Gut Check: Drs Brian Lacy and Santhi Vege on Exocrine Pancreatic Insufficiency

Host Brian Lacy, MD, discusses the challenges of accurately diagnosing and treating exocrine pancreatic insufficiency with guest Santhi Swaroop Vege, MD, from the Mayo Clinic in Rochester, Minnesota.

Brian Lacy, MD, is a professor of medicine at the Mayo Clinic-Florida in Jacksonville. Santhi Swaroop Vege, MD, is a professor of medicine at the Mayo Clinic in Rochester, Minnesota, and president of the International Association of Pancreatology.

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TRANSCRIPT:

Brian Lacy:

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. Santhi Vege, professor of medicine in the division of gastroenterology and hepatology at Mayo Clinic Rochester. He's also the president of the International Association of Pancreatology and he's the associate editor of the journal Pancreatology. More importantly, he's an international expert in pancreatic disease and has been the author or coauthor of many of the key guidelines on both acute and chronic pancreatitis.

And today we're going to be discussing a topic that comes up frequently during office visits with any provider who is evaluating a patient with chronic diarrhea. And the question is, is the diarrhea due to pancreatic insufficiency? So Dr. Vege, welcome. Let's begin by trying to understand the scope of the problem. How common is pancreatic insufficiency? And for today's discussion, we'll focus just on exocrine pancreatic insufficiency and of course not diabetes.

Santhi Vege:

Yeah. Hello everyone and I'm so happy to be with you all. And actually this is an extremely common problem in general practice as well as in GI practice. So any patient with chronic diarrhea, which as you know is an extremely common situation, the question of pancreatic insufficiency, the so-called exocrine pancreatic insufficiency, comes into picture. There are some studies where they looked at chronic diarrhea patients, mostly IBS and others, without obvious clinical pancreatic diagnosis. When they tested them with, say for example, fecal elastase, which it's almost taken over like a tsunami, and they looked at fecal elastase abnormality and they said anywhere from 5% to 10% of chronic diarrhea patients attending clinic will have a low fecal elastase—less than 200. And so they say, and the author said, that that could be because of exocrine pancreatic insufficiency. However, I have to caution you that's not correct for multiple reasons.

Fecal elastase is not a very good test and we'll talk about it later, but more important is that when subsequently people try to rigorously look into chronic diarrhea cohorts and then do various tests to see whether it's pancreatic exocrine insufficiency or not, it's really probably less than 2%. But we need to understand that when you say EPI, I think we almost, for all practical purposes, it's a chronic pancreatitis, usually. There are other causes. And the chronic pancreatitis frequency is what we need to know also. Not that all of them will have EPI, but probably anywhere from 30% to 50% to 60% over a period of time get that, too. And we have population-based studies about chronic pancreatitis. The prevalence of chronic pancreatitis is about 50 to 60 per 100,000. That means if you take a town of 100,000 people anywhere in the United States— these are American statistics—you'll find about 50 people with chronic pancreatitis. So about half of them may have EPI. So you can look at it that way too.

Brian Lacy:

That's a great way to put things in perspective— that although we hear commercials and see a lot of things, it's probably not as common as people believe. And you kind of briefly touched on this, but I want to just pin you down a little bit. On a cellular basis, why does pancreatic insufficiency develop?

Santhi Vege:

Okay. So again, we as practicing clinicians, we like to make things simple. We are not here to give complex names and terms and make it unnecessarily complicated. The pancreas has mainly 2 functions for a human being. One is digesting the food and other is maintaining the blood sugar levels in proper range. So the exocrine function is the acinar part of the pancreas on a pathology level and the endocrine maintenance is the eyelet cell part of the pancreas. So the acinar cells of the pancreas, the acina which secrete the enzymes, trypsin, chymotrypsin, lipase, and so forth, elastase, they get destroyed by any process which causes fibrosis or scarring, that is chronic pancreatitis, but they can also be destroyed sometimes temporarily numbed if you have acute pancreatitis edema, which is actually numbing them.

And also any infiltrator process of the pancreas, not necessarily cancer, but a diffuse infiltrative process due to granulomatous disease or sometimes lymphoma can also cause this particular thing, but at a cellular level, it is the acinar cell dysfunction, which is most commonly in chronic pancreatitis because by definition it is inflammation, fibrosis, and destruction of the architecture. That's where the acina really get lost and you don't have enzymes.

Brian Lacy:

So just such a perfect segue into thinking about some of the most common causes of pancreatic insufficiency, and as you've mentioned, chronic pancreatitis and infiltrative disorders. What else should a busy clinician think about in terms of common causes?

Santhi Vege:

So the 2 common pancreatic causes of exocrine pancreatic insufficiency are chronic pancreatitis and cystic fibrosis. Now we are seeing more and more cystic fibrosis as adult gastroenterologists and practitioners earlier than we used to reach the adult birth. So here, what is important is selectively because of the very thick secretions, the exocrine function gets disturbed. But the gland, when you look at it on a CT or MRI, may look relatively normal, but it is because of the specific secretions, the exocrine function gets lost while structurally it may look normal. So these are the 2 pancreatic conditions, but you can have pancreatic resections, partial pancreatectomy, distal pancreatectomy, or even total pancreatectomy for chronic pancreatitis. That can cause this problem.

The other thing is if you have a severe duodenal disease that is affecting the mucosa of the duodenum where you have the CCK and other things which enter okinase, which stimulate the pancreas to produce both the ductal bicarbonate secretion as well as the acinar enzyme secretion, the pancreas may look normal for you on your CT and MRI, but it's not getting any stimulation from the duodenum and mucosa, which usually sends off this particular stimuli when the food reaches there. So when the duodenum and mucosa is gone for some reason then you don't have stimulus, pancreas looks normal, but you can have exocrine pancreatic insufficiency. So resections of the pancreas, duodenal mucosal disease, and then altered anatomy. Suppose if the pancreatic enzymes are still coming into the duodenum, but you have altered it by various surgical and other procedures, then the pancreatic enzymes are going to a different place in the duodenum, but food is going into a different place. They don't mix and you can get. So these are some of the things that can happen like that.

Brian Lacy:

Wonderful. That's perfect. Thank you. Santhi, thinking about these common causes, let's think a little bit more about risk factors and if somebody's in clinic and considering the diagnosis of EPI, should we be thinking more about a young woman or an older man or other issues with ethnicity?

Santhi Vege:

So starting off with the presumption that the common prototype of EPI is chronic pancreatitis for which we know there are many causes, so let's talk about that. And usually chronic pancreatitis we know for many decades, more common in men than women for obvious reasons we can talk about it. More common in blacks and more common in people who have familial pancreatitis, although it's a small percentage. But the two important risk factors for chronic pancreatitis are alcohol and smoking. And if they're present together, which most often they're present together, they're actually almost like multiplicative rather than additive. They actually potentiate each other. However, in about 20% of the cases of chronic pancreatitis, we don't find a cause, 20%, 25%, and we call it idiopathic. Maybe in future with so many new genes being discovered, we may be coming out with some genes for this so-called idiopathic or no cause, but the genetic causes, right now we have about 6 genes that we can test, and if you have a problem in some of those genes, then also you can get chronic pancreatitis.

And usually this goes through repeated attacks of acute pancreatitis, then scar tissue laying down, and then chronic pancreatitis. So these are the usual risk factors. One thing I want to mention here, in the last 10 years particularly, we are knowing more and more that even acute pancreatitis can cause exocrine pancreatic insufficiency during the acute phase because the gland is practically stunned and all the SNA are not functioning because of the pressure. Most of them recover, but in about 15% of the patients where you don't have any necrosis of the pancreas during the acute stage and then the gland returns back to normal on your CT MRI after they recover, but still they continue to have exocrine pancreatic insufficiency. So now we are saying that a proportion of the people for various reasons, both the endocrine and exocrine cells get stunned during the process even if there is no morphologic damage and they continue to have dysfunction going forward for years.

Brian Lacy:

So that's a great teaching point that it may just be a single episode that could lead to exocrine pancreatic insufficiency. So you mentioned some of those risk factors. So let's consider a black male who smokes and drinks alcohol to excess and he comes in with symptoms you think are characteristic of exocrine pancreatic insufficiency, can we just make the diagnosis and start him on treatment that day or do we need to check a fecal fat or is imaging required?

Santhi Vege:

This actually is a very, very important question, extremely important question. Even if you have the typical patient with the risk factors and with this chronic diarrhea, without proving that there is a pancreatic disease, I would not advocate treating that patient as EPI. Of course you can give a trial for 2 weeks. Maybe there's no big deal happening there, but that in the long run, probably that's not the right thing. I think we have to have a proof of pancreatic disease at the minimum by a cross-structural imaging, which is usually CT scan. And without that, I don't advocate straight off the bat doing.

But if you had a CT scan and you know 1 of the 3 cardinal features on CT scan are calcifications, dilated duct due to strictures, and atrophy of the gland. If all 3 of them are presented it is slam dunk, but if calcifications are present, that's also pretty clear. In those patients if you have a chronic diarrhea and particularly if the chronic diarrhea is foul smelling, bulky, difficult to flush in the toilet, and oil droplets seen, then I don't usually test anything more for those people, particularly if they also have low albumin and other malnutrition things, I straight off the bat start there.

Brian Lacy:

Wonderful. So just to recapitulate for our listeners thinking about cross-sectional imaging, atrophy of the pancreas, calcification, and dilated ducts.

Santhi Vege:

Yes.

Brian Lacy:

So you started the conversation about pancreatic elastase, kind of a lot of misinformation, but let's just dig into that a little bit better. Is it a good test? Is it valid? Is it reproducible? Should the stool be solid? Can it be loose?

Santhi Vege:

This I think is probably even more important than your previous question that I thought is extremely important, but I think we have to clarify this. Human beings, we all know, we just want whatever is easy. We want a quick fix. We want something simple. Fecal elastase is simple. You just give a stool sample. It can stay for a long time. No need for any specific preservations. And even if you're taking pancreatic enzymes, you can even give a stool. All these advantages. Whereas fecal fat, which is the gold standard, even in 2023, 2 to 3 days of 100 grams fat diet. Then you have to do probably 48 hours, if not 72, of stool collection. Cumbersome. No patient is happy to do it. Then you have to mail that whole thing here. No lab person is happy to do it, but, still, thankfully there are good reference laboratories doing it.

That's the gold standard. But because it's not possible, everybody started doing fecal elastase, the physicians, the specialists, the gastroenterologists, the public, everybody. So it became a tsunami. Now anybody who has a chronic diarrhea, even if it is IBS, they get an elastase, and if it is less than 200, you said EPI and they start patients on enzymes. There are 2 big dangers here. One is giving a wrong label of EPI, which is a very serious label. Almost you have to take it as serious as a cancer diagnosis. You cannot just give that label because it's a lifelong condition. Two, pancreatic enzymes are extremely expensive. Already our health care is just going down because of the cost of the health care here. We spend so many billions every year, but we are the least in the outcomes in the 15 economically developed countries. So we have to be careful about it.

So I would strongly suggest that fecal elastase is not the test, particularly if you say anything less than 200, you are bound to over treat many people and give them a label of EPI, which is a serious mistake. When people have compared fecal elastase, actually fecal elastase values 200, 100 have been set up with a very small group of 44 or 45 patients with EPI and about 25 controls. But when people looked at fecal fat and fecal elastase with the CCK pancreas enzyme and testing of the enzymes, the fecal elastase has very low specificity sensitivity, PPV, positive predictive value, negative predictive value compared to the gold standard fecal fat. So do not diagnose EPI with fecal elastase, but once you have a definite pancreatic disease like calcifications, dilated duct atrophy, then you have diarrhea. And if it is not very typical with the 4 features I mentioned, then you can do fecal elastase, but in the new classification scheme that we proposed and published, only fecal elastase less than 50 you can say, "Yes. I can give the patient enzyme treatment."

Brian Lacy:

Wonderful. So educational and thank you for pulling in the information about the comparison of fecal elastase to the traditional gold standard test of measuring fecal fat. But let me jump ahead. Some clinicians take the patient, maybe with chronic diarrhea, they're considering the diagnosis and they try to do something maybe a little bit different. Let's just measure vitamin A or vitamin E, 2 fat soluble vitamins. Could we use those as surrogate markers, diagnostic markers of EPI?

Santhi Vege:

Once again, a great question. So if you take most of the guidelines published in the last 5 to 8 years on chronic pancreatitis, including American College of Gastroenterology, then European guidelines, then the British guidelines, they've all come in the last 5 years. Almost all the guidelines said that you have fat soluble vitamin deficiency in chronic pancreatitis, A, D, E, K, and you have to measure them probably at baseline and then periodically. Some people said every year, but some people said periodically. But if you look at the meta-analysis of the published things, the deficiency of particularly vitamin D, we all say chronic pancreatitis you don't absorb D. You get osteoporosis probably 40%, 45%. So bone mineral scan has to be done, calcium, et cetera. But interestingly when you look at meta-analysis, the normal non-CP group and the CP group, there's not much difference.

Both of them have nearly 50%, 55% osteoporosis. So you probably can test and treat, but it is not because of CP. It's like it is so prevalent in the normal people. Even the vitamin E is also just not that different. So I would say probably once at baseline you can do these things just to see if they're low, you can replace, but the guidelines saying that you replace, their quality of life gets better, the bloating and other things get better, they may have prolonged survival because there is decreased survival in CP, it is not yet proven clearly. And particularly when pancreatic enzymes are very expensive, we have to be careful, but I do not test them to usually give pancreatic enzyme replacement therapy if you don't have characteristic diarrhea. Without that I don't.

Brian Lacy:

Wonderful. So let's shift gears now, Santhi, and let's move from diagnosis and to discuss treatment. Is there a validated stepwise approach to the treatment of exocrine pancreatic insufficiency or does this really depend on symptoms and the degree of pancreatic insufficiency?

Santhi Vege:

Yeah. So once again, a very practical question. So once we decide there is an indication for pancreatic enzyme replacement therapy in a patient with EPI. So usually stage three and stage four are where we advise pancreatic enzymes. Both are with fecal elastase less than 50, both are with fecal fat greater than 15, and the only difference between stage 3 and stage 4 is the A, D, E, K deficiency and probably magnesium, zinc, and B12 deficient. The only difference between 3 and 4 is these are deficient and you replace them, but both we say you have to give pancreatic enzyme replacement therapy. Once we make a decision that we have to give the enzymes, usually I would think starting off with 36,000 units of lipase, United States pharmacopeia units, is probably adequate. Guidelines say 40 to 50,000, most of the things, and some of the experts who are involved in the FDA approval trial, they say you have to start with 72,000.

Actually I'm strongly against that because I don't want to my patient to spend unnecessary money. So this high dose is not benefiting the patient, it's benefiting somebody else. So I think I usually start with 36,000 units of lipase and I usually don't give one capsule 36,000. There are about 5 coated and 1 uncoated preparations available in the United States, total 6. Uncoated via case is very difficult to get, but you can get. 36,000, I don't start with one 36,000. Say for example, if you take a particular brand, it can have a 36,000. I usually see that at least two of 24 or three 12. The reason being, when you are giving pancreatic enzymes, it is now accepted by everybody that throughout the meal, it is better than at the beginning than at the end. So if you have three of 12, I give one at the beginning, one in the middle of the meal, one at the end of the meal. So you spread it out.

There is no physiological way that you can ever supplement pancreatic enzymes. Just zero. You can never do that. And also you can never improve the fecal fat to actually less than 10 with these enzyme therapies. You go only up to a point. So I start with 36,000 and then if they don't respond, you can increase by 12,000 and usually I go up to 72,000, and very rarely people can go up to 96,000, but 36 to 72,000 is your range. If they're not responding with that, because mostly these are potted, then you give them a PPI so that you make the gastric and the duodenum juice less acidic so that these enzymes act. In chronic pancreatic is what happens you don't secrete bicarbonate in your pancreatic juice to come into the duodenum. So the duodenum is more acidic because of lack of alkylate.

Then these enzymes coated preparations do not get dissolved in acidic things. So they go down into the lower [inaudible 00:21:56] and get activated there. But we need to have in the same place where food is there for the action to happen that's in the lack of alkylate. So you can add step two is PPI. Even with going up to 72,000, then you have step two PPI adding, but still if they have diarrhea, then you have to check for bacterial old growth, which is very common in these people and treat them with that. Even then if they have the problem, then you can probably try the uncoated enzymes, which are even more expensive, but they have to be given with PPI too. Even then if you have a problem, then you have to actually just see, is the patient taking them or is your diagnosis wrong? So that's how I would go.

Brian Lacy:

Wow. So this is amazing. So a great stepwise approach. I learned a wonderful clinical pearl. You do not like to use the 36,000 dose all at once, but you like to do 12,000 before the meal, 12,000 during the meal, and 12,000 afterwards. Thank you. I've never heard that. That's wonderful. I bet most providers have not. And also to clarify, it sounds as if you do not start every patient on a PPI at the start. Only if they do not respond. Is that true?

Santhi Vege:

Yes.

Brian Lacy:

And one other clinical question comes up all the time, what about the size of the meal? What happens if I just have a half a sandwich versus that big gourmet Italian meal? Does the size of the meal matter?

Santhi Vege:

Yes. So usually if you have a small meal or a snack or something, then usually we say half of what you're taking. That's the thing. Or even one-third depending on the size.

Brian Lacy:

Santhi, this has been an absolutely wonderful and educational discussion today. I've learned an awful lot. I know our listeners have learned an awful lot. Any last thoughts for our listeners?

Santhi Vege:

Do not make a diagnosis of exocrine pancreatic insufficiency lightly. That is because it equates with chronic pancreatitis, which is a serious diagnosis, as serious as a diagnosis of cancer. Number two, know the right way to give the enzymes and the right dose. And just going by fecal elastase in a chronic diarrhea, which is not EPI, starting a patient on expensive pancreatic enzymes, which then have to be lifelong. Every month it may be $500, $600 if insurance doesn't cover, is not a good thing. And lastly, fecal elastase, because it is so easy to use, let's not make our diagnosis based on such tests, which are more tests of convenience rather than accurate tests. So these are my thoughts on exocrine pancreatic insufficiency.

Brian Lacy:

So we've been listening today to Dr. Santhi Vege, professor of medicine at the Mayo Clinic in Rochester, Minnesota and president of the International Association of Pancreatology. We've heard this amazing discussion on pancreatic insufficiency. I'm Brian Lacy, professor of medicine at Mayo Clinic in Jacksonville. Welcome again to Gut Check. We hope you listen in in the future for other wonderful podcasts and thank you for listening in today.

Santhi Vege:

Thank you.