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December 16, 2019 – Dr. Kelly Diehl talks with Dr. Jody Gookin, Professor of Small Animal Internal Medicine at North Carolina State University, about gallbladder mucoceles, an increasingly common, and potentially deadly, disease of dogs. Dr. Gookin discusses the disease, her research on how mucoceles form and how we might prevent them in the future.

00:17 Dr. Kelly Diehl: Welcome to Fresh Scoop episode 15, Research Insights on Gallbladder Mucoceles. I'm your host, Dr. Kelly Diehl, Morris Animal Foundation's Senior Director of Science and Communication. And today we'll talk to Dr. Jody Gookin, a professor and veterinary internist at North Carolina State University College of Veterinary Medicine and a Morris Animal Foundation funded researcher and our incoming chairperson of our Small Animal Advisory Board. Fresh Scoop is the monthly podcast of Morris Animal Foundation, one of the largest non-profit foundations in the world dedicated to funding studies to find solutions to serious health threats to animals. And in each episode, we'll feature one of the researchers we fund or one of our staff members discussing their work in advancing animal health. Whether you're a practicing veterinarian, technician or a student or just an animal-loving science geek, Fresh Scoop is the podcast for you. You can learn more about us at morrisanimalfoundation.org.

01:18 DD: Okay, on to today's show. Today, we welcome Dr. Jody Gookin, a distinguished professor which I don't, I'll ask you about that, what that means later, in the Department of Clinical Sciences at North Carolina State University. Dr. Gookin completed her DVM at the University of California, Davis, and her PhD in Gastrointestinal Physiology at North Carolina State University. She is a foundation-funded researcher with her primary research interests focused on gallbladder disease and diarrheal diseases. Today, we'll be focusing on her foundation funded work on gallbladder mucoceles in dogs. Dr. Gookin also will be chairing our Small Animal Advisory Board as mentioned this year. And she does Yoda imitation. Jody, thanks for joining us today.

02:10 Dr. Jody Gookin: Thank you very much, Kelly.

[laughter]

02:12 DD: Perfect. Thank you for doing your great Yoda imitation. So, I have a question about what a distinguished professor... Does that mean you have to have gray hair or something like that?

02:23 DG: Gray hair probably helps. But basically, I was fortunate enough to have a donor give a large sum of money to North Carolina State University to support veterinary students to do research over the summers in the laboratory of a faculty member in the College of Veterinary Medicine. And that is a unique opportunity for veterinary students to realize the importance of research, which is something that I'm very passionate about. And along with that large donation that pays for those students, it came with this title that I hold as co-director of the program.

03:03 DD: Wow. That's really cool. Good for you for doing that. Before we start, and you just mentioned here when we talked about all your great credentials, but can you tell us a little bit why you decided to become a veterinarian and why you decided to focus on gastrointestinal disease?

03:23 DG: Well, that's a good question. So I grew up in Southern California, and I was tickled that you described some of the listeners as animal-loving science geeks because that's essentially what I was. And I always wanted to go to veterinary school from as long as I can remember. And, so I ended up pursuing that dream, and that dream carried me ultimately to after I became a veterinarian, graduated from University of California, Davis, traveled across the country to North Carolina State University and found a unique program that trains veterinarians to be clinicians and scientists. So, you get advanced clinical training, but at the same time, have to get a second doctoral degree. So, a PhD degree in research. And, to be honest with you, I didn't have an idea that it would be in gastrointestinal physiology. It happened to be that I found a mentor that I thought would really provide me with good training in research. I really liked him. I liked his research. And, I knew that he would be a good mentor for me. And so, in the course of being mentored by him, I fell in love with GI physiology, which was his passion. And that's sort of how it all ended up.

04:44 DD: Before we move on. Most of our listeners are veterinarians. But for the lay audience that's there, can you talk about what a gallbladder mucocele is and then speak a little to its incidence in dogs.

05:01 DG: Sure, well to go down to the real basics here, the gallbladder is a really small organ in the abdominal cavity, and its job is to store bile that's made by the liver and then it delivers that bile to the small intestine where that bile is really important to aid in the digestion of fat. And, the gallbladder mucocele disease is a disease of this gallbladder. And, we just started recognizing this about 20 years ago. And what happens in dogs with this disease is that the lining of the gallbladder starts to secrete this very thick rubber-like mucus. And what happens is this mucus keeps being made by the gallbladder and eventually it fills and then over-fills the gallbladder, leading to basically rupture of the gallbladder and its contents into the abdominal cavity of the dog, which is a catastrophic, terrible thing to happen. Bile and that mucus is very irritating, and that's basically an emergency

06:09 DG: The other thing that could happen is that this mucus actually gets pushed up into sort of the plumbing of the liver obstructing the flow of bile and causing the animal to become jaundiced. The only treatment that we know for these dogs is a surgical removal of the gallbladder. And, typically this occurs on an emergency basis, and it costs the owners a lot of money. And it has a high mortality rate. And also, what happens in older dogs, so we have a dog that's been a beloved member of the family for many many years and now has this sudden serious illness that's going to cost a lot of money, and that creates a huge dilemma for dog owners, whether or not they want to put their older dog through the surgery or invest that much money not knowing what the outcome is going to be, it's just sort of an emotional roller coaster for these dog owners. We really don't know in terms of how common this is, we don't know what the exact incidence is, we know that we're recognizing it increasingly over time, and in terms of veterinarians’ impression about the disease, it's broadly accepted that it's probably now the most common extrahepatic biliary disease of the dog.

07:27 DD: So I have a quick question for because I know people who are listening, we think about gallbladder problems in people, and my impression, you can correct me, two things: One is that people don't get this condition and I think a lot of people think of stones in the gallbladder which this is obviously not, so can you address why you think this happens in dogs but not in people unless I'm wrong about that.

07:54 DG: No you're right about that. I am, obviously, very passionate about this disease and have really talked to human gastroenterologist, read the literature and there's no human counterpart to this condition. It's very unique, which is one reason that I got attracted to it. I think that we're increasingly recognizing that there's genetic differences between men and between women, between certain ethnicities and disease manifestations. And I believe that gallbladder mucocele formation in dogs is something that is happening to dogs because they are somehow genetically predisposed to respond in this unique way, whereas the same stimuli, if they happen to a cat or a person just doesn't manifest in a similar manner. So I think it's sort of a pharmacogenomic predisposition of the dog that creates this manifestation that just wouldn't happen in another type of animal.

09:01 DD: Okay so I have two questions that are somewhat related. One is, can you tell everyone the incidence breed-wise, me and veterinarians are going to kind of know this, and then can you speculate because I’m going to date myself but boy, when I was in vet school we never heard of this and you're right, I don't think until I got into private practice in the late 90s did I ever even see a case of mucocele, right? And you look at them under ultrasound and for the folks at home if you've never seen them, they're really cool, not cool for the dog but they're really cool looking on ultrasound, and you see them for the first time and you're like, "I don't even know what this is". So can you talk about incidence and why you think it's cropped up in the last 20 years?

09:48 DG: Yeah, well, first of all I agree with you that's one reason why I'm really fascinated with this disease. Let's say, like you did, they're cool to look at, and I'm fascinated but it's equally disheartening, but it's not something that I learned about in vet school, I had never even heard of a gallbladder mucocele or a disease like this of the gallbladder, so this is something that literally during the course of your own and my career, we started diagnosing and we’ve never seen before. And not only do we start diagnosing something we’ve never seen before, but then it becomes extremely common and dogs are getting this thing and they're actually virtually dying of this disease and that is... there's not very many diseases that just appear in your lifetime like that. So I think that something has happened over time that's now causing this disease to happen.

10:50 DG: And what makes that complicated is that there is this strong breed predisposition. So when you think about breed-associated diseases, you think about puppies and kittens and animals showing something but at a young age, because they have this genetic defect, but here we see this strong breed predisposition, but a disease that actually this manifests later in life. So my idea is that sometime 20 years ago, there's emergence of an environmental exposure to which certain breeds of dog are genetically predisposed to reacting in this unusual way with their gallbladder. It doesn't make sense to me that all these breeds of dog, and I'll share them with you have been getting this disease and been predisposed to this disease for a long period of time, because we never saw this before. So it's not like 20 years ago, we beamed some genetic mutation into half a dozen different specific breeds of dogs and now they get this disease, it's more likely these dogs have had this genetic predisposition for centuries but now they're getting exposed to something that makes them susceptible to this.

12:12 DD: And that dovetails a little with your research, because we talked really eloquently about why you're studying this and you're correct, and every veterinarian who's out there listening knows what a terrible, terrible disease this can be. So talk a little bit about your research in general, your Morris-funded project but your other research as well as you've tried to dive into the reasons behind this appearance of this disease.

12:38 DG: Yeah, I mean first of all, I just when I started coming across this, I really found that the unique manifestation of this disease and how devastating it is. It's both fascinating and disheartening. And I felt like when I came across this disease that I was disappointed that it was generally being regarded as a surgical disease, sort of a new surgical disease of dogs, like, "Oh, dogs, now, they get this gallbladder thing, and we have to go in surgically and remove it." And I felt like we were selling these patients short by just accepting that it was just some surgical disease, when in fact, we'd ever seen it before. It had to have a cause, there has to be a reason for this. Dogs are dying of this.

13:31 DG: The surgery, 25% of dogs don't make it home after the surgery because they're older. They have comorbidities, it's just... it's unacceptable. And when I looked at the disease process, what I saw, really, was a perfect storm of things that I felt like I could make a difference if I studied. So we have a gallbladder. It's lined by an epithelium. My PhD has to do with intestinal epithelium, so I'm trained to understand epithelium and how it makes mucus and how it secretes and how that's abnormal. And I happened to learn techniques, as a PhD student, that allows me to specifically study epithelium in this... using this approach called a Ussing chamber, where you can really interrogate those secretory processes and figure out what goes wrong with epithelium.

14:25 DG: I'm fortunate to work in a wonderful environment with colleagues in soft tissue surgery and in ultrasound. And I work in the Research Triangle Park where there's people that specialize in mucin pathobiology and people that do all types of all makes and things. And my research lab is literally a building next to an OR where I could take one of these mucoceles into my lab and perform these studies. And all of this just really spoke to me and said, "We all want to make a difference in our career doing something." And I just felt like, "You know what? I could devote myself and everything and all my colleagues that I can tap to join me, and I bet we can figure this out and we can make a big difference." And that really motivates me.

15:14 DD: So what did you find? What have you found so far because it's pretty interesting, because you've looked at it from a lot of different aspects?

15:23 DG: Yeah, a lot of different aspects. What have we found so far? Well, some of the first things we did was simply to ask the question, "What is inside the gallbladder? What is this mucousy stuff?" Everyone says, "Oh, it's mucus," but no one has actually even analyzed it. So one of the first things we did was just to say, "What is that stuff?" And we found out that it is a specific type of mucus that forms gel, it's called MUC5AC. It's made by a lot of abnormal... In a lot of abnormal situations, like mucin-secreting tumors, people with cystic fibrosis make a lot of MUC5AC. And we found that this mucus is not only being made in excess, but it's being secreted with other proteins that cross-link and form bonds with the mucus, that when it's actually delivered out in the lumen of the gallbladder, most mucus is supposed to become hydrated and slimy and slippery, and this mucus just stays all hard and stuck together. It doesn't hydrate normally. And so that gave us some real key insight to begin with, that this was an abnormal mucous disorder in terms of probably an inability to hydrate mucus. So in the absence of appropriate sodium chloride and water and the right ionic environment and the right acidity, mucus is not going to behave normally.

17:00 DG: So we knew we had to focus on the epithelium and figure out what is going wrong with its ability to secrete. Is it not secreting, or maybe it's absorbing too much? And those were the exact kind of questions we could ask on the Ussing chamber. So some of the work that, like you said, quite diverse, that Morris Animal Foundation is currently funding us to do is at all levels. So at one level, we're looking at these gallbladders in the Ussing chambers that we get from surgical patients, and we're able to determine that normal gallbladders, for example, secrete very well via a certain pathway. But if we put a mucocele gallbladder in the chamber, it doesn't work well through that pathway. So there's something wrong with the main pathway by which the gallbladder secretes. But we recognize that it actually does a better job secreting via a different pathway. So can we stimulate that different pathway to rescue the abnormal secretion? Can we give the dog certain medications that cause the gallbladder to be stimulated by this other pathway, and maybe that'll help hydrate the mucus and resolve the mucocele?

18:11 DG: Other areas that we've looked at are the genetics. So we have been fortunate to be able to perform whole genome sequencing on dogs diagnosed with mucocele formation and to compare the genetic defects that were identified to a pool of over 200 dog genomes that represent breeds that don't form mucoceles and create a relatively short list of possible genetic defects that are associated with the pre-disposition. Right now, that is a process of picking the most likely genes that could be involved, and then interrogating those individually, one at a time, in a larger pool of dogs that have mucoceles and don't have mucoceles. So that work is ongoing. And then another layer that Morris Animal Foundation has been instrumental in supporting us is to examine the gallbladder epithelium and do gene expression analysis on the gallbladder epithelium.

19:18 DG: So like as I said, the epithelium is really what's making the mucus and responsible for hydrating the mucus, so at a cellular level, there's a defect in those epithelial cells. So the question is, what are they thinking? What are they doing? What are they making? What genes are they transcribing? Like, what's driving their process?

19:41 DG: And that data has identified a number of genes that are transporters. Ion transporters. Ion channels, pathways for secretion of water and sodium and potassium chloride and things like that. So a lot of high-yield targets but a very complex data set because if you think about it, my theory is that we have an environmental exposure and a genetic predisposition. So, simply finding a genetic marker might be difficult because it's not just the genetic marker that causes the disease, it's the genetic marker plus the environmental exposure. So there would be lots of animals walking around or dogs that have maybe this genetic predisposition, but they don't have the exposure.

20:30 DD: Right. So, just to wind back for a second, for the folks out there who don't know, you know, we talked about... You talked about genetics. Remind every one of the breeds that are... Most commonly get this disease.

20:46 DG: For sure. Yeah. So the one that we recognized for a very long period of time is the Shetland Sheepdog. Very prevalent. Once Shetland Sheepdogs get to be about 10 years of age, it's kind of hard to find a Shetland Sheepdog that has a normal gallbladder. So there's a high prevalence of the disease in that breed. More recently, a less common breed was identified as being predisposed and that's the Border Terrier. And Border Terriers aren't an incredibly popular breed or as popular as Shetland Sheepdogs, but they're highly predisposed to forming mucoceles. Then we have American and English Cocker Spaniels, Bichon Frise, Pugs, Beagles, Poodles, Schnauzers. What's interesting is that we have all of these different pure breeds of dogs that really don't have any other kind of genetic defects in common if you think about it but we don't see this disease, very rarely in a mixed breed dog. Almost always a pure-bred dog.

21:53 DD: And the commonality and some of those is they're all small breed dogs. So have you... I know you've looked and I know the environmental piece is really hard to sort out. I think we're finding that as you can imagine with the golden retriever lifetime study, right?

22:08 DG: Yeah.

22:09 DD: Where you're trying to sort that out. But have you found anything yet when you've been looking? Like, some kind of common thread with these guys.

22:17 DG: As far as environment?

22:18 DD: Yeah.

22:19 DG: We are active on this. So one thing that was really, probably one of the exciting aspects of the study so far is that we have taken that gene expression data from the gallbladder epithelium and put it in software that can look at the specific gene that's being differentially expressed. By differentially expressed I mean, it's higher or lower in dogs with mucoceles than in normal gallbladders and the magnitude of how its expression is altered and the relationship between those genes and predict instigators for that profile.

23:08 DD: Okay.

23:08 DG: So it's like a pathway analysis. What do these genes have in common? If you put them in a software program that can mine all the inter-relationships between these genes and what the results of that assay suggested was that the dogs are being exposed to a xenobiotic.

23:27 DD: Okay, can you explain what a xenobiotic is for everyone?

23:30 DG: You bet. So a xenobiotic is a drug or an environmental contaminant or pollutant or something which is not natural to the dog. So it's a synthetic molecule, something the dog doesn't make on their own, doesn't normally see. And when dogs are exposed to these things, it activates in the body pathways to eliminate those things. The body will detoxify them, alter them, prepare them for excretion. Either to urinate out or eliminate through the bile, which is interesting. And so what showed is that a lot of the genes that are needed to detoxify these types of substances are turned on in these dogs which excitingly dovetails nicely with the overall theory that it's environmental exposure plus genetic predisposition that's happening in these dogs.

24:28 DD: So where... What are you looking for? This is skipping ahead a bit, but your... Like, this gives to be a lot of confusing pathways forward. What are you...where are you going next? Like, you're... I know you've got ongoing research, but where do you see you going following this pathway further?

24:47 DG: I mean it's a great question because I think that what we're trying to do is...what we have been trying to do is gather as much information as we can to refine as deep an understanding as we can about what's going on with these dogs in order to give us some direction to really focus. And so, what I would like to do is to get more information about the drugs or xenobiotics to which these dogs are exposed or have in their bodies and examine what potential impact those identified xenobiotics could have on the gallbladder and the gallbladder epithelium that might explain why this disease is occurring.

25:38 DG: We could test the ability of certain xenobiotics to cause this disease if we can develop better models in the laboratory to look at the interactions between drugs with gallbladder epithelium. Now fortunately, dog gallbladder epithelium is pretty easy to culture. So what we plan to do is expand our laboratory bench-based studies so that we can start to model this in the laboratory. As of now, we actually are dependent on getting gallbladders from dogs that undergo surgery and studying their actual gallbladder in the laboratory, very labor-intense and very restricted by access to these gallbladders. We get them pretty often but think about how quickly you could answer important experimental questions, if you could actually reduce it down to just the epithelium in a laboratory setting.

26:33 DD: Right. So that would be a lot easier for you to test different substances.

26:37 DG: Yep.

26:39 DD: In your research, what is sort of the take-home message, do you think, for people right now? because a lot of what you're doing is really basic science.

26:48 DG: You bet. Yep.

26:49 DD: And trying to figure this out because it would be great to prevent them. I think you're right. There's a really high mortality rate with taking these dogs to surgery, and I think you and I both know and for the listeners out there, medical management, it's not like people [chuckle] where you can maybe take some drugs for your gallbladder problems. And as Jody probably knows, we're, and for the folks out there, I know gallbladder surgery has really improved in people, but we're talking gallbladder surgery in dogs. That reminds me a lot of when, 30 years ago, where it was a huge deal, right? For folks to...

27:24 DG: Yeah.

27:24 DD: It wasn't done on outpatients, so it is a big deal. So what do you think right now, if your take-home message for veterinarians and dog owners who are listening, that you're finding? And where do you think your... It sounds like you're right on the cusp of looking at this from in a different experimental model.

27:44 DG: Yeah, I mean, I think that my basic interest is to figure out what causes this disease and then obviously, all good things can derive from that. But I'm also interested in the immediacy of trying to find ways that we can help dogs with the disease now. Can we help them resolve their mucocele now by using some rational approach to doing that? And we have gathered other data that has shown us that there's a lot of metabolic disruption in dogs with mucoceles. And this was a metabolomics-based study. And that study identified not only a pretty profound metabolic disturbance in these dogs, but specific treatment targets that could potentially restore normal metabolism to these dogs. And we're talking like basic vitamins and amino acids and things that were deficient.

28:42 DD: Wow.

28:43 DG: And so, we're very excited because we just are beginning a clinical study in the next month, where we are going to follow dogs with mucoceles that are not yet requiring surgery. And we are going to give them standard of care therapy, which is sort of this medical management that no one thinks probably works that well, but no one's really followed. And then another group that gets that therapy plus this cocktail of nutraceuticals that is meant to help restore normal metabolism and hopefully gallbladder function to those dogs, to basically follow them by ultrasound for a year and determine whether or not we can slow, alter or reverse the progression of the disease in those dogs. So it's really kind of exciting because it's taken what's been very basic observations into an immediate need and that is to see if we can improve our medical management of these dogs, even before we even understand the disease.

29:51 DD: Oh, that is... That's really interesting. So I have a question for you for people who are listening are when are you going to start recruiting or are you recruiting for this trial?

30:01 DG: Yeah, we're going to start recruiting in about a month. We've got pretty strict inclusion criteria. So the mucocele will have to be in a certain degree of maturation where it's a slam dunk. It is a mucocele, but it's not close to being able to become a surgical or life-threatening mucocele. The owners will have to be very committed because they'll have to give a lot of nutraceuticals, they have their dog come to North Carolina State University every three months for an ultrasound for a year. We'll require the feeding of a prescription diet. By the way, all of this is paid for by the study, so it's like a year's worth of prescription diet.

30:42 DD: Cool.

30:44 DG: It's actually... If somebody wants to really dial their dog in on medical management, there's a big incentive to want to do it. And they need to be dogs that are in otherwise, good health, so that they're expected that they would live for at least a year because some of these dogs are older and have comorbidities. So yeah, so about a year for the study. But we're going to start ramping it up here in the beginning of October.

31:11 DD: Awesome, awesome. So that sounds... I think that's going to help a lot of dogs. I know that basic research is always needed, and it's really cool to see how you are still ongoing with that, but been able to translate some of the results. Jody, thanks so much for joining us today and telling us about this really important and just bizarre disease in some ways. And I am looking forward to hearing more of your work. And I'm hoping the clinical trial works well because we sure need something. So awesome. Great job.

31:18 DG: Well, thank you so much, Kelly. And let me just say thank you to the Morris Animal Foundation because none of this would be possible without their support. And I'm forever grateful for that.

31:18 DD: Okay, well, thanks, thanks a bunch, Jody. So that does it for another episode of A Fresh Scoop. So once again, thanks Dr. Jody Gookin for joining us, and we'll be back with another episode next month that we hope you'll find just as informative. The science of animal health is ever-changing and veterinarians need cutting-edge research like what Dr. Gookin is doing to give their patients their best possible care. And that's why we're here. You can find us on iTunesSpotifyGoogle Play Music, and Stitcher. And to learn more about Morris Animal Foundation's work, again, go to morrisanimalfoundation.org. There, you'll see just how we bridge science and resources to advance the health of animals. And you can also follow us on FacebookTwitter, and Instagram. I'm Dr. Kelly Diehl, and we'll talk soon.