Exocrine Pancreatic Insufficiency: Risk Factors and Management Approaches

What characteristics or symptoms do you look for to identify patients who are at risk for exocrine pancreatic insufficiency (EPI)?

Dr. Barkin: The first thing we have to understand is which patient populations we should consider. EPI traditionally has been a disease associated with chronic pancreatitis, and that still makes up the majority of patients. But in addition to those with chronic pancreatitis, we have to think about patients who have had severe acute pancreatitis and who may have had loss of functional pancreatic parenchyma or pancreatic surgery, as well as patients with pancreatic cancer that may cause both ductal obstruction and parenchyma loss.

This might also include patients with foregut surgery who may develop postcibal dyskinesia, meaning they do not get appropriate mixing of the gastric chyme and food contents with the pancreatic enzymes and pancreatic juice in the duodenum. For example, this might be evident in patients who have had a Roux-en-Y gastric bypass, or in patients with untreated celiac disease, who do not get stimulation for pancreatic secretion based on the amount of small bowel mucosal damage.

A series of other conditions may present with EPI, such as inflammatory bowel disease, although these make up the minority of cases. When we think about symptoms, the end symptom of EPI from fat malabsorption is gross steatorrhea. Unfortunately, by the time the patient gets to that point, the cat is out of the bag—especially in patients with chronic pancreatitis. So, we want to try to identify these patients earlier.

Realistically, a series of symptoms can be seen far earlier than gross steatorrhea. In fact, most patients will present with symptoms like increased stool frequency or decreased stool consistency in their daily life. Some abdominal discomfort or bloating may be seen that is associated with maldigestion of  food, among other factors.

In some patients, night vision changes from fat-soluble vitamin deficiencies may be the first or an early presenting symptom if they have other conditions masking their diarrheal symptoms. Patients who do not feel well when they are eating or feel uncomfortable after they eat may avoid certain types of foods. You may see weight loss in these populations because they are avoiding foods, feeling sitophobia, or not appropriately digesting their food.

Unfortunately, even before we see clinically relevant symptoms, we may see micronutrient deficiencies and fat-soluble vitamin deficiencies. That is why it is so important, for example, in the chronic pancreatitis population, to screen these patients on a regular basis for the presence of EPI, whether with symptom questionnaires or by testing.

Can you expand on some of the risk factors and the importance of screening, particularly for malnutrition?

Dr. Barkin: The risk factors usually involve patients who have had some kind of damage to the gland. For example, many patients with cystic fibrosis are actually exocrine pancreatic insufficient from early in life to diagnosis. They have loss of the gland and loss of function at the gland.

Our patients with chronic pancreatitis, who may have had either recurrent acute pancreatitis or chronic pancreatitis for a variety of reasons, are screened for EPI on a regular basis. That may mean that you ask them a symptom questionnaire at each clinic visit and check a fecal elastase level on a regular basis. It is not just the symptoms that we have to worry about; we have to think about the effects of maldigestion on a patient’s weight and nutritional status and the impact of micronutrient deficiencies.

A series of new studies has looked at the impact of exocrine insufficiency. For example, a study from Spain found an increased risk of all-cause mortality with exocrine insufficiency. When we think about metabolic bone disease in this population with exocrine insufficiency, we see that there is decreased bone density and increased risk of pathologic low-trauma fractures. For example, the patient who has fallen from a standing position at home and suddenly has a hip fracture has substantial morbidity and mortality associated with that fracture. The decreases in bone density and increased risk of fracture are reversed when we identify EPI and treat it appropriately.

What is your approach to diagnosing EPI?

Dr. Barkin: For a patient who walks in the door with an obvious diagnosis or prior diagnosis of chronic pancreatitis, it is relatively easy to ask them a series of questions about whether they have symptoms that may be associated with EPI. So, first, I ask them about their bowel habits and stool frequency and consistency.

A couple of years ago, we showed that if you treat a patient with EPI using pancreatic enzyme replacement therapy, their stool consistency and frequency are the two reliable markers that get better. They not only get better, but these improvements directly correlate with objective stool markers of improvement in fat maldigestion.

Obviously, we want improvement in other symptoms—abdominal discomfort, bloating, etc.—but I have to set very realistic expectations for patients. Along with stool frequency and consistency, there should be subsequent improvement of steatorrhea. I talk to them about the importance of taking a multivitamin to prevent those micronutrient deficiencies. We check for micronutrient deficiencies and fat-soluble vitamin deficiencies routinely.

Patients who do not have obvious chronic pancreatitis who get diagnosed with EPI are a little bit harder to parse out. I want to make sure that they do not have celiac disease, or that they do not have a concomitant mimicking symptom that may result in, for example, a low fecal elastase level. I also check for small intestinal bacterial overgrowth (SIBO) as a mimicking condition.

Regarding fecal elastase testing, the gold standard for diagnosis of EPI was historically a 72-hour fecal fat collection on a standardized-fat-intake diet. That required patient confinement in the hospital. It is cumbersome, not widely available, and not realistic in practice.

In some centers, endoscopic pancreatic function testing, secretin-enhanced magnetic resonance cholangiopancreatography (MRCP), or breath testing, as is done in Europe, may be options to help diagnose EPI, but these tests are not widely available. Unfortunately, we do not have a great diagnostic test for exocrine insufficiency. As a result, we use fecal elastase level. If you have a patient who has a high pretest probability of having EPI, it is a relatively good test. If they have a low pretest probability, then a series of false-positive test results may occur in this patient population. That means they may not actually have exocrine insufficiency.

If a diarrheal stool is submitted for testing, a false-positive fecal elastase test may result. That is really key, because I see a number of patients with potentially functional diarrheal symptoms who also have low fecal elastase levels. As a result, they have been labeled as exocrine insufficient when, in fact, they may not actually have the disease, which is why it is so important to understand and think about that.

How do you choose the appropriate approach to managing EPI, and how do you consider the impact it has on the quality of life overall?

Dr. Barkin: There are two key points. The treatment for EPI is not to tell your patient to not eat fat and hope that it gets better. Rather, it is appropriate supplementation of pancreatic enzymes. This is done with pancreatic enzyme replacement therapy. A few FDA-approved medications are on the market. I recommend against the ones that have been labeled as pancreatic enzyme digestive aids that are available online. Those are not pancreatic enzymes; a regulatory push about 15 to 20 years ago got these digestive aids appropriately regulated.

The FDA-approved medications are dosed at approximately 40,000 to 50,000 lipase units per meal to start, according to the guidelines. Some of us may prescribe higher doses than that to start. These are taken with meals and about a half-dose with snacks.

If you have a patient who is taking, for example, two pills per meal or two capsules per meal, it is important that they take one at the very beginning of the meal and one about halfway through the meal. The pills should not be taken a half hour before or a half hour after the meal. The goal is to simulate normal pancreatic function as much as possible to get the food contents mixing.

The pancreatic enzymes come in a coated version that does not require coadministration with proton pump inhibitors or an uncoated version that does require coadministration of proton pump inhibitors to prevent degradation by gastric acid. Patients need to understand that, although they may take a large number of pills per day, adhering to this regimen is important, not only for treating their symptoms, but also for combating long-term morbidity and mortality.

I use the symptomatic response to assess response to therapy because, as discussed, there is a direct correlation between improvements in stool frequency and consistency and objective markers of response to therapy.

If a patient is not responding, we first check to make sure that there are no adherence issues and that they are able to access therapy, because sometimes there are issues with cost or insurance approvals. Second, I make sure that patients are taking it correctly, and that they understand the difference between a meal and a snack. For example, if somebody says, “Oh, I just had a small cheeseburger and that's my snack,” that is actually a meal and may require more enzymes. Once we ensure that those are not issues, I make sure again, as part of my approach, that there are no comorbid conditions that may be driving some of the symptoms, such as celiac disease or SIBO, with SIBO being very common in this population.

Then we have to decide whether we need to change the dose. Do we need to increase the dose? Some of us start a little bit higher than the 40,000 to 50,000 units of lipase per meal, as suggested in some of our national and international guidelines, and go from there.

What characteristics or symptoms do you look for to identify patients who are at risk for exocrine pancreatic insufficiency (EPI)?

Dr. Barkin: The first thing we have to understand is which patient populations we should consider. EPI traditionally has been a disease associated with chronic pancreatitis, and that still makes up the majority of patients. But in addition to those with chronic pancreatitis, we have to think about patients who have had severe acute pancreatitis and who may have had loss of functional pancreatic parenchyma or pancreatic surgery, as well as patients with pancreatic cancer that may cause both ductal obstruction and parenchyma loss.

This might also include patients with foregut surgery who may develop postcibal dyskinesia, meaning they do not get appropriate mixing of the gastric chyme and food contents with the pancreatic enzymes and pancreatic juice in the duodenum. For example, this might be evident in patients who have had a Roux-en-Y gastric bypass, or in patients with untreated celiac disease, who do not get stimulation for pancreatic secretion based on the amount of small bowel mucosal damage.

A series of other conditions may present with EPI, such as inflammatory bowel disease, although these make up the minority of cases. When we think about symptoms, the end symptom of EPI from fat malabsorption is gross steatorrhea. Unfortunately, by the time the patient gets to that point, the cat is out of the bag—especially in patients with chronic pancreatitis. So, we want to try to identify these patients earlier.

Realistically, a series of symptoms can be seen far earlier than gross steatorrhea. In fact, most patients will present with symptoms like increased stool frequency or decreased stool consistency in their daily life. Some abdominal discomfort or bloating may be seen that is associated with maldigestion of  food, among other factors.

In some patients, night vision changes from fat-soluble vitamin deficiencies may be the first or an early presenting symptom if they have other conditions masking their diarrheal symptoms. Patients who do not feel well when they are eating or feel uncomfortable after they eat may avoid certain types of foods. You may see weight loss in these populations because they are avoiding foods, feeling sitophobia, or not appropriately digesting their food.

Unfortunately, even before we see clinically relevant symptoms, we may see micronutrient deficiencies and fat-soluble vitamin deficiencies. That is why it is so important, for example, in the chronic pancreatitis population, to screen these patients on a regular basis for the presence of EPI, whether with symptom questionnaires or by testing.

Can you expand on some of the risk factors and the importance of screening, particularly for malnutrition?

Dr. Barkin: The risk factors usually involve patients who have had some kind of damage to the gland. For example, many patients with cystic fibrosis are actually exocrine pancreatic insufficient from early in life to diagnosis. They have loss of the gland and loss of function at the gland.

Our patients with chronic pancreatitis, who may have had either recurrent acute pancreatitis or chronic pancreatitis for a variety of reasons, are screened for EPI on a regular basis. That may mean that you ask them a symptom questionnaire at each clinic visit and check a fecal elastase level on a regular basis. It is not just the symptoms that we have to worry about; we have to think about the effects of maldigestion on a patient’s weight and nutritional status and the impact of micronutrient deficiencies.

A series of new studies has looked at the impact of exocrine insufficiency. For example, a study from Spain found an increased risk of all-cause mortality with exocrine insufficiency. When we think about metabolic bone disease in this population with exocrine insufficiency, we see that there is decreased bone density and increased risk of pathologic low-trauma fractures. For example, the patient who has fallen from a standing position at home and suddenly has a hip fracture has substantial morbidity and mortality associated with that fracture. The decreases in bone density and increased risk of fracture are reversed when we identify EPI and treat it appropriately.

What is your approach to diagnosing EPI?

Dr. Barkin: For a patient who walks in the door with an obvious diagnosis or prior diagnosis of chronic pancreatitis, it is relatively easy to ask them a series of questions about whether they have symptoms that may be associated with EPI. So, first, I ask them about their bowel habits and stool frequency and consistency.

A couple of years ago, we showed that if you treat a patient with EPI using pancreatic enzyme replacement therapy, their stool consistency and frequency are the two reliable markers that get better. They not only get better, but these improvements directly correlate with objective stool markers of improvement in fat maldigestion.

Obviously, we want improvement in other symptoms—abdominal discomfort, bloating, etc.—but I have to set very realistic expectations for patients. Along with stool frequency and consistency, there should be subsequent improvement of steatorrhea. I talk to them about the importance of taking a multivitamin to prevent those micronutrient deficiencies. We check for micronutrient deficiencies and fat-soluble vitamin deficiencies routinely.

Patients who do not have obvious chronic pancreatitis who get diagnosed with EPI are a little bit harder to parse out. I want to make sure that they do not have celiac disease, or that they do not have a concomitant mimicking symptom that may result in, for example, a low fecal elastase level. I also check for small intestinal bacterial overgrowth (SIBO) as a mimicking condition.

Regarding fecal elastase testing, the gold standard for diagnosis of EPI was historically a 72-hour fecal fat collection on a standardized-fat-intake diet. That required patient confinement in the hospital. It is cumbersome, not widely available, and not realistic in practice.

In some centers, endoscopic pancreatic function testing, secretin-enhanced magnetic resonance cholangiopancreatography (MRCP), or breath testing, as is done in Europe, may be options to help diagnose EPI, but these tests are not widely available. Unfortunately, we do not have a great diagnostic test for exocrine insufficiency. As a result, we use fecal elastase level. If you have a patient who has a high pretest probability of having EPI, it is a relatively good test. If they have a low pretest probability, then a series of false-positive test results may occur in this patient population. That means they may not actually have exocrine insufficiency.

If a diarrheal stool is submitted for testing, a false-positive fecal elastase test may result. That is really key, because I see a number of patients with potentially functional diarrheal symptoms who also have low fecal elastase levels. As a result, they have been labeled as exocrine insufficient when, in fact, they may not actually have the disease, which is why it is so important to understand and think about that.

How do you choose the appropriate approach to managing EPI, and how do you consider the impact it has on the quality of life overall?

Dr. Barkin: There are two key points. The treatment for EPI is not to tell your patient to not eat fat and hope that it gets better. Rather, it is appropriate supplementation of pancreatic enzymes. This is done with pancreatic enzyme replacement therapy. A few FDA-approved medications are on the market. I recommend against the ones that have been labeled as pancreatic enzyme digestive aids that are available online. Those are not pancreatic enzymes; a regulatory push about 15 to 20 years ago got these digestive aids appropriately regulated.

The FDA-approved medications are dosed at approximately 40,000 to 50,000 lipase units per meal to start, according to the guidelines. Some of us may prescribe higher doses than that to start. These are taken with meals and about a half-dose with snacks.

If you have a patient who is taking, for example, two pills per meal or two capsules per meal, it is important that they take one at the very beginning of the meal and one about halfway through the meal. The pills should not be taken a half hour before or a half hour after the meal. The goal is to simulate normal pancreatic function as much as possible to get the food contents mixing.

The pancreatic enzymes come in a coated version that does not require coadministration with proton pump inhibitors or an uncoated version that does require coadministration of proton pump inhibitors to prevent degradation by gastric acid. Patients need to understand that, although they may take a large number of pills per day, adhering to this regimen is important, not only for treating their symptoms, but also for combating long-term morbidity and mortality.

I use the symptomatic response to assess response to therapy because, as discussed, there is a direct correlation between improvements in stool frequency and consistency and objective markers of response to therapy.

If a patient is not responding, we first check to make sure that there are no adherence issues and that they are able to access therapy, because sometimes there are issues with cost or insurance approvals. Second, I make sure that patients are taking it correctly, and that they understand the difference between a meal and a snack. For example, if somebody says, “Oh, I just had a small cheeseburger and that's my snack,” that is actually a meal and may require more enzymes. Once we ensure that those are not issues, I make sure again, as part of my approach, that there are no comorbid conditions that may be driving some of the symptoms, such as celiac disease or SIBO, with SIBO being very common in this population.

Then we have to decide whether we need to change the dose. Do we need to increase the dose? Some of us start a little bit higher than the 40,000 to 50,000 units of lipase per meal, as suggested in some of our national and international guidelines, and go from there.

What characteristics or symptoms do you look for to identify patients who are at risk for exocrine pancreatic insufficiency (EPI)?

Dr. Barkin: The first thing we have to understand is which patient populations we should consider. EPI traditionally has been a disease associated with chronic pancreatitis, and that still makes up the majority of patients. But in addition to those with chronic pancreatitis, we have to think about patients who have had severe acute pancreatitis and who may have had loss of functional pancreatic parenchyma or pancreatic surgery, as well as patients with pancreatic cancer that may cause both ductal obstruction and parenchyma loss.

This might also include patients with foregut surgery who may develop postcibal dyskinesia, meaning they do not get appropriate mixing of the gastric chyme and food contents with the pancreatic enzymes and pancreatic juice in the duodenum. For example, this might be evident in patients who have had a Roux-en-Y gastric bypass, or in patients with untreated celiac disease, who do not get stimulation for pancreatic secretion based on the amount of small bowel mucosal damage.

A series of other conditions may present with EPI, such as inflammatory bowel disease, although these make up the minority of cases. When we think about symptoms, the end symptom of EPI from fat malabsorption is gross steatorrhea. Unfortunately, by the time the patient gets to that point, the cat is out of the bag—especially in patients with chronic pancreatitis. So, we want to try to identify these patients earlier.

Realistically, a series of symptoms can be seen far earlier than gross steatorrhea. In fact, most patients will present with symptoms like increased stool frequency or decreased stool consistency in their daily life. Some abdominal discomfort or bloating may be seen that is associated with maldigestion of  food, among other factors.

In some patients, night vision changes from fat-soluble vitamin deficiencies may be the first or an early presenting symptom if they have other conditions masking their diarrheal symptoms. Patients who do not feel well when they are eating or feel uncomfortable after they eat may avoid certain types of foods. You may see weight loss in these populations because they are avoiding foods, feeling sitophobia, or not appropriately digesting their food.

Unfortunately, even before we see clinically relevant symptoms, we may see micronutrient deficiencies and fat-soluble vitamin deficiencies. That is why it is so important, for example, in the chronic pancreatitis population, to screen these patients on a regular basis for the presence of EPI, whether with symptom questionnaires or by testing.

Can you expand on some of the risk factors and the importance of screening, particularly for malnutrition?

Dr. Barkin: The risk factors usually involve patients who have had some kind of damage to the gland. For example, many patients with cystic fibrosis are actually exocrine pancreatic insufficient from early in life to diagnosis. They have loss of the gland and loss of function at the gland.

Our patients with chronic pancreatitis, who may have had either recurrent acute pancreatitis or chronic pancreatitis for a variety of reasons, are screened for EPI on a regular basis. That may mean that you ask them a symptom questionnaire at each clinic visit and check a fecal elastase level on a regular basis. It is not just the symptoms that we have to worry about; we have to think about the effects of maldigestion on a patient’s weight and nutritional status and the impact of micronutrient deficiencies.

A series of new studies has looked at the impact of exocrine insufficiency. For example, a study from Spain found an increased risk of all-cause mortality with exocrine insufficiency. When we think about metabolic bone disease in this population with exocrine insufficiency, we see that there is decreased bone density and increased risk of pathologic low-trauma fractures. For example, the patient who has fallen from a standing position at home and suddenly has a hip fracture has substantial morbidity and mortality associated with that fracture. The decreases in bone density and increased risk of fracture are reversed when we identify EPI and treat it appropriately.

What is your approach to diagnosing EPI?

Dr. Barkin: For a patient who walks in the door with an obvious diagnosis or prior diagnosis of chronic pancreatitis, it is relatively easy to ask them a series of questions about whether they have symptoms that may be associated with EPI. So, first, I ask them about their bowel habits and stool frequency and consistency.

A couple of years ago, we showed that if you treat a patient with EPI using pancreatic enzyme replacement therapy, their stool consistency and frequency are the two reliable markers that get better. They not only get better, but these improvements directly correlate with objective stool markers of improvement in fat maldigestion.

Obviously, we want improvement in other symptoms—abdominal discomfort, bloating, etc.—but I have to set very realistic expectations for patients. Along with stool frequency and consistency, there should be subsequent improvement of steatorrhea. I talk to them about the importance of taking a multivitamin to prevent those micronutrient deficiencies. We check for micronutrient deficiencies and fat-soluble vitamin deficiencies routinely.

Patients who do not have obvious chronic pancreatitis who get diagnosed with EPI are a little bit harder to parse out. I want to make sure that they do not have celiac disease, or that they do not have a concomitant mimicking symptom that may result in, for example, a low fecal elastase level. I also check for small intestinal bacterial overgrowth (SIBO) as a mimicking condition.

Regarding fecal elastase testing, the gold standard for diagnosis of EPI was historically a 72-hour fecal fat collection on a standardized-fat-intake diet. That required patient confinement in the hospital. It is cumbersome, not widely available, and not realistic in practice.

In some centers, endoscopic pancreatic function testing, secretin-enhanced magnetic resonance cholangiopancreatography (MRCP), or breath testing, as is done in Europe, may be options to help diagnose EPI, but these tests are not widely available. Unfortunately, we do not have a great diagnostic test for exocrine insufficiency. As a result, we use fecal elastase level. If you have a patient who has a high pretest probability of having EPI, it is a relatively good test. If they have a low pretest probability, then a series of false-positive test results may occur in this patient population. That means they may not actually have exocrine insufficiency.

If a diarrheal stool is submitted for testing, a false-positive fecal elastase test may result. That is really key, because I see a number of patients with potentially functional diarrheal symptoms who also have low fecal elastase levels. As a result, they have been labeled as exocrine insufficient when, in fact, they may not actually have the disease, which is why it is so important to understand and think about that.

How do you choose the appropriate approach to managing EPI, and how do you consider the impact it has on the quality of life overall?

Dr. Barkin: There are two key points. The treatment for EPI is not to tell your patient to not eat fat and hope that it gets better. Rather, it is appropriate supplementation of pancreatic enzymes. This is done with pancreatic enzyme replacement therapy. A few FDA-approved medications are on the market. I recommend against the ones that have been labeled as pancreatic enzyme digestive aids that are available online. Those are not pancreatic enzymes; a regulatory push about 15 to 20 years ago got these digestive aids appropriately regulated.

The FDA-approved medications are dosed at approximately 40,000 to 50,000 lipase units per meal to start, according to the guidelines. Some of us may prescribe higher doses than that to start. These are taken with meals and about a half-dose with snacks.

If you have a patient who is taking, for example, two pills per meal or two capsules per meal, it is important that they take one at the very beginning of the meal and one about halfway through the meal. The pills should not be taken a half hour before or a half hour after the meal. The goal is to simulate normal pancreatic function as much as possible to get the food contents mixing.

The pancreatic enzymes come in a coated version that does not require coadministration with proton pump inhibitors or an uncoated version that does require coadministration of proton pump inhibitors to prevent degradation by gastric acid. Patients need to understand that, although they may take a large number of pills per day, adhering to this regimen is important, not only for treating their symptoms, but also for combating long-term morbidity and mortality.

I use the symptomatic response to assess response to therapy because, as discussed, there is a direct correlation between improvements in stool frequency and consistency and objective markers of response to therapy.

If a patient is not responding, we first check to make sure that there are no adherence issues and that they are able to access therapy, because sometimes there are issues with cost or insurance approvals. Second, I make sure that patients are taking it correctly, and that they understand the difference between a meal and a snack. For example, if somebody says, “Oh, I just had a small cheeseburger and that's my snack,” that is actually a meal and may require more enzymes. Once we ensure that those are not issues, I make sure again, as part of my approach, that there are no comorbid conditions that may be driving some of the symptoms, such as celiac disease or SIBO, with SIBO being very common in this population.

Then we have to decide whether we need to change the dose. Do we need to increase the dose? Some of us start a little bit higher than the 40,000 to 50,000 units of lipase per meal, as suggested in some of our national and international guidelines, and go from there.