Bobbi Pritt, M.D. (00:04):

Hello, I'm Dr. Bobbi Pritt, a clinical microbiologist and laboratory leader at Mayo Clinic, and your host for today's episode. I'm excited to be here today with Mayo Clinic Laboratories CEO and president, Dr. Bill Morice, to get the latest news. And then Dr. Leslie Donato will join us to discuss a unique panel for bile acid malabsorption. Bill, welcome back.

William Morice II, M.D., Ph.D. (00:27):

It's great to be back as always, Bobbi.

Bobbi Pritt, M.D. (00:30):

Yeah, and we have some great topics to talk about today. You know, the first thing that caught my eye is that Mayo Clinic Laboratories recently collaborated with the Advisory Board on a survey of laboratory and health systems leaders, and I thought it'd be interesting to talk about some of the findings and what your major takeaways were.

William Morice II, M.D., Ph.D. (00:48):

Yeah, it's important to kind of get a sense for, just as we speak to people that are interested and invested in laboratory medicine and the laboratory community, get a sense of how healthcare and lab leaders in America are viewing the lab. So, that Advisory Board work was really important to do, and the results were quite gratifying.

Bobbi Pritt, M.D. (01:08):

Yeah, so let's get into those results. What did the survey show about how leaders view the laboratory and its role within their organizations?

William Morice II, M.D., Ph.D. (01:15):

Well, I think one of the things for sure is something you and I have talked a lot about, and that is the value that labs bring to healthcare and to providers and to patients. And that really is widely recognized. I mean, that's one thing the survey showed was that, pretty much universally, or not universally, pretty close to it, those surveyed recognize the importance and the value that the laboratory brings to their healthcare organization, to the patients that they serve. And as a result, really the majority see themselves as making investments in the laboratory to invest in, its growth and its performance. And I think 68% expected to make investments in the laboratory and only one in 50, so 2%, thought that their lab budgets would decrease over the next coming years. So overall, I think that the one really important takeaway is that, maybe in small part from our kind of messaging and others, that coming out of COVID, the question was, "Labs are really a focal point obviously during COVID, would that attention to the labs and their importance persist?" And, I think the survey says that it has, at least in the minds of leaders.

Bobbi Pritt, M.D. (02:22):

Yeah, it's really reassuring that these healthcare leaders see the value of the laboratory and that they're not slashing budgets. Hopefully that will all come to fruition. But it was good to see that 68% expect that the laboratory budgets will actually increase.

William Morice II, M.D., Ph.D. (02:37):

Yeah, I actually was surprised by that, especially with a lot of the other pressures on healthcare that we've talked about and on the laboratories. So, that was the other thing, we got in the survey that I should say. It went a little deeper on what these leaders are thinking for the laboratory, what are some of the things that they're working on, what are some of the challenges that they're confronting? And certainly, top of mind for many is the pricing pressure from payers, right? We've talked a lot and I'm sure we'll talk a lot more in the coming couple of months about PAMA. Which if there's not the RESULTS Act or some other mitigating legislation is not passed, there'll be up to 15% cuts in the fee schedule. I think, you know, lab leaders are preparing for that though and thinking ahead.

William Morice II, M.D., Ph.D. (03:19):

And at the same time, they're thinking about making other investments. It's not like they're just saying, "Oh, you know, we might get decreased reimbursements. We have to cut." As you said before, we actually have to invest. That's probably, again, very reassuring that leaders are seeing that challenge in that way.

Bobbi Pritt, M.D. (03:34):

Yeah, and I was really glad to see that they were thinking about investing in things like automation and innovative new testing and ways to address the workforce challenges that we're all seeing.

William Morice II, M.D., Ph.D. (03:46):

Yeah, I think that's right. I mean certainly that was something that came through loud and clear. There are workforce challenges. We've talked about them. Others are feeling them as well. What the survey is telling us though is that in response to that, there's more creative and innovative thinking in terms of, how do we use automation and automation tools like AI to help our labs be more efficient, to help the people working in the labs focus on kind of top-tier, or activities that really maximize the value that they contribute to the patients that are served by the laboratory? So, that's major. It's great to see that leaders are thinking in that way. And to your point too, number two is that they're really thinking about, what are some of the new tests that we need to continue to create to serve patients?

I mean, medicine is advancing so rapidly, labs have to advance with them. And then last but not least, certainly not least, is that with all that, they're still thinking with a growth mindset. So, those hospital laboratory leaders are thinking about how can they grow, how can they kind of reach more patients and reach more providers to provide more diagnostic answers for patients, but also, to increase the throughput in the laboratory to really make the investments that need to be made viable and producing the appropriate return for sustainability in the lab.

Bobbi Pritt, M.D. (05:04):

Yeah, all important things. And I'm glad that we have these survey results to really kind of give us an insight into what these healthcare leaders are thinking, and hopefully we'll be seeing these trends in the coming years.

William Morice II, M.D., Ph.D. (05:14):

Yeah, absolutely. And then again, too, that we continue to strengthen the laboratory community just like you and I do with this podcast again in some small way, right, to recognize that we all are kind of pulling the rope in the same direction. So, how can we help each other?

Bobbi Pritt, M.D. (05:29):

Well, now I talked about the coming years, but let's just talk about the coming months or should I even say the coming weeks? I thought it'd be good to just end on a brief discussion about the season coming up, and even though there's lots of wonderful things to look forward to with fall and winter and holidays, but also, we have some common respiratory viruses. We're entering flu season, and I think it's just a good reminder to start talking about what people can do to prepare and protect themselves.

William Morice II, M.D., Ph.D. (06:01):

Yeah, absolutely. Tis the season. As we mentioned before we started recording, my parents live in a group setting in a major city and the respiratory viruses are already making the rounds there, right? So, can't be too early to think about some of the preventive measures we've talked about before, particularly also with kids going back to school. If someone's sick in your family, you think about, if you need to go out and, you know, think about family gatherings and thinking about protecting yourself, with masking and hand-washing and all those really good practices, and those around you, because these viruses can cause serious illness, and they do cause serious illness every year. There's other things that people can do to protect themselves, too.

Bobbi Pritt, M.D. (06:41):

Yeah. I mean, one of the good ways is vaccination and healthcare providers are starting to talk about what they're going to offer this year. So, I think it's a great time to start thinking about what the current vaccine recommendations are and consult with the healthcare provider, your own clinician, to really find out what your eligibility is and what questions you might have.

William Morice II, M.D., Ph.D. (07:01):

Yeah. Really important to make an informed decision on that. I just was talking to my parents about it over the weekend, so I mean it really needs to be tailored to your health situation and your risk, and really there's a lot of good information out there. So, talk to your doctor, talk to your healthcare provider and make an informed choice to protect yourself, for sure.

Bobbi Pritt, M.D. (07:19):

Yeah. Well, on that, I think we'll wrap up for today, and I know that we'll be talking about some of these things again in the future. So Bill, again, it's great having you with us.

William Morice II, M.D., Ph.D. (07:29):

Well, it's always great to be here, Bobbi, and, I know there'll be no shortage of things to talk about here coming up, so I look forward to it.

Bobbi Pritt, M.D. (07:35):

Absolutely. Have a great week.

William Morice II, M.D., Ph.D. (07:37):

You too.

Bobbi Pritt, M.D. (07:43):

Welcome to the deep dive. We're going beyond the headlines today with Dr. Leslie Donato, a clinical chemist at Mayo Clinic, to discuss a unique panel she and her colleagues in Gastroenterology developed for bile acid malabsorption. Thank you for joining me, Dr. Donato.

Leslie Donato, Ph.D. (07:59):

Thank you for having me. It's a pleasure.

Bobbi Pritt, M.D. (08:01):

Yeah, it's a pleasure to have you here. So, I have a few questions for you. For listeners who aren't familiar with this syndrome, maybe we could start with what bile acid malabsorption is, including some of the common symptoms and underlying causes.

Leslie Donato, Ph.D. (08:17):

Sure. So, let's start from the beginning and the background of what bile acids are. They are synthesized in the liver and released into the small intestine where they function to solubilize dietary fats and then facilitate the absorption of those lipids in the small intestine. The ones that are initially made in the liver are called primary bile acids, mainly chenodeoxycholic acid and cholic acid. These primary bile acids are then metabolized and converted into what we call secondary bile acids by microbes in the GI tract. And this is mainly, lithocholic acid and deoxycholic acid, which are excreted in the stool. Interestingly, most of our bile acids are reabsorbed by an active transport mechanism in the terminal ileum. The remainder, and it's really only about 5% of our total synthesized bile acids, are actually excreted in a stool, so a very small portion. This process of reabsorption is really important for actually inhibiting the synthesis of more bile acids in our body.

It's essentially a negative feedback regulatory loop that we have. So in the condition of bile acid malabsorption, or sometimes called bile acid diarrhea, it's a condition where there's essentially too much bile acids that are excreted, and the increased bile acids in the colon actually cause an influx of water that leads to chronic diarrhea for these individuals. And it can be really debilitating. Bile acid diarrhea can be caused from a variety of different clinical conditions, such as ileal disease or resection, primary or idiopathic overproduction of bile acids or others. It's important to know that, however, that if a patient presents to their physician with chronic diarrhea, there actually are a lot of conditions that do lead to this condition and a lot of clinical diseases or conditions that are on the differential diagnosis. So, chronic diarrhea can be found in cases of infections, malignancy, food sensitivities, autoimmune or inflammatory conditions, et cetera.

So, bile acid malabsorption or bile acid diarrhea is only one of the many possible reasons for chronic diarrhea. Lastly, for patients with bile acid diarrhea, it's really important to identify the cause of it because there actually are quite effective treatments for these patients called bile acid sequestrants. They essentially bind up all the excess bile acids in the colon and prevent that influx of water, thus significantly restoring normal bowel consistency in those patients.

Bobbi Pritt, M.D. (10:55):

Well, it's really interesting, Dr. Donato, and I have to admit, this isn't something I've thought about before, although I've learned a little bit more about the power of microbes in the intestinal tract, and as a microbiologist, of course, that's of interest to me. It's very interesting to think of all these different causes of diarrhea, and of course our clinicians are trying to figure this out. So, let's talk about the tests that you have helped develop for diagnosis of malabsorption of the bile acids. I understand Mayo Clinic's bile acid malabsorption panel is a unique tool. Can you explain what it is and what makes it unique?

Leslie Donato, Ph.D. (11:31):

Yes, I can. It's actually important, I think, to know the history of the development of this panel test, so we'll go through a couple of iterations first until we get there. So historically, the gold standard to diagnose bile acid diarrhea, or bile acid malabsorption, has been a noninvasive test called the CCAT method that monitors an orally administered gamma-emitting molecule through the GI tract. Now, this method exposes patients to radiation, but is actually not even available in the United States. So, we have worked here at Mayo Clinic to fill this diagnostic gap. The first test that we brought up several years ago now is a stool-based, an only stool-based, test called a 48-hour fecal bile acid test. This test measures five different bile acids found in the stool. There's two primary bile acids and three secondary bile acids. We basically call this test the gold standard in the U.S. because it is the best approximation of true disease in the U.S.

For this test, the patient is placed on a high-fat diet for a total of five days. They are instructed to collect their stool excreted over a 48-hour period during that high-fat diet, and then send the entire volume of stool to the laboratory. We then extract the bile acids present in the stool and measure them by mass spectrometry. We're looking for two things that indicate bile acid malabsorption. The first thing we look for, is it increased in the total concentration of bile acids in the stool? The second thing we're looking for is actually an increased percent of primary bile acids in the stool. It turns out that increased primary bile acids is also a hallmark of bile acid malabsorption. So, these are the two things that we measure in that, what we now consider the gold standard test within the U.S., is this 48-hour stool collection.

As you can imagine, it might be unpalatable for patients to actually go on this very long, strict, high-fat diet, and then actually have to collect their stool for two full days and have to store it themselves and send the whole sample in. So, a little bit cumbersome for patients. So the second test we brought up is actually an indirect screening test that actually is a serum marker that we can test. It's an indirect way to identify bile acid malabsorption, looking at a metabolic precursor in the biosynthetic pathway for bile acids. The compound is called 7-alpha-hydroxy-4-cholesten-3-one, or we call it 7AlphaC4 for short. So again, it's found in the serum, not in a stool sample, so the patient doesn't have to collect a stool sample, and it's elevated when that negative feedback loop is disrupted, that I told you about before.

This test is less sensitive for identifying patients with bile acid malabsorption, but the sample collection process is more palatable. It does have to be collected in the fasting state though, so the patient does have to fast overnight and then come in for that serum collection in the morning. So that's the second test we brought up. So now we'll talk about the third test, which is actually the panel test that you're asking me about. It's actually maybe the best of both worlds here. It's kind of a combination of the two. It's a panel test that requires actually both the fasting serum collection and a stool collection. However, the nice thing about this panel test is that the stool is a random collection now. So, the patient doesn't have to go through that high-fat diet, collect their stool at home for two full days, and you know, store it in their own refrigerator at home and do that.

It's a random stool. So, one-time collection. Collect a sample, send it in. The test uses both the results from the 7AlphaC4 and the serum. And from the stool, the information we're collecting out of that is actually just the percent of primary bile acids from the stool sample. And from those two pieces of data now, we can identify patients with bile acid malabsorption. The test is nearly as good as that best-case scenario that we have in the U.S., that 48-hour collection. But it's really a nice option for patients and physicians because the ease of collecting a fasting serum, and most importantly, a random stool collection, is much more palatable for patients. So, allowing for a random stool collection in this panel is really a game-changer. For physicians, this means that during an encounter with a patient with chronic diarrhea, the patient could be asked to collect the random stool on the same day, even within the clinic, you know, even at the clinic during the visit itself, without having to go through somewhat cumbersome collection of that 48-hour collection.

The patient will still need to get that fasting serum sample drawn to complete the sample collection, of course, with the panel. And the collection really needs to be ideally within the same day, but we allow within three days just so we know that the patient condition hasn't changed between the two collections. But it really is a nice option for patients to have this panel test for a really good and accurate identification of patients with bile acid malabsorption. And this test actually is exclusively offered at Mayo Clinic at this point.

Bobbi Pritt, M.D. (16:47):

Well, that's wonderful, Dr. Donato. Sounds like an excellent option for patients. So, you've launched this test now, this third iteration. Can you share what you've learned about bile acid malabsorption? Anything that you've learned, especially from real-world use of this test?

Leslie Donato, Ph.D. (17:03):

Yeah, great question. Initially, this test was developed to identify a cause of chronic diarrhea in patients with a condition called irritable bowel syndrome, or IBS-D or IBS with diarrhea. Most of the initial clinical studies, many of which were performed here at Mayo Clinic with our GI physician, Dr. Michael Camilleri, were performed in this patient population. So, a lot of the initial studies and implementation was in IBS-D patients. But surprisingly, we've actually learned that the prevalence of bile acid diarrhea is really quite high in our total population. It's actually 1% of our entire population, which is actually pretty similar to that of celiac disease, which a lot of people know about, but we don't talk about this chronic diarrhea and bile acid malabsorption. Interestingly, within the IBS-D population, the prevalence of bile acid malabsorption is actually around 35 to 40%, so it really is quite substantial in that population.

And furthermore, we've actually expanded the testing of this in other diseases. So, we've actually identified and shown that bile acid malabsorption can be found in a variety of different clinical conditions, not only IBS. So it's been shown to be present in ulcerative colitis, Crohn's disease, microscopic colitis, and most recently, in patients with neuroendocrine tumors who can suffer from chronic diarrhea. So this means that if bile acid malabsorption is identified in these patients, there could be a therapy that, again, might alleviate their chronic diarrhea symptoms, which is really helpful in a broader clinical scenario.

Bobbi Pritt, M.D. (18:42):

Well, that's very interesting. Well, let's think about looking ahead. You've done so much great work in this area. What do you see as further opportunities for advancing diagnostic tools for conditions like bile acid malabsorption?

Leslie Donato, Ph.D. (18:55):

Yeah. Well, focusing on bile acid malabsorption, I'm really excited about future discoveries of clinical utility of our testing in various GI and non-GI conditions, because of course, we know chronic diarrhea and diarrheal symptoms can really be present in a variety of different clinical conditions. I'm confident that we'll actually find more patient groups that will benefit from testing, again, because testing really leads to a clinical use of a therapeutic that can really be beneficial for those patients. So, I'm really excited about that. And additionally, new studies are looking at different therapeutic approaches to treating patients with bile acid diarrhea or malabsorption, other than using those bile acid sequestrants, which can have some negative side effects, of course. Actually, a recent, small, randomized control trial, again, led by our internal GI physician, Dr. Camilleri, looked at probiotic supplementation, and it did show that this decreased the percentage of primary bile acids in the stool.

So, I'm hopeful that more investigation in this type of area, using our methodologies to kind of monitor treatment and then lowering of bile acid malabsorption, the bile acid malabsorption collaboratory phenotype that we see, can identify novel therapeutic options to alleviate the diarrhea symptoms in patients with bile acid malabsorption.

Bobbi Pritt, M.D. (20:17):

Very interesting. Well, Dr. Donato, I learned a lot from listening to you today. Thank you again for joining us and sharing your knowledge with our listeners. It was a pleasure having you.

Leslie Donato, Ph.D. (20:27):

Well, thank you so much for having me.

Bobbi Pritt, M.D. (20:34):

Let's wrap up with the top takeaways and how to learn even more on the topics we discussed. Dr. Morice joined me to discuss findings from a recent survey exploring the strategies laboratories are using to drive growth. We've included a link to the full report in the show notes. We also reminded listeners that now is the time to start preparing for seasonal virus vaccinations, and we've provided a link to Mayo Clinic guidance in the show notes as well. Then Dr. Donato joined me to discuss testing for bile acid malabsorption. And if you'd like to learn more about this topic, we've included several additional resources. The show notes include links to a free webinar featuring Dr. Donato and her GI colleague, Dr. Michael Camilleri. And there's a story about the development of the test discussed today, also a resource outlining the bile acid malabsorption tests and clinical case examples.

Thank you for joining us today. If you haven't already, make sure to subscribe so you never miss an episode. And then next time, Dr. Binnicker will be joining me to discuss seasonal viruses. I hope you can join us.