This review outlines a practical approach to distinguishing irritable bowel syndrome with diarrhea (IBS-D) from exocrine pancreatic insufficiency (EPI) and other common causes of chronic diarrhea. IBS is highly prevalent and is usually diagnosed using a positive, symptom-based strategy centered on Rome IV criteria, especially recurrent abdominal pain associated with defecation or changes in stool frequency or form, in the absence of alarm features. By contrast, EPI is more likely in patients with pancreatic disease, pancreatic risk factors such as alcohol use or smoking, pancreatic or gastric surgery, weight loss, nutritional deficiencies, and fatty or greasy stools. Because symptoms such as diarrhea, bloating, flatulence, and abdominal discomfort can overlap across IBS-D, EPI, celiac disease, inflammatory bowel disease, small intestinal bacterial overgrowth, and infections, narrowing the diagnosis can be challenging. The authors emphasize that careful history-taking, stool characterization, risk-factor review, and selective testing are essential for working through the differential.

The article proposes a four-step diagnostic process for chronic diarrhea: take a thorough history and physical exam, identify risk factors and prior diagnoses, rule out alarm features, and then perform targeted laboratory testing. For suspected IBS-D without red flags, minimal testing is recommended, such as screening for celiac disease, inflammatory bowel disease, and Giardia in selected patients. For suspected EPI, fecal elastase-1 is the most commonly used pancreatic function test, especially when symptoms suggest maldigestion or malabsorption, though false positives can occur in watery diarrhea and abnormal results should prompt pancreatic evaluation. Overall, the review argues that using a simple, structured diagnostic algorithm can reduce unnecessary testing, improve diagnostic accuracy, shorten delays in appropriate treatment, and help distinguish IBS-D from EPI more effectively in clinical practice.

Reference: Brenner DM, Domínguez-Muñoz JE. Differential Diagnosis of Chronic Diarrhea: An Algorithm to Distinguish Irritable Bowel Syndrome With Diarrhea From Other Organic Gastrointestinal Diseases, With Special Focus on Exocrine Pancreatic Insufficiency. J Clin Gastroenterol. 2023 Aug 1;57(7):663-670. doi: 10.1097/MCG.0000000000001855. PMID: 37115854; PMCID: PMC10321507.

This evidence-based United European Gastroenterology guideline reframes exocrine pancreatic insufficiency (EPI) as a maldigestion syndrome rather than simply an isolated pancreatic secretory defect. The authors emphasize that normal digestion depends not only on pancreatic enzyme output but also on gastrointestinal anatomy, timing of enzyme delivery, and intraluminal pH. It recommends considering EPI in the right clinical context by combining symptoms, nutritional status, and pancreatic function rather than relying on any single measure. High-risk settings include chronic pancreatitis, cystic fibrosis, pancreatic cancer, acute necrotizing pancreatitis, and prior pancreatic surgery. Symptoms such as steatorrhea, diarrhea, bloating, weight loss, and nutritional deficiencies can support the diagnosis but are not specific on their own. The guideline notes that fecal elastase and 13C-mixed triglyceride breath testing are the main noninvasive tools used in practice. Imaging cannot diagnose EPI directly and direct pancreatic function tests are not recommended for routine EPI diagnosis.

The guideline also stresses that EPI should always be treated with pancreatic enzyme replacement therapy (PERT) as first-line management because it improves fat and protein absorption, symptoms, nutritional status, body weight, and quality of life. Small enteric-coated pancreatin pellets are preferred. Adult starting doses generally begin around 40,000 to 50,000 units of lipase with main meals and half that with snacks, taken with food. If response is incomplete, clinicians should first check adherence and administration, then consider dose escalation, adding a proton pump inhibitor, and evaluating for other conditions that can mimic or coexist with EPI. Overall, the guideline highlights the need for long-term monitoring of symptoms, weight, nutritional markers, vitamins, and bone health. It also calls attention to persistent evidence gaps and the need for more high-quality prospective research across pancreatic and extra-pancreatic causes of EPI.

Reference: Dominguez-Muñoz JE, Vujasinovic M, de la Iglesia D, et al. European guidelines for the diagnosis and treatment of pancreatic exocrine insufficiency: UEG, EPC, EDS, ESPEN, ESPGHAN, ESDO, and ESPCG evidence-based recommendations. United European Gastroenterol J. 2025 Feb;13(1):125-172. doi: 10.1002/ueg2.12674. Epub 2024 Dec 5. PMID: 39639485; PMCID: PMC11866322.

This review explains that exocrine pancreatic insufficiency (EPI) can result from a wide range of pancreatic and non-pancreatic disorders, and that it is often underrecognized despite its impact on nutrition and quality of life. Among pancreatic causes, the review highlights acute and chronic pancreatitis, pancreatic tumors, cystic fibrosis, and pancreatic surgery as major contributors. Acute pancreatitis can lead to EPI even after mild disease. Chronic pancreatitis remains one of the most common and clinically significant causes because ongoing inflammation and fibrosis progressively reduce enzyme secretion. Pancreatic cancer and pancreatic resections also can cause EPI through duct obstruction, tissue loss, and disrupted digestive coordination. Cystic fibrosis causes pancreatic damage through CFTR-related duct obstruction and progressive destruction of exocrine tissue.

The review also emphasizes that EPI can develop in non-pancreatic conditions such as diabetes, celiac disease, inflammatory bowel disease, gastrointestinal surgery, advanced age, and even certain medications. In these settings, EPI may arise through impaired hormonal signaling, autoimmune mechanisms, neuropathy, altered anatomy, or reduced stimulation of pancreatic secretion. Because symptoms such as diarrhea, steatorrhea, bloating, and weight loss overlap with many other gastrointestinal disorders, diagnosis can be missed unless clinicians actively consider it. Fecal elastase-1 is noted as the most commonly used test. Overall, the article argues that broader awareness of EPI risk factors and earlier diagnosis are essential so patients can receive appropriate treatment, nutritional support, and pancreatic enzyme replacement when needed.

Reference: Tang C, Zhou J, Song Y, Liu S. Etiologies of exocrine pancreatic insufficiency. Gastroenterol Rep (Oxf). 2025 Mar 10;13:goaf019. doi: 10.1093/gastro/goaf019. PMID: 40066317; PMCID: PMC11893156.

This review focuses on causes of exocrine pancreatic insufficiency (EPI) beyond chronic pancreatitis. The authors emphasize that EPI can arise not only from clear pancreatic disorders such as pancreatic cancer, pancreatic resection, pancreatic duct obstruction, and cystic fibrosis, but also from conditions with less well-defined mechanisms, including diabetes, celiac disease, inflammatory bowel disease, certain gastrointestinal surgeries, Zollinger–Ellison syndrome, nonalcoholic fatty pancreas disease, aging, and microbiome-related changes. Across these conditions, EPI generally develops through one or more of three pathways: loss of pancreatic tissue, impaired enzyme secretion or activation, or poor coordination between food delivery and pancreatic enzyme release. The review highlights that EPI is often underrecognized despite its links to steatorrhea, weight loss, malnutrition, vitamin deficiencies, reduced quality of life, and worse outcomes. This is particularly evident in pancreatic cancer and after pancreatic surgery.

The authors stress that treatment should focus on recognizing symptomatic maldigestion early and starting pancreatic enzyme replacement therapy (PERT) when patients have steatorrhea, weight loss, or other clear signs of malabsorption. They note that PERT is especially important in pancreatic cancer, after pancreatic resections, and in cystic fibrosis. It also may benefit selected patients with diabetes, celiac disease, or inflammatory bowel disease when EPI is confirmed or strongly suspected. Management should include nutrition support, vitamin monitoring, and, in some cases, acid suppression to improve enzyme effectiveness. Overall, the review argues that clinicians should think more broadly about who may have EPI, because prompt diagnosis and treatment may improve symptoms, nutritional status, quality of life, and in some settings even survival.

Reference: Kunovský L, Dítě P, Jabandžiev P, et al. Causes of Exocrine Pancreatic Insufficiency Other Than Chronic Pancreatitis. J Clin Med. 2021 Dec 10;10(24):5779. doi: 10.3390/jcm10245779. PMID: 34945075; PMCID: PMC8708123.

This American Gastroenterological Association (AGA) clinical practice update provides practical guidance for recognizing, evaluating, and managing exocrine pancreatic insufficiency (EPI). The update recommends suspecting EPI in high-risk settings such as chronic pancreatitis, recurrent acute pancreatitis, pancreatic cancer, cystic fibrosis, and prior pancreatic surgery. It also advises considering EPI in moderate-risk conditions including celiac disease, Crohn’s disease, prior intestinal surgery, longstanding diabetes, and hypersecretory states. Common clinical features include steatorrhea, diarrhea, weight loss, bloating, flatulence, fat-soluble vitamin deficiencies, and protein-calorie malnutrition. The review identifies fecal elastase as the preferred initial test, noting that it can be performed while patients are taking pancreatic enzyme replacement therapy. It stresses that imaging can help detect pancreatic disease but cannot directly diagnose EPI.

The update also emphasizes that once EPI is diagnosed, treatment with pancreatic enzyme replacement therapy (PERT) is required to prevent ongoing malabsorption, nutritional decline, and reduced quality of life. Initial adult treatment should provide at least 40,000 units of lipase with meals and half that with snacks, taken during meals and adjusted based on meal size, fat content, symptoms, weight, and vitamin levels. The authors further recommend monitoring fat-soluble vitamins, nutritional status, and bone health, while encouraging a low-to-moderate fat diet with smaller frequent meals rather than very-low-fat diets. Overall, the review underscores that early diagnosis, appropriate PERT dosing, and routine follow-up are essential to improving symptoms, nutritional outcomes, and long-term health in patients with EPI.

Reference: Whitcomb DC, Buchner AM, Forsmark CE. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatic Insufficiency: Expert Review. Gastroenterology. 2023 Nov;165(5):1292-1301. doi: 10.1053/j.gastro.2023.07.007. Epub 2023 Sep 20. PMID: 37737818.

Exocrine pancreatic insufficiency (EPI) is a condition in which pancreatic enzyme activity falls below the level needed for normal digestion, leading to malabsorption, steatorrhea, bloating, abdominal discomfort, weight loss, and nutritional deficiencies. The most common causes are chronic pancreatitis in adults and cystic fibrosis in children. EPI also can occur with pancreatic cancer, diabetes, celiac disease, inflammatory bowel disease, HIV, bariatric surgery, and other conditions. Because symptoms are often nonspecific and overlap with other gastrointestinal disorders, diagnosis requires careful clinical evaluation along with testing. Fecal elastase-1 is the most commonly used noninvasive screening test. Other options include direct pancreatic function tests, 72-hour fecal fat testing, breath testing, and assessment of vitamin and micronutrient deficiencies.

Management focuses on correcting malabsorption, preventing complications, and improving quality of life. Pancreatic enzyme replacement therapy is the mainstay of treatment. It typically starts with weight-based lipase dosing taken with meals and snacks and then titrated to symptom control and stool normalization. Some patients also may need acid suppression to improve enzyme effectiveness. Ongoing care includes monitoring weight, body mass index, bone density, and fat-soluble vitamins, along with counseling on small frequent meals, alcohol abstinence, smoking cessation, and appropriate dietary adjustments. Because untreated EPI can lead to malnutrition, osteoporosis, cardiovascular complications, and reduced quality of life, early recognition and consistent management are important. The article emphasizes coordinated care across gastroenterology, primary care, pharmacy, dietetics, endocrinology, and other specialties to support diagnosis, adherence, and long-term management.

Reference: Tian C, Ghodeif AO, Arshad S, Gillespie E. Exocrine Pancreatic Insufficiency. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Updated September 14, 2025.