Gut Check: Sam Han, MD, on Pancreatitis
In this episode of Gut Check, Dr Brian Lacy talks with Dr Sam Han about the etiology, risk factors, diagnosis, and treatment of chronic pancreatitis.
Brian Lacy, MD, is a professor of medicine at Mayo Clinic-Florida in Jacksonville, Florida. Sam Han, MD, is associate professor of medicine in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minnesota.
Welcome to Gut Check, a podcast from the Gastroenterology Learning Network. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida. I am absolutely delighted to be speaking today with Dr. Sam Han, associate professor of medicine in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minnesota. Dr. Han is an expert in pancreatic disease and has been the author or coauthor of a number of different key articles on the evaluation and treatment of both acute and chronic pancreatitis. Today we're going to focus on chronic pancreatitis. Dr. Han, welcome. Let's begin by trying to understand the scope of the problem. How common is chronic pancreatitis?
Dr Han: Thanks for having me on the show, Brian. It's a pleasure to be here. To start off, though, the prevalence of chronic pancreatitis is estimated to be around 42 to 73 per 100,000 people with the highest prevalence seen in the 45 to 74 age group. And the incidence is estimated to be around 4 to 5 new cases a year per 100,000 people as well.
Dr Lacy: So definitely a lot more common than I think a lot of us believe or understand. And when we think about the pathophysiology of chronic pancreatitis, what changes really occur in the pancreas with chronic pancreatitis?
Dr Han: Yeah, I think it's most important to recognize chronic pancreatitis as a fibroinflammatory syndrome. So there's ongoing inflammation of the pancreas that results in progressive loss of the endocrine and excreting compartments from atrophy or replacement with fibrotic tissue. So early on, you have these repeated episodes of pancreatitis, which results inflammation. Then there's the resolution and regeneration, but with recurrence of these episodes you get progressive destruction of the gland.
Dr Lacy: Yeah, I like that great pathway you just described of inflammation, loss of both endocrine cells, exocrine cells, and then scarring and fibrosis with repeated episodes. So thinking about chronic pancreatitis, what are some of the most common etiologies?
Dr Han: Yeah, I think most health care providers recognize excessive alcohol, and when I say excessive alcohol, greater than 4 to 5 drinks a day, as the most common contributing factor for chronic pancreatitis. But cigarette smoking is also one of the most common etiologic risk factors for the development of chronic pancreatitis. So most providers forget that it's actually an independent risk factor in and out of itself, with odds ratio of nearly 3 for the development of chronic pancreatitis. Afterwards, genetic mutations likely play the third leading cause. So you can have mutations in the PRSS1 gene, which is commonly seen in hereditary pancreatitis, which is an autosomal dominant condition, as well as SPINK1 mutations, which can also be seen in up to 10% of patients with chronic pancreatitis. And then CFTR mutations, which we typically associate with cystic fibrosis, can also account for up to 7% of cases. I also want to make special note of autoimmune pancreatitis, which is very rare, actually, and only accounts for 1-2% of cases. And it's a very different kind of entity of chronic pancreatitis. And then it's also really important to note that 30% of cases are considered to be idiopathic even after a thorough workup, including genetic testing.
Dr Lacy: Okay, Sam, that was wonderful. Two great teaching points on, I just want to repeat, 1 is we all counsel our patients on tobacco cessation anyways, but an odds ratio of 3 is quite high. And for our listeners who might be taking the medicine boards or the GI boards, SPINK1 and PRSS are things that may come up on the board. So think about those genetic causes of chronic pancreatitis.
Sam, we haven't really even talked about it yet. We've understood now that it's common, said now that it's common, we understand the pathophysiology, but what are some of the most common symptoms of chronic pancreatitis?
Dr Han: So most patients with chronic pancreatitis will typically present with episodic upper abdominal pain and nausea and vomiting as well. And then the pain patterns typically include either intermittent severe attacks of pain or persistent chronic pain. And then once you get advanced disease, you can develop steatorrhea, where patients will have diarrhea, weight loss, decreased muscle mass, and eventually osteoporosis or osteopenia. And then patients can also eventually develop diabetes as well, which is commonly referred to as type 3C diabetes. And this is characterized by having these really wide swings in blood glucose levels.
Dr Lacy: Okay, very interesting. And I think a lot of our listeners may not be as familiar with the term of type 3C diabetes in the setting of chronic pancreatitis. So that's great. So thinking about the diagnosis then, are we pretty comfortable in clinic just seeing somebody with those symptoms— abdominal pain, nausea, vomiting, maybe steatorrhea—and making the diagnosis of chronic pancreatitis based on symptoms and maybe some risk factors? Or is imaging required?
Dr Han: This is a great question. And while symptoms and risk factors do play a role, you really do need imaging to make a definitive diagnosis. So CT or computer tomography is definitely the most readily available. And it's the best test to see calcifications, which are essentially pathognomonic for chronic pancreatitis. MRCP, particularly with secretin administration, allows for the best visualization of the pancreatic duct, but obviously takes longer to perform, it's more expensive than CT, and it can miss calcifications as well. So these imaging modalities are in general great at detecting advanced disease, but it's really challenging to make a diagnosis of early chronic pancreatitis, what we commonly refer to as minimal change chronic pancreatitis. So imaging findings that we're typically going to see on CT ultrasound or MRI even include atrophy of the pancreas which is really just loss of the parenchyma, chronic inflammation and fibrosis of the pancreatic gland itself, then you can have beading and dilation of the pancreatic duct, dilated side branches of the duct, as well as intraductal calcifications or stones. And I do want to make a point that ultrasound is good at seeing calcifications in the pancreas as well as pancreatic duct dilationand atrophy of the gland as well.
Dr Lacy: Wonderful. Great radiology review. Thank you, Sam. So some of us were taught that maybe low levels of amylase and lipase can be diagnostic of chronic pancreatitis. Is that correct or should we need to move on from there?
Dr Han: Yeah, I would agree with the latter. I think checking an amylase and lipase have no diagnostic value for diagnosing chronic pancreatitis. So while it is true that these levels can be low in patients with advanced chronic pancreatitis, having low values are not diagnostic of chronic pancreatitis. And we do check these levels when patients come in with a pain flare to see if they're having an episode of acute pancreatitis, but with progressive destruction of the acinar cells, these also may not be elevated as well.
Dr Lacy: Wonderful. So there's also a lot of information and also probably some misinformation about pancreatic elastase measured in stool samples. Is this a good test for chronic pancreatitis? Is it valid and reproducible?
Dr Han: Yeah, this is another great question as so many patients are referred to our pancreas clinic for low fecal elastase. So while fecal elastase is the most widely used stool test and most accurate among the pancreatic and stool enzymes, the threshold at which they are thought to be diagnostic of pancreatic exocrine insufficiency is controversial. So levels below 200 micrograms per gram of stool are abnormal, but only really low values. So when I say low values, I mean less than 50 micrograms per gram of stool are thought to be reasonably accurate for some steatorrhea. So other conditions such as diabetes, old age, inflammatory bowel disease, renal failure, and watery diarrhea can also be associated with low fecal and osteosil levels. And most importantly, I want to stress that the 48- to 72-hour quantitative fecal fat collection on 100 gram a day of fat diet is the best estimate of fat absorption, with normal levels being less than 7 grams of fat per day.
Dr Lacy: Right and that old test has stood the test of time stool sample— 48 to 72 hours, less than 7 grams of fat per day. So Sam, I just want to come back a little bit because it's so important—understanding the value of imaging for chronic pancreatitis and you gave us so many great tidbits. What about the role of EUS— endoscopic ultrasound? How does this compare to CT imaging or MRI and really is there any role for diagnostic ERCP anymore? Diagnostic ERCP, not therapeutic, or has MR imaging with secretin stimulation kind of replaced diagnostic ERCP?
Dr Han: Yeah, endoscopic ultrasound or EUS is really great at looking at the pancreas and offers to add a benefit of being able to sample the pancreas with a biopsy in addition to providing images of the pancreas. Compared to CT and MRI, however, there are no significant differences in detecting chronic pancreatitis with a sensitivity around 81% and specificity around 90%. The main issue is that we have all these criteria for detecting structural abnormalities in the parenchyma and the pancreatic duct, but these features are not necessarily pathologic and can occur with normal aging as well so we don't really know what the cutoff should be from making the diagnosis of chronic pancreatitis based on endoscopic ultrasound criteria.
As for your question about ERCP, there really isn't a role anymore for diagnostic ERCP and as you mentioned MRCP with secretin stimulation provides great imaging of the pancreatic duct without the risks associated forming in the ERCP.
Dr Lacy: Right, and without the risk of additional radiation from more and more CAT scans, right? So, Sam, this is great. So let's shift gears now and think a little bit about treatment. Is there a validated, stepwise approach that all of us can use for the treatment of chronic pancreatitis?
Dr Han: The simple answer is that there is no evidence-based algorithm for the treatment of chronic pancreatitis. The American College of Gastroenterology or ACG came out with some guidelines for chronic pancreatitis, which really largely consisted of how to approach pain with a single recommendation for exocrine pancreatic insufficiency, which was quite simply to prescribe pancreatic enzyme replacement therapy, or PERT.
There was an international consensus guideline for treatment of pain that came out in 2017, and this I think provides the most practical approach. It starts with trying to figure out whether the pain is actually coming from the pancreas or not. And while this is quite challenging to do, basically you're trying to kind of see what kind of pain patterns these patients are having. So if patients are having discrete episodes of pain, we think of them as having primary pancreatic pain. While if they're having kind of chronic pain all the time, they likely have some neuropathic component of pain as well with either central sensitization or peripheral sensitization. So if patients have this primary pancreatic pain, we wanna make sure that we're addressing any malnutrition, any lifestyle factors, be it alcohol or smoking, or even secondhand smoking. And that these patients have any structural complications we can intervene on, such as pancreatic duct strictures or stones, then we can consider either an endoscopic therapy via ERCP or have them see a surgeon for a drainage procedure.
Now for those patients with likely some component neuropathic pain, it is recommended to start treatment with either NSAIDs or acetaminophen or Tylenol. And if they really do appear to have some neuropathic pain, then we can consider something like pregabalin or gabapentin to help treat their pain.
Dr Lacy: Great, I like that nice approach recognizing what we don't have some prospective study in thousands of patients but of the more intermittent more versus more persistent pain. That's a nice approach. So if we think about a little bit more about pain and you know that's such a driving factor for many patients with chronic pancreatitis. Is there any data from randomized controlled studies for the use of nonopioid options?
Dr Han: Yeah, This is really the most pressing question, usually, for gastroenterologists, how to treat pain in patients with chronic pancreatitis. You know, surprisingly, there are actually no randomized trials in that investigating either NSAIDs or Tylenol or acetaminophen for chronic pancreatitis, but that's typically supposed to be our first line agent, at least outside the United States. I just actually completed a phase 2 randomized trial funded by the NIH with Dr. Darwin Conwell and Dr. Santhi Vege on oral indomethacin, which is an oral NSAID. And we're going to be actually presenting our results at the American Pancreatic Association meeting next month. But essentially after one month of treatment compared to placebo, we actually did find an improvement in pain. Now obviously we need a much bigger trial, but it looks like it may be promising.
And then in terms of other medications, there was a randomized trial published in Gastroenterology about a decade ago that looked at pregabalin or Lyrica in patients with chronic pancreatitis and persistent pain, the majority of whom were actually on opiates. And after 3 weeks of treatment, there was significantly improved pain compared to placebo, suggesting that it might be a nice adjuvant pain medication.
Lastly, I did want to mention that there was an international multicenter randomized placebo controll trial published in Gastroenterology this year, looking at chemostat, which is actually a nonopioid oral serine protease inhibitor. And while it was a negative study, it did highlight how nearly half the participants on placebo actually had a positive treatment response, which demonstrates the difficulty in doing placebo-controlled trials in this population.
Dr Lacy: Well, congratulations on that really innovative study. We look forward to hearing more about that. And yes, the power of placebo, it's impressive some days, isn't it? So, Sam, you kind of mentioned PERT, pancreatic enzyme replacement therapy, for symptoms. How about some simple tips and tricks for our audience? Should these agents always be taken before the meal? Should they be taken with the meal? Do you put them on a PPI? Do you not put them on a PPI or an H2 blocker? We hear a lot of conflicting advice.
Dr Han: Yeah, absolutely. This is a commonly asked question and it really does depend on the specific enzyme formulation, but in general, these should be taken with meals. It's important to remember to just swallow the capsules or have our patients just swallow the capsules and not chew them because of the risk of mucosal irritation. Then I typically recommend starting with half the dose at the beginning of the meal and then the second half of the dose towards the midpoint of the meal. And then in terms of an actual starting dose, it's good to start at about 500 units of lipase per kilogram of body weight per meal. So with half of that for snacks. So that would mean approximately 40,000 units of lipase for an 80-kilogram patient during your meal as a starting dose. And in general, we don't recommend doses greater than 120,000 units per meal, given that 90,000 units are really what you need during an average meal.
And in terms of the PPI or H2 blocker, so if patients are taking the nonenteric-coated preparations, which is primarily the brand name Viacase, which is actually a tablet, you should be taking them with either a proton pump inhibitor or H2 blocker. All other formulations, however, are capsules that are pH-sensitive. So though many patients are on PPIs or H2 blockers already, that's totally fine. And just for reference, the most common brand names are Creon, Pertzye, Zenpep, Pancreaze, and Viokace. And then there's Relizorb, but Relizorb is only for tube feeding purposes.
Dr Lacy: Sam, I like that about 5,000 units per kilogram for lipase, and that's a great reminder to our providers recommending this. And also, more is not always better. So these extravagant amounts of lipase, 100,000, 200,000, per meal, may not be necessary and may actually be harmful, so that's great.
So, Sam, as we start to wind down here a little bit, can you alert our listeners to some common complications of chronic pancreatitis? Which should our providers be concerned about?
Dr Han: There are a whole host of complications of chronic pancreatitis and honestly this is what we spend most of our time managing in this disease. So we already talked about some of the structural complications such as pancreatic duct strictures and stones but other structural complications include biliary strictures, which would typically present with elevated LFTs and jaundice, and it's important to treat those really to prevent secondary biliary cirrhosis. Alternatively, patients can also develop pseudocyst or gastric outlet obstruction, both of which can be treated endoscopically as well. Otherwise, exocrine insufficiency as we've discussed and endocrine insufficiency are really the most important complications.
For those patients who develop diabetes, I highly, highly recommend having an endocrinologist manage their diabetes as the episodes of hypoglycemia in particular can be quite severe. And then in terms of exocrine insufficiency, the downstream effects of malnutrition can lead to sarcopenia and osteopenia. So it's really also important to check their vitamin and mineral levels, specifically vitamins A, D, E, K, B12, and folate, and then in terms of minerals, magnesium, selenium, zinc, and iron. And we want to check those on an annual basis and basically supplement those if needed.
Dr Lacy: Wonderful, great teaching point. So Sam, this has been a wonderful conversation. Thank you so very much. Any last thoughts for our listeners?
Dr Han: Yeah, I think the downstream effects of chronic pancreatitis are really the most important ones that we need to keep an eye on. So one of the most important findings that the PROCEED study, which is the NIH-funded multicenter longitudinal cohort study in the US, is really how prevalent osteopathy is in chronic pancreatitis. So we've basically found that the majority of patients with chronic pancreatitis have either osteopenia or osteoporosis, including half of male patients. Additionally, among patients who are less than 50 years of age, almost 40% of them will have osteopathy as well. So again, this speaks to the importance of getting DEXA scans on a regular basis, typically every 2 years for these patients.
Lastly, research has also shown how many of these patients actually have psychiatric comorbidities. So work by one of my collaborators, Dr. Anna Evans-Philips at the University of Pittsburgh, has also shown that about half the patients with chronic pancreatitis suffer from anxiety and 40% of patients suffer from depression as well. Obviously, for many of us, treating psychiatric conditions is not our strength, but it's important to screen for them and at least make referrals to appropriate providers for these patients.
Dr Lacy: Wow, two great, wonderful pearls at the end. Think about bone health—and that's a shocking number for men—and think about mental health and if you're not comfortable dealing with it, just make that referral, right? Let's do the right thing for all of our patients. So Sam, thank you so much again for lending your expertise on this important topic.
To our listeners on Apple, Spotify, and other streaming networks, I'm Brian Lacy, a professor of medicine at the Mayo Clinic in Jacksonville, Florida. You've been listening to Gut Check, a podcast from the Gastroenterology Learning Network and our guest today was Dr. Samuel Han from the Mayo Clinic in Rochester, Minnesota. I hope you found this just as enjoyable as I did. And I look forward to having you join us for future Gut Check podcasts. Stay well.
