, when you first came in, you were having one bowel movement a week.” So just little things like that are helpful nuggets that the clinician can provide you.
DrIG: I totally agree.
DrMR: Awesome. Well, we really picked through that one. And I love the fact that you did all this work. I’m super appreciative that you did.
An Ozone Therapy Teaser
We wanted to talk about ozone therapy, and we definitely don’t have the time this episode. We will have you back on to discuss that. Is there a very short primer that you can tease people with now, for that future discussion?
DrIG: Ozone has become one of my starting places for my inflammatory bowel disease population in particular, because it is quite amazing at acting as an onsite anti-inflammatory. I’m using it almost ubiquitously in my IBD population (and my practice is about 70% IBD). So I’m using it a lot and I’m tracking these patients with calprotectins and with CRPs. Really, one of the things that it’s just amazing at doing is offering immediate anti-inflammatory effects, without me having to put patients on steroids. And steroids have terrible, terrible side effects that affect you for the rest of your life possibly. So I’m just really, really excited, and I want to educate as much of the IBD population as I possibly can. I’ve got, I don’t know, about 1000 clinical cases that I’ve been following using ozone as one of my treatments.
DrMR: Awesome. Is this something you buy as a topical agent?
DrIG: Nope. So patients can definitely buy a medical ozone machine to administer ozone to themselves. Or there are plenty of providers within the country—or even the world, honestly—that offer ozone as a clinical treatment within their offices.
Most of them are not using rectal administration. I know that because I have to touch base with their docs for wherever they are and explain my protocols. But ozone is one of the oldest antimicrobial therapies we’ve had. Tesla patented the first ozone generator in the 1920s and we’ve been using it medically on and off really since then.
DrMR: Okay, great. Well, we have a lot more to dig into the next time that we talk. Coming back to the topic at hand here with the functional markers, anything that you want to leave people with? And then, please also remind people where they can connect with you on the internet.
DrIG: So, you can find me on naturopathicgastro.com. I have a practice in Portland, Oregon and I’m a little while to get in with, but I also have residents who work under me who are amazingly trained and we supervise them. I feel like you’ve said it really, really well the whole time, which is—in my opinion—testing is really, really important and really, really valuable. I especially have a deep belief in the DNA PCR testing for microbes. However, testing can also be a bunch of bunk. And a lot of the time you have these tests all weave together, where you have some really, really good markers and markers that are completely clinically useless. So you really need to figure out if there is validation for any of the markers you’re using.
DrMR: Yep. I think that’s well said. So, we’ve done a good job providing that validation, or I should say you have. I contributed a small slice with the zonulin review, but you definitely took on the lion’s share of this. Again, really appreciate you doing that. For the audience, another reminder of how important it is not to assume too much, because unfortunately when we fact-check, what we’ve been told and what’s actually true are not always the same. So, Dr. Gurevich, thanks so much for performing the review. I’m sure it wasn’t easy, but…
DrIG: It was fun.
DrMR: I know it’s going to help a lot of people. So thank you again for doing that. I will look forward to our future conversation on ozone therapy.
I care about answering your questions and sharing my knowledge with you. Leave a comment or connect with me on social media asking any health question you may have and I just might incorporate it into our next listener questions podcast episode just for you!
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