And we'll move on to our next speaker, Dr. Darwin Conwell is a friend of mine and somebody whom I've looked up to in this field for a long time. He's a chief of GI at the Ohio State University, which is widely acknowledged to be inferior to the University of Michigan. All right, thank you very much, Joe. Let's get moving. So put on your seatbelts. We'll be covering a lot of material here today. No disclosures at all. So in 1788, Cawley described this free-living young male with calcifications in his pancreas as one of the earliest descriptions of chronic pancreatitis. Of course, the ACG guidelines are now out in chronic pancreatitis. And Tim Gardner led this effort along with some other experts. And I would encourage you to read this. We're going to go through some of these pretty quickly to give you an overview of how to manage patients with chronic pancreatitis. I am not a therapeutic endoscopist. I'm like Peter Banks. We always say we're medical pancreatologists. We have no skills. We just see patients in the office with belly pain. So these are tough clinics that we have. Okay, let's talk about diagnosis. So I'm going to answer some questions for you. So what should you use for diagnosis? Cross-sectional imaging should be done initially. That would be a CT scan, then followed by an MRI. If that's negative, then I would go for an endoscopic ultrasound. Pancreas function testing, pretty much indirect function testing with a fecal elastase is really supplemental to your diagnosis. There is no great test for early pancreatitis. And we'll talk about that a little bit more when we talk about some of the consortium work that we're doing in regard to biomarkers. Pancreatic histology is really not available via EUS. We had some really hopes for a while that EUS biopsy would help us. But this is not routinely done. The pancreas is very vascular. It leaks. You don't want to have any fluid collections to deal with from your cough or from your doing an EUS FNA. So diagnostic tests. These tests are very specific, primarily CT scan and MRI. EUS is probably too sensitive. And in patients that are older, overweight, that smoke, they're going to have a lot of the classic EUS features for fibrosis. So you have to be careful and interpret these in the right setting. But CT scan should be your test of choice, followed by MRI. And of course, we want to make sure a patient does not have a pancreas neoplasm. So a cross-sectional imaging study is very important to obtain. Now, this is just one paper that we put out looking at features of chronic pancreatitis and trying to develop a model to diagnose this based on an abnormal pancreas function test. And we looked at a lot of patients with PFTs at one center at the Cleveland Clinic, followed by the other center. I was at the Brigham Women's Hospital. And we came up with a model. And that model looks at whether or not they smoke, whether or not they have alcohol. And also, we look at the parenchymal and ductal features on EUS and whether or not they have calcifications. And based on that, you can develop a risk score. We're looking forward to validate this even further in our chronic pancreatitis consortium data. But this looks at trying to put some weight on the EUS features. Because I believe a hyperechoic foci is different than a dilated duct or a hyperechoic duct. So what exactly, how does that correlate with pancreas function testing or abnormal duct cell secretory function? And I think based on this study, we can actually add some weight to some of those parenchymal and ductal features to get us closer to whether or not a patient has a diagnosis of chronic pancreatitis. Now, remember, this has to be done in the right clinical setting. The patient has to be in your office. And you suspect that they have chronic pancreatitis. They have risk factors like recurrent pancreatitis or abdominal pain. They smoke or they drink. So keep that in mind in any of the tests that you order in patients for a diagnosis of chronic pancreatitis. Now, this is an algorithm, just a simple algorithm that Beach and Wu and I put together when we were working together in Boston. And we called this the STEPWISE approach. And S really stands for surveys. So a really good history, physical exam, review of all the records. I know it's challenging, but go through the records. Do they have recurrent pancreatitis? Do they really have acute pancreatitis? Is the live patient greater than three times the upper limit of normal? You have to look at the lab assay and make sure you know what the upper limit of normal is at the lab assay. It may be 60. It may be 200. So three times the upper limit of normal is very important for you to determine whether or not a patient has acute pancreatitis. And it's in that milieu of patients that are at risk for chronic pancreatitis. This is followed by tomography, which is standard CT scan, then MRI scan, endoscopic ultrasound, function testing. I do a lot of in my center because we have a strong research approach to these patients. But for the most part, you can get away without doing pancreas function testing. It's really not available in most academic centers. So the right risk factors, CT scan, secret and enhanced MRI scan, EUS. I order a lot of EUS procedures in our patients. Natural history. The guidelines talk about natural history. It's important for you to understand the etiology. This comes from the TIGAR O classification, toxic, idiopathic, genetic, acute recurrent, and obstructive. Very important to understand that. Also understanding the natural history of chronic pancreatitis, that patients usually have recurrent attacks of acute pancreatitis that then leads to scarring and dropout of aster cell function. And they'll get EPI and loss of islet cells. And they'll eventually develop diabetes. It's important for patients to stop smoking. We know for sure if you quit smoking, you're less likely to have more progression of your disease. You're less likely to have calcifications. So it's very important to keep that in mind. Screening for pancreas cancer. There's no guidelines for this. I can tell you in my practice, all my chronic pancreatitis patients that I see on a regular basis get some type of cross-sectional imaging every year. Insurance companies have no problem paying for that. I don't say I'm ordering it to rule out pancreas cancer. I order it to follow the progression of their disease. Natural history. Usually recurrent attacks of acute pancreatitis. And eventually, patients start to scar and lose function. And this is very important to keep in mind. What about pain control? Now, this is the elephant on the couch. This is what's really, really hard for us to manage. And how you manage chronic pancreatitis pain, if you have an answer, come and tell me. I would love to know. We've been doing this for over 30 years. And it's very, very challenging to put these patients together. Now, we have some clues. And there's a lot of hope around on the horizon. So just keep this in mind, that pain control is very, very difficult. And primarily, what we base this on is anatomy. If you have a dilated duct, if it's amenable to endoscopic therapy, we usually do that first. If it's amenable to surgical therapy, if endoscopic therapy fails, we usually go to surgical therapy. There's antioxidants should be used and tried. There's about a 50% response rate using antioxidants. Pancreas enzymes do not decrease pancreatic pain. Joe will tell you, the patients that we see in our pancreas clinics, by the time they see us, enzymes aren't helping. They're already on a lot of narcotics. Enzymes do not decrease pain. Enzyme will improve digestion. It will improve some of the functional malabsorptive, malassimilation symptoms that they have. But it will not decrease pancreatic pain. Celiac plexus block, head-to-head randomized controlled trial show, it's not long-term beneficial. But there are a subgroup of patients who really have visceral pain. And that's the question. What patient do you operate on? What patient do you do a celiac plexus block on? What patient do you give a neuromodulator? What patient do you give an antidepressant or an SSRI? And that's going to be the real problem. How do we characterize their pain, whether we know this person now has central processing, this person now has a visceral pain syndrome, or some other kind of pain syndrome that we can differentiate, and then that can target our therapy. And we'll talk a little bit more about that. And that's the hope that's on the horizon for pain control. It's also important to remember when we're doing any studies in chronic pancreatitis with pain, there's about a 30% placebo response rate. So that's got to be accounted for in all of your power calculations when you're trying to do studies in chronic pancreatitis. Now, this is very, very important recent data that comes out of the Pittsburgh group. Anna Evans, Dheeraj Yadav, also the Hopkins group and the Dutch group got together and formed a consortium looking at quantitative sensory testing. And this gets us closer. This gets us closer to characterizing the pain syndrome that these patients have. And then you can differentiate who's got more central processing of pain, who's got more visceral type pain, and will respond to a therapy directed at the viscera, which is the pancreas. If I have a patient that has central processing, I can remove their pancreas. They're going to wake up with the same pain. That's a big mistake. That's an error. Right now, we're limited, but this quantitative sensory testing gets us closer to understanding the pain syndrome that these patients have. And it's a chronic pain syndrome. It may start out as visceral pain. They may have had recurrent bouts of pancreatitis and chronic pancreatitis for 10 or 15 years, but over time, the pain can change. The other thing that's important is to understand the psychiatric comorbidities associated with chronic pancreatitis. A lot of these patients are depressed. They have a lot of anxiety. If they have constant pain, they have more depression and more anxiety. They have sleep disturbance. These things need to be treated. We've ignored these in the past. We haven't treated them very well, but this is contributing to the overall chronic pain syndrome. It's contributing to their quality of life. And if we can treat their sleep disturbance, they may have a markedly improved quality of life, and they may be able to manage their pain better and keep a job. So this is important to understand. A lot of recent data now looking at psychiatric comorbidities in chronic pancreatitis. So this comes from a Dutch group, comes from a lot of other researchers, an international consortium got together to say, how should we approach chronic pancreatitis pain? This is a mechanism-based approach. Is it a wiring problem in some patients? Is there a problem with tissue hypertension? Is this a plumbing problem where we have just, you know, stones in the duct and a big dilated duct with a stricture? Should we approach it that way? Is there a problem with motility, bacterial overgrowth? Is there increased CCK pressure stimulating the pancreas? So trying to break down exactly what is contributing to the overall pain syndrome in this patient with chronic pancreatitis is very, very important. What about endoscopy and surgery? I have told you before, you know, we go to endoscopy first, followed by surgery. In head-to-head studies, of course, surgery gives you more long-term benefit, but patients will tell you they'll prefer to have an endoscopic approach less invasive than a surgical approach initially. But the head-to-head studies, we all know this, show that endoscopic therapy is not as long-lasting as surgical therapy. And this is in your, you can get this off the slides. It's a nice review that goes over all the studies looking at endoscopy versus surgery. So what about extricate insufficiency? Pancreas enzymes definitely should be used. We have to replace what the pancreas is not producing. The aster cells are scarred, they're damaged, they're not secreting trypsin amylase and lipase, so you need to give that back to the patient. What about vitamin deficiencies? Of course, these patients have vitamin deficiencies, specifically vitamin D deficiency. They also have zinc deficiencies and magnesium deficiencies when they get severe chronic pancreatitis. And so the guidelines recommend periodic checking of nutritional markers. They don't give you the time window. We don't know. There's not enough data to tell us that. But this is something you should keep in mind when you're following these patients, at least a yearly assessment. What's their vitamin D status? You know, what's their magnesium level? What's their zinc level? Fecal elastase. So this is really the pancreas function test that most of us get. We don't usually do the direct test. The fecal elastase is done commonly in our patients. A couple things I want you to remember. Make sure they give you a solid stool sample. This is a concentration measurement. If they give you a diarrhea sample, it'll be a falsely low fecal elastase. It will be a positive test, and that's an error. And there's a lot of diseases also that contribute to an abnormal fecal elastase, like IBS and diabetes. So you have to interpret this in the right clinical setting. So whenever you get a test, make sure you're getting the test in the right patient, and then you know what you're gonna do with the information. It's very similar to what Anne Marie was saying about patients getting, when you're doing surveillance. If you're gonna get an MRI on a patient with a cyst, you gotta think about, why am I getting that? Because I'm thinking about this person may have a precancerous lesion, and I may need to do surgery on them. So make sure whenever you're ordering tests, you're gonna do something with the result that you have. So a little bit of research here. So inflammation induces an imbalance between osteoclast and osteoblast activity. And this is an idea I had back in the mid-1990s, and I didn't get to study this until I went to Boston. But there's an imbalance between osteoclast and osteoblast bone breakdown and bone development, and this is well-described in IBD. And I said to myself, do we have this in chronic pancreatitis? The problem is, I can't study DEXA scans retrospectively in patients with chronic pancreatitis, because you don't usually refer them for a DEXA scan. So if you're referring a patient with chronic pancreatitis for a DEXA scan, there's already a referral bias. So Beech and Wu was my fellow. He said, let's do this. Let's look at a hard endpoint, and let's look at fractures. And there's no referral bias to a fracture. You break a bone, you break a bone. So the question was, chronic pancreatitis is a risk factor for metabolic bone disease. Our aim was to compare the prevalence of fractures in chronic pancreatitis into controls and other high-risk GI illnesses that can predispose to metabolic bone disease and fractures. So what did we find? The odds ratio of fracture among chronic pancreatitis patients was comparable to other high-risk illnesses. As you can see, Crohn's disease, celiac disease, chronic pancreatitis patients fracture their bones. So we published this in the American Journal of Gastro several years ago, followed this up with a publication from the VA dataset, where it's like 97% men, and they have three times the odds of fracturing their hip as opposed to control. So we really believe this is a big problem and a risk. I would encourage you to go through this in terms of what do you do, how do you manage patients with chronic pancreatitis? Again, patient presentation is very, very important. Do they have the symptoms that suggest they are at risk? Recurrent pancreatitis, a bout of acute pancreatitis, chronic abdominal pain? Do they have steatorrhea or fat loss in their stools? Get a cross-sectional imaging study, which would be a CT scan. That may confirm they have calcifications, dilated duct, atrophy. They've got the disease. High suspicion still? Go to a secretly enhanced MRCP. That will help you. You'll look more at the ductal features. You'll look at duodenal filling, ductal compliance, other things that help you get an idea of whether or not they have chronic pancreatitis. If that's positive, you got the result. And the home run is EUS. The right patient in the right setting with EUS usually gives me my answer. I confirm this further with a fecal elastase, and that usually nails down the diagnosis. Now, in our setting, we get a lot of patients referred to us with equivocal imaging. And the question is, is there any decrease in duct cell function that may tell me they have early chronic pancreatitis? And we know now in longitudinal studies from the Beth Israel Group in Boston that even a pancreas function test is only 50% accurate long term. It's great at ruling out chronic pancreatitis, but it's not great at diagnosing chronic pancreatitis. And we thought for sure that was always the home run. The longitudinal studies now show, coin flip for diagnosis, but the negative predictive value is over 97%. So what do you do in terms of medical management? Of course, they need pancreas enzymes. If they have a dilated duct, consider endoscopic therapy, surgical therapy, and then select centers. I would do a TPIAT. I think this is a very viable option in the right patient. In our setting and most institutions that have a TPIAT program, this is treated very similar to your other transplant patients. They have pharmacologic consultation. They have psychiatric consultation. Do they have the great support services around them to get their pancreas removed? Will their insurance company pay for their enzymes? So we actually have embedded our TPIAT program in our transplant program and all the resources that are utilized there for it. And so you select the right patient and you do a TPIAT, you'll get great results. You select the wrong patient, you will get terrible, terrible results. So we must accept finite disappointment, but never lose infinite hope. So there is hope. This is a paper that Phil Hart and I wrote that looks at what's going on now in terms of research for chronic pancreatitis. There was a great symposium that looked at, brought everything together in terms of where are the gaps in chronic pancreatitis? And we thank Dana Anderson and the NIDDK colleagues for bringing this symposium together. One of the things that has now been established, what we call a mechanistic definition, and Dave Whitcomb's group has put this together with a lot of other researchers throughout the world, and actually stratifying patients based on, are you at risk? Do you have recurrent acute pancreatitis? Do you have early chronic pancreatitis, established chronic pancreatitis, or end-stage chronic pancreatitis? And this is really where we wanna try and make a diagnosis, is in this early group. I'm gonna move on to what I call the black box. So this is where we want to make a diagnosis. We know when someone has established chronic pancreatitis, it's very easy to see those patients, recognize those patients. End-stage disease, of course, diabetes, EPI, but what about early stage? If we can diagnose them earlier, we have the potential to give them therapy to retard or slow disease progression. So this is very important for us for biomarker development. So a consortium has been developed to study chronic pancreatitis, diabetes, and pancreas cancer and the interrelationship between that, and we're fortunate enough to be involved in this consortium with MB Anderson as a data collecting site. We've put together the PROCEED study, which is a prospective evaluation of chronic pancreatitis for epidemiologic and translational studies. This is really to establish a longitudinal research cohort and actually create a platform for us to understand the natural history, to do imaging over time, to collect blood samples and saliva and other biospecimens over time, to get closer to biomarker development and better understanding and treatment of chronic pancreatitis. A very large biorepository has been developed based on standard operating procedures. We have over 100,000 aliquots of samples now. We have over 1,600 patients have been enrolled in this PROCEED study, and we're following patients at different stages based on that mechanistic definition over time to see who progresses in the chronic pancreatitis, who stays where they are, and to help us understand the biology and the mechanisms of chronic pancreatitis. So what does that really look like? It looks like this. You may be healthy. You may have recurrent acute pancreatitis and have mild disease, moderate disease, severe disease. Histologically, things are changing, and this is where we want to try to make a diagnosis. Before you get here, this is that minimal change area, that black box that we want to do biomarker discovery on. This is a paper that we wrote looking at biomarkers in chronic pancreatitis, putting things together, setting the stage for biomarker development in our chronic pancreatitis patients based on what we call the probe design, this prospective specimen collection with a retrospective blinded evaluation called the probe design, and this is a design that's well-established for biomarker development by the EDRN and the NCIs. We've now taken this and brought it into the benign literature at the NIDDK. So I'll show you our first big publication. It's in press, high prevalence of osteopathy in chronic pancreatitis, cross-sectional analysis from the PROCEED study. So 56% of patients with chronic pancreatitis have abnormal DEXA scans. They're either osteopenia or osteoporosis, and we really need insurance companies to actually start paying for DEXA scans. So this is one of the important papers that are going to be coming out very soon. I want to thank my colleagues at Ohio State. I have been blessed to be surrounded by some fantastic people there. We just recruited George Papachristou from the University of Pittsburgh, and he's taken us to a totally different level. So we're really excited to be involved in a lot of NIH studies, EDR, EDRN, NIDDK. We were working with Joe in the SVI trial, Greg in the SHARP trial. So we're just really excited to be involved in pancreatic disease. I'll leave you with this. Hope in the face of difficulty, hope in the face of uncertainty, the audacity of hope. In the end, that's God's greatest gift to us, a belief in things not seen, a belief that there are better days ahead. And I really believe this consortium is going to give us a lot of hope for chronic pancreatitis patients. So thank you very much for your time.

chronic pancreatitis

diagnosis

management

patient presentation

risk factors

pain control