AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatic Insufficiency: Expert Review

DescriptionExocrine pancreatic insufficiency (EPI) is a disorder caused by the failure of the pancreas to deliver a minimum/threshold level of specific pancreatic digestive enzymes to the intestine, leading to the maldigestion of nutrients and macronutrients, resulting in their variable deficiencies. EPI is frequently underdiagnosed and, as a result, patients are often not treated appropriately. There is an urgent need to increase awareness of and treatment for this condition. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review was to provide Best Practice Advice on the epidemiology, evaluation, and management of EPI.MethodsThis Expert Review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations.Best Practice Advice StatementsBest Practice Advice 1EPI should be suspected in patients with high-risk clinical conditions, such as chronic pancreatitis, relapsing acute pancreatitis, pancreatic ductal adenocarcinoma, cystic fibrosis, and previous pancreatic surgery.Best Practice Advice 2EPI should be considered in patients with moderate-risk clinical conditions, such as duodenal diseases, including celiac and Crohn's disease; previous intestinal surgery; longstanding diabetes mellitus; and hypersecretory states (eg, Zollinger–Ellison syndrome).Best Practice Advice 3Clinical features of EPI include steatorrhea with or without diarrhea, weight loss, bloating, excessive flatulence, fat-soluble vitamin deficiencies, and protein-calorie malnutrition.Best Practice Advice 4Fecal elastase test is the most appropriate initial test and must be performed on a semi-solid or solid stool specimen. A fecal elastase level <100 μg/g of stool provides good evidence of EPI, and levels of 100–200 μg/g are indeterminate for EPI.Best Practice Advice 5Fecal elastase testing can be performed while on pancreatic enzyme replacement therapy.Best Practice Advice 6Fecal fat testing is rarely needed and must be performed when on a high-fat diet. Quantitative testing is generally not practical for routine clinical use.Best Practice Advice 7Response to a therapeutic trial of pancreatic enzymes is unreliable for EPI diagnosis.Best Practice Advice 8Cross-sectional imaging methods (computed tomography scan, magnetic resonance imaging, and endoscopic ultrasound) cannot identify EPI, although they play an important role in the diagnosis of benign and malignant pancreatic disease.Best Practice Advice 9Breath tests and direct pancreatic function tests hold promise, but are not widely available in the United States.Best Practice Advice 10Once EPI is diagnosed, treatment with pancreatic enzyme replacement therapy (PERT) is required. If EPI is left untreated, it will result in complications related to fat malabsorption and malnutrition, having a negative impact on quality of life.Best Practice Advice 11PERT formulations are all derived from porcine sources and are equally effective at equivalent doses. There is a need for H2 or proton pump inhibitor therapy with non–enteric-coated preparations.Best Practice Advice 12PERT should be taken during the meal, with the initial treatment of at least 40,000 USP units of lipase during each meal in adults and one-half of that with snacks. The subsequent dosage can be adjusted based on the meal size and fat content.Best Practice Advice 13Routine supplementation and monitoring of fat-soluble vitamin levels are appropriate. Dietary modifications include a low-moderate fat diet with frequent smaller meals and avoiding very-low-fat diets.Best Practice Advice 14Measures of successful treatment with PERT include reduction in steatorrhea and associated gastrointestinal symptoms; a gain of weight, muscle mass, and muscle function; and improvement in fat-soluble vitamin levels.Best Practice Advice 15EPI should be monitored and baseline measurements of nutritional status should be obtained (body mass index, quality-of-life measure, and fat-soluble vitamin levels). A baseline dual-energy x-ray absorptiometry scan should be obtained and repeated every 1–2 years. Exocrine pancreatic insufficiency (EPI) is a disorder caused by the failure of the pancreas to deliver a minimum/threshold level of specific pancreatic digestive enzymes to the intestine, leading to the maldigestion of nutrients and macronutrients, resulting in their variable deficiencies. EPI is frequently underdiagnosed and, as a result, patients are often not treated appropriately. There is an urgent need to increase awareness of and treatment for this condition. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review was to provide Best Practice Advice on the epidemiology, evaluation, and management of EPI. This Expert Review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. Best Practice Advice Statements EPI should be suspected in patients with high-risk clinical conditions, such as chronic pancreatitis, relapsing acute pancreatitis, pancreatic ductal adenocarcinoma, cystic fibrosis, and previous pancreatic surgery. EPI should be considered in patients with moderate-risk clinical conditions, such as duodenal diseases, including celiac and Crohn's disease; previous intestinal surgery; longstanding diabetes mellitus; and hypersecretory states (eg, Zollinger–Ellison syndrome). Clinical features of EPI include steatorrhea with or without diarrhea, weight loss, bloating, excessive flatulence, fat-soluble vitamin deficiencies, and protein-calorie malnutrition. Fecal elastase test is the most appropriate initial test and must be performed on a semi-solid or solid stool specimen. A fecal elastase level <100 μg/g of stool provides good evidence of EPI, and levels of 100–200 μg/g are indeterminate for EPI. Fecal elastase testing can be performed while on pancreatic enzyme replacement therapy. Fecal fat testing is rarely needed and must be performed when on a high-fat diet. Quantitative testing is generally not practical for routine clinical use. Response to a therapeutic trial of pancreatic enzymes is unreliable for EPI diagnosis. Cross-sectional imaging methods (computed tomography scan, magnetic resonance imaging, and endoscopic ultrasound) cannot identify EPI, although they play an important role in the diagnosis of benign and malignant pancreatic disease. Breath tests and direct pancreatic function tests hold promise, but are not widely available in the United States. Once EPI is diagnosed, treatment with pancreatic enzyme replacement therapy (PERT) is required. If EPI is left untreated, it will result in complications related to fat malabsorption and malnutrition, having a negative impact on quality of life. PERT formulations are all derived from porcine sources and are equally effective at equivalent doses. There is a need for H2 or proton pump inhibitor therapy with non–enteric-coated preparations. PERT should be taken during the meal, with the initial treatment of at least 40,000 USP units of lipase during each meal in adults and one-half of that with snacks. The subsequent dosage can be adjusted based on the meal size and fat content. Routine supplementation and monitoring of fat-soluble vitamin levels are appropriate. Dietary modifications include a low-moderate fat diet with frequent smaller meals and avoiding very-low-fat diets. Measures of successful treatment with PERT include reduction in steatorrhea and associated gastrointestinal symptoms; a gain of weight, muscle mass, and muscle function; and improvement in fat-soluble vitamin levels. EPI should be monitored and baseline measurements of nutritional status should be obtained (body mass index, quality-of-life measure, and fat-soluble vitamin levels). A baseline dual-energy x-ray absorptiometry scan should be obtained and repeated every 1–2 years. Exocrine pancreatic insufficiency (EPI) is caused by the failure of the pancreas to deliver a threshold level of pancreatic digestive enzymes to the intestine to digest meals and meet nutritional and metabolic needs. The threshold is dependent on specific macro- and micronutritional needs; nutrient intake; exocrine pancreatic function, and intestinal anatomy, function, intestinal diseases, and adaptative capacity.1Whitcomb D.C.M.R. Duggan S.N. Martindale R. et al.AGA-PancreasFest joint symposium on exocrine pancreatic insufficiency.Gastro Hep Adv. 2023; 2: 395-411Abstract Full Text Full Text PDF Google Scholar Clinically, EPI is characterized by variable deficiencies in micro- and macronutrients, especially essential fats and fat-soluble vitamins; gastrointestinal symptoms of nutrient maldigestion; and improvement with lifestyle changes, disease treatment, optimized diet, dietary supplements, and/or administration of adequate pancreatic enzyme replacement therapy (PERT) (Figure 1A and B).1Whitcomb D.C.M.R. Duggan S.N. Martindale R. et al.AGA-PancreasFest joint symposium on exocrine pancreatic insufficiency.Gastro Hep Adv. 2023; 2: 395-411Abstract Full Text Full Text PDF Google Scholar There is an urgent need for best practice updates to increase awareness of this condition and the importance of its adequate treatment. This review discusses the proposed Best Practice Advice statements, which should be used in conjunction with evolving literature as part of a shared decision-making process. EPI develops in more than one-half of patients with CP, and the risk depends on the disease's duration, stage, and etiology.2Das S.L. Kennedy J.I. Murphy R. et al.Relationship between the exocrine and endocrine pancreas after acute pancreatitis.World J Gastroenterol. 2014; 20: 17196-17205Crossref PubMed Scopus (85) Google Scholar,3Whitcomb D.C. Frulloni L. Garg P. et al.Chronic pancreatitis: an international draft consensus proposal for a new mechanistic definition.Pancreatology. 2016; 16: 218-224Crossref PubMed Google Scholar Chronic alcohol use, smoking, pancreatic ductal obstruction, atrophy, duct calcifications, and diabetes mellitus4Zhan W. Akshintala V. Greer P.J. et al.Low serum trypsinogen levels in chronic pancreatitis: correlation with parenchymal loss, exocrine pancreatic insufficiency, and diabetes but not CT-based Cambridge severity scores for fibrosis.Pancreatology. 2020; 20: 1368-1378Crossref PubMed Scopus (10) Google Scholar increase the likelihood of EPI in CP, and in patients with these features or etiologies, the risk of EPI is >80%. EPI typically occurs after 5–10 years of the disease.5Layer P. Yamamoto H. Kalthoff L. et al.The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis.Gastroenterology. 1994; 107: 1481-1487Crossref PubMed Scopus (623) Google Scholar Abstinence from smoking and alcohol may delay the onset of EPI. In AP and relapsing AP, the pooled prevalence during follow-up ranges from 27% to 62%, and the rate appears to be similar for both AP and recurrent AP.6Hollemans R.A. Hallensleben N.D.L. Mager D.J. et al.Pancreatic exocrine insufficiency following acute pancreatitis: systematic review and study level meta-analysis.Pancreatology. 2018; 18: 253-262Crossref PubMed Scopus (89) Google Scholar,7Huang W. de la Iglesia-Garcia D. Baston-Rey I. et al.Exocrine pancreatic insufficiency following acute pancreatitis: systematic review and meta-analysis.Dig Dis Sci. 2019; 64: 1985-2005Crossref PubMed Scopus (54) Google Scholar Autoimmune pancreatitis is often associated with EPI.8Lanzillotta M. Tacelli M. Falconi M. et al.Incidence of endocrine and exocrine insufficiency in patients with autoimmune pancreatitis at diagnosis and after treatment: a systematic review and meta-analysis.Eur J Intern Med. 2022; 100: 83-93Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Most patients with cystic fibrosis will have EPI presenting at birth or in infancy (85%). EPI is common in patients with pancreatic ductal adenocarcinoma due to obstruction of the main pancreatic duct with upstream atrophy and the effects of chemotherapy, radiation therapy, and/or surgery.9Forsmark C.E. Tang G. Xu H. et al.The use of pancreatic enzyme replacement therapy in patients with a diagnosis of chronic pancreatitis and pancreatic cancer in the US is infrequent and inconsistent.Aliment Pharmacol Ther. 2020; 51: 958-967Crossref PubMed Scopus (31) Google Scholar,10Iglesia D. Avci B. Kiriukova M. et al.Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: a systematic review and meta-analysis.United European Gastroenterol J. 2020; 8: 1115-1125Crossref PubMed Scopus (37) Google Scholar The rates of EPI in unresectable pancreatic ductal adenocarcinoma range from 50% to 92%, 40%–50% in resectable pancreatic ductal adenocarcinoma before treatment, and 75% after treatment.9Forsmark C.E. Tang G. Xu H. et al.The use of pancreatic enzyme replacement therapy in patients with a diagnosis of chronic pancreatitis and pancreatic cancer in the US is infrequent and inconsistent.Aliment Pharmacol Ther. 2020; 51: 958-967Crossref PubMed Scopus (31) Google Scholar,11Kumar T.K. Tewari M. Shukla S.K. et al.Pancreatic exocrine insufficiency occurs in most patients following pancreaticoduodenectomy.Indian J Cancer. 2021; 58: 511-517PubMed Google Scholar Surgical resection of the pancreas of any type predisposes to EPI.12Latenstein A.E.J. Blonk L. Tjahjadi N.S. et al.Long-term quality of life and exocrine and endocrine insufficiency after pancreatic surgery: a multicenter, cross-sectional study.HPB. 2021; 23: 1722-1731Abstract Full Text Full Text PDF Scopus (9) Google Scholar Ampullary cancer and main duct intraductal papillary mucinous neoplasm can also produce EPI by obstructing the pancreatic duct (Table 1).Table 1Exocrine Pancreatic Insufficiency Types, Pathomechanisms, and Examples of ConditionsEPI typePathomechanismExamples of conditionsLoss of pancreatic parenchymaReduced pancreatic enzymes synthesis and secretionReduced bicarbonate deliveryPancreatic cancerCPCystic fibrosisPancreatic resectionOther causesObstruction of pancreatic duct Reduced pancreatic enzymes deliveryReduced bicarbonate deliveryAmpullary tumorsDuctal stenosisPancreatic cancerReduced endogenous stimulation (reduced CCK-mediated secretion,Reduced enterokinase (pro-enzyme not converted to active enzymes)Duodenal resectionEnteropathies (eg, Crohn's disease, celiac disease)SomatostatinomasDecreased pancreatic enzymes activity in the small bowelInadequate mixing of pancreatic enzymes in the bile (dumping syndrome)Postcibal asynchrony (short gut syndrome, gastric resection)Intraluminal inactivation (hypersecretary states, gastrinomaSurgery reconstructions Open table in a new tab Digestion of nutrients by pancreatic digestive enzymes requires stimulation of pancreatic secretion, delivery of the enzymes to the intestine, and sufficient dwell time in a suitable environment to hydrolyze the nutrients for absorption. In patients without an underlying pancreatic disease, other diseases of the gastrointestinal tract may occasionally overlap with and mimic EPI.13Keller J. Aghdassi A.A. Lerch M.M. et al.Tests of pancreatic exocrine function - clinical significance in pancreatic and non-pancreatic disorders.Best Pract Res Clin Gastroenterol. 2009; 23: 425-439Crossref PubMed Scopus (64) Google Scholar The stomach and duodenum are sensory organs that activate the pancreas. Injury to the duodenal mucosa, as in untreated celiac disease, diminishes stimulation of pancreatic secretion and impairs the absorption of micronutrients, lipids, fat-soluble vitamins, and vitamin B12.1Whitcomb D.C.M.R. Duggan S.N. Martindale R. et al.AGA-PancreasFest joint symposium on exocrine pancreatic insufficiency.Gastro Hep Adv. 2023; 2: 395-411Abstract Full Text Full Text PDF Google Scholar,13Keller J. Aghdassi A.A. Lerch M.M. et al.Tests of pancreatic exocrine function - clinical significance in pancreatic and non-pancreatic disorders.Best Pract Res Clin Gastroenterol. 2009; 23: 425-439Crossref PubMed Scopus (64) Google Scholar Elevated duodenal acid, as in Zollinger–Ellison syndrome, may lead to EPI from the destruction of pancreatic enzymes by acid.13Keller J. Aghdassi A.A. Lerch M.M. et al.Tests of pancreatic exocrine function - clinical significance in pancreatic and non-pancreatic disorders.Best Pract Res Clin Gastroenterol. 2009; 23: 425-439Crossref PubMed Scopus (64) Google Scholar Surgery to remove or bypass portions of the stomach, duodenum, and jejunum may result in EPI.1Whitcomb D.C.M.R. Duggan S.N. Martindale R. et al.AGA-PancreasFest joint symposium on exocrine pancreatic insufficiency.Gastro Hep Adv. 2023; 2: 395-411Abstract Full Text Full Text PDF Google Scholar,14Roeyen G. Jansen M. Hartman V. et al.The impact of pancreaticoduodenectomy on endocrine and exocrine pancreatic function: a prospective cohort study based on pre- and postoperative function tests.Pancreatology. 2017; 17: 974-982Crossref PubMed Scopus (21) Google Scholar,15Uribarri-Gonzalez L. Nieto-Garcia L. Martis-Sueiro A. et al.Exocrine pancreatic function and dynamic of digestion after restrictive and malabsorptive bariatric surgery: a prospective, cross-sectional, and comparative study.Surg Obes Relat Dis. 2021; 17: 1766-1772Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar EPI is also common with loss of the pylorus, with dumping syndrome and various motility disorders causing asynchrony (delivery of enzymes not matching delivery of the meal in the upper intestine) (Table 1).16Keller J. Layer P. Human pancreatic exocrine response to nutrients in health and disease.Gut. 2005; 54 (vi1–28)Google Scholar Insulin is a trophic factor for pancreatic acinar cells and diabetes may impact the risk of developing EPI. Longstanding diabetes mellitus type 1 diminishes pancreatic digestive enzyme secretion and fecal human elastase-1 (FE-1) levels, but does not cause EPI alone.17Hardt P.D. Hauenschild A. Jaeger C. et al.High prevalence of steatorrhea in 101 diabetic patients likely to suffer from exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations: a prospective multicenter study.Dig Dis Sci. 2003; 48: 1688-1692Crossref PubMed Scopus (65) Google Scholar,18Hardt P.D. Hauenschild A. Nalop J. et al.High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study screening fecal elastase 1 concentrations in 1,021 diabetic patients.Pancreatology. 2003; 3: 395-402Crossref PubMed Scopus (157) Google Scholar In CP, EPI is more frequent in patients who also have diabetes.4Zhan W. Akshintala V. Greer P.J. et al.Low serum trypsinogen levels in chronic pancreatitis: correlation with parenchymal loss, exocrine pancreatic insufficiency, and diabetes but not CT-based Cambridge severity scores for fibrosis.Pancreatology. 2020; 20: 1368-1378Crossref PubMed Scopus (10) Google Scholar,19Bellin M.D. Whitcomb D.C. Abberbock J. et al.Patient and disease characteristics associated with the presence of diabetes mellitus in adults with chronic pancreatitis in the United States.Am J Gastroenterol. 2017; 112: 1457-1465Crossref PubMed Scopus (89) Google Scholar Of note, diabetes may also occur after AP and CP due to typical type 220Goodarzi M.O. Nagpal T. Greer P. et al.Genetic risk score in diabetes associated with chronic pancreatitis versus type 2 diabetes mellitus.Clin Transl Gastroenterol. 2019; 10e00057Crossref Scopus (34) Google Scholar or to loss of pancreatic islets from pancreatitis, including both α (glucagon) and β (insulin) cells (called type 3c diabetes mellitus).21American Diabetes AssociationDiagnosis and classification of diabetes mellitus.Diabetes Care. 2014; 37: S81-S90Crossref PubMed Scopus (4057) Google Scholar,22Hart P.A. Bellin M.D. Andersen D.K. et al.Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer.Lancet Gastroenterol Hepatol. 2016; 1: 226-237Abstract Full Text Full Text PDF PubMed Google Scholar As a syndrome, EPI is a combination of signs and symptoms (Table 2). In CP, EPI develops gradually over time, so clinical signs and symptoms may initially be few and mild compared with late-stage CP.23Johnson C.D. Arbuckle R. Bonner N. et al.Qualitative assessment of the symptoms and impact of pancreatic exocrine insufficiency (PEI) to inform the development of a patient-reported outcome (PRO) instrument.Patient. 2017; 10: 615-628Crossref PubMed Scopus (28) Google Scholar The intestinal effects are due to microbial digestion of unabsorbed nutrients, and the systemic effects are due to micro- and macronutrient maldigestion and malabsorption. Deficiencies in levels of vitamins A, D, E, and K are most common,24Sikkens E.C. Cahen D.L. Koch A.D. et al.The prevalence of fat-soluble vitamin deficiencies and a decreased bone mass in patients with chronic pancreatitis.Pancreatology. 2013; 13: 238-242Crossref PubMed Google Scholar,25Greer J.B. Greer P. Sandhu B.S. et al.Nutrition and inflammatory biomarkers in chronic pancreatitis patients.Nutr Clin Pract. 2019; 34: 387-399Crossref PubMed Scopus (26) Google Scholar but deficiencies of other vitamins and trace elements can also be seen.24Sikkens E.C. Cahen D.L. Koch A.D. et al.The prevalence of fat-soluble vitamin deficiencies and a decreased bone mass in patients with chronic pancreatitis.Pancreatology. 2013; 13: 238-242Crossref PubMed Google Scholar Osteoporosis and bone fracture,26Duggan S. O'Sullivan M. Feehan S. et al.Nutrition treatment of deficiency and malnutrition in chronic pancreatitis: a review.Nutr Clin Pract. 2010; 25: 362-370Crossref PubMed Scopus (49) Google Scholar,27Duggan S.N. Smyth N.D. Murphy A. et al.High prevalence of osteoporosis in patients with chronic pancreatitis: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2014; 12: 219-228Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar weight loss, sarcopenia,28Olesen S.S. Buyukuslu A. Kohler M. et al.Sarcopenia associates with increased hospitalization rates and reduced survival in patients with chronic pancreatitis.Pancreatology. 2019; 19: 245-251Crossref PubMed Scopus (56) Google Scholar,29Bundred J. Thakkar R.G. Pandanaboyana S. Systematic review of sarcopenia in chronic pancreatitis: prevalence, impact on surgical outcomes, and survival.Expert Rev Gastroenterol Hepatol. 2022; 16: 665-672Crossref PubMed Scopus (3) Google Scholar reduced quality of life,30Layer P. Kashirskaya N. Gubergrits N. Contribution of pancreatic enzyme replacement therapy to survival and quality of life in patients with pancreatic exocrine insufficiency.World J Gastroenterol. 2019; 25: 2430-2441Crossref PubMed Scopus (30) Google Scholar higher rates of surgical complications,29Bundred J. Thakkar R.G. Pandanaboyana S. Systematic review of sarcopenia in chronic pancreatitis: prevalence, impact on surgical outcomes, and survival.Expert Rev Gastroenterol Hepatol. 2022; 16: 665-672Crossref PubMed Scopus (3) Google Scholar and an increase in mortality are common systemic complications.31de la Iglesia-Garcia D. Vallejo-Senra N. Iglesias-Garcia J. et al.Increased risk of mortality associated with pancreatic exocrine insufficiency in patients with chronic pancreatitis.J Clin Gastroenterol. 2018; 52: e63-e72Crossref PubMed Scopus (74) Google ScholarTable 2Clinical Symptoms of Exocrine Pancreatic InsufficiencySymptomsGastrointestinal effects (microbial digestion of unabsorbed nutrients) Bloating Borborygmi Flatulency Osmotic diarrhea SteatorrheaNutritional systemic effects Micronutrients (fat-soluble vitamin deficiency A, D, E, K, vitamin B12, essential fatty acid malabsorption)Visual problems, night blindness (vitamins A, E, B12)Skin rash (vitamin A, B12, essential fatty acids)Osteoporosis, osteopenia (vitamin D)Neurologic effects (vitamin E, B12)Coagulopathy (vitamin E)Anemia (vitamin B12)Fatigue, weakness (vitamin E, B12)Depression (vitamin D, B12) Macronutrients (protein maldigestion, food avoidance)Unintendedly weight lossSarcopenia Open table in a new tab The differential diagnosis for EPI is broad and multiple disorders may be present in the same patient, making diagnosis challenging. EPI-specific patient-reported outcome measures have been developed but cannot distinguish EPI from other causes of similar symptoms.23Johnson C.D. Arbuckle R. Bonner N. et al.Qualitative assessment of the symptoms and impact of pancreatic exocrine insufficiency (PEI) to inform the development of a patient-reported outcome (PRO) instrument.Patient. 2017; 10: 615-628Crossref PubMed Scopus (28) Google Scholar,32Johnson C.D. Williamson N. Janssen-van Solingen G. et al.Psychometric evaluation of a patient-reported outcome measure in pancreatic exocrine insufficiency (PEI).Pancreatology. 2019; 19: 182-190Crossref PubMed Scopus (27) Google Scholar,33Guman M.S.S. van Olst N. Yaman Z.G. et al.Pancreatic exocrine insufficiency after bariatric surgery.Surg Obes Relat Dis. 2022; 18: 445-452Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Common diseases with symptoms that overlap with EPI include celiac disease34Jiang C. Barkin J. Barkin J. Exocrine pancreatic insufficiency is common in celiac disease: a systematic review and meta-analysis.Dig Dis Sci. 2023; 68: 3421-3427Crossref PubMed Scopus (2) Google Scholar; small intestinal bacterial overgrowth35Quigley E.M.M. Murray J.A. Pimentel M. AGA Clinical Practice Update on Small intestinal bacterial overgrowth: expert review.Gastroenterology. 2020; 159: 1526-1532Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar,36Lee A.A. Baker J.R. Wamsteker E.J. et al.Small intestinal bacterial overgrowth is common in chronic pancreatitis and associates with diabetes, chronic pancreatitis severity, low zinc levels, and opiate use.Am J Gastroenterol. 2019; 114: 1163-1171Crossref PubMed Scopus (24) Google Scholar; long-standing diabetes mellitus; and inflammatory bowel diseases, such as Crohn's disease.1Whitcomb D.C.M.R. Duggan S.N. Martindale R. et al.AGA-PancreasFest joint symposium on exocrine pancreatic insufficiency.Gastro Hep Adv. 2023; 2: 395-411Abstract Full Text Full Text PDF Google Scholar,37Maconi G. Dominici R. Molteni M. et al.Prevalence of pancreatic insufficiency in inflammatory bowel diseases. Assessment by fecal elastase-1.Dig Dis Sci. 2008; 53: 262-270Crossref PubMed Scopus (49) Google Scholar Less common causes include disaccharidase deficiencies38Henström M. Diekmann L. Bonfiglio F. et al.Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.Gut. 2018; 67: 263-270Crossref PubMed Scopus (106) Google Scholar,39Viswanathan L. Rao S.S.C. Kennedy K. et al.Prevalence of disaccharidase deficiency in adults with unexplained gastrointestinal symptoms.J Neurogastroenterol Motil. 2020; 26: 384-390Crossref PubMed Scopus (10) Google Scholar; bile acid diarrhea40Camilleri M. Bile acid diarrhea: prevalence, pathogenesis, and therapy.Gut Liver. 2015; 9332339Crossref PubMed Scopus (156) Google Scholar; and infectious etiologies, such as giardiasis.41Lacy B.E. Pimentel M. Brenner D.M. et al.ACG clinical guideline: management of irritable bowel syndrome.Am J Gastroenterol. 2021; 116: 17-44Crossref PubMed Scopus (304) Google Scholar These are most often considered when a patient with EPI does not respond to PERT. Pancreatic function tests are objective, quantitative measures of exocrine pancreatic or ductal synthetic and secretory activity. Direct measurements of pancreatic secretions into the duodenum are the most accurate, but are invasive, time-consuming, and a more significant burden to the patient than an indirect test.1Whitcomb D.C.M.R. Duggan S.N. Martindale R. et al.AGA-PancreasFest joint symposium on exocrine pancreatic insufficiency.Gastro Hep Adv. 2023; 2: 395-411Abstract Full Text Full Text PDF Google Scholar,4Zhan W. Akshintala V. Greer P.J. et al.Low serum trypsinogen levels in chronic pancreatitis: correlation with parenchymal loss, exocrine pancreatic insufficiency, and diabetes but not CT-based Cambridge severity scores for fibrosis.Pancreatology. 2020; 20: 1368-1378Crossref PubMed Scopus (10) Google Scholar,42Weintraub A. Blau H. Mussaffi H. et al.Exocrine pancreatic function testing in patients with cystic fibrosis and pancreatic sufficiency: a correlation study.J Pediatr Gastroenterol Nutr. 2009; 48: 306-310Crossref PubMed Scopus (38) Google Scholar Direct pancreatic function tests are available at some specialized centers using endoscopic methods.43Stevens T. Conwell D.L. Zuccaro Jr., G. et al.A prospective crossover study comparing secretin-stimulated endoscopic and Dreiling tube pancreatic function testing in patients evaluated for chr