Recently I was asked to give a talk to a group of endocrinologists and other diabetes providers about exocrine pancreatic insufficiency, and while building my presentation I was thinking through everything I wish endocrinologists knew about EPI. (We call it EPI in the US, but if you are elsewhere in the world you may see it referred to as PEI, for pancreatic exocrine insufficiency. This is the same condition.) 

This is targeted toward endocrinologists and other diabetes care providers and heavily focused on people with diabetes but this is also relevant to gastroenterologists and primary care providers as well, and includes info on prescribing enzymes that is relevant to anyone with EPI regardless of any co-condition.

1. Exocrine pancreatic insufficiency occurs – and is common – in people with diabetes. All types. 

I was diagnosed with EPI back at the end of 2023 by pure luck, because I saw a post about a dog with GI symptoms that were solved by dosing enzymes with their food. I was curious and looked up if this condition occurred in humans, too – and it does. It’s called exocrine pancreatic insufficiency (EPI or PEI) and happens when the pancreas no longer produces enough digestive enzymes to help digest the fat, protein, and carbohydrates that you eat. I had a textbook case of symptoms, yet despite ongoing investigations with a gastroenterologist for over a year, it was never brought up on the list of possibilities as a condition we should screen for. The more I read, particularly seeing that yes, it occurs in people with diabetes, and studies show around 30% prevalence in people with type 1 diabetes and people with type 2 diabetes, I was flabbergasted that my gastroenterologist never considered it.

And why had I never heard of it? I had heard of the connection between T1D and celiac, which is why I ended up getting screened and diagnosed with celiac very quickly during college when I developed GI symptoms. I hear of gastroparesis quite frequently as well in people with diabetes. But EPI is likely more common than celiac and gastroparesis combined and I never hear it talked about by endocrinologists, researchers, or people with diabetes.

I could have been saved from over a year of suffering if my gastroenterologist was more aware of this or if my endocrinologist was more aware of the prevalence of EPI in diabetes. It’s now my goal to make sure we cut this window of suffering for other people with diabetes. So the number one takeaway for endocrinologists is that EPI occurs in people with diabetes, it’s more common than celiac and gastroparesis, and even if you don’t screen for EPI first, if GI symptoms are occurring and you’ve ruled out celiac and gastroparesis, screen for EPI next! (If not first, depending on symptoms).

2. How do you screen for EPI in people with diabetes?

Endocrinologists can absolutely order the screening test for people with diabetes.

(Yes, you can refer to a gastroenterologist…but…sadly…many gastroenterologists are not necessarily more advanced in their care of EPI, as my experience has illustrated. Gastroenterologists also underscreen, underdiagnose, and undertreat EPI across a wide variety of conditions, so unless you have a top-notch GI you know personally who is familiar and treats EPI with the actual standard of care, more on that below, you should consider ordering the test yourself and managing the EPI process for your patient with diabetes.)

The screening test most commonly used is not perfect, admittedly, or fun. The fecal elastase test requires a stool sample and getting it back to the lab in a certain time frame. But, it can be illustrative of EPI or likely EPI. The typical guidelines say <=200 ug/g indicates EPI. Historically there have been cutoffs for <100 and <=200 for different categories, but it doesn’t really matter because you don’t prescribe based on severity level or treat any differently. The 100/200 cutoffs just give you data from past research on the accuracy (sensitivity and specificity) of the elastase test.

But human elastase fluctuates, so someone could have a test with a result of 205 ug/g, for example, at the time they are tested and other times be more obviously under the 200 cutoff, e.g. 155 ug/g or some other random number.  My plea for endocrinologists is to be aware of the limitations of the elastase test in both directions, and contextualize the fact that an elastase >500 ug/g likely means not EPI, but something in the 200-500 ug/g range, though, is worth repeating a test and/or considering a trial of enzymes. (There’s an interesting study showing people with 200-500 elastase benefit from enzymes, so keep that in mind). I wrote more about elastase testing and the sensitivity and specificity here.

The TLDR I wish people knew is that 200 is not a precise, exact cutoff. I think it is incorrect to treat 201 ug/g as “you don’t have EPI!”. This is where clinical judgement comes into play, depending on if you’ve already ruled out obvious other issues and symptoms continue, and you have an elastase near or below the 200 ug/g ‘cutoff’, then you may consider enzyme trials with your patients.

Another factor to take into account is EPI-specific symptom frequency and severity. See the EPI/PEI-SS section 5 below.

And yes, EPI occurs in people who are overweight and it’s possible to have EPI and not (yet) have vitamin deficiencies. It doesn’t require unexplained weight loss or pain/pancreatitis symptoms or vitamin deficiencies in order to diagnose EPI.

It was also interesting, during my presentation, to hear from an endocrinologist, the wonderful Dr. Marina Basina from Stanford, who was sharing how she is also screening some people with diabetes who are “asymptomatic” (GI-wise) but have unexplained extreme spikes and drops on their CGM. Once they are on enzymes, they’ve been telling her how they feel like different people and have so much energy compared to before. This “asymptomatic” presentation – with some possible ways to detect based on CGM data and other atypical symptoms – is something I hope we research more in the future.

3. Endocrinologists can prescribe pancreatic enzyme replacement therapy (PERT) and should do so according to guidelines.

Endos absolutely can and should be willing to prescribe enzymes (aka PERT) to their patients with diabetes, if they’re able and willing to help manage the prescription. But there’s a few things to know.

The first is that most guidelines recommend 40-50,000 units of lipase per meal. ( EPI in diabetes doesn’t have its own specific ‘guidelines’: because EPI is pretty similar across conditions, there’s no reason not to use guidelines developed for EPI in other conditions as a starting point for dosing. Here’s a systematic review of all dosing guidelines across conditions including the evidence and best practices for diabetes and EPI.)

Coming from units of insulin, this sounds like a lot, so you (and patients) have to wrap your brain around the dosing sizes, first. But it’s actually not that much. Pills come in a variety of sizes depending on which brand, ranging from 3,000 units of lipase per pill up to 60,000 units of lipase per pill. The pills actually contain THREE types of enzymes: lipase, for fat digestion; protease, for protein digestion; and amylase, for carbohydrate digestion. They all have different amounts per pill but fat is the most commonly (95+%) researched factor and so the pills are described solely by fat/lipase amounts. I’ll stick to that in this section, but read more about protein below.

Please, oh please, don’t prescribe 3,000 or 10,000 to “start small”. The dosing guidance is 50,000 (ish) per meal as a starting dose. Most people actually need more than that, depending on what they are eating (fat, protein, etc). Enzymes are like insulin in that underdosing can feel like a drop in the bucket. But, ‘too much’ is not like insulin. ‘Too much’ usually requires a lot more than the equivalent insulin dose to cause issues. Most people are massively underdosed and if you start with a 10,000 dose, for example, it’s common to then infer that “it’s not working” and it must not be EPI, and people stop taking it (or the prescription is ended). In reality, ‘it’s not working’ is usually “this is not enough” for the person’s individualized needs and what food they are consuming. Again, the starting dose is around 50,000 units of lipase per meal, with it being common to increase as high as 150-200,000 per meal, depending on diet. There are some studies that have some correlation to ‘severity’ of EPI, but it’s also very individual on the person’s body AND what they are eating. Someone who eats a higher fat diet – such as people with diabetes who might choose a lower carb diet with more fat and protein – will need more enzymes than someone else who eats a low fat, high carb diet. (And individual to individual it varies).

So how much should you prescribe? And how?

4. How do you prescribe enzymes to someone with EPI? 

Given the above, you can Rx a starting dose of around 40,000-50,000 units of lipase a few ways. One brand, Zenpep, has pills of 25,000 units of lipase. Let’s do the math: this means 2 pills of Zenpep 25,000 per meal. Another brand, Creon, has pills with 36,000 units of lipase. You could choose to start with 1 pill per meal (36,000 units of lipase) or two (72,000 units of lipase). Either would be suitable, BUT regardless of which brand and which dose you choose to START with, this has to come with a conversation and education to the patient about what they are taking, WHY, and WHEN.

I found that both fat and protein have to be titrated. You can give someone a low fat meal with enzymes that work and then give someone the same amount of fat with protein and get massive symptoms. Some people conclude that they can’t eat that food whereas in reality, it’s the protein that needs additional enzymes. (I have a lot of specific examples in this blog post showing how common low-fat high protein meals like chicken and veggies may need as much enzyme dosing as higher fat meals, because of the protein content.)

This means you need to teach people that they can expect to develop a ratio of lipase:fat and protease:protein similar to how they have an insulin:carb ratio. This is something they can self-titrate and figure out about how many grams of fat or protein one pill “covers”, keeping in mind that they can have different pill sizes.

You should write the Rx to be taken with food. Do NOT write this as “take three times a day” because you assume people eat three meals a day. This is faulty because 1) people don’t then understand it is WITH FOOD and if they’re not eating they shouldn’t take it and 2) some people eat snacks and they need to dose for snacks, too, plus 3) some people (especially those who also have gastroparesis or other situations) eat several small meals a day.

I would explicitly explain to people that they need to take this with food and drinks with nutrients (so water and diet soda do not need enzymes) and that you are writing the prescription for X pills a day to be taken with food. And, tell them that once they figure out what dose is working for them and how many pills a day they need to call/message in and that you will update the prescription for them. That’s what happened for me: my Rx was originally written for 2 pills per meal, so I got 6 pills per day. I ended up calling and asking them to change my Rx to 8 pills per day* so that I could have snacks some times, or to otherwise to support the flexibility of sometimes having a larger meal that requires more than 2 pills.

(* Remember the dose matters; I am not specifying my dose/pill size/brand here, but this is not to say that 8 pills is the magic number for everyone.)

The benefit of educating people this way is it helps anchor that 1) they need to figure out what dose works for them and 2) the starting dose may be not what they need.

I am over-emphasizing this because in online communities I see a huge number of people who are not told that this Rx is for consuming with food (or drinks with nutrients, e.g. milky drinks) so they take it on an empty stomach because “they’re supposed to take it”, or they don’t realize they need to adjust it in proportion to their food; or they run out and can’t get a refill because of how the original prescription was written and they for whatever reason can’t get in contact with a provider to increase the prescription. So yes, this type of education when you provide the prescription matters a lot to set people up for success! 

You can also, eventually, prescribe multiple ‘sizes’ (doses), e.g. a Creon 24,000 and Creon 36,000 or a Zenpep 25,000 and a Zenpep 60,000 based on what works for people. If someone can take 1 Zenpep 60,000 for most meals and is satisfied with that, great; they may not need that dose for small snacks though and would benefit from the additional size (e.g. Zenpep 25,000) to have on hand for snacks. Or to ‘top off’ a bigger meal without doubling up on the 60,000. (2x 60k is 120,000 whereas a 60k and a 25k becomes 85,000 units of lipase). That’s likely a follow up conversation after they’ve done some logging and titration work to figure out what works for them and what they typically eat, plus outlier meals.

Here are some common scenarios of when most people should take enzymes and some “it depends but most people don’t need enzymes”:

• One bite of something (e.g. tasting as you are cooking dinner) – because the amount of fat, protein, and carbs in a lick or taste is pretty minimal, people could maybe get away with no enzymes.
• Black coffee – probably doesn’t need enzymes, unless:
• Black coffee with milk/cream/etc added – probably needs enzymes depending on the quantity added.
• Grazing as you are at a buffet with a nibble here, a nibble there – probably needs enzymes as the grams of fat and protein go up.
• A snack that has more than a few grams of fat/protein – probably needs enzymes
• A piece of fruit – varies person to person. Some people can eat fruit standalone with no enzymes, others seem to need the enzymes. Why? Because of the carbohydrate digestion, even though there is little to zero fat and protein involved.
• A salad that is low fat – probably needs enzymes especially if it has protein, even though it doesn’t have “much fat”. (Also some fat likely still needs enzymes, in and of itself.)
• A high fat meal – needs enzymes and likely more enzymes than typical if it’s a bigger meal or a meal with a higher quantity of fat than typical. E.g. if a typical meal is around 45g of fat and someone takes two pills (of whatever size), that means their pill:fat ratio is 1 pill per ~22g of fat. If they were to then sit down to Thanksgiving dinner and have 60g of fat, they probably need at least 3 pills because the additional fat beyond 45g of fat needs to be dosed for. More examples here about figuring this out.

How many grams of fat and protein require enzymes? The great “it depends”. For me, I don’t have an absolute number but if it’s greater than 2-3 grams of fat or I am uncertain about the quantity I am eating, I take enzymes.

I do not take enzymes for “low” treats that have no fat and protein. So this means no enzymes (for me) for:

• Juice
• Soda
• Candy without significant fat/protein (airheads, gummies, fruit snacks, etc.)
• Glucose tabs

(It likely depends on the amount – probably a larger amount of carbs-only would still require enzymes. But for me since I do small or medium amounts of carbs for lows, I haven’t found a threshold where this seems to make a difference.)

I also don’t need enzymes normally if I was drinking water or diet soda.

I WOULD take enzymes for lows if I was consuming:

• Peanut butter crackers (fat and protein need enzymes)
• Hot chocolate made with milk (milk has fat and protein that need enzymes)
• A snickers bar (fat and protein, needs enzymes) or other candy like this that has fat and protein alongside the carbs.

There’s probably also a threshold for which you need enzymes for an amount of carbs, but both because enzymes have a rather large dose of amylase in them in every pill; there is little (zero?) research on carb digestion needs with amylase among EPI research; and I have little anecdata to give you on exactly where this falls, I think it is less typical to run into this. Probably most of the time people get away with dosing for mostly fat and protein and carbs are mostly covered by that; but it’s also common for people to dose for fat and underdose for protein and get symptoms as a result.

5. It gets better (EPI can be successfully treated) and we can track it with the EPI/PEI-SS

It does get better. This is an important message for people with EPI. It can be more challenging when there are multiple conditions going on at the same time, but EPI in and of itself can be managed with dosing enzymes.

And, we can track it getting better. I made the Exocrine Pancreatic Insufficiency Symptom Score (the EPI/PEI-SS) because there wasn’t a good symptom screening or tracking score for people with ALL types of EPI. (The existing ‘scores’ were developed only from people with EPI and chronic pancreatitis or cystic fibrosis and I found that the symptom list was too narrow and did not account for frequency and severity). It uses 15 symptoms and a self-rating of both frequency (0-5) and severity (0-3), and the resulting score can range from 0 to 225.

Like elastase, the ‘cutoff’ is not precise – based on an early real-world study of n=324 people, we found around 55 to be a cutoff indicating a greater likelihood of EPI. Can someone with a score of 45 have EPI? Yes. Can someone with a score of 62 not have EPI? Yes. It’s not that precise, but that doesn’t mean it’s not useful.

This symptom score can be used in a variety of ways:

1. To increase the pre-test probability for subsequent elastase screening
2. To help physicians and patients understand exactly what frequency and severity of symptoms the patient is dealing with.
3. To be able to see over time with enzyme dosing how the symptom experience is changing.

For example, someone who was diagnosed with EPI had a symptom score of 72. After they went on enzymes and titrated their dosing, their score is now 7. That is a huge improvement and puts their symptom experience on par with people who don’t have EPI (or any other GI condition).

Another scenario may be someone who had more extreme symptoms – imagine an EPI//PEI-SS score of 155. They went on enzymes, and a few months later their score was 96. That’s an improvement, yay! But, it shows that they still likely have room for improvement and their enzyme dosing likely needs ongoing review.

(Note: the EPI/PEI-SS was evaluated in an online, real-world study of n=324 people, including a large number of people with diabetes. The diabetes sub-analysis is here, showing that having either type 1 or type 2 diabetes did not significantly influence the EPI/PEI-SS scores. We have an ongoing clinical study right now based at University of Florida in partnership with Dr. Brittany Bruggeman evaluating the use of the EPI/PEI-SS with elastase screening for people with diabetes. We also have an EPI/PEI-SS study running in New Zealand and Australia, with Dr. Amanda Landers, for people with pancreatic cancer. All this is to say that EPI/PEI-SS is being evaluated further for screening for EPI but we have not yet kicked off studies for using it for ongoing titration of enzymes or for capturing what ‘asymptomatic’ presentations may look like. This is an area I’d love to study, though, so if you are interested in studying its use alongside titration protocols for enzymes or asymptomatic presentations – please reach out to collaborate!)

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If you read any or all of this – thank you for your interest in supporting people with exocrine pancreatic insufficiency. We need more of you! If I can help your work in any way – please reach out to me any time (Dana@OpenAPS.org).

TLDR summary:

1. EPI occurs in people with diabetes and is more common than gastroparesis and celiac. Screen for EPI in people with diabetes with GI symptoms! Some patterns of unexplained low energy/fatigue and extreme glucose spikes and drops on CGM also might warrant EPI screening in PWD.
2. Elastase is not perfect but what we can most easily access. Endocrinologists can test for it. A result around 200-ish or lower warrants an enzyme trial. Endos and diabetes teams should care about EPI because it impacts glucose levels!
3. Give a reasonable dose of enzymes to start. Reasonable means 40-50,000 units of lipase or more. Endocrinologists could manage the enzyme prescription.
4. Write an Rx for enzymes to take with food. Teach people to adjust their dose in relation to what they eat; the fact that it will take some time to figure out a dose; and encourage them to call back and ask for an adjusted Rx based on what they need.
5. EPI sucks when untreated, but it does get better and we should continue pursuing better and adjusting enzyme doses until symptoms are improved.