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Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.
EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”1 It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article,
EPI Diagnosis
EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.2
A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).3Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.
The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.
Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.
Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).
Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.
Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.
Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.
A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.7
Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.
Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.8
Treatment
The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.9
In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.
PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.10
Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.
PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.11 If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.
Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.4, 12
Conclusion
EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.
Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.
Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.
References
1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.
2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.
3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.
4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.
5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.
6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.
7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.
8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.
9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.
10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.
11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.
12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.
Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.
EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”1 It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article,
EPI Diagnosis
EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.2
A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).3Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.
The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.
Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.
Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).
Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.
Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.
Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.
A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.7
Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.
Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.8
Treatment
The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.9
In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.
PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.10
Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.
PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.11 If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.
Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.4, 12
Conclusion
EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.
Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.
Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.
References
1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.
2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.
3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.
4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.
5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.
6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.
7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.
8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.
9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.
10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.
11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.
12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.
Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.
EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”1 It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article,
EPI Diagnosis
EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.2
A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).3Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.
The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.
Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.
Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).
Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.
Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.
Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.
A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.7
Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.
Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.8
Treatment
The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.9
In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.
PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.10
Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.
PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.11 If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.
Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.4, 12
Conclusion
EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.
Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.
Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.
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